Gut microbial balance and liver transplantation: alteration, management, and prediction.

PubMed

Tian, Xinyao; Yang, Zhe; Luo, Fangzhou; Zheng, Shusen

2018-04-01

Liver transplantation is a conventional treatment for terminal stage liver diseases. However, several complications still hinder the survival rate. Intestinal barrier destruction is widely observed among patients receiving liver transplant and suffering from ischemia-reperfusion or rejection injuries because of the relationship between the intestine and the liver, both in anatomy and function. Importantly, the resulting alteration of gut microbiota aggravates graft dysfunctions during the process. This article reviews the research progress for gut microbial alterations and liver transplantation. Especially, this work also evaluates research on the management of gut microbial alteration and the prediction of possible injuries utilizing microbial alteration during liver transplantation. In addition, we propose possible directions for research on gut microbial alteration during liver transplantation and offer a hypothesis on the utilization of microbial alteration in liver transplantation. The aim is not only to predict perioperative injuries but also to function as a method of treatment or even inhibit the rejection of liver transplantation.

Exercise alters resting state functional connectivity of motor circuits in Parkinsonian rats

PubMed Central

Wang, Zhuo; Guo, Yumei; Myers, Kalisa G.; Heintz, Ryan; Peng, Yu-Hao; Maarek, Jean-Michel I.; Holschneider, Daniel P.

2014-01-01

Few studies have examined changes in functional connectivity after long-term aerobic exercise. We examined the effects of 4 weeks of forced running wheel exercise on the resting-state functional connectivity (rsFC) of motor circuits of rats subjected to bilateral 6-hydroxydopamine lesion of the dorsal striatum. Our results showed substantial similarity between lesion-induced changes in rsFC in the rats and alterations in rsFC reported in Parkinson’s disease subjects, including disconnection of the dorsolateral striatum. Exercise in lesioned rats resulted in: (a) normalization of many of the lesion-induced alterations in rsFC, including reintegration of the dorsolateral striatum into the motor network; (b) emergence of the ventrolateral striatum as a new broadly connected network hub; (c) increased rsFC among the motor cortex, motor thalamus, basal ganglia, and cerebellum. Our results showed for the first time that long-term exercise training partially reversed lesion-induced alterations in rsFC of the motor circuits, and in addition enhanced functional connectivity in specific motor pathways in the Parkinsonian rats, which could underlie recovery in motor functions observed in these rats. PMID:25219465

Alterations in mitochondrial respiratory functions, redox metabolism and apoptosis by oxidant 4-hydroxynonenal and antioxidants curcumin and melatonin in PC12 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Raza, Haider; John, Annie; Brown, Eric M.

Cellular oxidative stress and alterations in redox metabolisms have been implicated in the etiology and pathology of many diseases including cancer. Antioxidant treatments have been proven beneficial in controlling these diseases. We have recently shown that 4-hydroxynonenal (4-HNE), a by-product of lipid peroxidation, induces oxidative stress in PC12 cells by compromising the mitochondrial redox metabolism. In this study, we have further investigated the deleterious effects of 4-HNE on mitochondrial respiratory functions and apoptosis using the same cell line. In addition, we have also compared the effects of two antioxidants, curcumin and melatonin, used as chemopreventive agents, on mitochondrial redox metabolismmore » and respiratory functions in these cells. 4-HNE treatment has been shown to cause a reduction in glutathione (GSH) pool, an increase in reactive oxygen species (ROS), protein carbonylation and apoptosis. A marked inhibition in the activities of the mitochondrial respiratory enzymes, cytochrome c oxidase and aconitase was observed after 4-HNE treatment. Increased nuclear translocation of NF-kB/p65 protein was also observed after 4-HNE treatment. Curcumin and melatonin treatments, on the other hand, maintained the mitochondrial redox and respiratory functions without a marked effect on ROS production and cell viability. These results suggest that 4-HNE-induced cytotoxicity may be associated, at least in part, with the altered mitochondrial redox and respiratory functions. The alterations in mitochondrial energy metabolism and redox functions may therefore be critical in determining the difference between cell death and survival.« less

Altered functional and effective connectivity in anticorrelated intrinsic networks in children with benign childhood epilepsy with centrotemporal spikes.

PubMed

Luo, Cheng; Yang, Fei; Deng, Jiayan; Zhang, Yaodan; Hou, Changyue; Huang, Yue; Cao, Weifang; Wang, Jianjun; Xiao, Ruhui; Zeng, Nanlin; Wang, Xiaoming; Yao, Dezhong

2016-06-01

There are 2 intrinsic networks in the human brain: the task positive network (TPN) and task negative network (alternately termed the default mode network, DMN) in which inverse correlations have been observed during resting state and event-related functional magnetic resonance imaging (fMRI). The antagonism between the 2 networks might indicate a dynamic interaction in the brain that is associated with development.To evaluate the alterations in the relations of the 2 networks in children with benign childhood epilepsy with centrotemporal spikes (BECTS), resting state fMRI was performed in 17 patients with BECTS and 17 healthy controls. The functional and effective connectivities of 29 nodes in the TPN and DMN were analyzed. Positive functional connectivity (FC) within the networks and negative FC between the 2 networks were observed in both groups.The patients exhibited increased FC within both networks, particularly in the frontoparietal nodes such as the left superior frontal cortex, and enhanced antagonism between the 2 networks, suggesting abnormal functional integration of the nodes of the 2 networks in the patients. Granger causality analysis revealed a significant difference in the degree of outflow to inflow in the left superior frontal cortex and the left ventral occipital lobe.The alterations observed in the combined functional and effective connectivity analyses might indicate an association of an abnormal ability to integrate information between the DMN and TPN and the epileptic neuropathology of BECTS and provide preliminary evidence supporting the occurrence of abnormal development in children with BECTS.

Bisphenol A Alters Autonomic Tone and Extracellular Matrix Structure and Induces Sex-Specific Effects on Cardiovascular Function in Male and Female CD-1 Mice

PubMed Central

Gear, Robin B.; Kendig, Eric L.

2015-01-01

The aim of this study was to determine whether bisphenol A (BPA) has adverse effects on cardiovascular functions in CD-1 mice and define sex-specific modes of BPA action in the heart. Dams and analyzed progeny were maintained on a defined diet containing BPA (0.03, 0.3, 3, 30, or 300 ppm) that resulted in BPA exposures from 4–5 to approximately 5000 μg/kg · d or a diet containing 17α-ethinyl estradiol (EE; ∼0.02, 0.2, and 0.15 μg/kg · d) as an oral bioavailable estrogen control. Assessment of electrocardiogram parameters using noninvasive methods found that ventricular functions in both male and female mice were not altered by either BPA or EE. However, exposure-related changes in the rates of ventricular contraction, suggestive of a shift in sympathovagal balance of heart rate control toward increased parasympathetic activity, were detected in males. Decreased systolic blood pressure was observed in males exposed to BPA above 5 μg/kg · d and in females from the highest BPA exposure group. Morphometric histological measures revealed sexually dimorphic changes in the composition of the cardiac collagen extracellular matrix, increases in fibrosis, and evidence of modest exposure-related remodeling. Experiments using the α-selective adrenergic agonist phenylephrine found that BPA enhanced reflex bradycardia in females, but not males, revealed that BPA and EE exposure sex specifically altered the sympathetic regulation of the baroreflex circuits. Increased sensitivity to the cardiotoxic effects of the β-adrenergic agonist isoproterenol was observed in BPA- and EE-exposed females. This effect was not observed in males, in which BPA or EE exposures were protective of isoproterenol-induced ischemic damage and hypertrophy. The results of RNA sequence analysis identified significant sex-specific changes in gene expression in response to BPA that were consistent with the observed exposure-related phenotypic changes in the collagenous and noncollagenous extracellular matrix, cardiac remodeling, altered autonomic responses, changes in ion channel and transporter functions, and altered glycolytic and lipid metabolism. PMID:25594700

Altered interhemispheric functional connectivity in patients with anisometropic and strabismic amblyopia: a resting-state fMRI study.

PubMed

Liang, Minglong; Xie, Bing; Yang, Hong; Yin, Xuntao; Wang, Hao; Yu, Longhua; He, Sheng; Wang, Jian

2017-05-01

Altered brain functional connectivity has been reported in patients with amblyopia by recent neuroimaging studies. However, relatively little is known about the alterations in interhemispheric functional connectivity in amblyopia. The present study aimed to investigate the functional connectivity patterns between homotopic regions across hemispheres in patients with anisometropic and strabismic amblyopia under resting state. Nineteen monocular anisometropic amblyopia (AA), 18 strabismic amblyopia (SA), and 20 normal-sight controls (NC) were enrolled in this study. After a comprehensive ophthalmologic examination, resting-state fMRI scanning was performed in all participants. The pattern of the interhemispheric functional connectivity was measured with the voxel-mirrored homotopic connectivity (VMHC) approach. VMHC values differences within and between three groups were compared, and correlations between VMHC values and each the clinical variable were also analyzed. Altered VMHC was observed in AA and SA patients in lingual gyrus and fusiform gyrus compared with NC subjects. The altered VMHC of lingual gyrus showed a pattern of AA > SA > NC, while the altered VMHC of fusiform gyrus showed a pattern of AA > NC > SA. Moreover, the VMHC values of lingual gyrus were positively correlated with the stereoacuity both in AA and SA patients, and the VMHC values of fusiform gyrus were positively correlated with the amount of anisometropia just in AA patients. These findings suggest that interhemispheric functional coordination between several homotopic visual-related brain regions is impaired both in AA and SA patients under resting state and revealed the similarities and differences in interhemispheric functional connectivity between the anisometropic and strabismic amblyopia.

Neural correlates of consciousness during general anesthesia using functional magnetic resonance imaging (fMRI).

PubMed

Bonhomme, V; Boveroux, P; Brichant, J F; Laureys, S; Boly, M

2012-01-01

This paper reviews the current knowledge about the mechanisms of anesthesia-induced alteration of consciousness. It is now evident that hypnotic anesthetic agents have specific brain targets whose function is hierarchically altered in a dose-dependent manner. Higher order networks, thought to be involved in mental content generation, as well as sub-cortical networks involved in thalamic activity regulation seems to be affected first by increasing concentrations of hypnotic agents that enhance inhibitory neurotransmission. Lower order sensory networks are preserved, including thalamo-cortical connectivity into those networks, even at concentrations that suppress responsiveness, but cross-modal sensory interactions are inhibited. Thalamo-cortical connectivity into the consciousness networks decreases with increasing concentrations of those agents, and is transformed into an anti-correlated activity between the thalamus and the cortex for the deepest levels of sedation, when the subject is non responsive. Future will tell us whether these brain function alterations are also observed with hypnotic agents that mainly inhibit excitatory neurotransmission. The link between the observations made using fMRI and the identified biochemical targets of hypnotic anesthetic agents still remains to be identified.

Loss of Local Astrocyte Support Disrupts Action Potential Propagation and Glutamate Release Synchrony from Unmyelinated Hippocampal Axon Terminals In Vitro.

PubMed

Sobieski, Courtney; Jiang, Xiaoping; Crawford, Devon C; Mennerick, Steven

2015-08-05

Neuron-astrocyte interactions are critical for proper CNS development and function. Astrocytes secrete factors that are pivotal for synaptic development and function, neuronal metabolism, and neuronal survival. Our understanding of this relationship, however, remains incomplete due to technical hurdles that have prevented the removal of astrocytes from neuronal circuits without changing other important conditions. Here we overcame this obstacle by growing solitary rat hippocampal neurons on microcultures that were comprised of either an astrocyte bed (+astrocyte) or a collagen bed (-astrocyte) within the same culture dish. -Astrocyte autaptic evoked EPSCs, but not IPSCs, displayed an altered temporal profile, which included increased synaptic delay, increased time to peak, and severe glutamate release asynchrony, distinct from previously described quantal asynchrony. Although we observed minimal alteration of the somatically recorded action potential waveform, action potential propagation was altered. We observed a longer latency between somatic initiation and arrival at distal locations, which likely explains asynchronous EPSC peaks, and we observed broadening of the axonal spike, which likely underlies changes to evoked EPSC onset. No apparent changes in axon structure were observed, suggesting altered axonal excitability. In conclusion, we propose that local astrocyte support has an unappreciated role in maintaining glutamate release synchrony by disturbing axonal signal propagation. Certain glial cell types (oligodendrocytes, Schwann cells) facilitate the propagation of neuronal electrical signals, but a role for astrocytes has not been identified despite many other functions of astrocytes in supporting and modulating neuronal signaling. Under identical global conditions, we cultured neurons with or without local astrocyte support. Without local astrocytes, glutamate transmission was desynchronized by an alteration of the waveform and arrival time of axonal action potentials to synaptic terminals. GABA transmission was not disrupted. The disruption did not involve detectable morphological changes to axons of glutamate neurons. Our work identifies a developmental role for astrocytes in the temporal precision of excitatory signals. Copyright © 2015 the authors 0270-6474/15/3511105-13$15.00/0.

Loss of Local Astrocyte Support Disrupts Action Potential Propagation and Glutamate Release Synchrony from Unmyelinated Hippocampal Axon Terminals In Vitro

PubMed Central

Sobieski, Courtney; Jiang, Xiaoping; Crawford, Devon C.

2015-01-01

Neuron–astrocyte interactions are critical for proper CNS development and function. Astrocytes secrete factors that are pivotal for synaptic development and function, neuronal metabolism, and neuronal survival. Our understanding of this relationship, however, remains incomplete due to technical hurdles that have prevented the removal of astrocytes from neuronal circuits without changing other important conditions. Here we overcame this obstacle by growing solitary rat hippocampal neurons on microcultures that were comprised of either an astrocyte bed (+astrocyte) or a collagen bed (−astrocyte) within the same culture dish. −Astrocyte autaptic evoked EPSCs, but not IPSCs, displayed an altered temporal profile, which included increased synaptic delay, increased time to peak, and severe glutamate release asynchrony, distinct from previously described quantal asynchrony. Although we observed minimal alteration of the somatically recorded action potential waveform, action potential propagation was altered. We observed a longer latency between somatic initiation and arrival at distal locations, which likely explains asynchronous EPSC peaks, and we observed broadening of the axonal spike, which likely underlies changes to evoked EPSC onset. No apparent changes in axon structure were observed, suggesting altered axonal excitability. In conclusion, we propose that local astrocyte support has an unappreciated role in maintaining glutamate release synchrony by disturbing axonal signal propagation. SIGNIFICANCE STATEMENT Certain glial cell types (oligodendrocytes, Schwann cells) facilitate the propagation of neuronal electrical signals, but a role for astrocytes has not been identified despite many other functions of astrocytes in supporting and modulating neuronal signaling. Under identical global conditions, we cultured neurons with or without local astrocyte support. Without local astrocytes, glutamate transmission was desynchronized by an alteration of the waveform and arrival time of axonal action potentials to synaptic terminals. GABA transmission was not disrupted. The disruption did not involve detectable morphological changes to axons of glutamate neurons. Our work identifies a developmental role for astrocytes in the temporal precision of excitatory signals. PMID:26245971

Addiction Related Alteration in Resting-state Brain Connectivity

PubMed Central

Ma, Ning; Liu, Ying; Li, Nan; Wang, Chang-Xin; Zhang, Hao; Jiang, Xiao-Feng; Xu, Hu-Sheng; Fu, Xian-Ming; Hu, Xiaoping; Zhang, Da-Ren

2009-01-01

It is widely accepted that addictive drug use is related to abnormal functional organization in the user’s brain. The present study aimed to identify this type of abnormality within the brain networks implicated in addiction by resting-state functional connectivity measured with functional magnetic resonance imaging (fMRI). With fMRI data acquired during resting state from 14 chronic heroin users (12 of whom were being treated with methadone) and 13 non-addicted controls, we investigated the addiction related alteration in functional connectivity between the regions in the circuits implicated in addiction with seed-based correlation analysis. Compared with controls, chronic heroin users showed increased functional connectivity between nucleus accumbens and ventral/rostral anterior cingulate cortex (ACC), and orbital frontal cortex (OFC), between amygdala and OFC; and reduced functional connectivity between prefrontal cortex and OFC, and ACC. These observations of altered resting-state functional connectivity suggested abnormal functional organization in the addicted brain and may provide additional evidence supporting the theory of addiction that emphasizes enhanced salience value of a drug and its related cues but weakened cognitive control in the addictive state. PMID:19703568

Altered Actin Dynamics and Functions of Osteoblast-Like Cells in Parabolic Flight may Involve ERK1/2

NASA Astrophysics Data System (ADS)

Dai, Zhongquan; Tan, Yingjun; Yang, Fen; Qu, Lina; Zhang, Hongyu; Wan, Yumin; Li, Yinghui

2011-01-01

Osteoblasts are sensitive to mechanical stressors such as gravity and alter their cytoskeletons and functions to adapt; however, the contribution of gravity to this phenomenon is not well understood. In this study, we investigated the effects of acute gravitational changes on the structure and function of osteoblast ROS17/2.8 as generated by parabolic flight. The changes in microfilament cytoskeleton was observed by immunofluorescence stain of Texas red conjugated Phalloidin and Alexa Fluor 488 conjugated DNase I for F-actin and G-actin, respectively. To examine osteoblast function, ALP (alkaline phosphatase) activity, osteocalcin secretions and the expression of ALP, COL1A1 (collagen type I alpha 1 chain) and osteocalcin were detected by modified Gomori methods, radioimmunity and RT-PCR, respectively. Double fluorescence staining of phosphorylated p44/42 and F-actin were performed to observe their colocalization relationship. The established semi-quantitative analysis method of fluorescence intensity of EGFP was used to detect the activity changes of COL1A1 promoter in EGFP-ROS cells with MAPK inhibitor PD98059 or F-actin inhibitor cytochalasin B. Results indicate that the altered gravity induced the reorganization of microfilament cytoskeletons of osteoblasts. After 3 h parabolic flight, F-actin of osteoblast cytoskeleton became thicker and directivity, whereas G-actin shrunk and became more concentrated at the edge of nucleus. The excretion of osteocalcin, the activity of ALP and the expression of mRNA decreased. Colocalization analysis indicated that phosphorylated p44/42 MAPK was coupled with F-actin. Inhibitor PD98059 and cytochalasin B decreased the fluorescence intensity of EGFP-ROS cells. Above results suggest that short time gravity variations induce the adjustment of osteoblast structure and functional and ERK1/2 signaling maybe involve these responses. We believe that it is an adaptive method of the osteoblasts to gravity alteration that structure alteration inhibits the function performing.

Mitochondrial Dynamics in Diabetic Cardiomyopathy

PubMed Central

Galloway, Chad A.

2015-01-01

Abstract Significance: Cardiac function is energetically demanding, reliant on efficient well-coupled mitochondria to generate adenosine triphosphate and fulfill the cardiac demand. Predictably then, mitochondrial dysfunction is associated with cardiac pathologies, often related to metabolic disease, most commonly diabetes. Diabetic cardiomyopathy (DCM), characterized by decreased left ventricular function, arises independently of coronary artery disease and atherosclerosis. Dysregulation of Ca2+ handling, metabolic changes, and oxidative stress are observed in DCM, abnormalities reflected in alterations in mitochondrial energetics. Cardiac tissue from DCM patients also presents with altered mitochondrial morphology, suggesting a possible role of mitochondrial dynamics in its pathological progression. Recent Advances: Abnormal mitochondrial morphology is associated with pathologies across diverse tissues, suggesting that this highly regulated process is essential for proper cell maintenance and physiological homeostasis. Highly structured cardiac myofibers were hypothesized to limit alterations in mitochondrial morphology; however, recent work has identified morphological changes in cardiac tissue, specifically in DCM. Critical Issues: Mitochondrial dysfunction has been reported independently from observations of altered mitochondrial morphology in DCM. The temporal relationship and causative nature between functional and morphological changes of mitochondria in the establishment/progression of DCM is unclear. Future Directions: Altered mitochondrial energetics and morphology are not only causal for but also consequential to reactive oxygen species production, hence exacerbating oxidative damage through reciprocal amplification, which is integral to the progression of DCM. Therefore, targeting mitochondria for DCM will require better mechanistic characterization of morphological distortion and bioenergetic dysfunction. Antioxid. Redox Signal. 22, 1545–1562. PMID:25738230

The human Nav1.5 F1486 deletion associated with long QT syndrome leads to impaired sodium channel inactivation and reduced lidocaine sensitivity

PubMed Central

Song, Weihua; Xiao, Yucheng; Chen, Hanying; Ashpole, Nicole M; Piekarz, Andrew D; Ma, Peilin; Hudmon, Andy; Cummins, Theodore R; Shou, Weinian

2012-01-01

The deletion of phenylalanine 1486 (F1486del) in the human cardiac voltage-gated sodium channel (hNav1.5) is associated with fatal long QT (LQT) syndrome. In this study we determined how F1486del impairs the functional properties of hNav1.5 and alters action potential firing in heterologous expression systems (human embryonic kidney (HEK) 293 cells) and their native cardiomyocyte background. Cells expressing hNav1.5-F1486del exhibited a loss-of-function alteration, reflected by an 80% reduction of peak current density, and several gain-of-function alterations, including reduced channel inactivation, enlarged window current, substantial augmentation of persistent late sodium current and an increase in ramp current. We also observed substantial action potential duration (APD) prolongation and prominent early afterdepolarizations (EADs) in neonatal cardiomyocytes expressing the F1486del channels, as well as in computer simulations of myocyte activity. In addition, lidocaine sensitivity was dramatically reduced, which probably contributed to the poor therapeutic outcome observed in the patient carrying the hNav1.5-F1486del mutation. Therefore, despite the significant reduction in peak current density, the F1486del mutation also leads to substantial gain-of-function alterations that are sufficient to cause APD prolongation and EADs, the predominant characteristic of LQTs. These data demonstrate that hNav1.5 mutations can have complex functional consequences and highlight the importance of identifying the specific molecular defect when evaluating potential treatments for individuals with prolonged QT intervals. PMID:22826127

Exercise alters resting-state functional connectivity of motor circuits in parkinsonian rats.

PubMed

Wang, Zhuo; Guo, Yumei; Myers, Kalisa G; Heintz, Ryan; Peng, Yu-Hao; Maarek, Jean-Michel I; Holschneider, Daniel P

2015-01-01

Few studies have examined changes in functional connectivity after long-term aerobic exercise. We examined the effects of 4 weeks of forced running wheel exercise on the resting-state functional connectivity (rsFC) of motor circuits of rats subjected to bilateral 6-hydroxydopamine lesion of the dorsal striatum. Our results showed substantial similarity between lesion-induced changes in rsFC in the rats and alterations in rsFC reported in Parkinson's disease subjects, including disconnection of the dorsolateral striatum. Exercise in lesioned rats resulted in: (1) normalization of many of the lesion-induced alterations in rsFC, including reintegration of the dorsolateral striatum into the motor network; (2) emergence of the ventrolateral striatum as a new broadly connected network hub; and (3) increased rsFC among the motor cortex, motor thalamus, basal ganglia, and cerebellum. Our results showed for the first time that long-term exercise training partially reversed lesion-induced alterations in rsFC of the motor circuits, and in addition enhanced functional connectivity in specific motor pathways in the parkinsonian rats, which could underlie recovery in motor functions observed in these animals. Copyright © 2015 Elsevier Inc. All rights reserved.

GABA Neurons and the Mechanisms of Network Oscillations: Implications for Understanding Cortical Dysfunction in Schizophrenia

PubMed Central

Gonzalez-Burgos, Guillermo; Lewis, David A.

2008-01-01

Synchronization of neuronal activity in the neocortex may underlie the coordination of neural representations and thus is critical for optimal cognitive function. Because cognitive deficits are the major determinant of functional outcome in schizophrenia, identifying their neural basis is important for the development of new therapeutic interventions. Here we review the data suggesting that phasic synaptic inhibition mediated by specific subtypes of cortical γ-aminobutyric acid (GABA) neurons is essential for the production of synchronized network oscillations. We also discuss evidence indicating that GABA neurotransmission is altered in schizophrenia and propose mechanisms by which such alterations can decrease the strength of inhibitory connections in a cell-type–specific manner. We suggest that some alterations observed in the neocortex of schizophrenia subjects may be compensatory responses that partially restore inhibitory synaptic efficacy. The findings of altered neural synchrony and impaired cognitive function in schizophrenia suggest that such compensatory responses are insufficient and that interventions aimed at augmenting the efficacy of GABA neurotransmission might be of therapeutic value. PMID:18586694

GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia.

PubMed

Gonzalez-Burgos, Guillermo; Lewis, David A

2008-09-01

Synchronization of neuronal activity in the neocortex may underlie the coordination of neural representations and thus is critical for optimal cognitive function. Because cognitive deficits are the major determinant of functional outcome in schizophrenia, identifying their neural basis is important for the development of new therapeutic interventions. Here we review the data suggesting that phasic synaptic inhibition mediated by specific subtypes of cortical gamma-aminobutyric acid (GABA) neurons is essential for the production of synchronized network oscillations. We also discuss evidence indicating that GABA neurotransmission is altered in schizophrenia and propose mechanisms by which such alterations can decrease the strength of inhibitory connections in a cell-type-specific manner. We suggest that some alterations observed in the neocortex of schizophrenia subjects may be compensatory responses that partially restore inhibitory synaptic efficacy. The findings of altered neural synchrony and impaired cognitive function in schizophrenia suggest that such compensatory responses are insufficient and that interventions aimed at augmenting the efficacy of GABA neurotransmission might be of therapeutic value.

Association between functional alterations of senescence and senility and disorders of gait and balance

PubMed Central

Teixeira-Leite, Homero; Manhães, Alex C.

2012-01-01

OBJECTIVES: Declines in cognition and mobility are frequently observed in the elderly, and it has been suggested that the appearance of gait disorders in older individuals may constitute a marker of cognitive decline that precedes significant findings in functional performance screening tests. This study sought to evaluate the relationship between functional capacities and gait and balance in an elderly community monitored by the Preventive and Integrated Care Unit of the Hospital Adventista Silvestre in Rio de Janeiro, RJ, Brazil. METHODS: Elderly individuals (193 females and 90 males) were submitted to a broad geriatric evaluation, which included the following tests: 1) a performance-oriented mobility assessment (POMA) to evaluate gait; 2) a mini-mental state examination (MMSE); 3) the use of Katz and Lawton scales to assess functional capacity; 4) the application of the geriatric depression scale (GDS); and 5) a mini-nutritional assessment (MNA) scale. RESULTS: Reductions in MMSE, Katz and Lawton scores were associated with reductions in POMA scores, and we also observed that significant reductions in POMA scores were present in persons for whom the MMSE and Katz scores did not clearly indicate cognitive dysfunction. We also demonstrated that a decline in the scores obtained with the GDS and MNA scales was associated with a decline in the POMA scores. CONCLUSIONS: Considering that significant alterations in the POMA scores were observed prior to the identification of significant alterations in cognitive capacity using either the MMSE or the Katz systems, a prospective study seems warranted to assess the predictive capacity of POMA scores regarding the associated decline in functional capacity. PMID:22892914

Association between functional alterations of senescence and senility and disorders of gait and balance.

PubMed

Teixeira-Leite, Homero; Manhães, Alex C

2012-07-01

Declines in cognition and mobility are frequently observed in the elderly, and it has been suggested that the appearance of gait disorders in older individuals may constitute a marker of cognitive decline that precedes significant findings in functional performance screening tests. This study sought to evaluate the relationship between functional capacities and gait and balance in an elderly community monitored by the Preventive and Integrated Care Unit of the Hospital Adventista Silvestre in Rio de Janeiro, RJ, Brazil. Elderly individuals (193 females and 90 males) were submitted to a broad geriatric evaluation, which included the following tests: 1) a performance-oriented mobility assessment (POMA) to evaluate gait; 2) a mini-mental state examination (MMSE); 3) the use of Katz and Lawton scales to assess functional capacity; 4) the application of the geriatric depression scale (GDS); and 5) a mini-nutritional assessment (MNA) scale. Reductions in MMSE, Katz and Lawton scores were associated with reductions in POMA scores, and we also observed that significant reductions in POMA scores were present in persons for whom the MMSE and Katz scores did not clearly indicate cognitive dysfunction. We also demonstrated that a decline in the scores obtained with the GDS and MNA scales was associated with a decline in the POMA scores. Considering that significant alterations in the POMA scores were observed prior to the identification of significant alterations in cognitive capacity using either the MMSE or the Katz systems, a prospective study seems warranted to assess the predictive capacity of POMA scores regarding the associated decline in functional capacity.

Overexpression of Dyrk1A, a Down Syndrome Candidate, Decreases Excitability and Impairs Gamma Oscillations in the Prefrontal Cortex.

PubMed

Ruiz-Mejias, Marcel; Martinez de Lagran, Maria; Mattia, Maurizio; Castano-Prat, Patricia; Perez-Mendez, Lorena; Ciria-Suarez, Laura; Gener, Thomas; Sancristobal, Belen; García-Ojalvo, Jordi; Gruart, Agnès; Delgado-García, José M; Sanchez-Vives, Maria V; Dierssen, Mara

2016-03-30

The dual-specificity tyrosine phosphorylation-regulated kinase DYRK1A is a serine/threonine kinase involved in neuronal differentiation and synaptic plasticity and a major candidate of Down syndrome brain alterations and cognitive deficits. DYRK1A is strongly expressed in the cerebral cortex, and its overexpression leads to defective cortical pyramidal cell morphology, synaptic plasticity deficits, and altered excitation/inhibition balance. These previous observations, however, do not allow predicting how the behavior of the prefrontal cortex (PFC) network and the resulting properties of its emergent activity are affected. Here, we integrate functional, anatomical, and computational data describing the prefrontal network alterations in transgenic mice overexpressingDyrk1A(TgDyrk1A). Usingin vivoextracellular recordings, we show decreased firing rate and gamma frequency power in the prefrontal network of anesthetized and awakeTgDyrk1Amice. Immunohistochemical analysis identified a selective reduction of vesicular GABA transporter punctae on parvalbumin positive neurons, without changes in the number of cortical GABAergic neurons in the PFC ofTgDyrk1Amice, which suggests that selective disinhibition of parvalbumin interneurons would result in an overinhibited functional network. Using a conductance-based computational model, we quantitatively demonstrate that this alteration could explain the observed functional deficits including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome. DYRK1Ais a major candidate gene in Down syndrome. Its overexpression results into altered cognitive abilities, explained by defective cortical microarchitecture and excitation/inhibition imbalance. An open question is how these deficits impact the functionality of the prefrontal cortex network. Combining functional, anatomical, and computational approaches, we identified decreased neuronal firing rate and deficits in gamma frequency in the prefrontal cortices of transgenic mice overexpressingDyrk1A We also identified a reduction of vesicular GABA transporter punctae specifically on parvalbumin positive interneurons. Using a conductance-based computational model, we demonstrate that this decreased inhibition on interneurons recapitulates the observed functional deficits, including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome. Copyright © 2016 the authors 0270-6474/16/363649-12$15.00/0.

Perturbations in reward-related decision-making induced by reduced prefrontal cortical GABA transmission: Relevance for psychiatric disorders.

PubMed

Piantadosi, Patrick T; Khayambashi, Shahin; Schluter, Magdalen G; Kutarna, Agnes; Floresco, Stan B

2016-02-01

The prefrontal cortex (PFC) is critical for higher-order cognitive functions, including decision-making. In psychiatric conditions such as schizophrenia, prefrontal dysfunction co-occurs with pronounced alterations in decision-making ability. These alterations include a diminished ability to utilize probabilistic reinforcement in guiding future choice, and a reduced willingness to expend effort to receive reward. Among the neurochemical abnormalities observed in the PFC of individuals with schizophrenia are alterations in the production and function of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). To probe how PFC GABA hypofunction may contribute to alterations in cost/benefit decision-making, we assessed the effects GABAA-receptor antagonist bicuculline (BIC; 50 ng in 0.5 μl saline/hemisphere) infusion in the medial PFC of rats during performance on a series of well-validated cost/benefit decision-making tasks. Intra-PFC BIC reduced risky choice and reward sensitivity during probabilistic discounting and decreased the preference for larger rewards associated with a greater effort cost, similar to the behavioral sequelae observed in schizophrenia. Additional experiments revealed that these treatments did not alter instrumental responding on a progressive ratio schedule, nor did they impair the ability to discriminate between reward and no reward. However, BIC induced a subtle but consistent impairment in preference for larger vs. smaller rewards of equal cost. BIC infusion also increased decision latencies and impaired the ability to "stay on task" as indexed by reduced rates of instrumental responding. Collectively, these results implicate prefrontal GABAergic dysfunction as a key contributing factor to abnormal decision-making observed in schizophrenia and other neuropsychiatric conditions with similar neurobiological and behavioral alterations. Copyright © 2015 Elsevier Ltd. All rights reserved.

Altered neuromuscular control and ankle joint kinematics during walking in subjects with functional instability of the ankle joint.

PubMed

Delahunt, Eamonn; Monaghan, Kenneth; Caulfield, Brian

2006-12-01

The ankle joint requires very precise neuromuscular control during the transition from terminal swing to the early stance phase of the gait cycle. Altered ankle joint arthrokinematics and muscular activity have been cited as potential factors that may lead to an inversion sprain during the aforementioned time periods. However, to date, no study has investigated patterns of muscle activity and 3D joint kinematics simultaneously in a group of subjects with functional instability compared with a noninjured control group during these phases of the gait cycle. To compare the patterns of lower limb 3D joint kinematics and electromyographic activity during treadmill walking in a group of subjects with functional instability with those observed in a control group. Controlled laboratory study. Three-dimensional angular velocities and displacements of the hip, knee, and ankle joints, as well as surface electromyography of the rectus femoris, peroneus longus, tibialis anterior, and soleus muscles, were recorded simultaneously while subjects walked on a treadmill at a velocity of 4 km/h. Before heel strike, subjects with functional instability exhibited a decrease in vertical foot-floor clearance (12.62 vs 22.84 mm; P < .05), as well as exhibiting a more inverted position of the ankle joint before, at, and immediately after heel strike (1.69 degrees , 2.10 degrees , and -0.09 degrees vs -1.43 degrees , -1.43 degrees , and -2.78 degrees , respectively [minus value = eversion]; P < .05) compared with controls. Subjects with functional instability were also observed to have an increase in peroneus longus integral electromyography during the post-heel strike time period (107.91%.millisecond vs 64.53%.millisecond; P < .01). The altered kinematics observed in this study could explain the reason subjects with functional instability experience repeated episodes of ankle inversion injury in situations with only slight or no external provocation. It is hypothesized that the observed increase in peroneus longus activity may be the result of a change in preprogrammed feed-forward motor control.

Altered nutrition during hot droughts will impair forest functions in the future

NASA Astrophysics Data System (ADS)

Grossiord, C.; Gessler, A.; Reed, S.; Dickman, L. T.; Collins, A.; Schönbeck, L.; Sevanto, S.; Vilagrosa, A.; McDowell, N. G.

2017-12-01

Rising greenhouse gas emissions will increase atmospheric temperature globally and alter hydrological cycles resulting in more extreme and recurrent droughts in the coming century. Nutrition is a key component affecting the vulnerability of forests to extreme climate. Models typically assume that global warming will enhance nitrogen cycling in terrestrial ecosystems and lead to improved plant functions. Drought on the other hand is expected to weaken the same processes, leading to a clear conflict and inability to predict how nutrition and plant functions will be impacted by a simultaneously warming and drying climate. We used a unique setup consisting of long-term manipulation of climate on mature trees to examine how individual vs. combined warming and drought would alter soil N cycling and tree functions. The site consists of the longest record of tree responses to experimental warming and precipitation reduction in natural conditions.Changes in soil nitrogen cycling (e.g. microbial activity, nitrification and ammonification rates, N concentration) occurred in response to the treatments. In addition, temperature rise and precipitation reduction altered the ability of trees to take up nitrogen and modified nitrogen allocation patterns between aboveground and belowground compartments. Although no additive effect of warming and drying were found for the two studied species, contrasting responses to warming and droughts were observed between the two functional types. Overall, our results show that higher temperature and reduced precipitation will alter the nutrition of forest ecosystems in the future with potentially large consequences for forest functions, structure and biodiversity.

Decorin expression is important for age-related changes in tendon structure and mechanical properties

PubMed Central

Dunkman, Andrew A.; Buckley, Mark R.; Mienaltowski, Michael J.; Adams, Sheila M.; Thomas, Stephen J.; Satchell, Lauren; Kumar, Akash; Pathmanathan, Lydia; Beason, David P.; Iozzo, Renato V.; Birk, David E.; Soslowsky, Louis J.

2013-01-01

The aging population is at an increased risk of tendon injury and tendinopathy. Elucidating the molecular basis of tendon aging is crucial to understanding the age-related changes in structure and function in this vulnerable tissue. In this study, the structural and functional features of tendon aging are investigated. In addition, the roles of decorin and biglycan in the aging process were analyzed using transgenic mice at both mature and aged time points. Our hypothesis is that the increase in tendon injuries in the aging population is the result of altered structural properties that reduce the biomechanical function of the tendon and consequently increase susceptibility to injury. Decorin and biglycan are important regulators of tendon structure and therefore, we further hypothesized that decreased function in aged tendons is partly the result of altered decorin and biglycan expression. Biomechanical analyses of mature (day 150) and aged (day 570) patellar tendons revealed deteriorating viscoelastic properties with age. Histology and polarized light microscopy demonstrated decreased cellularity, alterations in tenocyte shape, and reduced collagen fiber alignment in the aged tendons. Ultrastructural analysis of fibril diameter distributions indicated an altered distribution in aged tendons with an increase of large diameter fibrils. Aged wild type tendons maintained expression of decorin which was associated with the structural and functional changes seen in aged tendons. Aged patellar tendons exhibited altered and generally inferior properties across multiple assays. However, decorin-null tendons exhibited significantly decreased effects of aging compared to the other genotypes. The amelioration of the functional deficits seen in the absence of decorin in aged tendons was associated with altered tendon fibril structure. Fibril diameter distributions in the decorin-null aged tendons were comparable to those observed in the mature wild type tendon with the absence of the subpopulation containing large diameter fibrils. Collectively, our findings provide evidence for age-dependent alterations in tendon architecture and functional activity, and further show that lack of stromal decorin attenuates these changes. PMID:23178232

The influence of altered working-side occlusal guidance on masticatory muscles and related jaw movement.

PubMed

Belser, U C; Hannam, A G

1985-03-01

The effect of four different occlusal situations (group function, canine guidance, working side occlusal interference, and hyperbalancing occlusal interference) on EMG activity in jaw elevator muscles and related mandibular movement was investigated on 12 subjects. With a computer-based system, EMG and displacement signals were collected simultaneously during specific functional (unilateral chewing) and parafunctional tasks (mandibular gliding movements and various tooth clenching efforts) and analyzed quantitatively. When a naturally acquired group function was temporarily and artificially changed into a dominant canine guidance, a significant general reduction of elevator muscle activity was observed when subjects exerted full isometric tooth-clenching efforts in a lateral mandibular position. The original muscular coordination pattern (relative contraction from muscle to muscle) remained unaltered during this test. With respect to unilateral chewing, no significant alterations in the activity or coordination of the muscles occurred when an artificial canine guidance was introduced. Introduction of a hyperbalancing occlusal contact caused significant alterations in muscle activity and coordination during maximal tooth clenching in a lateral mandibular position. A marked shift of temporal muscle EMG activity toward the side of the interference and unchanged bilateral activity of the two masseter muscles were observed. The results suggest that canine-protected occlusions do not significantly alter muscle activity during mastication but significantly reduce muscle activity during parafunctional clenching. They also suggest that non-working side contacts dramatically alter the distribution of muscle activity during parafunctional clenching, and that this redistribution may affect the nature of reaction forces at the temporomandibular joints.

A prospective study of grey matter and cognitive function alterations in chemotherapy-treated breast cancer patients.

PubMed

Lepage, Chris; Smith, Andra M; Moreau, Jeremy; Barlow-Krelina, Emily; Wallis, Nancy; Collins, Barbara; MacKenzie, Joyce; Scherling, Carole

2014-01-01

Subsequent to chemotherapy treatment, breast cancer patients often report a decline in cognitive functioning that can adversely impact many aspects of their lives. Evidence has mounted in recent years indicating that a portion of breast cancer survivors who have undergone chemotherapy display reduced performance on objective measures of cognitive functioning relative to comparison groups. Neurophysiological support for chemotherapy-related cognitive impairment has been accumulating due to an increase in neuroimaging studies in this field; however, longitudinal studies are limited and have not examined the relationship between structural grey matter alterations and neuropsychological performance. The aim of this study was to extend the cancer-cognition literature by investigating the association between grey matter attenuation and objectively measured cognitive functioning in chemotherapy-treated breast cancer patients. Female breast cancer patients (n = 19) underwent magnetic resonance imaging after surgery but before commencing chemotherapy, one month following treatment, and one year after treatment completion. Individually matched controls (n = 19) underwent imaging at similar intervals. All participants underwent a comprehensive neuropsychological battery comprising four cognitive domains at these same time points. Longitudinal grey matter changes were investigated using voxel-based morphometry. One month following chemotherapy, patients had distributed grey matter volume reductions. One year after treatment, a partial recovery was observed with alterations persisting predominantly in frontal and temporal regions. This course was not observed in the healthy comparison group. Processing speed followed a similar trajectory within the patient group, with poorest scores obtained one month following treatment and some improvement evident one year post-treatment. This study provides further credence to patient claims of altered cognitive functioning subsequent to chemotherapy treatment.

Loss of Mitochondrial Function Impairs Lysosomes.

PubMed

Demers-Lamarche, Julie; Guillebaud, Gérald; Tlili, Mouna; Todkar, Kiran; Bélanger, Noémie; Grondin, Martine; Nguyen, Angela P; Michel, Jennifer; Germain, Marc

2016-05-06

Alterations in mitochondrial function, as observed in neurodegenerative diseases, lead to disrupted energy metabolism and production of damaging reactive oxygen species. Here, we demonstrate that mitochondrial dysfunction also disrupts the structure and function of lysosomes, the main degradation and recycling organelle. Specifically, inhibition of mitochondrial function, following deletion of the mitochondrial protein AIF, OPA1, or PINK1, as well as chemical inhibition of the electron transport chain, impaired lysosomal activity and caused the appearance of large lysosomal vacuoles. Importantly, our results show that lysosomal impairment is dependent on reactive oxygen species. Given that alterations in both mitochondrial function and lysosomal activity are key features of neurodegenerative diseases, this work provides important insights into the etiology of neurodegenerative diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Altered neural activation during prepotent response inhibition in breast cancer survivors treated with chemotherapy: an fMRI study.

PubMed

Kam, Julia W Y; Boyd, Lara A; Hsu, Chun L; Liu-Ambrose, Teresa; Handy, Todd C; Lim, Howard J; Hayden, Sherri; Campbell, Kristin L

2016-09-01

While impairments in executive functions have been reported in breast cancer survivors (BCS) who have undergone adjuvant chemotherapy, only a limited number of functional neuroimaging studies have associated alterations in cerebral activity with executive functions deficits in BCS. Using fMRI, the current study assessed the neural basis underlying a specific facet of executive function, namely prepotent response inhibition. 12 BCS who self-reported cognitive problems up to 3 years following cancer treatment and 12 female healthy comparisons (HC) performed the Stroop task. We compared their neural activation between the incongruent and neutral experimental conditions. Relative to the HC group, BCS showed lower blood-oxygen level dependent signal in several frontal regions, including the anterior cingulate cortex, a region critical for response inhibition. Our data indicates reduced neural activation in BCS during a prepotent response inhibition task, providing support for the prevailing notion of neural alterations observed in BCS treated with chemotherapy.

Evaluation of the effects of electric fields on implanted cardiac pacemakers. Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moss, A.J.; Carstensen, E.

1985-02-01

The effects of extra high voltage (EHV) transmission line electric fields on pacemaker function were evaluated in 11 patients with seven different implanted pacemaker models from four manufacturers. Alteration in pacemaker function was demonstrated in five unipolar units (three different models) from two manufacturers during exposure to electric fields ranging from 2 to 9 kV/m, with total body currents from 47 to 175 ..mu..A. These electric fields and body currents are representative of values that can be encountered by individuals standing beneath EHV transmission lines. Transient alterations in pacemaker function observed in this study included inappropriate triggered activity, inhibition ofmore » impulse generation, reduction in rate, and reversion from demand to asynchronous mode. Electromagnetic interference from high voltage transmission lines can induce alterations in pacemaker function in certain designs of these devices. However, pacemaker manufacturers can incorporate appropriate circuits in the pacemaker design to eliminate this problem. 8 references.« less

Effects of moderate heart failure and functional overload on rat plantaris muscle

NASA Technical Reports Server (NTRS)

Spangenburg, Espen E.; Lees, Simon J.; Otis, Jeff S.; Musch, Timothy I.; Talmadge, Robert J.; Williams, Jay H.

2002-01-01

It is thought that changes in sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) of skeletal muscle contribute to alterations in skeletal muscle function during congestive heart failure (CHF). It is well established that exercise training can improve muscle function. However, it is unclear whether similar adaptations will result from exercise training in a CHF patient. Therefore, the purpose of this study was to determine whether skeletal muscle during moderate CHF adapts to increased activity, utilizing the functional overload (FO) model. Significant increases in plantaris mass of the CHF-FO and sham-FO groups compared with the CHF and control (sham) groups were observed. Ca(2+) uptake rates were significantly elevated in the CHF group compared with all other groups. No differences were detected in Ca(2+) uptake rates between the CHF-FO, sham, and sham-FO groups. Increases in Ca(2+) uptake rates in moderate-CHF rats were not due to changes in SERCA isoform proportions; however, FO may have attenuated the CHF-induced increases through alterations in SERCA isoform expression. Therefore, changes in skeletal muscle Ca(2+) handling during moderate CHF may be due to alterations in regulatory mechanisms, which exercise may override, by possibly altering SERCA isoform expression.

Altered osteoblast structure and function in parabolic flight

NASA Astrophysics Data System (ADS)

Zhong-Quan, Dai; Ying-Hui, Li; Fen, Yang; Bai, Ding; Ying-Jun, Tan

Introduction Bone loss has a significant impact on astronauts during spaceflight being one of the main obstacles preventing interplanetary missions However the exact mechanism is not well understood In the present study we investigated the effects of acute gravitational changes generated by parabolic flight on the structure and function of osteoblasts ROS17 2 8 carried by airbus A300 Methods The alteration of microfilament cytoskeleton was observed by the Texas red conjugated Phalloidin and Alexa Fluor 488 conjugated DNase I immunofluorescence stain ALP activity and expression COL1A1 expression osteocalcin secrete which presenting the osteoblast function were detected by modified calcium and cobalt method RT-PCR and radioimmunity methods respectively Results The changed gravity induced the reorganization of microfilament cytoskeleton of osteoblast After 3 hours parabolic flight F-actin of osteoblast cytoskeleton became more thickness and directivity whereas G-actin reduced and relatively concentrated at the edge of nucleus observed by confocal fluorescence microscopy This phenomenon is identical with structure alternation observed in hypergravity but the osteoblast function decrease The excretion of osteocalcin the activity and mRNA expression of ALP decrease but the COL1A1 expression has no changes These results were similar to the changes in simulated or real microgravity Conclusion Above results suggest that short time gravity alternative change induce osteoblast structure and function

A key role of the prefrontal cortex in the maintenance of chronic tinnitus: An fMRI study using a Stroop task.

PubMed

Araneda, Rodrigo; Renier, Laurent; Dricot, Laurence; Decat, Monique; Ebner-Karestinos, Daniela; Deggouj, Naïma; De Volder, Anne G

2018-01-01

Since we recently showed in behavioural tasks that the top-down cognitive control was specifically altered in tinnitus sufferers, here we wanted to establish the link between this impaired executive function and brain alterations in the frontal cortex in tinnitus patients. Using functional magnetic resonance imaging (fMRI), we monitored the brain activity changes in sixteen tinnitus patients (TP) and their control subjects (CS) while they were performing a spatial Stroop task, both in audition and vision. We observed that TP differed from CS in their functional recruitment of the dorsolateral prefrontal cortex (dlPFC, BA46), the cingulate gyrus and the ventromedial prefrontal cortex (vmPFC, BA10). This recruitment was higher during interference conditions in tinnitus participants than in controls, whatever the sensory modality. Furthermore, the brain activity level in the right dlPFC and vmPFC correlated with the performance in the Stroop task in TP. Due to the direct link between poor executive functions and prefrontal cortex alterations in TP, we postulate that a lack of inhibitory modulation following an impaired top-down cognitive control may maintain tinnitus by hampering habituation mechanisms. This deficit in executive functions caused by prefrontal cortex alterations would be a key-factor in the generation and persistence of tinnitus.

Biodiversity in a complex world: consolidation and progress in functional biodiversity research.

PubMed

Hillebrand, Helmut; Matthiessen, Birte

2009-12-01

The global decline of biodiversity caused by human domination of ecosystems worldwide is supposed to alter important process rates and state variables in these ecosystems. However, there is considerable debate on the prevalence and importance of biodiversity effects on ecosystem function (BDEF). Here, we argue that much of the debate stems from two major shortcomings. First, most studies do not directly link the traits leading to increased or decreased function to the traits needed for species coexistence and dominance. We argue that implementing a trait-based approach and broadening the perception of diversity to include trait dissimilarity or trait divergence will result in more realistic predictions on the consequences of altered biodiversity. Second, the empirical and theoretical studies do not reflect the complexity of natural ecosystems, which makes it difficult to transfer the results to natural situations of species loss. We review how different aspects of complexity (trophic structure, multifunctionality, spatial or temporal heterogeneity, and spatial population dynamics) alter our perception of BDEF. We propose future research avenues concisely testing whether acknowledging this complexity will strengthen the observed biodiversity effects. Finally, we propose that a major future task is to disentangle biodiversity effects on ecosystem function from direct changes in function due to human alterations of abiotic constraints.

Observing and Understanding Arterial and Venous Circulation Differences in a Physiology Laboratory Activity

ERIC Educational Resources Information Center

Altermann, Caroline; Gonçalves, Rithiele; Lara, Marcus Vinícius S.; Neves, Ben-Hur S.; Mello-Carpes, Pâmela B.

2015-01-01

The purpose of the present article is to describe three simple practical experiments that aim to observe and discuss the anatomic and physiological functions and differences between arteries and veins as well as the alterations observed in skin blood flow in different situations. For this activity, students were divided in small groups. In each…

Blink Rate in Boys with Fragile X Syndrome: Preliminary Evidence for Altered Dopamine Function

ERIC Educational Resources Information Center

Roberts, J. E.; Symons, F. J.; Johnson, A.-M.; Hatton, D. D.; Boccia, M. L.

2005-01-01

Background: Dopamine, a neurotransmitter involved in motor and cognitive functioning, can be non-invasively measured via observation of spontaneous blink rates. Blink rates have been studied in a number of clinical conditions including schizophrenia, autism, Parkinsons, and attention deficit/hyperactivity disorder with results implicating either…

Subchronic Toluene Exposure alters Retinal Function in Long Evans Rats: Experimental Evidence Supporting Observations from Studies of Exposed Humans.

EPA Science Inventory

Studies of humans chronically exposed to volatile organic solvents commonly report impaired visual functions, including low contrast sensitivity and reduced color discrimination. These reports have been controversial, however, in part due to a lack of confirmation from controlled...

Examination of Physiological Function and Biochemical Disorders in a Rat Model of Prolonged Asphyxia-Induced Cardiac Arrest followed by Cardio Pulmonary Bypass Resuscitation

PubMed Central

Kim, Junhwan; Yin, Tai; Yin, Ming; Zhang, Wei; Shinozaki, Koichiro; Selak, Mary A.; Pappan, Kirk L.; Lampe, Joshua W.; Becker, Lance B.

2014-01-01

Background Cardiac arrest induces whole body ischemia, which causes damage to multiple organs particularly the heart and the brain. There is clinical and preclinical evidence that neurological injury is responsible for high mortality and morbidity of patients even after successful cardiopulmonary resuscitation. A better understanding of the metabolic alterations in the brain during ischemia will enable the development of better targeted resuscitation protocols that repair the ischemic damage and minimize the additional damage caused by reperfusion. Method A validated whole body model of rodent arrest followed by resuscitation was utilized; animals were randomized into three groups: control, 30 minute asphyxial arrest, or 30 minutes asphyxial arrest followed by 60 min cardiopulmonary bypass (CPB) resuscitation. Blood gases and hemodynamics were monitored during the procedures. An untargeted metabolic survey of heart and brain tissues following cardiac arrest and after CPB resuscitation was conducted to better define the alterations associated with each condition. Results After 30 min cardiac arrest and 60 min CPB, the rats exhibited no observable brain function and weakened heart function in a physiological assessment. Heart and brain tissues harvested following 30 min ischemia had significant changes in the concentration of metabolites in lipid and carbohydrate metabolism. In addition, the brain had increased lysophospholipid content. CPB resuscitation significantly normalized metabolite concentrations in the heart tissue, but not in the brain tissue. Conclusion The observation that metabolic alterations are seen primarily during cardiac arrest suggests that the events of ischemia are the major cause of neurological damage in our rat model of asphyxia-CPB resuscitation. Impaired glycolysis and increased lysophospholipids observed only in the brain suggest that altered energy metabolism and phospholipid degradation may be a central mechanism in unresuscitatable brain damage. PMID:25383962

Examination of physiological function and biochemical disorders in a rat model of prolonged asphyxia-induced cardiac arrest followed by cardio pulmonary bypass resuscitation.

PubMed

Kim, Junhwan; Yin, Tai; Yin, Ming; Zhang, Wei; Shinozaki, Koichiro; Selak, Mary A; Pappan, Kirk L; Lampe, Joshua W; Becker, Lance B

2014-01-01

Cardiac arrest induces whole body ischemia, which causes damage to multiple organs particularly the heart and the brain. There is clinical and preclinical evidence that neurological injury is responsible for high mortality and morbidity of patients even after successful cardiopulmonary resuscitation. A better understanding of the metabolic alterations in the brain during ischemia will enable the development of better targeted resuscitation protocols that repair the ischemic damage and minimize the additional damage caused by reperfusion. A validated whole body model of rodent arrest followed by resuscitation was utilized; animals were randomized into three groups: control, 30 minute asphyxial arrest, or 30 minutes asphyxial arrest followed by 60 min cardiopulmonary bypass (CPB) resuscitation. Blood gases and hemodynamics were monitored during the procedures. An untargeted metabolic survey of heart and brain tissues following cardiac arrest and after CPB resuscitation was conducted to better define the alterations associated with each condition. After 30 min cardiac arrest and 60 min CPB, the rats exhibited no observable brain function and weakened heart function in a physiological assessment. Heart and brain tissues harvested following 30 min ischemia had significant changes in the concentration of metabolites in lipid and carbohydrate metabolism. In addition, the brain had increased lysophospholipid content. CPB resuscitation significantly normalized metabolite concentrations in the heart tissue, but not in the brain tissue. The observation that metabolic alterations are seen primarily during cardiac arrest suggests that the events of ischemia are the major cause of neurological damage in our rat model of asphyxia-CPB resuscitation. Impaired glycolysis and increased lysophospholipids observed only in the brain suggest that altered energy metabolism and phospholipid degradation may be a central mechanism in unresuscitatable brain damage.

Alteration in 5-HT₂C, NMDA receptor and IP3 in cerebral cortex of epileptic rats: restorative role of Bacopa monnieri.

PubMed

Krishnakumar, Amee; Anju, T R; Abraham, Pretty Mary; Paulose, C S

2015-01-01

Bacopa monnieri is effective in stress management, brain function and a balanced mood. 5-HT2C receptors have been implicated in stress whereas NMDA receptors and mGlu5 play crucial role in memory and cognition. In the present study, we investigated the role of B. monnieri extract in ameliorating pilocarpine induced temporal lobe epilepsy through regulation of 5-HT2C and NMDA receptors in cerebral cortex. Our studies confirmed an increased 5-HT2C receptor function during epilepsy thereby facilitating IP3 release. We also observed an decreased NMDA receptor function with an elevated mGlu5 and GLAST gene expression in epileptic condition indicating the possibility for glutamate mediated excitotoxicity. These alterations lead to impaired behavioural functions as indicated by the Elevated Plus maze test. Carbamazepine and B. monnieri treatments to epileptic rats reversed the alterations in 5-HT2C, NMDA receptor functions and IP3 content thereby effectively managing the neurotransmitter balance in the cerebral cortex.

Effects of Simulated Microgravity on Functions of Neutrophil-like HL-60 Cells

NASA Astrophysics Data System (ADS)

Wang, Chengzhi; Li, Ning; Zhang, Chen; Sun, Shujin; Gao, Yuxin; Long, Mian

2015-11-01

Altered gravity, especially microgravity affects cellular functions of immune cells and can result in immune dysfunction for long-term, manned spaceflight and space exploration. The underlying mechanism, however, of sensing and responding to the gravity alteration is poorly understood. Here, a rotary cell culture system (RCCS) bioreactor was used to elucidate the effects of simulated microgravity on polymorphonuclear neutrophils (PMN)-like HL-60 cells. Alteration of cell morphology, up-regulation of (nitric oxide) NO production, enhancement of interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemotactic protein 1 (MCP-1) secretion, and diversity of cellular adhesion molecule expression were observed for the cells cultured in RCCS, leading to the up-regulated inflammatory immune responses and host defense. It was also indicated that such alterations in biological responses of PMNs mediated the reduced rolling velocity and decreased adhesion of PMN-like HL-60 cells on endothelial cells under shear flow. This work furthers the understandings in the effects and mechanism of microgravity on PMN functions, which are potentially helpful for optimizing the countermeasures to immune suppression in the future long-term, manned spaceflight.

Programmed Effects in Neurobehavior and Antioxidative Physiology in Zebrafish Embryonically Exposed to Cadmium: Observations and Hypothesized Adverse Outcome Pathway Framework.

PubMed

Ruiter, Sander; Sippel, Josefine; Bouwmeester, Manon C; Lommelaars, Tobias; Beekhof, Piet; Hodemaekers, Hennie M; Bakker, Frank; van den Brandhof, Evert-Jan; Pennings, Jeroen L A; van der Ven, Leo T M

2016-11-02

Non-communicable diseases (NCDs) are a major cause of premature mortality. Recent studies show that predispositions for NCDs may arise from early-life exposure to low concentrations of environmental contaminants. This developmental origins of health and disease (DOHaD) paradigm suggests that programming of an embryo can be disrupted, changing the homeostatic set point of biological functions. Epigenetic alterations are a possible underlying mechanism. Here, we investigated the DOHaD paradigm by exposing zebrafish to subtoxic concentrations of the ubiquitous contaminant cadmium during embryogenesis, followed by growth under normal conditions. Prolonged behavioral responses to physical stress and altered antioxidative physiology were observed approximately ten weeks after termination of embryonal exposure, at concentrations that were 50-3200-fold below the direct embryotoxic concentration, and interpreted as altered developmental programming. Literature was explored for possible mechanistic pathways that link embryonic subtoxic cadmium to the observed apical phenotypes, more specifically, the probability of molecular mechanisms induced by cadmium exposure leading to altered DNA methylation and subsequently to the observed apical phenotypes. This was done using the adverse outcome pathway model framework, and assessing key event relationship plausibility by tailored Bradford-Hill analysis. Thus, cadmium interaction with thiols appeared to be the major contributor to late-life effects. Cadmium-thiol interactions may lead to depletion of the methyl donor S -adenosyl-methionine, resulting in methylome alterations, and may, additionally, result in oxidative stress, which may lead to DNA oxidation, and subsequently altered DNA methyltransferase activity. In this way, DNA methylation may be affected at a critical developmental stage, causing the observed apical phenotypes.

Altered resting state neuromotor connectivity in men with chronic prostatitis/chronic pelvic pain syndrome: A MAPP

PubMed Central

Kutch, Jason J.; Yani, Moheb S.; Asavasopon, Skulpan; Kirages, Daniel J.; Rana, Manku; Cosand, Louise; Labus, Jennifer S.; Kilpatrick, Lisa A.; Ashe-McNalley, Cody; Farmer, Melissa A.; Johnson, Kevin A.; Ness, Timothy J.; Deutsch, Georg; Harris, Richard E.; Apkarian, A. Vania; Clauw, Daniel J.; Mackey, Sean C.; Mullins, Chris; Mayer, Emeran A.

2015-01-01

Brain network activity associated with altered motor control in individuals with chronic pain is not well understood. Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a debilitating condition in which previous studies have revealed altered resting pelvic floor muscle activity in men with CP/CPPS compared to healthy controls. We hypothesized that the brain networks controlling pelvic floor muscles would also show altered resting state function in men with CP/CPPS. Here we describe the results of the first test of this hypothesis focusing on the motor cortical regions, termed pelvic-motor, that can directly activate pelvic floor muscles. A group of men with CP/CPPS (N = 28), as well as group of age-matched healthy male controls (N = 27), had resting state functional magnetic resonance imaging scans as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. Brain maps of the functional connectivity of pelvic-motor were compared between groups. A significant group difference was observed in the functional connectivity between pelvic-motor and the right posterior insula. The effect size of this group difference was among the largest effect sizes in functional connectivity between all pairs of 165 anatomically-defined subregions of the brain. Interestingly, many of the atlas region pairs with large effect sizes also involved other subregions of the insular cortices. We conclude that functional connectivity between motor cortex and the posterior insula may be among the most important markers of altered brain function in men with CP/CPPS, and may represent changes in the integration of viscerosensory and motor processing. PMID:26106574

The functional alterations associated with motor imagery training: a comparison between motor execution and motor imagery of sequential finger tapping

NASA Astrophysics Data System (ADS)

Zhang, Hang; Yao, Li; Long, Zhiying

2011-03-01

Motor imagery training, as an effective strategy, has been more and more applied to mental disorders rehabilitation and motor skill learning. Studies on the neural mechanism underlying motor imagery have suggested that such effectiveness may be related to the functional congruence between motor execution and motor imagery. However, as compared to the studies on motor imagery, the studies on motor imagery training are much fewer. The functional alterations associated with motor imagery training and the effectiveness of motor imagery training on motor performance improvement still needs further investigation. Using fMRI, we employed a sequential finger tapping paradigm to explore the functional alterations associated with motor imagery training in both motor execution and motor imagery task. We hypothesized through 14 consecutive days motor imagery training, the motor performance could be improved and the functional congruence between motor execution and motor imagery would be sustained form pre-training phase to post-training phase. Our results confirmed the effectiveness of motor imagery training in improving motor performance and demonstrated in both pre and post-training phases, motor imagery and motor execution consistently sustained the congruence in functional neuroanatomy, including SMA (supplementary motor cortex), PMA (premotor area); M1( primary motor cortex) and cerebellum. Moreover, for both execution and imagery tasks, a similar functional alteration was observed in fusiform through motor imagery training. These findings provided an insight into the effectiveness of motor imagery training and suggested its potential therapeutic value in motor rehabilitation.

Abnormal Striatal BOLD Responses to Reward Anticipation and Reward Delivery in ADHD

PubMed Central

Furukawa, Emi; Bado, Patricia; Tripp, Gail; Mattos, Paulo; Wickens, Jeff R.; Bramati, Ivanei E.; Alsop, Brent; Ferreira, Fernanda Meireles; Lima, Debora; Tovar-Moll, Fernanda; Sergeant, Joseph A.; Moll, Jorge

2014-01-01

Altered reward processing has been proposed to contribute to the symptoms of attention deficit hyperactivity disorder (ADHD). The neurobiological mechanism underlying this alteration remains unclear. We hypothesize that the transfer of dopamine release from reward to reward-predicting cues, as normally observed in animal studies, may be deficient in ADHD. Functional magnetic resonance imaging (fMRI) was used to investigate striatal responses to reward-predicting cues and reward delivery in a classical conditioning paradigm. Data from 14 high-functioning and stimulant-naïve young adults with elevated lifetime symptoms of ADHD (8 males, 6 females) and 15 well-matched controls (8 males, 7 females) were included in the analyses. During reward anticipation, increased blood-oxygen-level-dependent (BOLD) responses in the right ventral and left dorsal striatum were observed in controls, but not in the ADHD group. The opposite pattern was observed in response to reward delivery; the ADHD group demonstrated significantly greater BOLD responses in the ventral striatum bilaterally and the left dorsal striatum relative to controls. In the ADHD group, the number of current hyperactivity/impulsivity symptoms was inversely related to ventral striatal responses during reward anticipation and positively associated with responses to reward. The BOLD response patterns observed in the striatum are consistent with impaired predictive dopamine signaling in ADHD, which may explain altered reward-contingent behaviors and symptoms of ADHD. PMID:24586543

Spaceflight and clinorotation cause cytoskeleton and mitochondria changes and increases in apoptosis in cultured cells

NASA Technical Reports Server (NTRS)

Schatten, H.; Lewis, M. L.; Chakrabarti, A.

2001-01-01

The cytoskeleton is a complex network of fibers that is sensitive to environmental factors including microgravity and altered gravitational forces. Cellular functions such as transport of cell organelles depend on cytoskeletal integrity; regulation of cytoskeletal activity plays a role in cell maintenance, cell division, and apoptosis. Here we report cytoskeletal and mitochondria alterations in cultured human lymphocyte (Jurkat) cells after exposure to spaceflight and in insect cells of Drosophila melanogaster (Schneider S-1) after exposure to conditions created by clinostat rotation. Jurkat cells were flown on the space shuttle in Biorack cassettes while Schneider S-1 cells were exposed to altered gravity forces as produced by clinostat rotation. The effects of both treatments were similar in the different cell types. Fifty percent of cells displayed effects on the microtubule network in both cell lines. Under these experimental conditions mitochondria clustering and morphological alterations of mitochondrial cristae was observed to various degrees after 4 and 48 hours of culture. Jurkat cells underwent cell divisions during exposure to spaceflight but a large number of apoptotic cells was also observed. Similar results were obtained in Schneider S-1 cells cultured under clinostat rotation. Both cell lines displayed mitochondria abnormalities and mitochondria clustering toward one side of the cells which is interpreted to be the result of microtubule disruption and failure of mitochondria transport along microtubules. The number of mitochondria was increased in cells exposed to altered gravity while cristae morphology was severely affected indicating altered mitochondria function. These results show that spaceflight as well as altered gravity produced by clinostat rotation affects microtubule and mitochondria organization and results in increases in apoptosis. Grant numbers: NAG 10-0224, NAG2-985. c 2001. Elsevier Science Ltd. All rights reserved.

Altered Odor-Induced Brain Activity as an Early Manifestation of Cognitive Decline in Patients With Type 2 Diabetes.

PubMed

Zhang, Zhou; Zhang, Bing; Wang, Xin; Zhang, Xin; Yang, Qing X; Qing, Zhao; Lu, Jiaming; Bi, Yan; Zhu, Dalong

2018-05-01

Type 2 diabetes is reported to be associated with olfactory dysfunction and cognitive decline. However, whether and how olfactory neural circuit abnormalities involve cognitive impairment in diabetes remains uncovered. This study thus aimed to investigate olfactory network alterations and the associations of odor-induced brain activity with cognitive and metabolic parameters in type 2 diabetes. Participants with normal cognition, including 51 patients with type 2 diabetes and 41 control subjects without diabetes, underwent detailed cognitive assessment, olfactory behavior tests, and odor-induced functional MRI measurements. Olfactory brain regions showing significantly different activation between the two groups were selected for functional connectivity analysis. Compared with the control subjects, patients with diabetes demonstrated significantly lower olfactory threshold score, decreased brain activation, and disrupted functional connectivity in the olfactory network. Positive associations of the disrupted functional connectivity with decreased neuropsychology test scores and reduced pancreatic function were observed in patients with diabetes. Notably, the association between pancreatic function and executive function was mediated by olfactory behavior and olfactory functional connectivity. Our results suggested the alteration of olfactory network is present before clinically measurable cognitive decrements in type 2 diabetes, bridging the gap between the central olfactory system and cognitive decline in diabetes. © 2018 by the American Diabetes Association.

Protein change in plant evolution: tracing one thread connecting molecular and phenotypic diversity

PubMed Central

Bartlett, Madelaine E.; Whipple, Clinton J.

2013-01-01

Proteins change over the course of evolutionary time. New protein-coding genes and gene families emerge and diversify, ultimately affecting an organism’s phenotype and interactions with its environment. Here we survey the range of structural protein change observed in plants and review the role these changes have had in the evolution of plant form and function. Verified examples tying evolutionary change in protein structure to phenotypic change remain scarce. We will review the existing examples, as well as draw from investigations into domestication, and quantitative trait locus (QTL) cloning studies searching for the molecular underpinnings of natural variation. The evolutionary significance of many cloned QTL has not been assessed, but all the examples identified so far have begun to reveal the extent of protein structural diversity tolerated in natural systems. This molecular (and phenotypic) diversity could come to represent part of natural selection’s source material in the adaptive evolution of novel traits. Protein structure and function can change in many distinct ways, but the changes we identified in studies of natural diversity and protein evolution were predicted to fall primarily into one of six categories: altered active and binding sites; altered protein–protein interactions; altered domain content; altered activity as an activator or repressor; altered protein stability; and hypomorphic and hypermorphic alleles. There was also variability in the evolutionary scale at which particular changes were observed. Some changes were detected at both micro- and macroevolutionary timescales, while others were observed primarily at deep or shallow phylogenetic levels. This variation might be used to determine the trajectory of future investigations in structural molecular evolution. PMID:24124420

Immunoendocrine alterations following Marine Corps Martial Arts training are associated with changes in moral cognitive processes.

PubMed

Siedlik, Jacob A; Deckert, Jake A; Clopton, Aaron W; Gigliotti, Nicole; Chan, Marcia A; Benedict, Stephen H; Herda, Trent J; Gallagher, Philip M; Vardiman, John P

2016-02-01

Combined physical and psychological stress events have been associated with exacerbated endocrine responses and increased alterations in immune cell trafficking when compared to exercise stress alone. Military training programs are rigorous in nature and often purposefully delivered in environments combining high levels of both physical and mental stress. The objective of this study was to assess physiological and cognitive changes following U.S. Marine Corps Martial Arts training. Seven active-duty, male Marines were observed during a typical Marine Corps Martial Arts training session. Immune parameters, including immunomodulatory cytokines, and hormone concentrations were determined from blood samples obtained at baseline, immediately post training (IP) and at 15min intervals post-training to 1h (R15, R30, R45, R60). Assessments of cognitive moral functioning (moral judgment and intent) were recorded at intervals during recovery. There were significant fluctuations in immunoendocrine parameters. Peak endocrine measures were observed within the IP-R15 time interval. Distributions of circulating immune cells were significantly altered with neutrophils and all lymphocyte subsets elevated at IP. IFN-γ and IL-17a exhibited small, non-significant, parallel increases over the recovery period. Moral functioning was informed by different social identities during the recovery resulting in changes in moral decision-making. These data demonstrate that the Marine Corps Martial Arts Program induces significant alterations in lymphocyte and leukocyte distributions, but does not shift the balance of Th1/Th2 cytokines or induce a systemic inflammatory response. The program does, however, induce alterations in moral decision-making ability associated with the observed endocrine responses, even suggesting a potential interaction between one's social identities and endocrine responses upon moral decision-making. Copyright © 2015. Published by Elsevier Inc.

Distinct alterations in colonic morphology and physiology in two rat models of enhanced stress-induced anxiety and depression-like behaviour.

PubMed

O'Malley, Dervla; Julio-Pieper, Marcela; Gibney, Sinead M; Dinan, Timothy G; Cryan, John F

2010-03-01

Stress and anxiety are important causal and exacerbating factors in functional gastro-intestinal (GI) disorders such as irritable bowel syndrome. Stress affects GI motility, faecal transit and visceral pain sensitivity. Additionally, permeability and function of the gut epithelium, which acts as a barrier between the external environment and the body's internal milieu is altered by stress. However, the effects of an enhanced stress response on colonic morphology require further investigation. We have used two animal models of stress and anxiety, the maternally separated (MS) and Wistar Kyoto (WKY) rats to examine colonic morphology. These rats exhibit increased anxiety behaviours, visceral hypersensitivity and increased stress-induced defecation in the open field arena. At a morphological level, increased mucus secretion and an associated elevation in the number of mucosal goblet cells was observed in the high anxiety rats. Additionally, the mucosal layer was flattened in MS and WKY rats, a finding indicative of mild mucosal damage. Furthermore, the muscular layer of the distal colon in these animals was thickened, an observation that may have implications for faecal transit and visceral pain perception. This study provides evidence of altered colonic function and morphology in two animal models with a heightened response to stress.

Functional Organization of the Action Observation Network in Autism: A Graph Theory Approach.

PubMed

Alaerts, Kaat; Geerlings, Franca; Herremans, Lynn; Swinnen, Stephan P; Verhoeven, Judith; Sunaert, Stefan; Wenderoth, Nicole

2015-01-01

The ability to recognize, understand and interpret other's actions and emotions has been linked to the mirror system or action-observation-network (AON). Although variations in these abilities are prevalent in the neuro-typical population, persons diagnosed with autism spectrum disorders (ASD) have deficits in the social domain and exhibit alterations in this neural network. Here, we examined functional network properties of the AON using graph theory measures and region-to-region functional connectivity analyses of resting-state fMRI-data from adolescents and young adults with ASD and typical controls (TC). Overall, our graph theory analyses provided convergent evidence that the network integrity of the AON is altered in ASD, and that reductions in network efficiency relate to reductions in overall network density (i.e., decreased overall connection strength). Compared to TC, individuals with ASD showed significant reductions in network efficiency and increased shortest path lengths and centrality. Importantly, when adjusting for overall differences in network density between ASD and TC groups, participants with ASD continued to display reductions in network integrity, suggesting that also network-level organizational properties of the AON are altered in ASD. While differences in empirical connectivity contributed to reductions in network integrity, graph theoretical analyses provided indications that also changes in the high-level network organization reduced integrity of the AON.

Long-duration transcutaneous electric acupoint stimulation alters small-world brain functional networks.

PubMed

Zhang, Yue; Jiang, Yin; Glielmi, Christopher B; Li, Longchuan; Hu, Xiaoping; Wang, Xiaoying; Han, Jisheng; Zhang, Jue; Cui, Cailian; Fang, Jing

2013-09-01

Acupuncture, which is recognized as an alternative and complementary treatment in Western medicine, has long shown efficiencies in chronic pain relief, drug addiction treatment, stroke rehabilitation and other clinical practices. The neural mechanism underlying acupuncture, however, is still unclear. Many studies have focused on the sustained effects of acupuncture on healthy subjects, yet there are very few on the topological organization of functional networks in the whole brain in response to long-duration acupuncture (longer than 20 min). This paper presents a novel study on the effects of long-duration transcutaneous electric acupoint stimulation (TEAS) on the small-world properties of brain functional networks. Functional magnetic resonance imaging was used to construct brain functional networks of 18 healthy subjects (9 males and 9 females) during the resting state. All subjects received both TEAS and minimal TEAS (MTEAS) and were scanned before and after each stimulation. An altered functional network was found with lower local efficiency and no significant change in global efficiency for healthy subjects after TEAS, while no significant difference was observed after MTEAS. The experiments also showed that the nodal efficiencies in several paralimbic/limbic regions were altered by TEAS, and those in middle frontal gyrus and other regions by MTEAS. To remove the psychological effects and the baseline, we compared the difference between diffTEAS (difference between after and before TEAS) and diffMTEAS (difference between after and before MTEAS). The results showed that the local efficiency was decreased and that the nodal efficiencies in frontal gyrus, orbitofrontal cortex, anterior cingulate gyrus and hippocampus gyrus were changed. Based on those observations, we conclude that long-duration TEAS may modulate the short-range connections of brain functional networks and also the limbic system. Copyright © 2013 Elsevier Inc. All rights reserved.

Sex-Specific Patterns of Aberrant Brain Function in First-Episode Treatment-Naive Patients with Schizophrenia.

PubMed

Lei, Wei; Li, Mingli; Deng, Wei; Zhou, Yi; Ma, Xiaohong; Wang, Qiang; Guo, Wanjun; Li, Yinfei; Jiang, Lijun; Han, Yuanyuan; Huang, Chaohua; Hu, Xun; Li, Tao

2015-07-16

Male and female patients with schizophrenia show significant differences in a number of important clinical features, yet the neural substrates of these differences are still poorly understood. Here we explored the sex differences in the brain functional aberrations in 124 treatment-naïve patients with first-episode schizophrenia (61 males), compared with 102 age-matched healthy controls (50 males). Maps of degree centrality (DC) and amplitude of low-frequency fluctuations (ALFF) were constructed using resting-state functional magnetic resonance imaging data and compared between groups. We found that: (1) Selective DC reduction was observed in the right putamen (Put_R) in male patients and the left middle frontal gyrus (MFG) in female patients; (2) Functional connectivity analysis (using Put_R and MFG as seeds) found that male and female patients have disturbed functional integration in two separate networks, i.e., the sensorimotor network and the default mode network; (3) Significant ALFF alterations were also observed in these two networks in both genders; (4) Sex specific brain functional alterations were associated with various symptoms in patients. These results suggested that sex-specific patterns of functional aberration existed in schizophrenia, and these patterns were associated with the clinical features both in male and female patients.

Comparative studies of cellular viability levels on 2D and 3D in vitro culture matrices.

PubMed

Gargotti, M; Lopez-Gonzalez, U; Byrne, H J; Casey, A

2018-02-01

In this study, the cellular viability and function of immortalized human cervical and dermal cells are monitored and compared in conventional 2D and two commercial 3D membranes, Collagen and Geltrex, of varying working concentration and volume. Viability was monitored with the aid of the Alamar Blue assay, cellular morphology was monitored with confocal microscopy, and cell cycle studies and cell death mechanism studies were performed with flow cytometry. The viability studies showed apparent differences between the 2D and 3D culture systems, the differences attributed in part to the physical transition from 2D to 3D environment causing alterations to effective resazurin concentration, uptake and conversion rates, which was dependent on exposure time, but also due to the effect of the membrane itself on cellular function. These effects were verified by flow cytometry, in which no significant differences in viable cell numbers between 2D and 3D systems were observed after 24 h culture. The results showed the observed effect was different after shorter exposure periods, was also dependent on working concentration of the 3D system and could be mediated by altering the culture vessel size. Cell cycle analysis revealed cellular function could be altered by growth on the 3D substrates and the alterations were noted to be dependent on 3D membrane concentration. The use of 3D culture matrices has been widely interpreted to result in "improved viability levels" or "reduced" toxicity or cellular "resistance" compared to cells cultured on traditional 2D systems. The results of this study show that cellular health and viability levels are not altered by culture in 3D environments, but their normal cycle can be altered as indicated in the cell cycle studies performed and such variations must be accounted for in studies employing 3D membranes for in vitro cellular screening.

Altered Primary Motor Cortex Structure, Organization, and Function in Chronic Pain: A Systematic Review and Meta-Analysis.

PubMed

Chang, Wei-Ju; O'Connell, Neil E; Beckenkamp, Paula R; Alhassani, Ghufran; Liston, Matthew B; Schabrun, Siobhan M

2018-04-01

Chronic pain can be associated with movement abnormalities. The primary motor cortex (M1) has an essential role in the formulation and execution of movement. A number of changes in M1 function have been reported in studies of people with chronic pain. This review systematically evaluated the evidence for altered M1 structure, organization, and function in people with chronic pain of neuropathic and non-neuropathic origin. Database searches were conducted and a modified STrengthening the Reporting of OBservational studies in Epidemiology checklist was used to assess the methodological quality of included studies. Meta-analyses, including preplanned subgroup analyses on the basis of condition were performed where possible. Sixty-seven studies (2,290 participants) using various neurophysiological measures were included. There is conflicting evidence of altered M1 structure, organization, and function for neuropathic and non-neuropathic pain conditions. Meta-analyses provided evidence of increased M1 long-interval intracortical inhibition in chronic pain populations. For most measures, the evidence of M1 changes in chronic pain populations is inconclusive. This review synthesizes the evidence of altered M1 structure, organization, and function in chronic pain populations. For most measures, M1 changes are inconsistent between studies and more research with larger samples and rigorous methodology is required to elucidate M1 changes in chronic pain populations. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Seizure Control and Memory Impairment Are Related to Disrupted Brain Functional Integration in Temporal Lobe Epilepsy.

PubMed

Park, Chang-Hyun; Choi, Yun Seo; Jung, A-Reum; Chung, Hwa-Kyoung; Kim, Hyeon Jin; Yoo, Jeong Hyun; Lee, Hyang Woon

2017-01-01

Brain functional integration can be disrupted in patients with temporal lobe epilepsy (TLE), but the clinical relevance of this disruption is not completely understood. The authors hypothesized that disrupted functional integration over brain regions remote from, as well as adjacent to, the seizure focus could be related to clinical severity in terms of seizure control and memory impairment. Using resting-state functional MRI data acquired from 48 TLE patients and 45 healthy controls, the authors mapped functional brain networks and assessed changes in a network parameter of brain functional integration, efficiency, to examine the distribution of disrupted functional integration within and between brain regions. The authors assessed whether the extent of altered efficiency was influenced by seizure control status and whether the degree of altered efficiency was associated with the severity of memory impairment. Alterations in the efficiency were observed primarily near the subcortical region ipsilateral to the seizure focus in TLE patients. The extent of regional involvement was greater in patients with poor seizure control: it reached the frontal, temporal, occipital, and insular cortices in TLE patients with poor seizure control, whereas it was limited to the limbic and parietal cortices in TLE patients with good seizure control. Furthermore, TLE patients with poor seizure control experienced more severe memory impairment, and this was associated with lower efficiency in the brain regions with altered efficiency. These findings indicate that the distribution of disrupted brain functional integration is clinically relevant, as it is associated with seizure control status and comorbid memory impairment.

Mitochondrial dysfunction and insulin resistance from the outside in: extracellular matrix, the cytoskeleton, and mitochondria

PubMed Central

Coletta, Dawn K.

2011-01-01

Insulin resistance in skeletal muscle is a prominent feature of obesity and type 2 diabetes. The association between mitochondrial changes and insulin resistance is well known. More recently, there is growing evidence of a relationship between inflammation, extracellular remodeling, and insulin resistance. The intent of this review is to propose a potentially novel mechanism for the development of insulin resistance, focusing on the underappreciated connections among inflammation, extracellular remodeling, cytoskeletal interactions, mitochondrial function, and insulin resistance in human skeletal muscle. Several sources of inflammation, including expansion of adipose tissue resulting in increased lipolysis and alterations in pro- and anti-inflammatory cytokines, contribute to the insulin resistance observed in obesity and type 2 diabetes. In the experimental model of lipid oversupply, an inflammatory response in skeletal muscle leads to altered expression extracellular matrix-related genes as well as nuclear encoded mitochondrial genes. A similar pattern also is observed in “naturally” occurring insulin resistance in muscle of obese nondiabetic individuals and patients with type 2 diabetes mellitus. More recently, alterations in proteins (including α-actinin-2, desmin, proteasomes, and chaperones) involved in muscle structure and function have been observed in insulin-resistant muscle. Some of these cytoskeletal proteins are mechanosignal transducers that allow muscle fibers to sense contractile activity and respond appropriately. The ensuing alterations in expression of genes coding for mitochondrial proteins and cytoskeletal proteins may contribute to the mitochondrial changes observed in insulin-resistant muscle. These changes in turn may lead to a reduction in fat oxidation and an increase in intramyocellular lipid, which contributes to the defects in insulin signaling in insulin resistance. PMID:21862724

The Role of Glucose Transporters in Brain Disease: Diabetes and Alzheimer’s Disease

PubMed Central

Shah, Kaushik; DeSilva, Shanal; Abbruscato, Thomas

2012-01-01

The occurrence of altered brain glucose metabolism has long been suggested in both diabetes and Alzheimer’s diseases. However, the preceding mechanism to altered glucose metabolism has not been well understood. Glucose enters the brain via glucose transporters primarily present at the blood-brain barrier. Any changes in glucose transporter function and expression dramatically affects brain glucose homeostasis and function. In the brains of both diabetic and Alzheimer’s disease patients, changes in glucose transporter function and expression have been observed, but a possible link between the altered glucose transporter function and disease progress is missing. Future recognition of the role of new glucose transporter isoforms in the brain may provide a better understanding of brain glucose metabolism in normal and disease states. Elucidation of clinical pathological mechanisms related to glucose transport and metabolism may provide common links to the etiology of these two diseases. Considering these facts, in this review we provide a current understanding of the vital roles of a variety of glucose transporters in the normal, diabetic and Alzheimer’s disease brain. PMID:23202918

Impact of neonatal iron deficiency on hippocampal DNA methylation and gene transcription in a porcine biomedical model of cognitive development.

PubMed

Schachtschneider, Kyle M; Liu, Yingkai; Rund, Laurie A; Madsen, Ole; Johnson, Rodney W; Groenen, Martien A M; Schook, Lawrence B

2016-11-03

Iron deficiency is a common childhood micronutrient deficiency that results in altered hippocampal function and cognitive disorders. However, little is known about the mechanisms through which neonatal iron deficiency results in long lasting alterations in hippocampal gene expression and function. DNA methylation is an epigenetic mark involved in gene regulation and altered by environmental factors. In this study, hippocampal DNA methylation and gene expression were assessed via reduced representation bisulfite sequencing and RNA-seq on samples from a previous study reporting reduced hippocampal-based learning and memory in a porcine biomedical model of neonatal iron deficiency. In total 192 differentially expressed genes (DEGs) were identified between the iron deficient and control groups. GO term and pathway enrichment analysis identified DEGs associated with hypoxia, angiogenesis, increased blood brain barrier (BBB) permeability, and altered neurodevelopment and function. Of particular interest are genes previously implicated in cognitive deficits and behavioral disorders in humans and mice, including HTR2A, HTR2C, PAK3, PRSS12, and NETO1. Altered genome-wide DNA methylation was observed across 0.5 million CpG and 2.4 million non-CpG sites. In total 853 differentially methylated (DM) CpG and 99 DM non-CpG sites were identified between groups. Samples clustered by group when comparing DM non-CpG sites, suggesting high conservation of non-CpG methylation in response to neonatal environment. In total 12 DM sites were associated with 9 DEGs, including genes involved in angiogenesis, neurodevelopment, and neuronal function. Neonatal iron deficiency leads to altered hippocampal DNA methylation and gene regulation involved in hypoxia, angiogenesis, increased BBB permeability, and altered neurodevelopment and function. Together, these results provide new insights into the mechanisms through which neonatal iron deficiency results in long lasting reductions in cognitive development in humans.

Automated identification of functional dynamic networks from X-ray crystallography

PubMed Central

van den Bedem, Henry; Bhabha, Gira; Yang, Kun; Wright, Peter E.; Fraser, James S.

2013-01-01

Protein function often depends on the exchange between conformational substates. Allosteric ligand binding or distal mutations can stabilize specific active site conformations and consequently alter protein function. In addition to comparing independently determined X-ray crystal structures, alternative conformations observed at low levels of electron density have the potential to provide mechanistic insights into conformational dynamics. Here, we report a new multi-conformer contact network algorithm (CONTACT) that identifies networks of conformationally heterogeneous residues directly from high-resolution X-ray crystallography data. Contact networks in Escherichia coli dihydrofolate reductase (ecDHFR) predict the long-range pattern of NMR chemical shift perturbations of an allosteric mutation. A comparison of contact networks in wild type and mutant ecDHFR suggests how mutations that alter optimized networks of coordinated motions can impair catalytic function. Thus, CONTACT-guided mutagenesis will allow the structure-dynamics-function relationship to be exploited in protein engineering and design. PMID:23913260

Programmed Effects in Neurobehavior and Antioxidative Physiology in Zebrafish Embryonically Exposed to Cadmium: Observations and Hypothesized Adverse Outcome Pathway Framework

PubMed Central

Ruiter, Sander; Sippel, Josefine; Bouwmeester, Manon C.; Lommelaars, Tobias; Beekhof, Piet; Hodemaekers, Hennie M.; Bakker, Frank; van den Brandhof, Evert-Jan; Pennings, Jeroen L. A.; van der Ven, Leo T. M.

2016-01-01

Non-communicable diseases (NCDs) are a major cause of premature mortality. Recent studies show that predispositions for NCDs may arise from early-life exposure to low concentrations of environmental contaminants. This developmental origins of health and disease (DOHaD) paradigm suggests that programming of an embryo can be disrupted, changing the homeostatic set point of biological functions. Epigenetic alterations are a possible underlying mechanism. Here, we investigated the DOHaD paradigm by exposing zebrafish to subtoxic concentrations of the ubiquitous contaminant cadmium during embryogenesis, followed by growth under normal conditions. Prolonged behavioral responses to physical stress and altered antioxidative physiology were observed approximately ten weeks after termination of embryonal exposure, at concentrations that were 50–3200-fold below the direct embryotoxic concentration, and interpreted as altered developmental programming. Literature was explored for possible mechanistic pathways that link embryonic subtoxic cadmium to the observed apical phenotypes, more specifically, the probability of molecular mechanisms induced by cadmium exposure leading to altered DNA methylation and subsequently to the observed apical phenotypes. This was done using the adverse outcome pathway model framework, and assessing key event relationship plausibility by tailored Bradford-Hill analysis. Thus, cadmium interaction with thiols appeared to be the major contributor to late-life effects. Cadmium-thiol interactions may lead to depletion of the methyl donor S-adenosyl-methionine, resulting in methylome alterations, and may, additionally, result in oxidative stress, which may lead to DNA oxidation, and subsequently altered DNA methyltransferase activity. In this way, DNA methylation may be affected at a critical developmental stage, causing the observed apical phenotypes. PMID:27827847

Opioids and the immune system: what is their mechanism of action?

PubMed

Eisenstein, Toby K

2011-12-01

There is a significant amount of literature showing that morphine and other opioids modulate immune responses. The findings support many mechanisms by which this may occur. In vitro experiments provide evidence for direct actions of opioids on immune cells using a variety of functional end points. When these drugs are given in vivo, a plethora of immune parameters are also altered. The paper in this issue of the journal by Zhang et al. provides new information on morphine alteration of immune cell subsets in the spleen and thymus of mice and the potential role of glucocorticoids in these observed phenomena. This Commentary reviews the in vitro activities of morphine on leucocytes, as well as other documented mechanisms by which morphine can alter immune function in vivo. © 2011 The Author. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Altered functional connectivity of amygdala underlying the neuromechanism of migraine pathogenesis.

PubMed

Chen, Zhiye; Chen, Xiaoyan; Liu, Mengqi; Dong, Zhao; Ma, Lin; Yu, Shengyuan

2017-12-01

The amygdala is a large grey matter complex in the limbic system, and it may contribute in the neurolimbic pain network in migraine. However, the detailed neuromechanism remained to be elucidated. The objective of this study is to investigate the amygdala structural and functional changes in migraine and to elucidate the mechanism of neurolimbic pain-modulating in the migraine pathogenesis. Conventional MRI, 3D structure images and resting state functional MRI were performed in 18 normal controls (NC), 18 patients with episodic migraine (EM), and 16 patients with chronic migraine (CM). The amygdala volume was measured using FreeSurfer software and the functional connectivity (FC) of bilateral amygdala was computed over the whole brain. Analysis of covariance was performed on the individual FC maps among groups. The increased FC of left amygdala was observed in EM compared with NC, and the decreased of right amygdala was revealed in CM compared with NC. The increased FC of bilateral amygdala was observed in CM compared with EM. The correlation analysis showed a negative correlation between the score of sleep quality (0, normal; 1, mild sleep disturbance; 2, moderate sleep disturbance; 3, serious sleep disturbance) and the increased FC strength of left amygdala in EM compared with NC, and a positive correlation between the score of sleep quality and the increased FC strength of left amygdala in CM compared with EM, and other clinical variables showed no significant correlation with altered FC of amygdala. The altered functional connectivity of amygdala demonstrated that neurolimbic pain network contribute in the EM pathogenesis and CM chronicization.

Remodeling of Sensorimotor Brain Connectivity in Gpr88-Deficient Mice.

PubMed

Arefin, Tanzil Mahmud; Mechling, Anna E; Meirsman, Aura Carole; Bienert, Thomas; Hübner, Neele Saskia; Lee, Hsu-Lei; Ben Hamida, Sami; Ehrlich, Aliza; Roquet, Dan; Hennig, Jürgen; von Elverfeldt, Dominik; Kieffer, Brigitte Lina; Harsan, Laura-Adela

2017-10-01

Recent studies have demonstrated that orchestrated gene activity and expression support synchronous activity of brain networks. However, there is a paucity of information on the consequences of single gene function on overall brain functional organization and connectivity and how this translates at the behavioral level. In this study, we combined mouse mutagenesis with functional and structural magnetic resonance imaging (MRI) to determine whether targeted inactivation of a single gene would modify whole-brain connectivity in live animals. The targeted gene encodes GPR88 (G protein-coupled receptor 88), an orphan G protein-coupled receptor enriched in the striatum and previously linked to behavioral traits relevant to neuropsychiatric disorders. Connectivity analysis of Gpr88-deficient mice revealed extensive remodeling of intracortical and cortico-subcortical networks. Most prominent modifications were observed at the level of retrosplenial cortex connectivity, central to the default mode network (DMN) whose alteration is considered a hallmark of many psychiatric conditions. Next, somatosensory and motor cortical networks were most affected. These modifications directly relate to sensorimotor gating deficiency reported in mutant animals and also likely underlie their hyperactivity phenotype. Finally, we identified alterations within hippocampal and dorsal striatum functional connectivity, most relevant to a specific learning deficit that we previously reported in Gpr88 -/- animals. In addition, amygdala connectivity with cortex and striatum was weakened, perhaps underlying the risk-taking behavior of these animals. This is the first evidence demonstrating that GPR88 activity shapes the mouse brain functional and structural connectome. The concordance between connectivity alterations and behavior deficits observed in Gpr88-deficient mice suggests a role for GPR88 in brain communication.

Modality-Spanning Deficits in Attention-Deficit/Hyperactivity Disorder in Functional Networks, Gray Matter, and White Matter

PubMed Central

Kessler, Daniel; Angstadt, Michael; Welsh, Robert C.

2014-01-01

Previous neuroimaging investigations in attention-deficit/hyperactivity disorder (ADHD) have separately identified distributed structural and functional deficits, but interconnections between these deficits have not been explored. To unite these modalities in a common model, we used joint independent component analysis, a multivariate, multimodal method that identifies cohesive components that span modalities. Based on recent network models of ADHD, we hypothesized that altered relationships between large-scale networks, in particular, default mode network (DMN) and task-positive networks (TPNs), would co-occur with structural abnormalities in cognitive regulation regions. For 756 human participants in the ADHD-200 sample, we produced gray and white matter volume maps with voxel-based morphometry, as well as whole-brain functional connectomes. Joint independent component analysis was performed, and the resulting transmodal components were tested for differential expression in ADHD versus healthy controls. Four components showed greater expression in ADHD. Consistent with our a priori hypothesis, we observed reduced DMN-TPN segregation co-occurring with structural abnormalities in dorsolateral prefrontal cortex and anterior cingulate cortex, two important cognitive control regions. We also observed altered intranetwork connectivity in DMN, dorsal attention network, and visual network, with co-occurring distributed structural deficits. There was strong evidence of spatial correspondence across modalities: For all four components, the impact of the respective component on gray matter at a region strongly predicted the impact on functional connectivity at that region. Overall, our results demonstrate that ADHD involves multiple, cohesive modality spanning deficits, each one of which exhibits strong spatial overlap in the pattern of structural and functional alterations. PMID:25505309

Altered cytokine production by dendritic cells from infants with atopic dermatitis.

PubMed

Yao, Weiguo; Chang, JiHoon; Sehra, Sarita; Travers, Jeffrey B; Chang, Cheong-Hee; Tepper, Robert S; Kaplan, Mark H

2010-12-01

Dendritic cells (DC) are potent initiators of immune responses, compared to other professional antigen-presenting cells, based on their ability to capture antigen, express high amounts of MHC and co-stimulatory molecules, and to secrete immunostimulatory cytokines. Altered functions of DC in atopic individuals have been observed, though it is not clear if this is a cause or a result of the development of allergic disease. In this report we demonstrate altered cytokine production by DC isolated from infants with atopic dermatitis but without a diagnosis of asthma, compared to infants with non-atopic dermatitis. Increased production of IL-6, IL-10 and IFNα from DC isolated from atopic infants is less apparent when DC from infants were examined 1 year later. An increase in the same cytokines was observed in neonatal mice that are genetically predisposed towards allergic inflammation. These results suggest that an atopic environment promotes altered cytokine production by DC from infants. Copyright © 2010 Elsevier Inc. All rights reserved.

Functional capacity and muscular abnormalities in subclinical hypothyroidism.

PubMed

Reuters, Vaneska S; Teixeira, Patrícia de Fátima S; Vigário, Patrícia S; Almeida, Cloyra P; Buescu, Alexandre; Ferreira, Márcia M; de Castro, Carmen L N; Gold, Jaime; Vaisman, Mario

2009-10-01

Neuromuscular abnormalities and low exercise tolerance are frequently observed in overt hypothyroidism, but it remains controversial if they can also occur in subclinical hypothyroidism (sHT). The aim of this study is to evaluate neuromuscular symptoms, muscle strength, and exercise capacity in sHT, compared with healthy euthyroid individuals. A cross-sectional study was performed with 44 sHT and 24 euthyroid outpatients from a university hospital. Neuromuscular symptoms were questioned. Muscle strength was tested for neck, shoulder, arm, and hip muscle groups, using manual muscle testing (MMT). Quadriceps muscle strength was tested with a chair dynamometer and inspiratory muscle strength (IS) by a manuvacuometer. Functional capacity was estimated based on the peak of oxygen uptake (mL/kg/min), using the Bruce treadmill protocol. Cramps (54.8% versus 25.0%; P < 0.05), weakness (45.2% versus 12.6; P < 0.05), myalgia (47.6% versus 25.0%; P = 0.07), and altered MMT (30.8% versus 8.3%; P = 0.040) were more frequent in sHT. Quadriceps strength and IS were not impaired in sHT and the same was observed for functional capacity. IS was significantly lower in patients complaining of fatigue and weakness (P < 0.05) and tended to be lower in those with altered MMT (P = 0.090). Neuromuscular complaints and altered MMT were significantly more frequent in sHT than in controls, and IS was lower in patients with these abnormalities. Results suggest that altered muscle strength by MMT and the coexistence of neuromuscular complaints in patients with sHT may indicate neuromuscular dysfunction.

BIOAVAILABLE AIR PARTICULATE POLLUTION CONSTITUENTS DIRECTLY ALTER CARDIOVASCULAR FUNCTION EX VIVO

EPA Science Inventory

Epidemiological studies have reported associations between particulate air pollution exposure and cardiovascular (CV) effects within susceptible individuals. Particle characteristics and biological mechanisms responsible for these observations are not known. We examined whether s...

Structural connectivity in schizophrenia and its impact on the dynamics of spontaneous functional networks

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cabral, Joana; Department of Psychiatry, University of Oxford, Oxford OX3 7JX; Fernandes, Henrique M.

The neuropathology of schizophrenia remains unclear. Some insight has come from modern neuroimaging techniques, which offer an unparalleled opportunity to explore in vivo the structure and function of the brain. Using functional magnetic resonance imaging, it has been found that the large-scale resting-state functional connectivity (rsFC) in schizophrenia — measured as the temporal correlations of the blood-oxygen-level-dependent (BOLD) signal — exhibit altered network topology, with lower small-world index. The origin of these rsFC alterations and link with the underlying structural connectivity remain unclear. In this work, we used a computational model of spontaneous large-scale brain activity to explore the rolemore » of the structural connectivity in the large-scale dynamics of the brain in health and schizophrenia. The structural connectomes from 15 adolescent patients with early-onset schizophrenia and 15 age- and gender-matched controls were built from diffusion tensor imaging data to detect the white matter tracts between 90 brain areas. Brain areas, simulated using a reduced dynamic mean-field model, receive excitatory input from other areas in proportion to the number of fibre tracts between them. The simulated mean field activity was transformed into BOLD signal, and the properties of the simulated functional networks were analyzed. Our results suggest that the functional alterations observed in schizophrenia are not directly linked to alterations in the structural topology. Instead, subtly randomized and less small-world functional networks appear when the brain operates with lower global coupling, which shifts the dynamics from the optimal healthy regime.« less

Structural connectivity in schizophrenia and its impact on the dynamics of spontaneous functional networks

NASA Astrophysics Data System (ADS)

Cabral, Joana; Fernandes, Henrique M.; Van Hartevelt, Tim J.; James, Anthony C.; Kringelbach, Morten L.; Deco, Gustavo

2013-12-01

The neuropathology of schizophrenia remains unclear. Some insight has come from modern neuroimaging techniques, which offer an unparalleled opportunity to explore in vivo the structure and function of the brain. Using functional magnetic resonance imaging, it has been found that the large-scale resting-state functional connectivity (rsFC) in schizophrenia — measured as the temporal correlations of the blood-oxygen-level-dependent (BOLD) signal — exhibit altered network topology, with lower small-world index. The origin of these rsFC alterations and link with the underlying structural connectivity remain unclear. In this work, we used a computational model of spontaneous large-scale brain activity to explore the role of the structural connectivity in the large-scale dynamics of the brain in health and schizophrenia. The structural connectomes from 15 adolescent patients with early-onset schizophrenia and 15 age- and gender-matched controls were built from diffusion tensor imaging data to detect the white matter tracts between 90 brain areas. Brain areas, simulated using a reduced dynamic mean-field model, receive excitatory input from other areas in proportion to the number of fibre tracts between them. The simulated mean field activity was transformed into BOLD signal, and the properties of the simulated functional networks were analyzed. Our results suggest that the functional alterations observed in schizophrenia are not directly linked to alterations in the structural topology. Instead, subtly randomized and less small-world functional networks appear when the brain operates with lower global coupling, which shifts the dynamics from the optimal healthy regime.

Regulation of sympathetic nervous system function after cardiovascular deconditioning

NASA Technical Reports Server (NTRS)

Hasser, E. M.; Moffitt, J. A.

2001-01-01

Humans subjected to prolonged periods of bed rest or microgravity undergo deconditioning of the cardiovascular system, characterized by resting tachycardia, reduced exercise capability, and a predisposition for orthostatic intolerance. These changes in cardiovascular function are likely due to a combination of factors, including changes in control of body fluid balance or cardiac alterations resulting in inadequate maintenance of stroke volume, altered arterial or venous vascular function, reduced activation of cardiovascular hormones, and diminished autonomic reflex function. There is evidence indicating a role for each of these mechanisms. Diminished reflex activation of the sympathetic nervous system and subsequent vasoconstriction appear to play an important role. Studies utilizing the hindlimb-unloaded (HU) rat, an animal model of deconditioning, evaluated the potential role of altered arterial baroreflex control of the sympathetic nervous system. These studies indicate that HU results in blunted baroreflex-mediated activation of both renal and lumbar sympathetic nerve activity in response to a hypotensive stimulus. HU rats are less able to maintain arterial pressure during hemorrhage, suggesting that diminished ability to increase sympathetic activity has functional consequences for the animal. Reflex control of vasopressin secretion appears to be enhanced following HU. Blunted baroreflex-mediated sympathoexcitation appears to involve altered central nervous system function. Baroreceptor afferent activity in response to changes in arterial pressure is unaltered in HU rats. However, increases in efferent sympathetic nerve activity for a given decrease in afferent input are blunted after HU. This altered central nervous system processing of baroreceptor inputs appears to involve an effect at the rostral ventrolateral medulla (RVLM). Specifically, it appears that tonic GABAA-mediated inhibition of the RVLM is enhanced after HU. Augmented inhibition apparently arises from sources other than the caudal ventrolateral medulla. If similar alterations in control of the sympathetic nervous system occur in humans in response to cardiovascular deconditioning, it is likely that they play an important role in the observed tendency for orthostatic intolerance. Combined with potential changes in vascular function, cardiac function, and hypovolemia, the predisposition for orthostatic intolerance following cardiovascular deconditioning would be markedly enhanced by blunted ability to reflexly activate the sympathetic nervous system.

Restriction of Receptor Movement Alters Cellular Response: Physical Force Sensing by EphA2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Salaita, Khalid; Nair, Pradeep M; Petit, Rebecca S

2009-09-09

Activation of the EphA2 receptor tyrosine kinase by ephrin-A1 ligands presented on apposed cell surfaces plays important roles in development and exhibits poorly understood functional alterations in cancer. We reconstituted this intermembrane signaling geometry between live EphA2-expressing human breast cancer cells and supported membranes displaying laterally mobile ephrin-A1. Receptor-ligand binding, clustering, and subsequent lateral transport within this junction were observed. EphA2 transport can be blocked by physical barriers nanofabricated onto the underlying substrate. This physical reorganization of EphA2 alters the cellular response to ephrin-A1, as observed by changes in cytoskeleton morphology and recruitment of a disintegrin and metalloprotease 10. Quantitativemore » analysis of receptor-ligand spatial organization across a library of 26 mammary epithelial cell lines reveals characteristic differences that strongly correlate with invasion potential. These observations reveal a mechanism for spatio-mechanical regulation of EphA2 signaling pathways.« less

Urban field guide: applying social forestry observation techniques to the east coast megalopolis

Treesearch

E. Svendsen; V. Marshall; M.F. Ufer

2006-01-01

A changing economy and different lifestyles have altered the meaning of the forest in the northeastern United States, prompting scientists to reconsider the spatial form, stewardship and function of the urban forest. The Authors describe how social observation techniques and the employment of a novel, locally based, participatory hand-held monitoring system could aid...

Neonatal Odor-Shock Conditioning Alters the Neural Network Involved in Odor Fear Learning at Adulthood

ERIC Educational Resources Information Center

Sevelinges, Yannick; Sullivan, Regina M.; Messaoudi, Belkacem; Mouly, Anne-Marie

2008-01-01

Adult learning and memory functions are strongly dependent on neonatal experiences. We recently showed that neonatal odor-shock learning attenuates later life odor fear conditioning and amygdala activity. In the present work we investigated whether changes observed in adults can also be observed in other structures normally involved, namely…

Alterations in protein glycosylation in PMA-differentiated U-937 cells exposed to mineral particles.

PubMed Central

Trabelsi, N; Greffard, A; Pairon, J C; Bignon, J; Zanetti, G; Fubini, B; Pilatte, Y

1997-01-01

Carbohydrate moieties of cell glycoconjugates play a pivotal role in molecular recognition phenomena involved in the regulation of most biological systems and the changes observed in cell surface carbohydrates during cell activation or differentiation frequently modulate certain cell functions. Consequently, some aspects of macrophage response to particle exposure might conceivably result from alterations in glycosylation. Therefore, the effect of mineral particles on protein glycosylation was investigated in phorbol myristate acetate (PMA)-differentiated U-937. Jacalin, a lectin specific for O-glycosylated structures, showed a global increase in O-glycosylation in particle-treated cells. In contrast, no significant modifications were observed with concanavalin A, a lectin that recognizes certain N-glycosylated structures. The sialic acid-specific lectins Sambucus nigra agglutinin and Maackia amurensis agglutinin and the galactose-specific lectin Ricinus communis agglutinin revealed a complex pattern of alterations in glycoprotein glycosylation after crystalline silica or manganese dioxide treatments. Expression of sialyl Lewis(x), a glycosylated structure implicated in leukocyte trafficking, could not be detected in control or treated cells. This finding was consistent with the decrease in sialyl Lewis(x) expression observed during PMA-induced differentiation. In conclusion, various treatments used in this study induced quantitative as well as qualitative changes in protein glycosylation. Whether these changes are due to glycosidase release or to an alteration in glycosyltransferase expression remains to be determined. The potential functional implications of these changes are currently under investigation. Images Figure 1. A Figure 1. B Figure 2. A Figure 2. B Figure 3. A Figure 3. B Figure 3. C Figure 4. PMID:9400716

Consequences of Increasing Hypoxic Disturbance on Benthic Communities and Ecosystem Functioning

PubMed Central

Villnäs, Anna; Norkko, Joanna; Lukkari, Kaarina; Hewitt, Judi; Norkko, Alf

2012-01-01

Disturbance-mediated species loss has prompted research considering how ecosystem functions are changed when biota is impaired. However, there is still limited empirical evidence from natural environments evaluating the direct and indirect (i.e. via biota) effects of disturbance on ecosystem functioning. Oxygen deficiency is a widespread threat to coastal and estuarine communities. While the negative impacts of hypoxia on benthic communities are well known, few studies have assessed in situ how benthic communities subjected to different degrees of hypoxic stress alter their contribution to ecosystem functioning. We studied changes in sediment ecosystem function (i.e. oxygen and nutrient fluxes across the sediment water-interface) by artificially inducing hypoxia of different durations (0, 3, 7 and 48 days) in a subtidal sandy habitat. Benthic chamber incubations were used for measuring responses in sediment oxygen and nutrient fluxes. Changes in benthic species richness, structure and traits were quantified, while stress-induced behavioral changes were documented by observing bivalve reburial rates. The initial change in faunal behavior was followed by non-linear degradation in benthic parameters (abundance, biomass, bioturbation potential), gradually impairing the structural and functional composition of the benthic community. In terms of ecosystem function, the increasing duration of hypoxia altered sediment oxygen consumption and enhanced sediment effluxes of NH4 + and dissolved Si. Although effluxes of PO4 3− were not altered significantly, changes were observed in sediment PO4 3− sorption capability. The duration of hypoxia (i.e. number of days of stress) explained a minor part of the changes in ecosystem function. Instead, the benthic community and disturbance-driven changes within the benthos explained a larger proportion of the variability in sediment oxygen- and nutrient fluxes. Our results emphasize that the level of stress to the benthic habitat matters, and that the link between biodiversity and ecosystem function is likely to be affected by a range of factors in complex, natural environments. PMID:23091592

Modeling human perception of orientation in altered gravity

PubMed Central

Clark, Torin K.; Newman, Michael C.; Oman, Charles M.; Merfeld, Daniel M.; Young, Laurence R.

2015-01-01

Altered gravity environments, such as those experienced by astronauts, impact spatial orientation perception, and can lead to spatial disorientation and sensorimotor impairment. To more fully understand and quantify the impact of altered gravity on orientation perception, several mathematical models have been proposed. The utricular shear, tangent, and the idiotropic vector models aim to predict static perception of tilt in hyper-gravity. Predictions from these prior models are compared to the available data, but are found to systematically err from the perceptions experimentally observed. Alternatively, we propose a modified utricular shear model for static tilt perception in hyper-gravity. Previous dynamic models of vestibular function and orientation perception are limited to 1 G. Specifically, they fail to predict the characteristic overestimation of roll tilt observed in hyper-gravity environments. To address this, we have proposed a modification to a previous observer-type canal-otolith interaction model based upon the hypothesis that the central nervous system (CNS) treats otolith stimulation in the utricular plane differently than stimulation out of the utricular plane. Here we evaluate our modified utricular shear and modified observer models in four altered gravity motion paradigms: (a) static roll tilt in hyper-gravity, (b) static pitch tilt in hyper-gravity, (c) static roll tilt in hypo-gravity, and (d) static pitch tilt in hypo-gravity. The modified models match available data in each of the conditions considered. Our static modified utricular shear model and dynamic modified observer model may be used to help quantitatively predict astronaut perception of orientation in altered gravity environments. PMID:25999822

Protective Effects of Morus alba Leaves Extract on Ocular Functions of Pups from Diabetic and Hypercholesterolemic Mother Rats

PubMed Central

El-Sayyad, H.I.H.; El-Sherbiny, M.A.; Sobh, M.A.; Abou-El-Naga, A.M.; Ibrahim, M.A.N.; Mousa, S.A.

2011-01-01

Phytotherapy is frequently considered to be less toxic and free from side effects than synthetic drugs. Hence, the present study was designed to investigate the protective use of crude water extract of Morus alba leaves on ocular functions including cataractogenesis, biochemical diabetic and hypercholesterolemic markers, retinal neurotransmitters and retinopathy of rat pups maternally subjected to either diabetes and/or hypercholesterolemia. Application of crude water extract of Morus alba resulted in amelioration of the alterations of maternal serum glucose, LDL, HDL, total cholesterol and creatine phosphokinase activity as well as retinal neurotransmitters including acetylcholine (ACE), adrenaline (AD), nor-adrenaline (NAD), serotonin (5-HT), histamine (HS), dopamine (DA) and gamma amino butyric acid (GABA). The retina of pups of either diabetic and/or hypercholesterolemia mothers exhibited massive alterations of retinal neurotransmitters. The alterations of retinal neurotransmitters were correlated with the observed pathological alterations of retinal pigmented epithelium, photoreceptor inner segment and ganglion cells and increased incidence of DNA fragmentation and apoptosis cell death. However, protection with Morus alba extract led to amelioration of the pathological alterations of retinal neurons and estimated neurotransmitters. Furthermore, a striking incidence of cataract was detected in pups of either diabetic and/or hypercholesterolemic mothers. Highest cataractogenesis was observed in pups of combined -treated groups. Our data indicate that experimental maternal diabetes alone or in combination with hypercholesterolemia led to alteration in the ocular structures of their pups, with an increasing incidence of cataract and retinopathy, and the effects of the extract might be attributed to the hypoglycaemic, antihypercholesterolemic and anti-oxidative potential of flavonoids, the major components of the plant extract. PMID:21697998

Protective effects of Morus alba leaves extract on ocular functions of pups from diabetic and hypercholesterolemic mother rats.

PubMed

El-Sayyad, H I H; El-Sherbiny, M A; Sobh, M A; Abou-El-Naga, A M; Ibrahim, M A N; Mousa, S A

2011-01-01

Phytotherapy is frequently considered to be less toxic and free from side effects than synthetic drugs. Hence, the present study was designed to investigate the protective use of crude water extract of Morus alba leaves on ocular functions including cataractogenesis, biochemical diabetic and hypercholesterolemic markers, retinal neurotransmitters and retinopathy of rat pups maternally subjected to either diabetes and/or hypercholesterolemia. Application of crude water extract of Morus alba resulted in amelioration of the alterations of maternal serum glucose, LDL, HDL, total cholesterol and creatine phosphokinase activity as well as retinal neurotransmitters including acetylcholine (ACE), adrenaline (AD), nor-adrenaline (NAD), serotonin (5-HT), histamine (HS), dopamine (DA) and gamma amino butyric acid (GABA). The retina of pups of either diabetic and/or hypercholesterolemia mothers exhibited massive alterations of retinal neurotransmitters. The alterations of retinal neurotransmitters were correlated with the observed pathological alterations of retinal pigmented epithelium, photoreceptor inner segment and ganglion cells and increased incidence of DNA fragmentation and apoptosis cell death. However, protection with Morus alba extract led to amelioration of the pathological alterations of retinal neurons and estimated neurotransmitters. Furthermore, a striking incidence of cataract was detected in pups of either diabetic and/or hypercholesterolemic mothers. Highest cataractogenesis was observed in pups of combined -treated groups. Our data indicate that experimental maternal diabetes alone or in combination with hypercholesterolemia led to alteration in the ocular structures of their pups, with an increasing incidence of cataract and retinopathy, and the effects of the extract might be attributed to the hypoglycaemic, antihypercholesterolemic and anti-oxidative potential of flavonoids, the major components of the plant extract.

Laminin alterations after in vitro nonenzymatic glycosylation.

PubMed

Charonis, A S; Reger, L A; Dege, J E; Kouzi-Koliakos, K; Furcht, L T; Wohlhueter, R M; Tsilibary, E C

1990-07-01

Laminin, a basement membrane protein derived from the matrix of the Engelbreth-Holm-Swarm murine tumor, was nonenzymatically glycosylated in vitro in the presence of increasing glucose concentrations. The amount of glucose incorporated per laminin molecule was shown to be proportional to the molarity of glucose used. Nonenzymatic glycosylation resulted in formation of cross-links and alterations of the cruciform shape of laminin molecules; these alterations were dramatic when high concentrations of glucose were used. One of the functions of laminin, the process of self-assembly, was shown to be impaired after in vitro nonenzymatic glycosylation. Glucose incorporation resulted in a dramatic decrease of long-to-long laminin dimers, which normally form during the initial steps of assembly. Furthermore, nonenzymatic glycosylation of laminin reduced its ability to self-associate into complexes larger than dimers, as judged by turbidimetry. The observed decrease of maximal turbidity was proportional to the degree of nonenzymatic glycosylation. Aminoguanidine, which has been suggested to inhibit cross-link formation, was shown to restore to a large extent the shape of laminin, the percentage of long-to-long arm dimers, and the maximal turbidity when included in the mixtures of laminin and glucose. These data suggest that structural and functional alterations of laminin may be primarily due to formation of cross-links. Such modifications of laminin (along with our basement membrane components) may contribute to the morphological and physiological changes observed in basement membranes under diabetic conditions.

Serum concentrations of trace elements and their relationships with paraoxonase-1 in morbidly obese women.

PubMed

Luciano-Mateo, Fedra; Cabré, Noemí; Nadal, Martí; García-Heredia, Anabel; Baiges-Gaya, Gerard; Hernández-Aguilera, Anna; Camps, Jordi; Joven, Jorge; Domingo, José Luis

2018-07-01

The metabolic alterations associated with obesity include mineral dysregulation. Essential trace elements are nutrients with a relevant function in a large number of cellular processes and multiple roles in the correct functioning of metabolic enzymes. Paraoxonase-1 (PON1) is an antioxidant and anti-inflammatory enzyme that is compromised in obesity. In the present study, the potential alterations in trace elements in morbidly obese women were assessed in relation to serum PON1 activity and concentration, as well as to other obesity-related comorbidities such as diabetes mellitus and fatty liver. We recruited 41 morbidly obese women and 51 control individuals. The serum concentrations of 30 elements, PON1 paraoxonase and lactonase activities, and PON1 concentration were measured. We observed significant alterations in the levels of As, Ba, Cu, Ca, Fe, Mg, Na, Se, Sr, and Zn in obese women; some of them (As, Ca, Cr, Cu, Mg, and Se) being significantly correlated with serum PON1 values. The most relevant changes were observed in the concentrations of As, Sr and Mg, the last of which was also significantly associated with diabetes mellitus. The current results raise the possibility that increased ingestion and/or storage of a number of trace elements may be factors predisposing to obesity-related comorbidities and metabolic alterations. Copyright © 2018 Elsevier GmbH. All rights reserved.

Interleukin 1 and Tumor Necrosis Factor Inhibit Cardiac Myocyte β -adrenergic Responsiveness

NASA Astrophysics Data System (ADS)

Gulick, Tod; Chung, Mina K.; Pieper, Stephen J.; Lange, Louis G.; Schreiner, George F.

1989-09-01

Reversible congestive heart failure can accompany cardiac allograft rejection and inflammatory myocarditis, conditions associated with an immune cell infiltrate of the myocardium. To determine whether immune cell secretory products alter cardiac muscle metabolism without cytotoxicity, we cultured cardiac myocytes in the presence of culture supernatants from activated immune cells. We observed that these culture supernatants inhibit β -adrenergic agonist-mediated increases in cultured cardiac myocyte contractility and intracellular cAMP accumulation. The myocyte contractile response to increased extracellular Ca2+ concentration is unaltered by prior exposure to these culture supernatants, as is the increase in myocyte intracellular cAMP concentration in response to stimulation with forskolin, a direct adenyl cyclase activator. Inhibition occurs in the absence of alteration in β -adrenergic receptor density or ligand binding affinity. Suppressive activity is attributable to the macrophage-derived cytokines interleukin 1 and tumor necrosis factor. Thus, these observations describe a role for defined cytokines in regulating the hormonal responsiveness and function of contractile cells. The effects of interleukin 1 and tumor necrosis factor on intracellular cAMP accumulation may be a model for immune modulation of other cellular functions dependent upon cyclic nucleotide metabolism. The uncoupling of agonist-occupied receptors from adenyl cyclase suggests that β -receptor or guanine nucleotide binding protein function is altered by the direct or indirect action of cytokines on cardiac muscle cells.

Functional Organization of the Action Observation Network in Autism: A Graph Theory Approach

PubMed Central

Alaerts, Kaat; Geerlings, Franca; Herremans, Lynn; Swinnen, Stephan P.; Verhoeven, Judith; Sunaert, Stefan; Wenderoth, Nicole

2015-01-01

Background The ability to recognize, understand and interpret other’s actions and emotions has been linked to the mirror system or action-observation-network (AON). Although variations in these abilities are prevalent in the neuro-typical population, persons diagnosed with autism spectrum disorders (ASD) have deficits in the social domain and exhibit alterations in this neural network. Method Here, we examined functional network properties of the AON using graph theory measures and region-to-region functional connectivity analyses of resting-state fMRI-data from adolescents and young adults with ASD and typical controls (TC). Results Overall, our graph theory analyses provided convergent evidence that the network integrity of the AON is altered in ASD, and that reductions in network efficiency relate to reductions in overall network density (i.e., decreased overall connection strength). Compared to TC, individuals with ASD showed significant reductions in network efficiency and increased shortest path lengths and centrality. Importantly, when adjusting for overall differences in network density between ASD and TC groups, participants with ASD continued to display reductions in network integrity, suggesting that also network-level organizational properties of the AON are altered in ASD. Conclusion While differences in empirical connectivity contributed to reductions in network integrity, graph theoretical analyses provided indications that also changes in the high-level network organization reduced integrity of the AON. PMID:26317222

Induction of oxidative stress causes functional alterations in mouse urothelium via a TRPM8-mediated mechanism: implications for aging.

PubMed

Nocchi, Linda; Daly, Donna M; Chapple, Christopher; Grundy, David

2014-06-01

The incidence of bladder conditions such as overactive bladder syndrome and its associated urinary incontinence is highly prevalent in the elderly. However, the mechanisms underlying these disorders are unclear. Studies suggest that the urothelium forms a 'sensory network' with the underlying innervation, alterations in which, could compromise bladder function. As the accumulation of reactive oxygen species can cause functional alterations with age, the aim of this study was to investigate whether oxidative stress alters urothelial sensory signalling and whether the mechanism underlying the effect of oxidative stress on the urothelium plays a role in aging. Five-month-old(young) and 24-month-old (aged) mice were used. H2O2 , used to induce oxidative stress, resulted in an increase in bladder afferent nerve activity and urothelial intracellular calcium in preparations from young mice. These functional changes were concurrent with upregulation of TRPM8 in the urothelium. Moreover, application of a TRPM8 antagonist significantly attenuated the H2O2 -induced calcium responses. Interestingly, an upregulation of TRPM8 was also found in the urothelium from aged mice, where high oxidative stress levels were observed, together with a greater calcium response to the TRPM8 agonist WS12. Furthermore, these calcium responses were attenuated by pretreatment with the antioxidant N-acetyl-cysteine. This study shows that oxidative stress affects urothelial function involving a TRPM8-mediated mechanism and these effects may have important implications for aging. These data provide an insight into the possible mechanisms by which oxidative stress causes physiological alterations in the bladder, which may also occur in other organs susceptible to aging. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Induction of oxidative stress causes functional alterations in mouse urothelium via a TRPM8-mediated mechanism: implications for aging

PubMed Central

Nocchi, Linda; Daly, Donna M; Chapple, Christopher; Grundy, David

2014-01-01

The incidence of bladder conditions such as overactive bladder syndrome and its associated urinary incontinence is highly prevalent in the elderly. However, the mechanisms underlying these disorders are unclear. Studies suggest that the urothelium forms a ‘sensory network’ with the underlying innervation, alterations in which, could compromise bladder function. As the accumulation of reactive oxygen species can cause functional alterations with age, the aim of this study was to investigate whether oxidative stress alters urothelial sensory signalling and whether the mechanism underlying the effect of oxidative stress on the urothelium plays a role in aging. Five-month-old(young) and 24-month-old (aged) mice were used. H2O2, used to induce oxidative stress, resulted in an increase in bladder afferent nerve activity and urothelial intracellular calcium in preparations from young mice. These functional changes were concurrent with upregulation of TRPM8 in the urothelium. Moreover, application of a TRPM8 antagonist significantly attenuated the H2O2-induced calcium responses. Interestingly, an upregulation of TRPM8 was also found in the urothelium from aged mice, where high oxidative stress levels were observed, together with a greater calcium response to the TRPM8 agonist WS12. Furthermore, these calcium responses were attenuated by pretreatment with the antioxidant N-acetyl-cysteine. This study shows that oxidative stress affects urothelial function involving a TRPM8-mediated mechanism and these effects may have important implications for aging. These data provide an insight into the possible mechanisms by which oxidative stress causes physiological alterations in the bladder, which may also occur in other organs susceptible to aging. PMID:24593692

The bogeyman cometh: a strategic approach for difficult adolescents.

PubMed

O'Connor, J J; Hoorwitz, A N

1984-06-01

Unpredictable and threatening events can sometimes alter one's view of reality. The altered perception may in turn result in altered forms of behavior and interaction with others. Deliberate efforts to facilitate this altered perception is sometimes attempted by invoking mythical forces such as the Bogeyman, Death, Satan, a shaman, or a sorcerer. Anthropological observations of shamanic magic suggest a number of components that appear to be responsible for these reality-altering experiences. These can be employed to create such experiences in the treatment of difficult adolescents for whom usual solutions have been ineffective. The experience results in systemic changes that render the adolescent accessible to more usual forms of treatment and more functional interactions with adults. The crafting of this kind of experience is illustrated in a case example. Parallels with other clinical practices as well as ethical considerations are discussed.

Alterations in left ventricular diastolic function in conscious dogs with pacing-induced heart failure

NASA Technical Reports Server (NTRS)

Komamura, K.; Shannon, R. P.; Pasipoularides, A.; Ihara, T.; Lader, A. S.; Patrick, T. A.; Bishop, S. P.; Vatner, S. F.

1992-01-01

We investigated in conscious dogs (a) the effects of heart failure induced by chronic rapid ventricular pacing on the sequence of development of left ventricular (LV) diastolic versus systolic dysfunction and (b) whether the changes were load dependent or secondary to alterations in structure. LV systolic and diastolic dysfunction were evident within 24 h after initiation of pacing and occurred in parallel over 3 wk. LV systolic function was reduced at 3 wk, i.e., peak LV dP/dt fell by -1,327 +/- 105 mmHg/s and ejection fraction by -22 +/- 2%. LV diastolic dysfunction also progressed over 3 wk of pacing, i.e., tau increased by +14.0 +/- 2.8 ms and the myocardial stiffness constant by +6.5 +/- 1.4, whereas LV chamber stiffness did not change. These alterations were associated with increases in LV end-systolic (+28.6 +/- 5.7 g/cm2) and LV end-diastolic stresses (+40.4 +/- 5.3 g/cm2). When stresses and heart rate were matched at the same levels in the control and failure states, the increases in tau and myocardial stiffness were no longer observed, whereas LV systolic function remained depressed. There were no increases in connective tissue content in heart failure. Thus, pacing-induced heart failure in conscious dogs is characterized by major alterations in diastolic function which are reversible with normalization of increased loading condition.

Gut-Brain Axis and Behavior.

PubMed

Martin, Clair R; Mayer, Emeran A

2017-01-01

In the last 5 years, interest in the interactions among the gut microbiome, brain, and behavior has exploded. Preclinical evidence supports a role of the gut microbiome in behavioral responses associated with pain, emotion, social interactions, and food intake. Limited, but growing, clinical evidence comes primarily from associations of gut microbial composition and function to behavioral and clinical features and brain structure and function. Converging evidence suggests that the brain and the gut microbiota are in bidirectional communication. Observed dysbiotic states in depression, chronic stress, and autism may reflect altered brain signaling to the gut, while altered gut microbial signaling to the brain may play a role in reinforcing brain alterations. On the other hand, primary dysbiotic states due to Western diets may signal to the brain, altering ingestive behavior. While studies performed in patients with depression and rodent models generated by fecal microbial transfer from such patients suggest causation, evidence for an influence of acute gut microbial alterations on human behavioral and clinical parameters is lacking. Only recently has an open-label microbial transfer therapy in children with autism tentatively validated the gut microbiota as a therapeutic target. The translational potential of preclinical findings remains unclear without further clinical investigation. © 2017 Nestec Ltd., Vevey/S. Karger AG, Basel.

Hemodynamic Response Alterations in Sensorimotor Areas as a Function of Barbell Load Levels during Squatting: An fNIRS Study

PubMed Central

Kenville, Rouven; Maudrich, Tom; Carius, Daniel; Ragert, Patrick

2017-01-01

Functional near-infrared spectroscopy (fNIRS) serves as a promising tool to examine hemodynamic response alterations in a sports-scientific context. The present study aimed to investigate how brain activity within the human motor system changes its processing in dependency of different barbell load conditions while executing a barbell squat (BS). Additionally, we used different fNIRS probe configurations to identify and subsequently eliminate potential exercise induced systemic confounders such as increases in extracerebral blood flow. Ten healthy, male participants were enrolled in a crossover design. Participants performed a BS task with random barbell load levels (0% 1RM (1 repetition maximum), 20% 1RM and 40% 1RM for a BS) during fNIRS recordings. Initially, we observed global hemodynamic response alterations within and outside the human motor system. However, short distance channel regression of fNIRS data revealed a focalized hemodynamic response alteration within bilateral superior parietal lobe (SPL) for oxygenated hemoglobin (HbO2) and not for deoxygenated hemoglobin (HHb) when comparing different load levels. These findings indicate that the previously observed load/force-brain relationship for simple and isolated movements is also present in complex multi-joint movements such as the BS. Altogether, our results show the feasibility of fNIRS to investigate brain processing in a sports-related context. We suggest for future studies to incorporate short distance channel regression of fNIRS data to reduce the likelihood of false-positive hemodynamic response alterations during complex whole movements. PMID:28555098

Changes in the Functional Potential of the Gut Microbiome Following Probiotic Supplementation during Helicobacter Pylori Treatment.

PubMed

Oh, Bumjo; Kim, Ji Won; Kim, Bong-Soo

2016-12-01

Probiotic supplementation is utilized to alleviate the side effects associated with antibiotic therapy for Helicobacter pylori infection. Several studies have described the effects of administration of probiotics on the gut microbiota during antibiotic therapy. However, most of these studies have focused on specific bacteria, thereby providing limited information on the functional roles of the altered microbiota. Therefore, we examined the impact of probiotic supplementation on the structure and functional dynamics of the gut microbiota during H. pylori eradication, using whole-metagenomic sequence analysis. Subjects were divided into two groups: the antibiotics group, which received only antibiotics, and the probiotics group, which received antibiotics with probiotic supplementation. The structural and functional profiles of gut microbiota was analyzed using metagenomic DNA extracted from the feces during treatment by Illumina MiSeq system. The overall alterations in microbiota, as revealed by whole metagenome sequencing, were similar with results from our previous 16S rRNA gene-based analysis. The proportional shift in functional gene families was greater in the antibiotics group than in the probiotics group. In particular, the proportion of genes related to selenocompound metabolism was reduced in the probiotics group, whereas genes associated with the metabolism of nucleotide sugars were increased. The functional alterations of gut microbiota may link to the reduction in intestinal irritation and maintenance of bacterial diversity observed following probiotic supplementation with antibiotic therapy. The potential beneficial roles of altered gut microbiota following probiotic supplementation are expected a reduction in side effects such as intestinal irritation and antibiotics resistance. © 2016 John Wiley & Sons Ltd.

Cardiovascular effects of weightlessness and ground-based simulation

NASA Technical Reports Server (NTRS)

Sandler, Harold

1988-01-01

A large number of animal and human flight and ground-based studies were conducted to uncover the cardiovascular effects of weightlessness. Findings indicate changes in cardiovascular function during simulations and with spaceflight that lead to compromised function on reambulation and/or return to earth. This altered state termed cardiovascular deconditioning is most clearly manifest when in an erect body state. Hemodynamic parameters inidicate the presence of excessive tachnycardia, hypotension (leading to presyncope in one-third of the subjects), decreased heart volume, decreased plasma and circulating blood volumes and loss of skeletal muscle mass, particularly in the lower limbs. No clinically harmful effects were observed to date, but in-depth follow-ups were limited, as was available physiologic information. Available data concerning the causes for the observed changes indicate significant roles for mechanisms involved with body fluid-volume regulation, altered cardiac function, and the neurohumoral control of the control of the peripheral circulation. Satisfactory measures are not found. Return to preflight state was variable and only slightly dependent on flight duration. Future progress awaits availability of flight durations longer than several weeks.

Analysis of pulmonary surfactant by Fourier-transform infrared spectroscopy following exposure to Stachybotrys chartarum (atra) spores.

PubMed

McCrae, K C; Rand, T; Shaw, R A; Mason, C; Oulton, M R; Hastings, C; Cherlet, T; Thliveris, J A; Mantsch, H H; MacDonald, J; Scott, J E

2001-03-01

Lung cells are among the first tissues of the body to be exposed to air-borne environmental contaminants. Consequently the function of these cells may be altered before other cells are affected. As gas exchange takes place in the lungs, changes in cellular function may have serious implications for the processes of oxygen uptake and carbon dioxide elimination. In order for these processes to occur, the lung must maintain a high degree of expandability. This latter function is accomplished in part by the pulmonary surfactant which is synthesized and released by alveolar type II cells. Earlier studies have shown that exposure to gas phase materials such as smoke or organic solvents can alter the composition and function of the surfactant. The present study examines the ability of highly toxigenic mold spores to alter surfactant composition. Stachybotrys chartarum spores suspended in saline were instilled into mouse trachea as described earlier. After 24 h, the lungs were lavaged and the different processing stages of surfactant isolated by repeated centrifugation. Intracellular surfactant was isolated from the homogenized lung tissue by centrifugation on a discontinuous sucrose gradient. Samples were extracted into chloroform-methanol, dried and analyzed by Fourier-Transform infrared spectroscopy (FTIR). Exposure to S. chartarum induced an overall reduction of phospholipid among the three surfactant subfractions. The intermediate and spent surfactant fractions in particular were reduced to about half of the values observed in the saline-treated group. The relative distribution of phospholipid was also altered by spore exposure. Within the intracellular surfactant pool, higher levels of phospholipid were detected after spore exposure. In addition, changes were observed in the nature of the phospholipids. In particular strong intramolecular hydrogen bonding, together with other changes, suggested that spore exposure was associated with absence of an acyl chain esterified on the glycerol backbone, resulting in elevated levels of lysophospholipid in the samples. This study shows that mold spores and their products induce changes in regulation of both secretion and synthesis of surfactant, as well as alterations in the pattern of phospholipid targeting to the pulmonary surfactant pools.

[Effects of infrasound on ultrastructure of testis cell in mice].

PubMed

Wei, Ya-Ning; Liu, Jing; Shu, Qing; Huang, Xiao-Feng; Chen, Jing-Zao

2002-01-01

To investigate the effects of infrasound on ultrastructure of testis in mouse. Twelve male BALB/C mice were randomly divided into three groups according to exposed duration on 1, 7 and 14 day. The mice were separately exposed to infrasound environment under 8 Hz/90 dB, 8 Hz/130 dB, 16 Hz/90 dB, 16 Hz/130 dB 2 hours per day. There was another control group which had three mice were separated into module with no infrasound. All the mice were killed on schedule. Then all the sections of testis were observed under electronic microscope. The alterations of structure and the chromatin were observed. Some acute alteration in one day group was found in testis cell, such as cellular denaturation and necrosis, intercellular edema, mitochondria swelling, liposome hyperplasia. When the infrasound was up to 8 Hz/130 dB, the damage showed seriously. In 7 and 14 day group, the acute alteration was gradually decreased. A plenty of abnormal sperm were found. And other alteration was chromatin condense. The effect of variational frequency was important in ultrastructure. The infrasound markedly effected to testicular cell morphology and secreting function. Infrasound will lead to the alteration of procreation in mouse.

Identification of functional modules that correlate with phenotypic difference: the influence of network topology

PubMed Central

2010-01-01

One of the important challenges to post-genomic biology is relating observed phenotypic alterations to the underlying collective alterations in genes. Current inferential methods, however, invariably omit large bodies of information on the relationships between genes. We present a method that takes account of such information - expressed in terms of the topology of a correlation network - and we apply the method in the context of current procedures for gene set enrichment analysis. PMID:20187943

Embryonic exposure to an aqueous coal dust extract results in gene expression alterations associated with the development and function of connective tissue and the hematological system, immunological and inflammatory disease, and cancer in zebrafish.

PubMed

Caballero-Gallardo, Karina; Wirbisky-Hershberger, Sara E; Olivero-Verbel, Jesus; de la Rosa, Jesus; Freeman, Jennifer L

2018-03-01

Coal mining is one of the economic activities with the greatest impact on environmental quality. At all stages contaminants are released as particulates such as coal dust. The first aim of this study was to obtain an aqueous coal dust extract and characterize its composition in terms of trace elements by ICP-MS. In addition, the developmental toxicity of the aqueous coal extract was evaluated using zebrafish (Danio rerio) after exposure to different concentrations (0-1000 ppm; μg mL -1 ) to establish acute toxicity, morphology and transcriptome changes. Trace elements within the aqueous coal dust extract present at the highest concentrations (>10 ppb) included Sr, Zn, Ba, As, Cu and Se. In addition, Cd and Pb were found in lower concentrations. No significant difference in mortality was observed (p > 0.05), but a delay in hatching was found at 0.1 and 1000 ppm (p < 0.05). No significant differences in morphological characteristics were observed in any of the treatment groups (p > 0.05). Transcriptomic results of zebrafish larvae revealed alterations in 77, 61 and 1376 genes in the 1, 10, and 100 ppm groups, respectively. Gene ontology analysis identified gene alterations associated with the development and function of connective tissue and the hematological system, as well as pathways associated with apoptosis, the cell cycle, transcription, and oxidative stress including the MAPK signaling pathway. In addition, altered genes were associated with cancer; connective tissue, muscular, and skeletal disorders; and immunological and inflammatory diseases. Overall, this is the first study to characterize gene expression alterations in response to developmental exposure to aqueous coal dust residue from coal mining with transcriptome results signifying functions and systems to target in future studies.

The Posterior Medial Cortex in Urologic Chronic Pelvic Pain Syndrome: Detachment from Default Mode Network. A Resting-State Study from the MAPP Research Network

PubMed Central

Martucci, Katherine T.; Shirer, William R.; Bagarinao, Epifanio; Johnson, Kevin A.; Farmer, Melissa A.; Labus, Jennifer S.; Apkarian, A. Vania; Deutsch, Georg; Harris, Richard E.; Mayer, Emeran A.; Clauw, Daniel J.; Greicius, Michael D.; Mackey, Sean C.

2015-01-01

Altered resting-state brain activity, as a measure of functional connectivity, is commonly observed in chronic pain. Identifying a reliable signature pattern of altered resting-state activity for chronic pain could provide strong mechanistic insights and serve as a highly beneficial neuroimaging-based diagnostic tool. We collected and analyzed resting-state fMRI data from female patients with urologic chronic pelvic pain syndrome (UCPPS, N = 45) and matched healthy participants (N = 45) as part of a NIDDK funded multicenter project (www.mappnetwork.org). Using dual regression and seed-based analyses, we observed significantly decreased functional connectivity of the default mode network (DMN) to two regions in the posterior medial cortex (PMC): the posterior cingulate cortex (PCC) and left precuneus (TFCE, FWE corrected p<0.05). Further investigation revealed that patients demonstrated increased functional connectivity between the PCC and several brain regions implicated in pain, sensory, motor, and emotion regulation processes (e.g., insular cortex, dorsolateral prefrontal cortex, thalamus, globus pallidus, putamen, amygdala, hippocampus). The left precuneus demonstrated decreased functional connectivity to several regions of pain processing, reward, and higher executive functioning within the prefrontal (orbitofrontal, anterior cingulate, ventromedial prefrontal) and parietal cortices (angular gyrus, superior and inferior parietal lobules). The altered PMC connectivity was associated with several phenotype measures, including pain and urologic symptom intensity, depression, anxiety, quality of relationships and self-esteem levels in patients. Collectively, these findings indicate that in UCPPS patients, regions of the PMC are detached from the DMN, while neurological processes of self-referential thought and introspection may be joined to pain and emotion regulatory processes. PMID:26010458

Altered Network Oscillations and Functional Connectivity Dynamics in Children Born Very Preterm.

PubMed

Moiseev, Alexander; Doesburg, Sam M; Herdman, Anthony T; Ribary, Urs; Grunau, Ruth E

2015-09-01

Structural brain connections develop atypically in very preterm children, and altered functional connectivity is also evident in fMRI studies. Such alterations in brain network connectivity are associated with cognitive difficulties in this population. Little is known, however, about electrophysiological interactions among specific brain networks in children born very preterm. In the present study, we recorded magnetoencephalography while very preterm children and full-term controls performed a visual short-term memory task. Regions expressing task-dependent activity changes were identified using beamformer analysis, and inter-regional phase synchrony was calculated. Very preterm children expressed altered regional recruitment in distributed networks of brain areas, across standard physiological frequency ranges including the theta, alpha, beta and gamma bands. Reduced oscillatory synchrony was observed among task-activated brain regions in very preterm children, particularly for connections involving areas critical for executive abilities, including middle frontal gyrus. These findings suggest that inability to recruit neurophysiological activity and interactions in distributed networks including frontal regions may contribute to difficulties in cognitive development in children born very preterm.

Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas.

PubMed

Knijnenburg, Theo A; Wang, Linghua; Zimmermann, Michael T; Chambwe, Nyasha; Gao, Galen F; Cherniack, Andrew D; Fan, Huihui; Shen, Hui; Way, Gregory P; Greene, Casey S; Liu, Yuexin; Akbani, Rehan; Feng, Bin; Donehower, Lawrence A; Miller, Chase; Shen, Yang; Karimi, Mostafa; Chen, Haoran; Kim, Pora; Jia, Peilin; Shinbrot, Eve; Zhang, Shaojun; Liu, Jianfang; Hu, Hai; Bailey, Matthew H; Yau, Christina; Wolf, Denise; Zhao, Zhongming; Weinstein, John N; Li, Lei; Ding, Li; Mills, Gordon B; Laird, Peter W; Wheeler, David A; Shmulevich, Ilya; Monnat, Raymond J; Xiao, Yonghong; Wang, Chen

2018-04-03

DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

The neurobiological basis of binge-eating disorder.

PubMed

Kessler, Robert M; Hutson, Peter H; Herman, Barry K; Potenza, Marc N

2016-04-01

Relatively little is known about the neuropathophysiology of binge-eating disorder (BED). Here, the evidence from neuroimaging, neurocognitive, genetics, and animal studies are reviewed to synthesize our current understanding of the pathophysiology of BED. Binge-eating disorder may be conceptualized as an impulsive/compulsive disorder, with altered reward sensitivity and food-related attentional biases. Neuroimaging studies suggest there are corticostriatal circuitry alterations in BED similar to those observed in substance abuse, including altered function of prefrontal, insular, and orbitofrontal cortices and the striatum. Human genetics and animal studies suggest that there are changes in neurotransmitter networks, including dopaminergic and opioidergic systems, associated with binge-eating behaviors. Overall, the current evidence suggests that BED may be related to maladaptation of the corticostriatal circuitry regulating motivation and impulse control similar to that found in other impulsive/compulsive disorders. Further studies are needed to understand the genetics of BED and how neurotransmitter activity and neurocircuitry function are altered in BED and how pharmacotherapies may influence these systems to reduce BED symptoms. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Potato plants with genetically engineered tropane alkaloid precursors.

PubMed

Küster, Nadine; Rosahl, Sabine; Dräger, Birgit

2017-02-01

Solanum tuberosum tropinone reductase I reduced tropinone in vivo. Suppression of tropinone reductase II strongly reduced calystegines in sprouts. Overexpression of putrescine N -methyltransferase did not alter calystegine accumulation. Calystegines are hydroxylated alkaloids formed by the tropane alkaloid pathway. They accumulate in potato (Solanum tuberosum L., Solanaceae) roots and sprouting tubers. Calystegines inhibit various glycosidases in vitro due to their sugar-mimic structure, but functions of calystegines in plants are not understood. Enzymes participating in or competing with calystegine biosynthesis, including putrescine N-methyltransferase (PMT) and tropinone reductases (TRI and TRII), were altered in their activity in potato plants by RNA interference (RNAi) and by overexpression. The genetically altered potato plants were investigated for the accumulation of calystegines and for intermediates of their biosynthesis. An increase in N-methylputrescine provided by DsPMT expression was not sufficient to increase calystegine accumulation. Overexpression and gene knockdown of StTRI proved that S. tuberosum TRI is a functional tropinone reductase in vivo, but no influence on calystegine accumulation was observed. When StTRII expression was suppressed by RNAi, calystegine formation was severely compromised in the transformed plants. Under phytochamber and green house conditions, the StTRII RNAi plants did not show phenotypic alterations. Further investigation of calystegines function in potato plants under natural conditions is enabled by the calystegine deprived StTRII RNAi plants.

Comparison of the Functional microRNA Expression in Immune Cell Subsets of Neonates and Adults

PubMed Central

Yu, Hong-Ren; Hsu, Te-Yao; Huang, Hsin-Chun; Kuo, Ho-Chang; Li, Sung-Chou; Yang, Kuender D.; Hsieh, Kai-Sheng

2016-01-01

Diversity of biological molecules in newborn and adult immune cells contributes to differences in cell function and atopic properties. Micro RNAs (miRNAs) are reported to involve in the regulation of immune system. Therefore, determining the miRNA expression profile of leukocyte subpopulations is important for understanding immune system regulation. In order to explore the unique miRNA profiling that contribute to altered immune in neonates, we comprehensively analyzed the functional miRNA signatures of eight leukocyte subsets (polymorphonuclear cells, monocytes, CD4+ T cells, CD8+ T cells, natural killer cells, B cells, plasmacytoid dendritic cells, and myeloid dendritic cells) from both neonatal and adult umbilical cord and peripheral blood samples, respectively. We observed distinct miRNA profiles between adult and neonatal blood leukocyte subsets, including unique miRNA signatures for each cell lineage. Leukocyte miRNA signatures were altered after stimulation. Adult peripheral leukocytes had higher let-7b-5p expression levels compared to neonatal cord leukocytes across multiple subsets, irrespective of stimulation. Transfecting neonatal monocytes with a let-7b-5p mimic resulted in a reduction of LPS-induced interleukin (IL)-6 and TNF-α production, while transfection of a let-7b-5p inhibitor into adult monocytes enhanced IL-6 and TNF-α production. With this functional approach, we provide intact differential miRNA expression profiling of specific immune cell subsets between neonates and adults. These studies serve as a basis to further understand the altered immune response observed in neonates and advance the development of therapeutic strategies. PMID:28066425

Inhalational exposure to carbonyl sulfide produces altered brainstem auditory and somatosensory-evoked potentials in Fischer 344N rats.

PubMed

Herr, David W; Graff, Jaimie E; Moser, Virginia C; Crofton, Kevin M; Little, Peter B; Morgan, Daniel L; Sills, Robert C

2007-01-01

Carbonyl sulfide (COS), a chemical listed by the original Clean Air Act, was tested for neurotoxicity by a National Institute of Environmental Health Sciences/National Toxicology Program and U.S. Environmental Protection Agency collaborative investigation. Previous studies demonstrated that COS produced cortical and brainstem lesions and altered auditory neurophysiological responses to click stimuli. This paper reports the results of expanded neurophysiological examinations that were an integral part of the previously published experiments (Morgan et al., 2004, Toxicol. Appl. Pharmacol. 200, 131-145; Sills et al., 2004, Toxicol. Pathol. 32, 1-10). Fisher 334N rats were exposed to 0, 200, 300, or 400 ppm COS for 6 h/day, 5 days/week for 12 weeks, or to 0, 300, or 400 ppm COS for 2 weeks using whole-body inhalation chambers. After treatment, the animals were studied using neurophysiological tests to examine: peripheral nerve function, somatosensory-evoked potentials (SEPs) (tail/hindlimb and facial cortical regions), brainstem auditory-evoked responses (BAERs), and visual flash-evoked potentials (2-week study). Additionally, the animals exposed for 2 weeks were examined using a functional observational battery (FOB) and response modification audiometry (RMA). Peripheral nerve function was not altered for any exposure scenario. Likewise, amplitudes of SEPs recorded from the cerebellum were not altered by treatment with COS. In contrast, amplitudes and latencies of SEPs recorded from cortical areas were altered after 12-week exposure to 400 ppm COS. The SEP waveforms were changed to a greater extent after forelimb stimulation than tail stimulation in the 2-week study. The most consistent findings were decreased amplitudes of BAER peaks associated with brainstem regions after exposure to 400 ppm COS. Additional BAER peaks were affected after 12 weeks, compared to 2 weeks of treatment, indicating that additional regions of the brainstem were damaged with longer exposures. The changes in BAERs were observed in the absence of altered auditory responsiveness in FOB or RMA. This series of experiments demonstrates that COS produces changes in brainstem auditory and cortical somatosensory neurophysiological responses that correlate with previously described histopathological damage.

Characterization of early communicative behavior in mouse models of Neurofibromatosis type 1

PubMed Central

Maloney, Susan E.; Chandler, Krystal C.; Anastasaki, Corina; Rieger, Michael A.; Gutmann, David H.; Dougherty, Joseph D.

2017-01-01

Scientific Abstract Neurofibromatosis type 1 (NF1) is a monogenic neurodevelopmental disease caused by germline loss-of-function mutations in the NF1 tumor suppressor gene. Cognitive impairments are observed in approximately 80% of children with this disease, with 45–60% exhibiting autism spectrum disorder (ASD) symptomatology. In light of the high comorbidity rate between ASD and NF1, we assessed early communicative behavior by maternal-separation induced pup ultrasonic vocalizations (USV) and developmental milestones in two distinct Nf1 genetically-engineered models, one modeling clinical germline heterozygous loss of Nf1 function (Nf1+/− mice), and a second with somatic biallelic Nf1 inactivation in neuroglial progenitor cells (Nf1GFAPCKO mice). We observed altered USV production in both models: Nf1+/− mice exhibited both increased USVs across development and alterations in aspects of pitch, while Nf1GFAPCKO mice demonstrated a decrease in USVs. Developmental milestones, such as weight, pinnae detachment and eye opening, were not disrupted in either model, indicating the USV deficits were not due to gross developmental delay, and likely reflected more specific alterations in USV circuitry. In this respect, increased whole-brain serotonin was observed in Nf1+/− mice, but whole-brain levels of dopamine and its metabolites were unchanged at the age of peak USV disruption, and USV alterations did not correlate with overall level of neurofibromin loss. The early communicative phenotypes reported herein should motivate further studies into the risks mediated by haploinsufficiency and biallelic deletion of Nf1 across a full battery of ASD-relevant behavioral phenotypes, and a targeted analysis of underlying circuitry disruptions. PMID:28842941

IMMUNOLOGIC EFFECTS OF ELECTROMAGNETIC FIELDS (1981-1983)

EPA Science Inventory

In vitro studies provide evidence that support and EM field induced thermal mechanism for immune effects. When proper control of culture temperatures has been achieved during in vitro exposure to EM fields, no alterations have been observed for a variety of immune cell functions....

Altered Distant Synchronization of Background Network in Mild Cognitive Impairment during an Executive Function Task.

PubMed

Wang, Pengyun; Li, Rui; Yu, Jing; Huang, Zirui; Yan, Zhixiong; Zhao, Ke; Li, Juan

2017-01-01

Few studies to date have investigated the background network in the cognitive state relying on executive function in mild cognitive impairment (MCI) patients. Using the index of degree of centrality (DC), we explored distant synchronization of background network in MCI during a hybrid delayed-match-to-sample task (DMST), which mainly relies on the working memory component of executive function. We observed significant interactions between group and cognitive state in the bilateral posterior cingulate cortex (PCC) and the ventral subregion of precuneus. For normal control (NC) group, the long distance functional connectivity (FC) of the PCC/precuneus with the other regions of the brain was higher in rest state than that working memory state. For MCI patients, however, this pattern altered. There was no significant difference between rest and working memory state. The similar pattern was observed in the other cluster located in the right angular gyrus. To examine whether abnormal DC in PCC/precuneus and angular gyrus partially resulted from the deficit of FC between these regions and the other parts in the whole brain, we conducted a seed-based correlation analysis with these regions as seeds. The results indicated that the FC between bilateral PCC/precuneus and the right inferior parietal lobule (IPL) increased from rest to working memory state for NC participants. For MCI patients, however, there was no significant change between rest and working memory state. The similar pattern was observed for the FC between right angular gyrus and right anterior insula. However, there was no difference between MCI and NC groups in global efficiency and modularity. It may indicate a lack of efficient reorganization from rest state to a working memory state in the brain network of MCI patients. The present study demonstrates the altered distant synchronization of background network in MCI during a task relying on executive function. The results provide a new perspective regarding the neural mechanisms of executive function deficits in MCI patients, and extend our understanding of brain patterns in task-evoked cognitive states.

Deficiency in Aryl Hydrocarbon Receptor (AHR) Expression throughout Aging Alters Gene Expression Profiles in Murine Long-Term Hematopoietic Stem Cells

PubMed Central

Bennett, John A.; Singh, Kameshwar P.; Unnisa, Zeenath; Welle, Stephen L.; Gasiewicz, Thomas A.

2015-01-01

Dysregulation of hematopoietic stem cell (HSC) signaling can contribute to the development of diseases of the blood system. Lack of aryl hydrocarbon receptor (AhR) has been associated with alterations in gene expression related to HSC function and the subsequent development of a myeloproliferative disorder in aging female mice. We sorted the most primitive population of HSCs with the highest stem cell potential (Long-term, or LT-HSCs) from 18-month-old AhR-null-allele (AhR-KO) and WT mice and analyzed gene expression using microarray to determine alterations in gene expression and cell signaling networks in HSCs that could potentially contribute to the aging phenotype of AhR-KO mice. Comparisons with previous array data from 8-week old mice indicated that aging alone is sufficient to alter gene expression. In addition, a significant number of gene expression differences were observed in aged LT-HSCs that are dependent on both aging and lack of AhR. Pathway analysis of these genes revealed networks related to hematopoietic stem cell activity or function. qPCR was used to confirm the differential expression of a subset of these genes, focusing on genes that may represent novel AhR targets due to the presence of a putative AhR binding site in their upstream regulatory region. We verified differential expression of PDGF-D, Smo, Wdfy1, Zbtb37 and Zfp382. Pathway analysis of this subset of genes revealed overlap between cellular functions of the novel AhR targets and AhR itself. Lentiviral-mediated knockdown of AhR in lineage-negative hematopoietic cells was sufficient to induce changes in all five of the candidate AhR targets identified. Taken together, these data suggest a role for AhR in HSC functional regulation, and identify novel HSC AhR target genes that may contribute to the phenotypes observed in AhR-KO mice. PMID:26208102

Genomic Heterogeneity of Osteosarcoma - Shift from Single Candidates to Functional Modules

PubMed Central

Maugg, Doris; Eckstein, Gertrud; Baumhoer, Daniel; Nathrath, Michaela; Korsching, Eberhard

2015-01-01

Osteosarcoma (OS), a bone tumor, exhibit a complex karyotype. On the genomic level a highly variable degree of alterations in nearly all chromosomal regions and between individual tumors is observable. This hampers the identification of common drivers in OS biology. To identify the common molecular mechanisms involved in the maintenance of OS, we follow the hypothesis that all the copy number-associated differences between the patients are intercepted on the level of the functional modules. The implementation is based on a network approach utilizing copy number associated genes in OS, paired expression data and protein interaction data. The resulting functional modules of tightly connected genes were interpreted regarding their biological functions in OS and their potential prognostic significance. We identified an osteosarcoma network assembling well-known and lesser-known candidates. The derived network shows a significant connectivity and modularity suggesting that the genes affected by the heterogeneous genetic alterations share the same biological context. The network modules participate in several critical aspects of cancer biology like DNA damage response, cell growth, and cell motility which is in line with the hypothesis of specifically deregulated but functional modules in cancer. Further, we could deduce genes with possible prognostic significance in OS for further investigation (e.g. EZR, CDKN2A, MAP3K5). Several of those module genes were located on chromosome 6q. The given systems biological approach provides evidence that heterogeneity on the genomic and expression level is ordered by the biological system on the level of the functional modules. Different genomic aberrations are pointing to the same cellular network vicinity to form vital, but already neoplastically altered, functional modules maintaining OS. This observation, exemplarily now shown for OS, has been under discussion already for a longer time, but often in a hypothetical manner, and can here be exemplified for OS. PMID:25848766

Evidence Report: Risk of Crew Adverse Health Event Due to Altered Immune Response

NASA Technical Reports Server (NTRS)

Crucian, Brian; Sams, Clarence F.

2013-01-01

The Risk of Crew Adverse Health Event Due to Altered Immune Response is identified by the National Aeronautics and Space Administration (NASA) Human Research Program (HRP) as a recognized risk to human health and performance in space. The HRP Program Requirements Document (PRD) defines these risks. This Evidence Report provides a summary of the evidence that has been used to identify and characterize this risk. It is known that human immune function is altered in- and post-flight, but it is unclear at present if such alterations lead to increased susceptibility to disease. Reactivation of latent viruses has been documented in crewmembers, although this reactivation has not been directly correlated with immune changes or with observed diseases. As described in this report, further research is required to better characterize the relationships between altered immune response and susceptibility to disease during and after spaceflight. This is particularly important for future deep-space exploration missions.

The Functional Role of Reactive Stroma in Benign Prostatic Hyperplasia

PubMed Central

Schauer, Isaiah G.; Rowley, David R.

2011-01-01

The human prostate gland is one of the only internal organs that continue to enlarge throughout adulthood. The specific mechanisms that regulate this growth, as well as the pathological changes leading to the phenotype observed in the disease benign prostatic hyperplasia (BPH), are essentially unknown. Recent studies and their associated findings have made clear that many complex alterations occur, involving persistent and chronic inflammation, circulating hormonal level deregulation, and aberrant wound repair processes. BPH has been etiologically characterized as a progressive, albeit discontinuous, hyperplasia of both the glandular epithelial and stromal cell compartments coordinately yielding an expansion of the prostate gland and clinical symptoms. Interestingly, the inflammatory and repair responses observed in BPH are also key components of general wound repair in post-natal tissues. These responses include altered expression of chemokines, cytokines, matrix remodeling factors, chronic inflammatory processes, altered immune surveillance and recognition, as well as the formation of a prototypical ‘reactive’ stroma which is similar to that observed across various fibroplasias and malignancies of a variety of tissue sites. Stromal tissue, both embryonic mesenchyme, and adult reactive stroma myofibroblasts, has been shown to exert potent and functional regulatory control over epithelial proliferation and differentiation as well as immunoresponsive modulation. Thus, the functional biology of a reactive stroma, within the context of an adult disease typified by epithelial and stromal aberrant hyperplasia, is critical to understand within the context of prostate disease and beyond. The mechanisms that regulate reactive stroma biology in BPH represent targets of opportunity for new therapeutic approaches that may extend to other tissue contexts. Accordingly, this review seeks to address the dissection of important factors, signaling pathways, genes, and other regulatory components that mediate the interplay between epithelium and stromal responses in BPH. PMID:21664759

Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fukunaga, Satoki; Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-8558; Kakehashi, Anna

To determine miRNAs and their predicted target proteins regulatory networks which are potentially involved in onset of pulmonary fibrosis in the bleomycin rat model, we conducted integrative miRNA microarray and iTRAQ-coupled LC-MS/MS proteomic analyses, and evaluated the significance of altered biological functions and pathways. We observed that alterations of miRNAs and proteins are associated with the early phase of bleomycin-induced pulmonary fibrosis, and identified potential target pairs by using ingenuity pathway analysis. Using the data set of these alterations, it was demonstrated that those miRNAs, in association with their predicted target proteins, are potentially involved in canonical pathways reflective ofmore » initial epithelial injury and fibrogenic processes, and biofunctions related to induction of cellular development, movement, growth, and proliferation. Prediction of activated functions suggested that lung cells acquire proliferative, migratory, and invasive capabilities, and resistance to cell death especially in the very early phase of bleomycin-induced pulmonary fibrosis. The present study will provide new insights for understanding the molecular pathogenesis of idiopathic pulmonary fibrosis. - Highlights: • We analyzed bleomycin-induced pulmonary fibrosis in the rat. • Integrative analyses of miRNA microarray and proteomics were conducted. • We determined the alterations of miRNAs and their potential target proteins. • The alterations may control biological functions and pathways in pulmonary fibrosis. • Our result may provide new insights of pulmonary fibrosis.« less

The CB1 receptor is required for the establishment of the hyperlocomotor phenotype in developmentally-induced hypothyroidism in mice.

PubMed

Giné, Elena; Echeverry-Alzate, Victor; Lopez-Moreno, Jose Antonio; Rodriguez de Fonseca, Fernando; Perez-Castillo, Ana; Santos, Angel

2017-04-01

Alterations in motor functions are well-characterized features observed in humans and experimental animals with thyroid hormone dysfunctions during development. We have previously suggested the implication of the endocannabinoid system in the hyperlocomotor phenotype observed in developmentally induced hypothyroidism in rats. In this work we have further analyzed the implication of endocannabinoids in the effect of hypothyroidism on locomotor activity. To this end, we evaluated the locomotor activity in adult mice lacking the cannabinoid receptor type 1 (CB1R -/- ) and in their wild type littermates (CB1R +/+ ), whose hypothyroidism was induced in day 12 of gestation and maintained during the experimental period. Our results show that hypothyroidism induced a hyperlocomotor phenotype only in CB1R +/+ , but not in CB1R -/- mice. In contrast with our previous results in rats, the expression of CB1R in striatum and the motor response to the cannabinoid agonist HU210 was unaltered in hypothyroid CB1R +/+ mice suggesting that the cannabinoid system is not altered by hypothyroidism. Also, no effect of HU210 was observed in locomotion of CB1R -/- mice. Finally, since the dopaminergic system plays a major role in the control of locomotor activity we studied its function in hypothyroid wild type and knockout animals. Our results show no alteration in the behavioral response induced by the dopamine D1 receptor agonist SKF38393. However we observed a decreased response to the dopamine D2 receptor antagonist haloperidol only in hypothyroid CB1R +/+ mice, which might indicate potential alterations in D2R signaling in these animals. In conclusion, our data suggest that the cannabinoid system is necessary for the induction of hyperlocomotor phenotype in mice with developmentally induced hypothyroidism. Copyright © 2016 Elsevier Ltd. All rights reserved.

41 CFR 102-76.70 - When are the costs of alterations to provide an accessible path of travel to an altered area...

Code of Federal Regulations, 2013 CFR

2013-07-01

... alterations to provide an accessible path of travel to an altered area containing a primary function... to an altered area containing a primary function disproportionate to the costs of the overall... area containing a primary function are disproportionate to the costs of the overall alterations when...

41 CFR 102-76.70 - When are the costs of alterations to provide an accessible path of travel to an altered area...

Code of Federal Regulations, 2010 CFR

2010-07-01

... alterations to provide an accessible path of travel to an altered area containing a primary function... to an altered area containing a primary function disproportionate to the costs of the overall... area containing a primary function are disproportionate to the costs of the overall alterations when...

41 CFR 102-76.70 - When are the costs of alterations to provide an accessible path of travel to an altered area...

Code of Federal Regulations, 2014 CFR

2014-01-01

... alterations to provide an accessible path of travel to an altered area containing a primary function... to an altered area containing a primary function disproportionate to the costs of the overall... area containing a primary function are disproportionate to the costs of the overall alterations when...

41 CFR 102-76.70 - When are the costs of alterations to provide an accessible path of travel to an altered area...

Code of Federal Regulations, 2012 CFR

2012-01-01

... alterations to provide an accessible path of travel to an altered area containing a primary function... to an altered area containing a primary function disproportionate to the costs of the overall... area containing a primary function are disproportionate to the costs of the overall alterations when...

41 CFR 102-76.70 - When are the costs of alterations to provide an accessible path of travel to an altered area...

Code of Federal Regulations, 2011 CFR

2011-01-01

... alterations to provide an accessible path of travel to an altered area containing a primary function... to an altered area containing a primary function disproportionate to the costs of the overall... area containing a primary function are disproportionate to the costs of the overall alterations when...

CI chondrite-like clasts in the Nilpena polymict ureilite - Implications for aqueous alteration processes in CI chondrites

NASA Technical Reports Server (NTRS)

Brearley, Adrian J.; Prinz, Martin

1992-01-01

Petrographic studies of Nilpena polymict ureilite have revealed the presence of small quantities of carbonaceous chondrite matrix clasts. Detailed electron microprobe and TEM studies show that the chemistry and fine-scale mineralogy of one of these clasts is consistent with CI carbonaceous chondrite matrix. Compared to Orgeuil, the phyllosilicate, sulfide, and oxide mineralogy suggests that the Nilpena clasts may represent a less altered type of CI matrix. It is suggested that increased oxidation and aqueous alteration of Nilpena-type materials could result in the formation of the type of mineral assemblage observed in Orgueil. Increased alteration produces progressive more Mg-rich phyllosilicates and more Fe(3+)-rich iron oxides, such as ferrihydrite. As a function of increased alteration, Ca is also progressively leached from the matrix material to form carbonate veins. The depletion of Ca in CI chondrite matrices suggests the Ivuna and Alais may be intermediate in their degree of alteration to Nilpena and Orgueil.

[Sex-linked juvenile retinoschisis].

PubMed

François, P; Turut, P; Soltysik, C; Hache, J C

1976-02-01

About 13 observations of sexe linked juvenile retinoschisis, the authors describe the ophthalmoscopic, fluorographic and functional aspects of the disease whose caracteristics are:--its sexe linked recessive heredity; --its clinical characterestics associating: a microcystic macular degeneration, peripheral retinal lesions, vitreous body alterations, --an electroretinogram of the negative type.

Transcriptional specificity in various p53-mutant cells.

PubMed

Okaichi, Kumio; Izumi, Nanaka; Takamura, Yuma; Fukui, Shoichi; Kudo, Takashi

2013-03-01

Mutation of the tumor suppressor gene p53 is the most common genetic alteration observed in human tumors. However, the relationship between the mutation point of p53 and the transcriptional specificity is not so obvious. We prepared Saos-2 cells with various mutations of p53 that are found in human tumors, and examined the resulting transcriptional alterations in the cells. Loss of function and gain of function were observed in all p53 mutants. Hot-spot mutations of p53 are frequently found in tumor cells. We compared hot-spot mutations and other mutations of p53 and found that a more than 2-fold transcription of CADPS2, PIWIL4 and TRIM9 was induced by hot spot mutations, but not by other mutations. As PIWIL4 suppresses the p16(INK4A) and ARF pathway, restraining cell growth and genomic instability, induction of PIWIL4 expression may be one reason why hot-spot mutations are frequently found in tumor cells.

Altered intrinsic functional connectivity in the latent period of epileptogenesis in a temporal lobe epilepsy model.

PubMed

Lee, Hyoin; Jung, Seungmoon; Lee, Peter; Jeong, Yong

2017-10-01

The latent period, a seizure-free phase, is the duration between brain injury and the onset of spontaneous recurrent seizures (SRSs) during epileptogenesis. The latent period is thought to involve several progressive pathophysiological events that lead to the evolution of the chronic epilepsy phase. Hence, it is vital to investigate the changes in the latent period during epileptogenesis in order to better understand temporal lobe epilepsy (TLE), and to achieve early diagnosis and appropriate management of the condition. Accordingly, recent studies with patients with TLE using resting-state functional magnetic resonance imaging (rs-fMRI) have reported that alterations of resting-state functional connectivity (rsFC) during the chronic period are associated with some clinical manifestations, including learning and memory impairments, emotional instability, and social behavior deficits, in addition to repetitive seizure episodes. In contrast, the changes in the intrinsic rsFC during epileptogenesis, particularly during the latent period, remain unclear. In this study, we investigated the alterations in intrinsic rsFC during the latent and chronic periods in a pilocarpine-induced TLE mouse model using intrinsic optical signal imaging (IOSI). This technique can monitor the changes in the local hemoglobin concentration according to neuronal activity and can help investigate large-scale brain intrinsic networks. After seeding on the anatomical regions of interest (ROIs) and calculating the correlation coefficients between each ROI, we established and compared functional correlation matrices and functional connectivity maps during the latent and chronic periods of epilepsy. We found a decrease in the interhemispheric rsFC at the frontal and temporal regions during both the latent and chronic periods. Furthermore, a significant decrease in the interhemispheric rsFC was observed in the somatosensory area during the chronic period. Changes in network configurations during epileptogenesis were examined by graph theoretical network analysis. Interestingly, increase in the power of low frequency oscillations was observed during the latent period. These results suggest that, even if there are no apparent ictal seizure events during the latent period, there are ongoing changes in the rsFC in the epileptic brain. Furthermore, these results suggest that the pathophysiology of epilepsy may be related to widespread altered intrinsic functional connectivity. These findings can help enhance our understanding of epileptogenesis, and accordingly, changes in intrinsic functional connectivity can serve as an early diagnosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Dopaminergic Challenge With Bromocriptine One Month After Mild Traumatic Brain Injury: Altered Working Memory and BOLD Response

PubMed Central

McAllister, Thomas W.; Flashman, Laura A.; McDonald, Brenna C.; Ferrell, Richard B.; Tosteson, Tor D.; Yanofsky, Norman N.; Grove, Margaret R.; Saykin, Andrew J.

2014-01-01

Catecholamines, particularly dopamine, modulate working memory (WM). Altered sensitivity to dopamine might play a role in WM changes observed after traumatic brain injury (TBI). Thirty-one healthy controls (HC) and 26 individuals with mild TBI (MTBI) 1 month after injury were challenged with bromocriptine versus placebo before administration of a verbal WM functional MRI task. Bromocriptine was associated with improved WM performance in the HC but not the MTBI group. On bromocriptine, the MTBI group showed increased activation outside of a task-specific region of interest. Findings are consistent with the hypothesis that individuals with MTBI have altered responsivity to dopamine. PMID:21948888

α-Viniferin-Induced Structural and Functional Alterations in Raillietina echinobothrida, a Poultry Tapeworm.

PubMed

Roy, Bishnupada; Giri, Bikash R

2015-04-01

α-Viniferin, an active component of the plant Carex baccans L., is known for its anticancer, antidiabetic, and anti-inflammatory properties. In Northeast India, different tribes traditionally consume C. baccans to control intestinal helminth infections. Therefore, the present study was carried out to assess the extent of tegumental alteration caused by α-viniferin in Raillietina echinobothrida, a widely prevalent poultry helminth in northeast India. Helminths were exposed in vitro to various doses of α-viniferin (50, 100, and 200 µM/mL of physiological buffered saline) and their motility and mortality were recorded. Stereoscan observations on the parasite exposed to the active compound showed extensive distortion and destruction of the surface fine topography of the tegument compared with controls. The compound also caused extensive damage to the tegument by disintegration of microtriches, disorganization of muscle bundles, and loss of cellular organelles combined with distortion and disruption of the plasma membrane, nuclear membrane, nucleolus, mitochondrial membrane, and cristae. Histochemical and biochemical studies carried out parasites exposed to α-viniferin revealed a decline in the activity of vital tegumental enzymes like acid phosphatase, alkaline phosphatase, and adenosine triphosphatase. Extensive structural and functional alterations observed in the treated parasites are indicative of efficient cestocidal activity of the compound.

The FBPase Encoding Gene glpX Is Required for Gluconeogenesis, Bacterial Proliferation and Division In Vivo of Mycobacterium marinum

PubMed Central

Lyu, Liangdong; Wang, Chuan; Li, Yang; Gao, Qian; Yang, Chen

2016-01-01

Lipids have been identified as important carbon sources for Mycobacterium tuberculosis (Mtb) to utilize in vivo. Thus gluconeogenesis bears a key role for Mtb to survive and replicate in host. A rate-limiting enzyme of gluconeogenesis, fructose 1, 6-bisphosphatase (FBPase) is encoded by the gene glpX. The functions of glpX were studied in M. marinum, a closely related species to Mtb. The glpX deletion strain (ΔglpX) displayed altered gluconeogenesis, attenuated virulence, and altered bacterial proliferation. Metabolic profiles indicate an accumulation of the FBPase substrate, fructose 1, 6-bisphosphate (FBP) and altered gluconeogenic flux when ΔglpX is cultivated in a gluconeogenic carbon substrate, acetate. In both macrophages and zebrafish, the proliferation of ΔglpX was halted, resulting in dramatically attenuated virulence. Intracellular ΔglpX exhibited an elongated morphology, which was also observed when ΔglpX was grown in a gluconeogenic carbon source. This elongated morphology is also supported by the observation of unseparated multi-nucleoid cell, indicating that a complete mycobacterial division in vivo is correlated with intact gluconeogenesis. Together, our results indicate that glpX has essential functions in gluconeogenesis, and plays an indispensable role in bacterial proliferation in vivo and virulence of M. marinum. PMID:27233038

The FBPase Encoding Gene glpX Is Required for Gluconeogenesis, Bacterial Proliferation and Division In Vivo of Mycobacterium marinum.

PubMed

Tong, Jingfeng; Meng, Lu; Wang, Xinwei; Liu, Lixia; Lyu, Liangdong; Wang, Chuan; Li, Yang; Gao, Qian; Yang, Chen; Niu, Chen

2016-01-01

Lipids have been identified as important carbon sources for Mycobacterium tuberculosis (Mtb) to utilize in vivo. Thus gluconeogenesis bears a key role for Mtb to survive and replicate in host. A rate-limiting enzyme of gluconeogenesis, fructose 1, 6-bisphosphatase (FBPase) is encoded by the gene glpX. The functions of glpX were studied in M. marinum, a closely related species to Mtb. The glpX deletion strain (ΔglpX) displayed altered gluconeogenesis, attenuated virulence, and altered bacterial proliferation. Metabolic profiles indicate an accumulation of the FBPase substrate, fructose 1, 6-bisphosphate (FBP) and altered gluconeogenic flux when ΔglpX is cultivated in a gluconeogenic carbon substrate, acetate. In both macrophages and zebrafish, the proliferation of ΔglpX was halted, resulting in dramatically attenuated virulence. Intracellular ΔglpX exhibited an elongated morphology, which was also observed when ΔglpX was grown in a gluconeogenic carbon source. This elongated morphology is also supported by the observation of unseparated multi-nucleoid cell, indicating that a complete mycobacterial division in vivo is correlated with intact gluconeogenesis. Together, our results indicate that glpX has essential functions in gluconeogenesis, and plays an indispensable role in bacterial proliferation in vivo and virulence of M. marinum.

Atypical within- and between-hemisphere motor network functional connections in children with developmental coordination disorder and attention-deficit/hyperactivity disorder.

PubMed

McLeod, Kevin R; Langevin, Lisa Marie; Dewey, Deborah; Goodyear, Bradley G

2016-01-01

Developmental coordination disorder (DCD) and attention-deficit hyperactivity disorder (ADHD) are highly comorbid neurodevelopmental disorders; however, the neural mechanisms of this comorbidity are poorly understood. Previous research has demonstrated that children with DCD and ADHD have altered brain region communication, particularly within the motor network. The structure and function of the motor network in a typically developing brain exhibits hemispheric dominance. It is plausible that functional deficits observed in children with DCD and ADHD are associated with neurodevelopmental alterations in within- and between-hemisphere motor network functional connection strength that disrupt this hemispheric dominance. We used resting-state functional magnetic resonance imaging to examine functional connections of the left and right primary and sensory motor (SM1) cortices in children with DCD, ADHD and DCD + ADHD, relative to typically developing children. Our findings revealed that children with DCD, ADHD and DCD + ADHD exhibit atypical within- and between-hemisphere functional connection strength between SM1 and regions of the basal ganglia, as well as the cerebellum. Our findings further support the assertion that development of atypical motor network connections represents common and distinct neural mechanisms underlying DCD and ADHD. In children with DCD and DCD + ADHD (but not ADHD), a significant correlation was observed between clinical assessment of motor function and the strength of functional connections between right SM1 and anterior cingulate cortex, supplementary motor area, and regions involved in visuospatial processing. This latter finding suggests that behavioral phenotypes associated with atypical motor network development differ between individuals with DCD and those with ADHD.

Altered T-Cell Balance in Lymphoid Organs of a Mouse Model of Colorectal Cancer

PubMed Central

Tanner, Scott M.; Daft, Joseph G.; Hill, Stephanie A.; Martin, Colin A.; Lorenz, Robin G.

2016-01-01

The adenomatous polyposis coli (APC) gene is a known tumor suppressor gene, and mice with mutations in Apc (ApcMin/+) spontaneously form multiple intestinal neoplasms. In this model of human colorectal cancer (CRC), it has been reported that CD4+ T-cell-derived interleukin 17 (IL-17) promotes intestinal tumor development, but it is not known if the Apc mutation actually directly alters T-cell function and subsequently tumor immunosurveillance. To investigate the ApcMin/+ mutation on T-cell function, flow cytometric, histochemical, and immunofluorescent studies on both wild-type (Apc+/+) and ApcMin/+ mice were performed. We identified decreased levels of interferon gamma (IFN-γ+)IL-17+ double-positive CD4+ cells in the mesenteric lymph nodes and Peyer’s patches of ApcMin/+ mice. In addition, altered levels of CD8+ cells, and changes in CD8+ production of IFN-γ and granzyme B were observed. These T-cell alterations did modify tumor immunosurveillance, as the adoptive transfer of splenocytes from ApcMin/+ animals into a chemically induced CRC model resulted in the inability to prevent epithelial dysplasia. These results suggest an altered T-cell balance in ApcMin/+ mice may disrupt intestinal homeostasis, consequently limiting intestinal tumor immunosurveillance. PMID:27798287

Altered T-Cell Balance in Lymphoid Organs of a Mouse Model of Colorectal Cancer.

PubMed

Tanner, Scott M; Daft, Joseph G; Hill, Stephanie A; Martin, Colin A; Lorenz, Robin G

2016-12-01

The adenomatous polyposis coli (APC) gene is a known tumor suppressor gene, and mice with mutations in Apc (Apc Min/+ ) spontaneously form multiple intestinal neoplasms. In this model of human colorectal cancer (CRC), it has been reported that CD4 + T-cell-derived interleukin 17 (IL-17) promotes intestinal tumor development, but it is not known if the Apc mutation actually directly alters T-cell function and subsequently tumor immunosurveillance. To investigate the Apc Min/+ mutation on T-cell function, flow cytometric, histochemical, and immunofluorescent studies on both wild-type (Apc +/+ ) and Apc Min/+ mice were performed. We identified decreased levels of interferon gamma (IFN-γ + )IL-17 + double-positive CD4 + cells in the mesenteric lymph nodes and Peyer's patches of Apc Min/+ mice. In addition, altered levels of CD8 + cells, and changes in CD8 + production of IFN-γ and granzyme B were observed. These T-cell alterations did modify tumor immunosurveillance, as the adoptive transfer of splenocytes from Apc Min/+ animals into a chemically induced CRC model resulted in the inability to prevent epithelial dysplasia. These results suggest an altered T-cell balance in Apc Min/+ mice may disrupt intestinal homeostasis, consequently limiting intestinal tumor immunosurveillance. © 2016 The Histochemical Society.

Sex-related differences in striatal dopaminergic system after traumatic brain injury.

PubMed

Xu, Xiupeng; Cao, Shengwu; Chao, Honglu; Liu, Yinlong; Ji, Jing

2016-06-01

Several studies have demonstrated alterations in the dopamine (DA) system after traumatic brain injury (TBI). Additionally, the existence of significant sex-related differences in the dopaminergic system has long been recognized. Accordingly, the purpose of the present study was to investigate whether TBI would differentially alter, in female and male mice, the expression and the function of the striatal vesicular monoamine transporter-2 (VMAT-2), an important DA transporter. After controlled cortical impact (CCI) injury, female mice showed significantly lower striatal DA concentrations and K(+)-evoked DA output. By contrast, no significant sex-related differences were observed in the mRNA and protein levels of striatal dopamine transporter (DAT) and VMAT-2 and the methamphetamine (MA)-evoked DA output. These results demonstrated clear sex-related differences in striatal VMAT-2 function in response to TBI and suggested that female mice may be more sensitive to the TBI-induced inhibition of the VMAT-2 function, as indicated by the greater degree of deficits observed when the VMAT-2 DA-storage function was inhibited by TBI. Moreover, the TBI-induced suppression of locomotion was more pronounced than female mice. Such findings highlight the need for sex-specific considerations when examining differences among brain injury conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

Leukocyte subsets and neutrophil function after short-term spaceflight

NASA Technical Reports Server (NTRS)

Stowe, R. P.; Sams, C. F.; Mehta, S. K.; Kaur, I.; Jones, M. L.; Feeback, D. L.; Pierson, D. L.

1999-01-01

Changes in leukocyte subpopulations and function after spaceflight have been observed but the mechanisms underlying these changes are not well defined. This study investigated the effects of short-term spaceflight (8-15 days) on circulating leukocyte subsets, stress hormones, immunoglobulin levels, and neutrophil function. At landing, a 1.5-fold increase in neutrophils was observed compared with preflight values; lymphocytes were slightly decreased, whereas the results were variable for monocytes. No significant changes were observed in plasma levels of immunoglobulins, cortisol, or adrenocorticotropic hormone. In contrast, urinary epinephrine, norepinephrine, and cortisol were significantly elevated at landing. Band neutrophils were observed in 9 of 16 astronauts. Neutrophil chemotactic assays showed a 10-fold decrease in the optimal dose response after landing. Neutrophil adhesion to endothelial cells was increased both before and after spaceflight. At landing, the expression of MAC-1 was significantly decreased while L-selectin was significantly increased. These functional alterations may be of clinical significance on long-duration space missions.

Virus-induced gene silencing offers a functional genomics platform for studying plant cell wall formation.

PubMed

Zhu, Xiaohong; Pattathil, Sivakumar; Mazumder, Koushik; Brehm, Amanda; Hahn, Michael G; Dinesh-Kumar, S P; Joshi, Chandrashekhar P

2010-09-01

Virus-induced gene silencing (VIGS) is a powerful genetic tool for rapid assessment of plant gene functions in the post-genomic era. Here, we successfully implemented a Tobacco Rattle Virus (TRV)-based VIGS system to study functions of genes involved in either primary or secondary cell wall formation in Nicotiana benthamiana plants. A 3-week post-VIGS time frame is sufficient to observe phenotypic alterations in the anatomical structure of stems and chemical composition of the primary and secondary cell walls. We used cell wall glycan-directed monoclonal antibodies to demonstrate that alteration of cell wall polymer synthesis during the secondary growth phase of VIGS plants has profound effects on the extractability of components from woody stem cell walls. Therefore, TRV-based VIGS together with cell wall component profiling methods provide a high-throughput gene discovery platform for studying plant cell wall formation from a bioenergy perspective.

Small mitochondria-targeting molecules as anti-cancer agents

PubMed Central

Wang, Feng; Ogasawara, Marcia A.; Huang, Peng

2009-01-01

Alterations in mitochondrial structure and functions have long been observed in cancer cells. Targeting mitochondria as a cancer therapeutic strategy has gained momentum in the recent years. The signaling pathways that govern mitochondrial function, apoptosis and molecules that affect mitochondrial integrity and cell viability have been important topics of the recent review in the literature. In this article, we first briefly summarize the rationale and biological basis for developing mitochondrial-targeted compounds as potential anticancer agents, and then provide key examples of small molecules that either directly impact mitochondria or functionally affect the metabolic alterations in cancer cells with mitochondrial dysfunction. The main focus is on the small molecular weight compounds with potential applications in cancer treatment. We also summarize information on the drug developmental stages of the key mitochondria-targeted compounds and their clinical trial status. The advantages and potential shortcomings of targeting the mitochondria for cancer treatment are also discussed. PMID:19995573

Calcium as a cardiovascular toxin in CKD-MBD.

PubMed

Moe, Sharon M

2017-07-01

Disordered calcium balance and homeostasis are common in patients with chronic kidney disease. Such alterations are commonly associated with abnormal bone remodeling, directly and indirectly. Similarly, positive calcium balance may also be a factor in the pathogenesis of extra skeletal soft tissue and arterial calcification. Calcium may directly affect cardiac structure and function through direct effects to alter cell signaling due to abnormal intracellular calcium homeostasis 2) extra-skeletal deposition of calcium and phosphate in the myocardium and small cardiac arterioles, 3) inducing cardiomyocyte hypertrophy through calcium and hormone activation of NFAT signaling mechanisms, and 4) increased aorta calcification resulting in chronic increased afterload leading to hypertrophy. Similarly, calcium may alter vascular smooth muscle cell function and affect cell signaling which may predispose to a proliferative phenotype important in arteriosclerosis and arterial calcification. Thus, disorders of calcium balance and homeostasis due to CKD-MBD may play a role in the high cardiovascular burden observed in patients with CKD. Published by Elsevier Inc.

Opioids and the immune system: what is their mechanism of action?

PubMed Central

Eisenstein, Toby K

2011-01-01

There is a significant amount of literature showing that morphine and other opioids modulate immune responses. The findings support many mechanisms by which this may occur. In vitro experiments provide evidence for direct actions of opioids on immune cells using a variety of functional end points. When these drugs are given in vivo, a plethora of immune parameters are also altered. The paper in this issue of the journal by Zhang et al. provides new information on morphine alteration of immune cell subsets in the spleen and thymus of mice and the potential role of glucocorticoids in these observed phenomena. This Commentary reviews the in vitro activities of morphine on leucocytes, as well as other documented mechanisms by which morphine can alter immune function in vivo. LINKED ARTICLE This article is a commentary on Zhang et al., pp. 1829–1844 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2011.01475.x PMID:21627636

Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders.

PubMed

O'Donnell, Cian; Gonçalves, J Tiago; Portera-Cailliau, Carlos; Sejnowski, Terrence J

2017-10-11

A leading theory holds that neurodevelopmental brain disorders arise from imbalances in excitatory and inhibitory (E/I) brain circuitry. However, it is unclear whether this one-dimensional model is rich enough to capture the multiple neural circuit alterations underlying brain disorders. Here, we combined computational simulations with analysis of in vivo two-photon Ca 2+ imaging data from somatosensory cortex of Fmr1 knock-out (KO) mice, a model of Fragile-X Syndrome, to test the E/I imbalance theory. We found that: (1) The E/I imbalance model cannot account for joint alterations in the observed neural firing rates and correlations; (2) Neural circuit function is vastly more sensitive to changes in some cellular components over others; (3) The direction of circuit alterations in Fmr1 KO mice changes across development. These findings suggest that the basic E/I imbalance model should be updated to higher dimensional models that can better capture the multidimensional computational functions of neural circuits.

Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders

PubMed Central

Gonçalves, J Tiago; Portera-Cailliau, Carlos

2017-01-01

A leading theory holds that neurodevelopmental brain disorders arise from imbalances in excitatory and inhibitory (E/I) brain circuitry. However, it is unclear whether this one-dimensional model is rich enough to capture the multiple neural circuit alterations underlying brain disorders. Here, we combined computational simulations with analysis of in vivo two-photon Ca2+ imaging data from somatosensory cortex of Fmr1 knock-out (KO) mice, a model of Fragile-X Syndrome, to test the E/I imbalance theory. We found that: (1) The E/I imbalance model cannot account for joint alterations in the observed neural firing rates and correlations; (2) Neural circuit function is vastly more sensitive to changes in some cellular components over others; (3) The direction of circuit alterations in Fmr1 KO mice changes across development. These findings suggest that the basic E/I imbalance model should be updated to higher dimensional models that can better capture the multidimensional computational functions of neural circuits. PMID:29019321

[Change in the lipid composition of the inner mitochondrial membranes in rat organs during adaptation to heat].

PubMed

Zubareva, E V; Seferova, R I; Denisova, N A

1991-01-01

Under conditions of adaptation to heating lipid composition in mitochondrial membranes of rat inner tissues was altered as follows: an increase in relative concentration of plasmalogenous forms of phospholipids (kidney, heart) and in content of saturated fatty acids (liver tissue), a decrease in the index of fatty acids unsaturation and in the ratio of fatty acids omega-3/omega-6. The alterations observed enabled the membranes to keep sufficient amount of liquidity essential for functional activity of mitochondria in heating.

DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia

PubMed Central

Rampal, Raajit; Alkalin, Altuna; Madzo, Jozef; Vasanthakumar, Aparna; Pronier, Elodie; Patel, Jay; Li, Yushan; Ahn, Jihae; Abdel-Wahab, Omar; Shih, Alan; Lu, Chao; Ward, Patrick S.; Tsai, Jennifer J.; Hricik, Todd; Tosello, Valeria; Tallman, Jacob E.; Zhao, Xinyang; Daniels, Danette; Dai, Qing; Ciminio, Luisa; Aifantis, Iannis; He, Chuan; Fuks, Francois; Tallman, Martin S.; Ferrando, Adolfo; Nimer, Stephen; Paietta, Elisabeth; Thompson, Craig B.; Licht, Jonathan D.; Mason, Chris; Godley, Lucy A.; Melnick, Ari; Figueroa, Maria E.; Levine, Ross L.

2014-01-01

Summary Somatic mutations in IDH1/2 and TET2 result in impaired TET2 mediated conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). The observation that WT1 inactivating mutations anti-correlate with TET2/IDH1/2 mutations in AML led us to hypothesize that WT1 mutations may impact TET2 function. WT1 mutant acute myeloid leukemia (AML) patients have reduced 5-hmC levels similar to TET2/IDH1/2-mutant AML. These mutations are characterized by convergent, site-specific alterations in DNA hydroxymethylation, which drive differential gene expression more than alterations in DNA promoter methylation. WT1 overexpression increases global levels of 5-hmC, and WT1 silencing reduced 5-hmC levels. WT1 physically interacts with TET2 and TET3, and WT1 loss of function results in a similar hematopoietic differentiation phenotype as observed with TET2 deficiency. These data provide a novel role for WT1 in regulating DNA hydroxymethylation and suggest that TET2 IDH1/2, and WT1 mutations define a novel AML subtype defined by dysregulated DNA hydroxymethylation. PMID:25482556

Environmental factors linked to depression vulnerability are associated with altered cerebellar resting-state synchronization.

PubMed

Córdova-Palomera, Aldo; Tornador, Cristian; Falcón, Carles; Bargalló, Nuria; Brambilla, Paolo; Crespo-Facorro, Benedicto; Deco, Gustavo; Fañanás, Lourdes

2016-11-28

Hosting nearly eighty percent of all human neurons, the cerebellum is functionally connected to large regions of the brain. Accumulating data suggest that some cerebellar resting-state alterations may constitute a key candidate mechanism for depressive psychopathology. While there is some evidence linking cerebellar function and depression, two topics remain largely unexplored. First, the genetic or environmental roots of this putative association have not been elicited. Secondly, while different mathematical representations of resting-state fMRI patterns can embed diverse information of relevance for health and disease, many of them have not been studied in detail regarding the cerebellum and depression. Here, high-resolution fMRI scans were examined to estimate functional connectivity patterns across twenty-six cerebellar regions in a sample of 48 identical twins (24 pairs) informative for depression liability. A network-based statistic approach was employed to analyze cerebellar functional networks built using three methods: the conventional approach of filtered BOLD fMRI time-series, and two analytic components of this oscillatory activity (amplitude envelope and instantaneous phase). The findings indicate that some environmental factors may lead to depression vulnerability through alterations of the neural oscillatory activity of the cerebellum during resting-state. These effects may be observed particularly when exploring the amplitude envelope of fMRI oscillations.

Dose Dependent Effects of Reactive Oxygen and Nitrogen Species on the Function of Neuronal Nitric Oxide Synthase

PubMed Central

Sun, Jian; Druhan, Lawrence J.; Zweier, Jay L.

2014-01-01

Reactive nitrogen species (RNS) and oxygen species (ROS) have been reported to modulate the function of nitric oxide synthase (NOS); however, the precise dosedependent effects of specific RNS and ROS on NOS function are unknown. Questions remain unanswered regarding whether pathophysiological levels of RNS and ROS alter NOS function, and if this alteration is reversible. We measured the effects of peroxynitrite (ONOO-), superoxide (O2.-), hydroxyl radical (.OH), and H2O2 on nNOS activity. The results showed that NO production was inhibited in a dose-dependent manner by all four oxidants, but only O2.- and ONOO- were inhibitory at pathophysiological concentrations (≤ 50 μM). Subsequent addition of tetrahydrobiopterin (BH4) fully restored activity after O2.- exposure, while BH4 partially rescued the activity decrease induced by the other three oxidants. Furthermore, treatment with either ONOO- or O2.- stimulated nNOS uncoupling with decreased NO and enhanced O2.- generation. Thus, nNOS is reversibly uncoupled by O2.- (≤ 50 μM), but irreversibly uncoupled and inactivated by ONOO-. Additionally, we observed that the mechanism by which oxidative stress alters nNOS activity involves not only BH4 oxidation, but also nNOS monomerization as well as possible degradation of the heme. PMID:18201545

Anastomotic Repair versus Free Graft Urethroplasty for Bulbar Strictures: A Focus on the Impact on Sexual Function

PubMed Central

Palminteri, Enzo; Spinoit, Anne-Françoise; Hoebeke, Piet; François, Philippe; Decaestecker, Karel

2015-01-01

Objectives. To evaluate alterations in sexual function and genital sensitivity after anastomotic repair (AR) and free graft urethroplasty (FGU) for bulbar urethral strictures. Methods. Patients treated with AR (n = 31) or FGU (n = 16) were prospectively evaluated before, 6 weeks and 6 months after urethroplasty. Evaluation included International Prostate Symptom Score (IPSS), 5-Item International Index of Erectile Function (IIEF-5), Ejaculation/Orgasm Score (EOS), and 3 questions on genital sensitivity. Results. At 6 weeks, there was a significant decline of IIEF-5 for AR (−4.8; p = 0.005), whereas there was no significant change for FGU (+0.9; p = 0.115). After 6 months, differences with baseline were not significant overall and among subgroups. At 6 weeks, there was a significant decline in EOS for AR (−1.4; p = 0.022). In the FGU group there was no significant change (+0.6; p = 0.12). Overall and among subgroups, EOS normalized at 6 months. After 6 weeks and 6 months, respectively, 62.2 and 52% of patients reported alterations in penile sensitivity with no significant differences among subgroups. Conclusions. AR is associated with a transient decline in erectile and ejaculatory function. This was not observed with FGU. Bulbar AR and FGU are likely to alter genital sensitivity. PMID:26494997

Functional network alterations and their structural substrate in drug-resistant epilepsy

PubMed Central

Caciagli, Lorenzo; Bernhardt, Boris C.; Hong, Seok-Jun; Bernasconi, Andrea; Bernasconi, Neda

2014-01-01

The advent of MRI has revolutionized the evaluation and management of drug-resistant epilepsy by allowing the detection of the lesion associated with the region that gives rise to seizures. Recent evidence indicates marked chronic alterations in the functional organization of lesional tissue and large-scale cortico-subcortical networks. In this review, we focus on recent methodological developments in functional MRI (fMRI) analysis techniques and their application to the two most common drug-resistant focal epilepsies, i.e., temporal lobe epilepsy related to mesial temporal sclerosis and extra-temporal lobe epilepsy related to focal cortical dysplasia. We put particular emphasis on methodological developments in the analysis of task-free or “resting-state” fMRI to probe the integrity of intrinsic networks on a regional, inter-regional, and connectome-wide level. In temporal lobe epilepsy, these techniques have revealed disrupted connectivity of the ipsilateral mesiotemporal lobe, together with contralateral compensatory reorganization and striking reconfigurations of large-scale networks. In cortical dysplasia, initial observations indicate functional alterations in lesional, peri-lesional, and remote neocortical regions. While future research is needed to critically evaluate the reliability, sensitivity, and specificity, fMRI mapping promises to lend distinct biomarkers for diagnosis, presurgical planning, and outcome prediction. PMID:25565942

Reflective mirrors: perspective-taking in autoscopic phenomena.

PubMed

Brugger, Peter

2002-08-01

''Autoscopic phenomena refer to different illusory reduplications of one's own body and self. This article proposes a phenomenological differentiation of autoscopic reduplication into three distinct classes, i.e., autoscopic hallucinations, heautoscopy, and out-of-body experiences (OBEs). Published cases are analysed with special emphasis on the subject's point of view from which the reduplication is observed. In an autoscopic hallucination the observer's perspective is clearly body-centred, and the visual image of one's own body appears as a mirror reversal. Heautoscopy (i.e., the encounter with an alter ego or doppelgänger), is defined as a reduplication not only of bodily appearance, but also of aspects of one's psychological self. The observer's perspective may alternate between egocentric and ''alter-ego-centred''. As a consequence of the projection of bodily feelings into the doppelgänger (implying a mental rotation of one's own body along the vertical axis), original and reduplicated bodies are not mirror images of one another. This also holds for OBEs, where one's self is not reduplicated but appears to be completely dissociated from the body and observing it from a location in extracorporeal space. It is argued that perspective-taking in a spatial sense may be meaningfully related to perspective-taking in a psychological sense. The mirror in the autoscopic hallucination is a ''cognitively nonreflective mirror'' (Jean Cocteau), both spatially and psychologically. The reflective abilities of the heautoscopic mirror are better developed, yet frequent shifts in the observer's spatial perspective render the nature of psychological interactions between self and alter ego highly unpredictable. The doppelgänger may serve a transitivistic (i.e., own suffering is transferred to the alter ego) or aggressive function when this behaviour is directed against a patient. The mirror in an OBE is always reflective: It allows the self to view both space and one's psychological state from a detached but stable perspective. Spatial perspective-taking should be more thoroughly assessed in patients reporting autoscopic phenomena. By elucidating the interactions between spatial phenomenology and psychological function, we may gain important insights into the relationships between the self, its body, and phenomenal space.

Long-term physiological alterations and recovery in a mouse model of separation associated with time-restricted feeding: a tool to study anorexia nervosa related consequences.

PubMed

Zgheib, Sara; Méquinion, Mathieu; Lucas, Stéphanie; Leterme, Damien; Ghali, Olfa; Tolle, Virginie; Zizzari, Philippe; Bellefontaine, Nicole; Legroux-Gérot, Isabelle; Hardouin, Pierre; Broux, Odile; Viltart, Odile; Chauveau, Christophe

2014-01-01

Anorexia nervosa is a primary psychiatric disorder, with non-negligible rates of mortality and morbidity. Some of the related alterations could participate in a vicious cycle limiting the recovery. Animal models mimicking various physiological alterations related to anorexia nervosa are necessary to provide better strategies of treatment. To explore physiological alterations and recovery in a long-term mouse model mimicking numerous consequences of severe anorexia nervosa. C57Bl/6 female mice were submitted to a separation-based anorexia protocol combining separation and time-restricted feeding for 10 weeks. Thereafter, mice were housed in standard conditions for 10 weeks. Body weight, food intake, body composition, plasma levels of leptin, adiponectin, IGF-1, blood levels of GH, reproductive function and glucose tolerance were followed. Gene expression of several markers of lipid and energy metabolism was assayed in adipose tissues. Mimicking what is observed in anorexia nervosa patients, and despite a food intake close to that of control mice, separation-based anorexia mice displayed marked alterations in body weight, fat mass, lean mass, bone mass acquisition, reproductive function, GH/IGF-1 axis, and leptinemia. mRNA levels of markers of lipogenesis, lipolysis, and the brown-like adipocyte lineage in subcutaneous adipose tissue were also changed. All these alterations were corrected during the recovery phase, except for the hypoleptinemia that persisted despite the full recovery of fat mass. This study strongly supports the separation-based anorexia protocol as a valuable model of long-term negative energy balance state that closely mimics various symptoms observed in anorexia nervosa, including metabolic adaptations. Interestingly, during a recovery phase, mice showed a high capacity to normalize these parameters with the exception of plasma leptin levels. It will be interesting therefore to explore further the central and peripheral effects of the uncorrected hypoleptinemia during recovery from separation-based anorexia.

Altered free radical metabolism in acute mountain sickness: implications for dynamic cerebral autoregulation and blood-brain barrier function.

PubMed

Bailey, D M; Evans, K A; James, P E; McEneny, J; Young, I S; Fall, L; Gutowski, M; Kewley, E; McCord, J M; Møller, Kirsten; Ainslie, P N

2009-01-15

We tested the hypothesis that dynamic cerebral autoregulation (CA) and blood-brain barrier (BBB) function would be compromised in acute mountain sickness (AMS) subsequent to a hypoxia-mediated alteration in systemic free radical metabolism. Eighteen male lowlanders were examined in normoxia (21% O(2)) and following 6 h passive exposure to hypoxia (12% O(2)). Blood flow velocity in the middle cerebral artery (MCAv) and mean arterial blood pressure (MAP) were measured for determination of CA following calculation of transfer function analysis and rate of regulation (RoR). Nine subjects developed clinical AMS (AMS+) and were more hypoxaemic relative to subjects without AMS (AMS-). A more marked increase in the venous concentration of the ascorbate radical (A(*-)), lipid hydroperoxides (LOOH) and increased susceptibility of low-density lipoprotein (LDL) to oxidation was observed during hypoxia in AMS+ (P < 0.05 versus AMS-). Despite a general decline in total nitric oxide (NO) in hypoxia (P < 0.05 versus normoxia), the normoxic baseline plasma and red blood cell (RBC) NO metabolite pool was lower in AMS+ with normalization observed during hypoxia (P < 0.05 versus AMS-). CA was selectively impaired in AMS+ as indicated both by an increase in the low-frequency (0.07-0.20 Hz) transfer function gain and decrease in RoR (P < 0.05 versus AMS-). However, there was no evidence for cerebral hyper-perfusion, BBB disruption or neuronal-parenchymal damage as indicated by a lack of change in MCAv, S100beta and neuron-specific enolase. In conclusion, these findings suggest that AMS is associated with altered redox homeostasis and disordered CA independent of barrier disruption.

CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function

PubMed Central

Guo, Ya; Xu, Quan; Canzio, Daniele; Shou, Jia; Li, Jinhuan; Gorkin, David U.; Jung, Inkyung; Wu, Haiyang; Zhai, Yanan; Tang, Yuanxiao; Lu, Yichao; Wu, Yonghu; Jia, Zhilian; Li, Wei; Zhang, Michael Q.; Ren, Bing; Krainer, Adrian R.; Maniatis, Tom; Wu, Qiang

2015-01-01

SUMMARY CTCF/cohesin play a central role in insulator function and higher-order chromatin organization of mammalian genomes. Recent studies identified a correlation between the orientation of CTCF-binding sites (CBSs) and chromatin loops. To test the functional significance of this observation, we combined CRISPR/Cas9-based genomic-DNA-fragment editing with chromosome-conformation-capture experiments to show that the location and relative orientations of CBSs determine the specificity of long-range chromatin looping in mammalian genomes, using protocadherin (Pcdh) and β-globin as model genes. Inversion of CBS elements within the Pcdh enhancer reconfigures the topology of chromatin loops between the distal enhancer and target promoters, and alters gene-expression patterns. Thus, although enhancers can function in an orientation-independent manner in reporter assays, in the native chromosome context the orientation of at least some enhancers carrying CBSs can determine both the architecture of topological chromatin domains and enhancer/promoter specificity. The findings reveal how 3D chromosome architecture can be encoded by genome sequence. PMID:26276636

Alkali-induced changes in functional properties and in vitro digestibility of wheat starch: the role of surface proteins and lipids.

PubMed

Wang, Shujun; Luo, Heyang; Zhang, Jian; Zhang, Yan; He, Zhonghu; Wang, Shuo

2014-04-23

The bread wheat starch was treated with 0.025 and 0.0625 M NaOH solution for 1, 2, and 3 weeks at 30 °C, and the changes in functionality and in vitro digestibility were evaluated. NaOH treatment reduced protein and lipid contents of wheat starch from 0.46 to 0.20% and from 0.59 to 0.25%, respectively. No significant changes were observed in the amylose content, relative crystallinity, and short-range order of double helices, but there was evidence showing that morphology of some starch granules was altered. The swelling power and starch solubility of wheat starch increased from 11.4 to 14.1 g/g and from 10.9 to 22.1%, respectively. The thermal transition temperatures were increased greatly, but the enthalpy change remained largely unchanged. Alkali treatment greatly decreased the pasting temperature, but the pasting viscosities were altered in different ways. The resistant starch (RS) content of wheat starch was decreased significantly from 69.9 to 45.2%, while the starch that is digested slowly (SDS) content was increased greatly from 13.6 to 34.5%. Our results showed that alkali treatment can significantly alter the functionality and in vitro digestibility of wheat starch granules by removing the surface proteins and lipids rather than significantly altering the internal structure of starch granules.

Altered neural circuits accompany lower performance during narrative comprehension in children with reading difficulties: an fMRI study.

PubMed

Horowitz-Kraus, Tzipi; Buck, Catherine; Dorrmann, Dana

2016-10-01

Narrative comprehension is a linguistic ability that is foundational for future reading ability. The aim of the current study was to examine the neural circuitry of children with reading difficulties (RD) compared to typical readers during a narrative-comprehension task. We hypothesized that due to deficient executive functions, which support narrative comprehension abilities, children with RD would display altered activation and functional connectivity, as well as lower performance on a narrative-comprehension task. Children with RD and typical readers were scanned during a narrative-comprehension task and administered reading behavioral tests. Children with RD scored significantly lower on the narrative-comprehension task than did typical readers. Composite activation maps showed more diffused activation during narrative comprehension in the RD group. Maps comparing the two reading groups showed more activation in the frontal lobes (regions responsible for executive functions), and functional connectivity showed higher global efficiency in children with RD than in typical readers. Global efficiency was negatively correlated with phonological awareness and reading and executive function scores in the entire study group. Children with RD may suffer from narrative-comprehension difficulties due to diffused activation of language areas, as was observed during a narrative-comprehension task. Greater effort in this task may be reflected by the engagement of brain regions related to executive functions and higher functional connectivity or attributed to difficulties in phonological processing and reading and executive functions. Therefore, the accommodation given to children with RD of reading aloud may need to be revised due to the observed difficulty in this domain.

Risk of Impaired Control of Spacecraft/Associated Systems and Decreased Mobility Due to Vestibular/Sensorimotor Alterations Associated with Space flight

NASA Technical Reports Server (NTRS)

Bloomberg, Jacob J.; Reschke, Millard F.; Clement, Gilles R.; Mulavara, Ajitkumar P.; Taylor, Laura C..

2015-01-01

Control of vehicles and other complex systems is a high-level integrative function of the central nervous system (CNS). It requires well-functioning subsystem performance, including good visual acuity, eye-hand coordination, spatial and geographic orientation perception, and cognitive function. Evidence from space flight research demonstrates that the function of each of these subsystems is altered by removing gravity, a fundamental orientation reference, which is sensed by vestibular, proprioceptive, and haptic receptors and used by the CNS for spatial orientation, posture, navigation, and coordination of movements. The available evidence also shows that the degree of alteration of each subsystem depends on a number of crew- and mission-related factors. There is only limited operational evidence that these alterations cause functional impacts on mission-critical vehicle (or complex system) control capabilities. Furthermore, while much of the operational performance data collected during space flight has not been available for independent analysis, those that have been reviewed are somewhat equivocal owing to uncontrolled (and/or unmeasured) environmental and/or engineering factors. Whether this can be improved by further analysis of previously inaccessible operational data or by development of new operational research protocols remains to be seen. The true operational risks will be estimable only after we have filled the knowledge gaps and when we can accurately assess integrated performance in off-nominal operational settings (Paloski et al. 2008). Thus, our current understanding of the Risk of Impaired Control of Spacecraft/Associated Systems and Decreased Mobility Due to Vestibular/Sensorimotor Alterations Associated with Space flight is limited primarily to extrapolation of scientific research findings, and, since there are limited ground-based analogs of the sensorimotor and vestibular changes associated with space flight, observation of their functional impacts is limited to studies performed in the space flight environment. Fortunately, many sensorimotor and vestibular experiments have been performed during and/or after space flight missions since 1959 (Reschke et al. 2007). While not all of these experiments were directly relevant to the question of vehicle/complex system control, most provide insight into changes in aspects of sensorimotor control that might bear on the physiological subsystems underlying this high-level integrated function.

Laser technique for anatomical-functional study of the medial prefrontal cortex of the brain

NASA Astrophysics Data System (ADS)

Sanchez-Huerta, Laura; Hernandez, Adan; Ayala, Griselda; Marroquin, Javier; Silva, Adriana B.; Khotiaintsev, Konstantin S.; Svirid, Vladimir A.; Flores, Gonzalo; Khotiaintsev, Sergei N.

1999-05-01

The brain represents one of the most complex systems that we know yet. In its study, non-destructive methods -- in particular, behavioral studies play an important role. By alteration of brain functioning (e.g. by pharmacological means) and observation of consequent behavior changes an important information on brain organization and functioning is obtained. For inducing local alterations, permanent brain lesions are employed. However, for correct results this technique has to be quasi-non-destructive, i.e. not to affect the normal brain function. Hence, the lesions should be very small, accurate and applied precisely over the structure (e.g. the brain nucleus) of interest. These specifications are difficult to meet with the existing techniques for brain lesions -- specifically, neurotoxical, mechanical and electrical means because they result in too extensive damage. In this paper, we present new laser technique for quasi-non- destructive anatomical-functional mapping in vivo of the medial prefrontal cortex (MPFC) of the rat. The technique is based on producing of small-size, well-controlled laser- induced lesions over some areas of the MPFC. The anesthetized animals are subjected to stereotactic surgery and certain points of the MPFC are exposed the confined radiation of the 10 W cw CO2 laser. Subsequent behavioral changes observed in neonatal and adult animals as well as histological data prove effectiveness of this technology for anatomical- functional studies of the brain by areas, and as a treatment method for some pathologies.

Functional brain correlates of heterosexual paedophilia.

PubMed

Schiffer, Boris; Paul, Thomas; Gizewski, Elke; Forsting, Michael; Leygraf, Norbert; Schedlowski, Manfred; Kruger, Tillmann H C

2008-05-15

Although the neuronal mechanisms underlying normal sexual motivation and function have recently been examined, the alterations in brain function in deviant sexual behaviours such as paedophilia are largely unknown. The objective of this study was to identify paedophilia-specific functional networks implicated in sexual arousal. Therefore a consecutive sample of eight paedophile forensic inpatients, exclusively attracted to females, and 12 healthy age-matched heterosexual control participants from a comparable socioeconomic stratum participated in a visual sexual stimulation procedure during functional magnetic resonance imaging. The visual stimuli were sexually stimulating photographs and emotionally neutral photographs. Immediately after the imaging session subjective responses pertaining to sexual desire were recorded. Principally, the brain response of heterosexual paedophiles to heteropaedophilic stimuli was comparable to that of heterosexual males to heterosexual stimuli, including different limbic structures (amygdala, cingulate gyrus, and hippocampus), the substantia nigra, caudate nucleus, as well as the anterior cingulate cortex, different thalamic nuclei, and associative cortices. However, responses to visual sexual stimulation were found in the orbitofrontal cortex in healthy heterosexual males, but not in paedophiles, in whom abnormal activity in the dorsolateral prefrontal cortex was observed. Thus, in line with clinical observations and neuropsychological studies, it seems that central processing of sexual stimuli in heterosexual paedophiles may be altered by a disturbance in the prefrontal networks, which, as has already been hypothesized, may be associated with stimulus-controlled behaviours, such as sexual compulsive behaviours. Moreover, these findings may suggest a dysfunction (in the functional and effective connectivity) at the cognitive stage of sexual arousal processing.

The role of psychoneuroendocrine factors on spaceflight-induced immunological alterations

NASA Technical Reports Server (NTRS)

Meehan, R.; Whitson, P.; Sams, C.

1993-01-01

This paper summarizes previous in-flight infections and novel conditions of spaceflight that may suppress immune function. Granulocytosis, monocytosis, and lymphopenia are routinely observed following short duration orbital flights. Subtle changes within the monocyte and T cell populations can also be noted by flow cytometric analysis. The similarity between the immunological changes observed after spaceflight and other diverse environmental stressors suggest that most of these alterations may be neuroendocrine-mediated. Available data support the hypothesis that spaceflight and other environmental stressors modulate normal immune regulation via stress hormones, other than exclusively glucocorticoids. It will be essential to simultaneously collect in-flight endocrine, immunologic, and infectious illness data to determine the clinical significance of these results. Additional research that delineates the neuroendocrine mechanisms of stress-induced changes in normal immune regulation will allow clinicians in the future to initiate prophylactic immunomodulator therapy to restore immune competence altered by the stress of long-duration spaceflight and therefore reduce morbidity from infectious illness, autoimmune disease, or malignancy.

Membrane permeability, a pivotal function involved in antibiotic resistance and virulence in Enterobacter aerogenes clinical isolates.

PubMed

Lavigne, J-P; Sotto, A; Nicolas-Chanoine, M-H; Bouziges, N; Bourg, G; Davin-Regli, A; Pagès, J-M

2012-06-01

Imipenem-susceptible E. aerogenes isolates exhibiting extended spectrum β-lactamases, target mutations and a basal efflux expression, were identified in five patients. After imipenem treatment, imipenem-intermediate susceptible (IMI-I) or resistant (IMI-R) isolates emerged in these patients. Alteration in porin synthesis and increase in efflux expression were observed in the IMI-I isolates whereas complete loss of the porins, LPS alteration and efflux overexpression were observed in the IMI-R isolates. Bacterial virulence of the strains was investigated by the Caenorhabditis elegans model. The IMI-R isolates were shown to be significantly less virulent than the IMI-susceptible or IMI-I isolates. The pleiotropic membrane alteration and its associated fitness burden exhibited by E. aerogenes isolates influence their antibiotic resistance and their virulence behaviour. These findings highlight the balance between the low permeability-related resistance and virulence and their relationships with the treatment of resistant pathogens. © 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.

Changes in Expression of Signal Transduction Proteins in T Lymphocytes of Patients with Leprosy

PubMed Central

Zea, Arnold H.; Ochoa, Maria T.; Ghosh, Paritosh; Longo, Dan L.; Alvord, W. Gregory; Valderrama, Liliana; Falabella, Rafael; Harvey, Linda K.; Saravia, Nancy; Moreno, Luis H.; Ochoa, Augusto C.

1998-01-01

Advanced stages of mycobacterial diseases such as leprosy and tuberculosis are characterized by a loss of T-cell function. The basis of this T-cell dysfunction is not well understood. The present report demonstrates major alterations in the expression of signal transduction molecules in T cells of leprosy patients. These alterations were most frequently observed in lepromatous leprosy (LL) patients. Of 29 LL patients, 69% had decreased T-cell receptor ζ-chain expression, 48% had decreased p56lck tyrosine kinase, and 63% had a loss of nuclear transcription factor NF-κB p65. An electrophoretic mobility shift assay with the gamma interferon core promoter region revealed a loss of the Th1 DNA-binding pattern in LL patients. In contrast, tuberculoid leprosy patients had only minor signal transduction alterations. These novel findings might improve our understanding of the T-cell dysfunction observed in leprosy and other infectious diseases and consequently might lead to better immunologic evaluation of patients. PMID:9453602

ELECTRORETINOGRAMS ARE ALTERED BY SUBCHRONIC TOLUENE EXPOSURE TO LONG EVANS RATS: EXPERIMENTAL EVIDENCE SUPPORTING OBSERVATIONS FROM STUDIES OF EXPOSED HUMANS

EPA Science Inventory

Impaired visual functions, including low contrast sensitivity and reduced color discrimination, have been reported in studies of humans chronically exposed to several volatile organic solvents. These reports remain controversial, however, in part due to a lack of confirmation fro...

Radiation-induced functional connectivity alterations in nasopharyngeal carcinoma patients with radiotherapy.

PubMed

Ma, Qiongmin; Wu, Donglin; Zeng, Ling-Li; Shen, Hui; Hu, Dewen; Qiu, Shijun

2016-07-01

The study aims to investigate the radiation-induced brain functional alterations in nasopharyngeal carcinoma (NPC) patients who received radiotherapy (RT) using functional magnetic resonance imaging (fMRI) and statistic scale.The fMRI data of 35 NPC patients with RT and 24 demographically matched untreated NPC patients were acquired. Montreal Cognitive Assessment (MoCA) was also measured to evaluate their global cognition performance. Multivariate pattern analysis was performed to find the significantly altered functional connections between these 2 groups, while the linear correlation level was detected between the altered functional connections and the MoCA scores.Forty-five notably altered functional connections were found, which were mainly located between 3 brain networks, the cerebellum, sensorimotor, and cingulo-opercular. With strictly false discovery rate correction, 5 altered functional connections were shown to have significant linear correlations with the MoCA scores, that is, the connections between the vermis and hippocampus, cerebellum lobule VI and dorsolateral prefrontal cortex, precuneus and dorsal frontal cortex, cuneus and middle occipital lobe, and insula and cuneus. Besides, the connectivity between the vermis and hippocampus was also significantly correlated with the attention score, 1 of the 7 subscores of the MoCA.The present study provides new insights into the radiation-induced functional connectivity impairments in NPC patients. The results showed that the RT may induce the cognitive impairments, especially the attention alterations. The 45 altered functional connections, especially the 5 altered functional connections that were significantly correlated to the MoCA scores, may serve as the potential biomarkers of the RT-induced brain functional impairments and provide valuable targets for further functional recovery treatment.

Toxic effects of multi-walled carbon nanotubes on bivalves: Comparison between functionalized and nonfunctionalized nanoparticles.

PubMed

De Marchi, Lucia; Neto, Victor; Pretti, Carlo; Figueira, Etelvina; Chiellini, Federica; Morelli, Andrea; Soares, Amadeu M V M; Freitas, Rosa

2018-05-01

Despite of the large array of available carbon nanotube (CNT) configurations that allow different industrial and scientific applications of these nanoparticles, their impacts on aquatic organisms, especially on invertebrate species, are still limited. To our knowledge, no information is available on how surface chemistry alteration (functionalization) of CNTs may impact the toxicity of these NPs to bivalve species after a chronic exposure. For this reason, the impacts induced by chronic exposure (28days) to unfunctionalized MWCNTs (Nf-MWCNTs) in comparison with functionalized MWCNTs (f-MWCNTs), were evaluated in R. philippinarum, by measuring alterations induced in clams' oxidative status, neurotoxicity and metabolic capacity. The results obtained revealed that exposure to both MWCNT materials altered energy-related responses, with higher metabolic capacity and lower glycogen, protein and lipid concentrations in clams exposed to these CNTs. Moreover, R. philippinarum exposed to Nf-MWCNTs and f-MWCNTs showed oxidative stress expressed in higher lipid peroxidation and lower ratio between reduced and oxidized glutathione, despite the activation of defense mechanisms (superoxide-dismutase, glutathione peroxidase and glutathione S-transferases) in exposed clams. Additionally, neurotoxicity was observed by inhibition of Cholinesterases activity in organisms exposed to both MWCNTs. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of Preload Alterations on Left Ventricular Systolic Parameters Including Speckle-Tracking Echocardiography Radial Strain During General Anesthesia.

PubMed

Weber, Ulrike; Base, Eva; Ristl, Robin; Mora, Bruno

2015-08-01

Frequently used parameters for evaluation of left ventricular systolic function are load-sensitive. However, the impact of preload alterations on speckle-tracking echocardiographic parameters during anesthesia has not been validated. Therefore, two-dimensional (2D) speckle-tracking echocardiography radial strain (RS) was assessed during general anesthesia, simulating 3 different preload conditions. Single-center prospective observational study. University hospital. Thirty-three patients with normal left ventricular systolic function undergoing major surgery. Transgastric views of the midpapillary level of the left ventricle were acquired at 3 different positions. Fractional shortening (FS), fractional area change (FAC), and 2D speckle-tracking echocardiography RS were analyzed in the transgastric midpapillary view. Considerable correlation above 0.5 was found for FAC and FS in the zero and Trendelenburg positions (r = 0.629, r = 0.587), and for RS and FAC in the anti-Trendelenburg position (r = 0.518). In the repeated-measures analysis, significant differences among the values measured at the 3 positions were found for FAC and FS. For FAC, there were differences up to 2.8 percentage points between the anti-Trendelenburg position and the other 2 positions. For FS, only the difference between position zero and anti-Trendelenburg was significant, with an observed change of 1.66. Two-dimensional RS was not significantly different at all positions, with observed changes below 1 percentage point. Alterations in preload did not result in clinically relevant changes of RS, FS, or FAC. Observed changes for RS were smallest; however, the variation of RS was larger than that of FS or FAC. Copyright © 2015 Elsevier Inc. All rights reserved.

Analyses of Dynein Heavy Chain Mutations Reveal Complex Interactions Between Dynein Motor Domains and Cellular Dynein Functions

PubMed Central

Sivagurunathan, Senthilkumar; Schnittker, Robert R.; Razafsky, David S.; Nandini, Swaran; Plamann, Michael D.; King, Stephen J.

2012-01-01

Cytoplasmic dynein transports cargoes for a variety of crucial cellular functions. However, since dynein is essential in most eukaryotic organisms, the in-depth study of the cellular function of dynein via genetic analysis of dynein mutations has not been practical. Here, we identify and characterize 34 different dynein heavy chain mutations using a genetic screen of the ascomycete fungus Neurospora crassa, in which dynein is nonessential. Interestingly, our studies show that these mutations segregate into five different classes based on the in vivo localization of the mutated dynein motors. Furthermore, we have determined that the different classes of dynein mutations alter vesicle trafficking, microtubule organization, and nuclear distribution in distinct ways and require dynactin to different extents. In addition, biochemical analyses of dynein from one mutant strain show a strong correlation between its in vitro biochemical properties and the aberrant intracellular function of that altered dynein. When the mutations were mapped to the published dynein crystal structure, we found that the three-dimensional structural locations of the heavy chain mutations were linked to particular classes of altered dynein functions observed in cells. Together, our data indicate that the five classes of dynein mutations represent the entrapment of dynein at five separate points in the dynein mechanochemical and transport cycles. We have developed N. crassa as a model system where we can dissect the complexities of dynein structure, function, and interaction with other proteins with genetic, biochemical, and cell biological studies. PMID:22649085

Prolonged Injury and Altered Lung Function after Ozone Inhalation in Mice with Chronic Lung Inflammation

PubMed Central

Groves, Angela M.; Gow, Andrew J.; Massa, Christopher B.; Laskin, Jeffrey D.

2012-01-01

Surfactant protein–D (Sftpd) is a pulmonary collectin important in down-regulating macrophage inflammatory responses. In these experiments, we analyzed the effects of chronic macrophage inflammation attributable to loss of Sftpd on the persistence of ozone-induced injury, macrophage activation, and altered functioning in the lung. Wild-type (Sftpd+/+) and Sftpd−/− mice (aged 8 wk) were exposed to air or ozone (0.8 parts per million, 3 h). Bronchoalveolar lavage (BAL) fluid and tissue were collected 72 hours later. In Sftpd−/− mice, but not Sftpd+/+ mice, increased BAL protein and nitrogen oxides were observed after ozone inhalation, indicating prolonged lung injury and oxidative stress. Increased numbers of macrophages were also present in BAL fluid and in histologic sections from Sftpd−/− mice. These cells were enlarged and foamy, suggesting that they were activated. This conclusion was supported by findings of increased BAL chemotactic activity, and increased expression of inducible nitric oxide synthase in lung macrophages. In both Sftpd+/+ and Sftpd−/− mice, inhalation of ozone was associated with functional alterations in the lung. Although these alterations were limited to central airway mechanics in Sftpd+/+ mice, both central airway and parenchymal mechanics were modified by ozone exposure in Sftpd−/− mice. The most notable changes were evident in resistance and elastance spectra and baseline lung function, and in lung responsiveness to changes in positive end-expiratory pressure. These data demonstrate that a loss of Sftpd is associated with prolonged lung injury, oxidative stress, and macrophage accumulation and activation in response to ozone, and with more extensive functional changes consistent with the loss of parenchymal integrity. PMID:22878412

Aberrant Hyperconnectivity in the Motor System at Rest Is Linked to Motor Abnormalities in Schizophrenia Spectrum Disorders.

PubMed

Walther, Sebastian; Stegmayer, Katharina; Federspiel, Andrea; Bohlhalter, Stephan; Wiest, Roland; Viher, Petra V

2017-09-01

Motor abnormalities are frequently observed in schizophrenia and structural alterations of the motor system have been reported. The association of aberrant motor network function, however, has not been tested. We hypothesized that abnormal functional connectivity would be related to the degree of motor abnormalities in schizophrenia. In 90 subjects (46 patients) we obtained resting stated functional magnetic resonance imaging (fMRI) for 8 minutes 40 seconds at 3T. Participants further completed a motor battery on the scanning day. Regions of interest (ROI) were cortical motor areas, basal ganglia, thalamus and motor cerebellum. We computed ROI-to-ROI functional connectivity. Principal component analyses of motor behavioral data produced 4 factors (primary motor, catatonia and dyskinesia, coordination, and spontaneous motor activity). Motor factors were correlated with connectivity values. Schizophrenia was characterized by hyperconnectivity in 3 main areas: motor cortices to thalamus, motor cortices to cerebellum, and prefrontal cortex to the subthalamic nucleus. In patients, thalamocortical hyperconnectivity was linked to catatonia and dyskinesia, whereas aberrant connectivity between rostral anterior cingulate and caudate was linked to the primary motor factor. Likewise, connectivity between motor cortex and cerebellum correlated with spontaneous motor activity. Therefore, altered functional connectivity suggests a specific intrinsic and tonic neural abnormality in the motor system in schizophrenia. Furthermore, altered neural activity at rest was linked to motor abnormalities on the behavioral level. Thus, aberrant resting state connectivity may indicate a system out of balance, which produces characteristic behavioral alterations. © The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Morphologic and functional alterations induced by low doses of mercuric chloride in the kidney OK cell line: ultrastructural evidence for an apoptotic mechanism of damage.

PubMed

Carranza-Rosales, Pilar; Said-Fernández, Salvador; Sepúlveda-Saavedra, Julio; Cruz-Vega, Delia E; Gandolfi, A Jay

2005-06-01

Mercury produces acute renal failure in experimental animal models, but the mechanism of tubular injury has not completely been clarified. There is an increased interest in the role of apoptosis in the pathogenesis of renal diseases that result primarily from injury to renal tubular epithelial cells. However, detailed studies of morpho-functional alterations induced by mercuric chloride in kidney cell lines are scarce. This work characterizes these alterations in OK cell cultures. Morphological alterations were profiled using light microscopy, transmission electron microscopy, and confocal microscopy, as well as mitochondrial functional assays in the cells exposed to low concentrations of HgCl2. At concentrations of 1 and 10 microM of HgCl2 there were no morphological or ultrastructural alterations, but the mitochondrial function (MTT assay) and intracellular ATP content was increased, especially at longer incubation times (6 and 9 h). At 15 microM HgCl2, both the mitochondrial activity and the endogenous ATP decreased significantly. At this concentration the OK cells rounded up, had increased number of cytoplasmic vacuoles, and detached from the cell monolayer. At 15 microM HgCl2 ultrastructural changes were characterized by dispersion of the ribosomes, dilatation of the cisterns of the rough endoplasmic reticulum, increase of number of cytoplasmic vacuoles, chromatin condensation, invaginations of the nuclear envelope, presence of cytoplasmic inclusion bodies, and alterations in the size and morphology of mitochondria. At 15 microM HgCl2 apoptotic signs included membrane blebbing, chromatin condensation, mitochondrial alterations, apoptotic bodies, and nuclear envelope rupture. Using confocal microscopy and the mitochondrial specific dye MitoTracker Red, it was possible to establish qualitative changes induced by mercury on the mitochondrial membrane potential after incubation of the cells for 6 and 9h with 15 microM HgCl2. This effect was not observed at short times (1 and 3h) with this same concentration, neither with 1 and 10 microM HgCl2 in all the studied times. Taken together, these findings indicate that low concentrations of HgCl2 induce apoptosis by inhibiting mitochondrial function, and the OK cell line may be considered a useful tool for the study of programmed cell death involving mercurial species and other heavy metals.

Altered host resistance to Listeria monocytogenes in mice exposed to 1-chloroacetophenone (CN) vapours

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumar, P.; Kumar, P.; Zachariah, K.

1992-06-01

Short term repeated exposure of 1-chloroacetophenone (CN) vapours at a concentration of 0.153 mg per litre for 15 minutes daily on 10 consecutive days in Swiss albino male mice resulted in increased mortality to Listeria monocytogenes. Significantly elevated bacterial growth was observed in the spleen and liver of the CN exposed animals. The increased bacterial count in these organs was evident within 4-6 days post challenge as compared to vehicle exposed infected and unexposed infected animals. Increased susceptibility to infection has been considered to be the function of immune alteration due to cumulative short term effects of CN vapour inhalation.more » This may be attributed to immunotoxic effects of CN on T-cells mediated macrophage functions.« less

Mitochondrionopathy phenotype in doxorubicin-treated Wistar rats depends on treatment protocol and is cardiac-specific.

PubMed

Pereira, Gonçalo C; Pereira, Susana P; Pereira, Claudia V; Lumini, José A; Magalhães, José; Ascensão, António; Santos, Maria S; Moreno, António J; Oliveira, Paulo J

2012-01-01

Although doxorubicin (DOX) is a very effective antineoplastic agent, its clinical use is limited by a dose-dependent, persistent and cumulative cardiotoxicity, whose mechanism remains to be elucidated. Previous works in animal models have failed to use a multi-organ approach to demonstrate that DOX-associated toxicity is selective to the cardiac tissue. In this context, the present work aims to investigate in vivo DOX cardiac, hepatic and renal toxicity in the same animal model, with special relevance on alterations of mitochondrial bioenergetics. To this end, male Wistar rats were sub-chronically (7 wks, 2 mg/Kg) or acutely (20 mg/Kg) treated with DOX and sacrificed one week or 24 hours after the last injection, respectively. Alterations of mitochondrial bioenergetics showed treatment-dependent differences between tissues. No alterations were observed for cardiac mitochondria in the acute model but decreased ADP-stimulated respiration was detected in the sub-chronic treatment. In the acute treatment model, ADP-stimulated respiration was increased in liver and decreased in kidney mitochondria. Aconitase activity, a marker of oxidative stress, was decreased in renal mitochondria in the acute and in heart in the sub-chronic model. Interestingly, alterations of cardiac mitochondrial bioenergetics co-existed with an absence of echocardiograph, histopathological or ultra-structural alterations. Besides, no plasma markers of cardiac injury were found in any of the time points studied. The results confirm that alterations of mitochondrial function, which are more evident in the heart, are an early marker of DOX-induced toxicity, existing even in the absence of cardiac functional alterations.

Mitochondrionopathy Phenotype in Doxorubicin-Treated Wistar Rats Depends on Treatment Protocol and Is Cardiac-Specific

PubMed Central

Pereira, Gonçalo C.; Pereira, Susana P.; Pereira, Claudia V.; Lumini, José A.; Magalhães, José; Ascensão, António; Santos, Maria S.; Moreno, António J.; Oliveira, Paulo J.

2012-01-01

Although doxorubicin (DOX) is a very effective antineoplastic agent, its clinical use is limited by a dose-dependent, persistent and cumulative cardiotoxicity, whose mechanism remains to be elucidated. Previous works in animal models have failed to use a multi-organ approach to demonstrate that DOX-associated toxicity is selective to the cardiac tissue. In this context, the present work aims to investigate in vivo DOX cardiac, hepatic and renal toxicity in the same animal model, with special relevance on alterations of mitochondrial bioenergetics. To this end, male Wistar rats were sub-chronically (7 wks, 2 mg/Kg) or acutely (20 mg/Kg) treated with DOX and sacrificed one week or 24 hours after the last injection, respectively. Alterations of mitochondrial bioenergetics showed treatment-dependent differences between tissues. No alterations were observed for cardiac mitochondria in the acute model but decreased ADP-stimulated respiration was detected in the sub-chronic treatment. In the acute treatment model, ADP-stimulated respiration was increased in liver and decreased in kidney mitochondria. Aconitase activity, a marker of oxidative stress, was decreased in renal mitochondria in the acute and in heart in the sub-chronic model. Interestingly, alterations of cardiac mitochondrial bioenergetics co-existed with an absence of echocardiograph, histopathological or ultra-structural alterations. Besides, no plasma markers of cardiac injury were found in any of the time points studied. The results confirm that alterations of mitochondrial function, which are more evident in the heart, are an early marker of DOX-induced toxicity, existing even in the absence of cardiac functional alterations. PMID:22745682

Impaired in vivo mitochondrial Krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy.

PubMed

Dodd, Michael S; Atherton, Helen J; Carr, Carolyn A; Stuckey, Daniel J; West, James A; Griffin, Julian L; Radda, George K; Clarke, Kieran; Heather, Lisa C; Tyler, Damian J

2014-11-01

Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial metabolic alterations caused by MI, thereby allowing a greater understanding of the interplay between metabolic and functional abnormalities. Using hyperpolarized carbon-13 ((13)C)-magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed for 22 weeks after surgically induced MI with reperfusion in female Wister rats. One week after MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of ejection fractions observed (from 28% to 84%). At 6 weeks after MI, in vivo mitochondrial Krebs cycle activity was impaired, with decreased (13)C-label flux into citrate, glutamate, and acetylcarnitine, which correlated with the degree of cardiac dysfunction. These changes were independent of alterations in pyruvate dehydrogenase flux. By 22 weeks, alterations were also seen in pyruvate dehydrogenase flux, which decreased at lower ejection fractions. These results were confirmed using in vitro analysis of enzyme activities and metabolomic profiles of key intermediates. The in vivo decrease in Krebs cycle activity in the 6-week post-MI heart may represent an early maladaptive phase in the metabolic alterations after MI in which reductions in Krebs cycle activity precede a reduction in pyruvate dehydrogenase flux. Changes in mitochondrial metabolism in heart disease are progressive and proportional to the degree of cardiac impairment. © 2014 American Heart Association, Inc.

Impaired In Vivo Mitochondrial Krebs Cycle Activity After Myocardial Infarction Assessed Using Hyperpolarized Magnetic Resonance Spectroscopy

PubMed Central

Carr, Carolyn A.; Stuckey, Daniel J.; West, James A.; Griffin, Julian L.; Radda, George K.; Clarke, Kieran; Heather, Lisa C.; Tyler, Damian J.

2015-01-01

Background Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial metabolic alterations caused by MI, thereby allowing a greater understanding of the interplay between metabolic and functional abnormalities. Methods and Results Using hyperpolarized carbon-13 (13C)-magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed for 22 weeks after surgically induced MI with reperfusion in female Wister rats. One week after MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of ejection fractions observed (from 28% to 84%). At 6 weeks after MI, in vivo mitochondrial Krebs cycle activity was impaired, with decreased 13C-label flux into citrate, glutamate, and acetylcarnitine, which correlated with the degree of cardiac dysfunction. These changes were independent of alterations in pyruvate dehydrogenase flux. By 22 weeks, alterations were also seen in pyruvate dehydrogenase flux, which decreased at lower ejection fractions. These results were confirmed using in vitro analysis of enzyme activities and metabolomic profiles of key intermediates. Conclusions The in vivo decrease in Krebs cycle activity in the 6-week post-MI heart may represent an early maladaptive phase in the metabolic alterations after MI in which reductions in Krebs cycle activity precede a reduction in pyruvate dehydrogenase flux. Changes in mitochondrial metabolism in heart disease are progressive and proportional to the degree of cardiac impairment. PMID:25201905

The relative abundance of predicted genes associated with ammonia-oxidation, nitrate reduction, and biomass decomposition in mineral soil are altered by intensive timber harvest.

NASA Astrophysics Data System (ADS)

Mushinski, R. M.; Zhou, Y.; Gentry, T. J.; Boutton, T. W.

2017-12-01

Forest ecosystems in the southern United States are substantially altered by anthropogenic disturbances such as timber harvest and land conversion, with effects being observed in carbon and nutrient pools as well as biogeochemical processes. Furthermore, the desire to develop renewable energy sources in the form of biomass extraction from logging residues may result in alterations in soil community structure and function. While the impact of forest management on soil physicochemical properties of the region has been studied, its' long-term effect on soil bacterial community composition and metagenomic potential is relatively unknown, especially at deeper soil depths. This study investigates how intensive organic matter removal intensities associated with timber harvest influence decadal-scale alterations in bacterial community structure and functional potential in the upper 1-m of the soil profile, 18 years post-harvest in a Pinus taeda L. forest of eastern Texas. Amplicon sequencing of the 16S rRNA gene was used in conjunction with soil chemical analyses to evaluate treatment-induced differences in community composition and potential environmental drivers of associated change. Furthermore, functional potential was assessed by using amplicon data to make metagenomic predictions. Results indicate that increasing organic matter removal intensity leads to altered community composition and the relative abundance of dominant OTUs annotated to Burkholderia and Aciditerrimonas. The relative abundance of predicted genes associated with dissimilatory nitrate reduction and denitrification were highest in the most intensively harvested treatment while genes involved in nitrification were significantly lower in the most intensively harvested treatment. Furthermore, genes associated with glycosyltransferases were significantly reduced with increasing harvest intensity while polysaccharide lyases increased. These results imply that intensive organic matter removal may create long-term alterations in bacterial community structure with concurrent alterations to mineral soil carbon and nutrient cycling which may have future consequences on forest regeneration and subsequent stand productivity.

Electrophysiologic alterations in the excitability of the sciatic and vagus nerves during early stages of sepsis.

PubMed

Diniz, Lúcio Ricardo Leite; Portella, Viviane Gomes; da Silva Alves, Kerly Shamira; Araújo, Pâmella Cristina da Costa; de Albuquerque Júnior, Ricardo Luiz Cavalcanti; Cavalcante de Albuquerque, Aline Alice; Coelho-de-Souza, Andrelina Noronha; Leal-Cardoso, José Henrique

2018-01-01

Nonspecific and delayed diagnosis of neurologic damage contributes to the development of neuropathies in patients with severe sepsis. The present study assessed the electrophysiologic parameters related to the excitability and conductibility of sciatic and vagus nerves during early stages of sepsis. Twenty-four hours after sepsis induced by cecal ligation and puncture (CLP) model, sciatic and vagus nerves of septic (CLP group) and control (sham group) rats were removed, and selected electric stimulations were applied to measure the parameters of the first and second components of the compound action potential. The first component originated from fibers with motor and sensory functions (Types A α and A β fibers) with a large conduction velocity (70-120 m/s), and the second component originated from fibers (Type A γ ) with sensorial function. To evaluate the presence of sensorial alterations, the sensitivity to non-noxious mechanical stimuli was measured by using the von Frey test. Hematoxylin and eosin staining of the nerves was performed. We observed an increase of rheobase followed by a decrease in the first component amplitude and a higher paw withdrawal threshold in response to the application of von Frey filaments in sciatic nerves from the CLP group compared to the sham group. Differently, a decrease in rheobase and an increase in the first component amplitude of vagal C fibers from CLP group were registered. No significant morphologic alteration was observed. Our data showed that the electrophysiologic alterations in peripheral nerves vary with the fiber type and might be identified in the first 24 h of sepsis, before clinical signs of neuromuscular disorders.

The bodily self and its disorders: neurological, psychological and social aspects.

PubMed

Brugger, Peter; Lenggenhager, Bigna

2014-12-01

The experience of ourselves as an embodied agent with a first-person perspective is referred to as 'bodily self'. We present a selective overview of relevant clinical and experimental studies. Sharing multisensory body space with others can be observed in patients with structurally altered bodies (amputations, congenital absence of limbs), with altered functionality after hemiplegia, such as denial of limb ownership (somatoparaphrenia) and with alterations in bodily self-consciousness on the level of the entire body (e.g. in autoscopic phenomena). In healthy participants, the mechanisms underpinning body ownership and observer perspective are empirically investigated by multisensory stimulation paradigms to alter the bodily self. The resulting illusions have promoted the understanding of complex disturbances of the bodily self, such as out-of-body experiences. We discuss the role of interoception in differentiating between self and others and review current advances in the study of body integrity identity disorder, a condition shaped as much by neurological as by social-psychological factors. We advocate a social neuroscience approach to the bodily self that takes into account the interactions between body, mind and society and might help close the divide between neurology and psychiatry.

[Selective alteration of the declarative memory systems in patients treated with a high number of electroconvulsive therapy sessions].

PubMed

Rami-González, L; Boget-Llucià, T; Bernardo, M; Marcos, T; Cañizares-Alejos, S; Penadés, R; Portella, M J; Castelví, M; Raspall, T; Salamero, M

The reversible electrochemical effects of electroconvulsive therapy (ECT) on specific areas of the brain enable the neuroanatomical bases of some cognitive functions to be studied. In research carried out on memory systems, a selective alteration of the declarative ones has been observed after treatment with ECT. Little work has been done to explore the differential alteration of the memory subsystems in patients with a high number of ECT sessions. AIM. To study the declarative and non declarative memory system in psychiatric patients submitted to maintenance ECT treatment, with a high number of previous ECT sessions. 20 patients submitted to treatment with ECT (10 diagnosed as having depression and 10 with schizophrenia) and 20 controls, who were paired by age, sex and psychopathological diagnosis. For the evaluation of the declarative memory system, the Wechsler Memory Scale (WMS) logical memory test was used. The Hanoi Tower procedural test was employed to evaluate the non declarative system. Patients treated with ECT performed worse in the WMS logical memory test, but this was only significant in patients diagnosed as suffering from depression. No significant differences were observed in the Hanoi Tower test. A selective alteration of the declarative systems was observed in patients who had been treated with a high number of ECT sessions, while the non declarative memory systems remain unaffected.

Mapping the brain correlates of borderline personality disorder: A functional neuroimaging meta-analysis of resting state studies.

PubMed

Visintin, Eleonora; De Panfilis, Chiara; Amore, Mario; Balestrieri, Matteo; Wolf, Robert Christian; Sambataro, Fabio

2016-11-01

Altered intrinsic function of the brain has been implicated in Borderline Personality Disorder (BPD). Nonetheless, imaging studies have yielded inconsistent alterations of brain function. To investigate the neural activity at rest in BPD, we conducted a set of meta-analyses of brain imaging studies performed at rest. A total of seven functional imaging studies (152 patients with BPD and 147 control subjects) were combined using whole-brain Signed Differential Mapping meta-analyses. Furthermore, two conjunction meta-analyses of neural activity at rest were also performed: with neural activity changes during emotional processing, and with structural differences, respectively. We found altered neural activity in the regions of the default mode network (DMN) in BPD. Within the regions of the midline core DMN, patients with BPD showed greater activity in the anterior as well as in the posterior midline hubs relative to controls. Conversely, in the regions of the dorsal DMN they showed reduced activity compared to controls in the right lateral temporal complex and bilaterally in the orbitofrontal cortex. Increased activity in the precuneus was observed both at rest and during emotional processing. Reduced neural activity at rest in lateral temporal complex was associated with smaller volume of this area. Heterogeneity across imaging studies. Altered activity in the regions of the midline core as well as of the dorsal subsystem of the DMN may reflect difficulties with interpersonal and affective regulation in BPD. These findings suggest that changes in spontaneous neural activity could underlie core symptoms in BPD. Copyright © 2016 Elsevier B.V. All rights reserved.

Using human brain imaging studies as a guide towards animal models of schizophrenia

PubMed Central

BOLKAN, Scott S.; DE CARVALHO, Fernanda D.; KELLENDONK, Christoph

2015-01-01

Schizophrenia is a heterogeneous and poorly understood mental disorder that is presently defined solely by its behavioral symptoms. Advances in genetic, epidemiological and brain imaging techniques in the past half century, however, have significantly advanced our understanding of the underlying biology of the disorder. In spite of these advances clinical research remains limited in its power to establish the causal relationships that link etiology with pathophysiology and symptoms. In this context, animal models provide an important tool for causally testing hypotheses about biological processes postulated to be disrupted in the disorder. While animal models can exploit a variety of entry points towards the study of schizophrenia, here we describe an approach that seeks to closely approximate functional alterations observed with brain imaging techniques in patients. By modeling these intermediate pathophysiological alterations in animals, this approach offers an opportunity to (1) tightly link a single functional brain abnormality with its behavioral consequences, and (2) to determine whether a single pathophysiology can causally produce alterations in other brain areas that have been described in patients. In this review we first summarize a selection of well-replicated biological abnormalities described in the schizophrenia literature. We then provide examples of animal models that were studied in the context of patient imaging findings describing enhanced striatal dopamine D2 receptor function, alterations in thalamo-prefrontal circuit function, and metabolic hyperfunction of the hippocampus. Lastly, we discuss the implications of findings from these animal models for our present understanding of schizophrenia, and consider key unanswered questions for future research in animal models and human patients. PMID:26037801

Altered intrinsic brain activity after chemotherapy in patients with gastric cancer: A preliminary study.

PubMed

Kim, Hyun Gi; Shin, Na-Young; Bak, Yunjin; Kim, Kyung Ran; Jung, Young-Chul; Han, Kyunghwa; Lee, Seung-Koo; Lim, Soo Mee

2017-07-01

To characterize the pattern of altered intrinsic brain activity in gastric cancer patients after chemotherapy (CTx). Patients before and after CTx (n = 14) and control subjects (n = 11) underwent resting-state functional MRI (rsfMRI) at baseline and 3 months after CTx. Regional homogeneity (ReHo), amplitude of low-frequency fluctuation (ALFF), and fractional ALFF (fALFF) were calculated and compared between the groups using the two-sample t test. Correlation analysis was also performed between rsfMRI values (i.e., ReHo, ALFF, and fALFF) and neuropsychological test results. Patients showed poor performance in verbal memory and executive function and decreased rsfMRI values in the frontal areas even before CTx and showed decreased attention/working memory and executive function after CTx compared to the control subjects. In direct comparison of values before and after CTx, there were no significant differences in neuropsychological test scores, but decreased rsfMRI values were observed at the frontal lobes and right cerebellar region. Among rsfMRI values, lower ALFF in the left inferior frontal gyrus was significantly associated with poor performance of the executive function test. We observed decreased attention/working memory and executive function that corresponded to the decline of frontal region activation in gastric cancer patients who underwent CTx. • Intrinsic brain activity of gastric cancer patients after chemotherapy was described. • Brain activity and neuropsychological test results were correlated. • Working memory and executive function decreased after chemotherapy. • Decreased cognitive function corresponded to decreased activation of the frontal region.

Administration of imatinib mesylate in rats impairs the neonatal development of intramuscular interstitial cells in bladder and results in altered contractile properties.

PubMed

Gevaert, Thomas; Hutchings, Graham; Everaerts, Wouter; Prenen, Hans; Roskams, Tania; Nilius, Bernd; De Ridder, Dirk

2014-04-01

The KIT receptor is considered as a reliable marker for a subpopulation of interstitial cells (IC), and by persistent neonatal inhibition of KIT we have investigated the role of this receptor in the development of IC-networks in bladder and we have observed the functional consequences of this inhibition. Newborn rat pups were treated daily with the KIT inhibitor imatinib mesylate (IM). After 7 days animals were sacrificed and bladder samples were dissected for morphological and functional studies. Morphological research consisted of immunohistochemistry with IC specific antigens (KIT and vimentin) and electron microscopy. The functional studies were based on isolated bladder strips in organ baths, in which spontaneous bladder contractility and the response to a non-subtype selective muscarinic agonist was evaluated. Suburothelial and intramuscular IC were found and characterized in neonatal rat bladder. IM-treatment induced a significant decrease in numbers of IC based on specific immunohistochemical markers, and electron microscopy revealed evidence of IC cell injury. These morphological alterations were observed on intramuscular IC only and not on IC in the suburothelium. Isolated muscle strips from IM-treated animals had a lower contractile frequency and an altered response to muscarinic agonists. The present study shows the presence of regional subpopulations of IC in neonatal rat bladder, provides evidence for a dependence on KIT of the development of intramuscular IC and supports the hypothesis that a poor development of networks of intramuscular IC might have repercussions on spontaneous and muscarinic-induced bladder contractility. © 2013 Wiley Periodicals, Inc.

Interaction of the P-Glycoprotein Multidrug Transporter with Sterols.

PubMed

Clay, Adam T; Lu, Peihua; Sharom, Frances J

2015-11-03

The ABC transporter P-glycoprotein (Pgp, ABCB1) actively exports structurally diverse substrates from within the lipid bilayer, leading to multidrug resistance. Many aspects of Pgp function are altered by the phospholipid environment, but its interactions with sterols remain enigmatic. In this work, the functional interaction between purified Pgp and various sterols was investigated in detergent solution and proteoliposomes. Fluorescence studies showed that dehydroergosterol, cholestatrienol, and NBD-cholesterol interact intimately with Pgp, resulting in both quenching of protein Trp fluorescence and enhancement of sterol fluorescence. Kd values indicated binding affinities in the range of 3-9 μM. Collisional quenching experiments showed that Pgp-bound NBD-cholesterol was protected from the external milieu, resonance energy transfer was observed between Pgp Trp residues and the sterol, and the fluorescence emission of bound sterol was enhanced. These observations suggested an intimate interaction of bound sterols with the transporter at a protected nonpolar site. Cholesterol hemisuccinate altered the thermal unfolding of Pgp and greatly stabilized its basal ATPase activity in both a detergent solution and reconstituted proteoliposomes of certain phospholipids. Other sterols, including dehydroergosterol, did not stabilize the basal ATPase activity of detergent-solubilized Pgp, which suggests that this is not a generalized sterol effect. The phospholipid composition and cholesterol hemisuccinate content of Pgp proteoliposomes altered the basal ATPase and drug transport cycles differently. Sterols may interact with Pgp and modulate its structure and function by occupying part of the drug-binding pocket or by binding to putative consensus cholesterol-binding (CRAC/CARC) motifs located within the transmembrane domains.

Radiation-induced functional connectivity alterations in nasopharyngeal carcinoma patients with radiotherapy

PubMed Central

Ma, Qiongmin; Wu, Donglin; Zeng, Ling-Li; Shen, Hui; Hu, Dewen; Qiu, Shijun

2016-01-01

Abstract The study aims to investigate the radiation-induced brain functional alterations in nasopharyngeal carcinoma (NPC) patients who received radiotherapy (RT) using functional magnetic resonance imaging (fMRI) and statistic scale. The fMRI data of 35 NPC patients with RT and 24 demographically matched untreated NPC patients were acquired. Montreal Cognitive Assessment (MoCA) was also measured to evaluate their global cognition performance. Multivariate pattern analysis was performed to find the significantly altered functional connections between these 2 groups, while the linear correlation level was detected between the altered functional connections and the MoCA scores. Forty-five notably altered functional connections were found, which were mainly located between 3 brain networks, the cerebellum, sensorimotor, and cingulo-opercular. With strictly false discovery rate correction, 5 altered functional connections were shown to have significant linear correlations with the MoCA scores, that is, the connections between the vermis and hippocampus, cerebellum lobule VI and dorsolateral prefrontal cortex, precuneus and dorsal frontal cortex, cuneus and middle occipital lobe, and insula and cuneus. Besides, the connectivity between the vermis and hippocampus was also significantly correlated with the attention score, 1 of the 7 subscores of the MoCA. The present study provides new insights into the radiation-induced functional connectivity impairments in NPC patients. The results showed that the RT may induce the cognitive impairments, especially the attention alterations. The 45 altered functional connections, especially the 5 altered functional connections that were significantly correlated to the MoCA scores, may serve as the potential biomarkers of the RT-induced brain functional impairments and provide valuable targets for further functional recovery treatment. PMID:27442663

Adaptor Protein-1 Complex Affects the Endocytic Trafficking and Function of Peptidylglycine α-Amidating Monooxygenase, a Luminal Cuproenzyme*

PubMed Central

Bonnemaison, Mathilde L.; Bäck, Nils; Duffy, Megan E.; Ralle, Martina; Mains, Richard E.; Eipper, Betty A.

2015-01-01

The adaptor protein-1 complex (AP-1), which transports cargo between the trans-Golgi network and endosomes, plays a role in the trafficking of Atp7a, a copper-transporting P-type ATPase, and peptidylglycine α-amidating monooxygenase (PAM), a copper-dependent membrane enzyme. Lack of any of the four AP-1 subunits impairs function, and patients with MEDNIK syndrome, a rare genetic disorder caused by lack of expression of the σ1A subunit, exhibit clinical and biochemical signs of impaired copper homeostasis. To explore the role of AP-1 in copper homeostasis in neuroendocrine cells, we used corticotrope tumor cells in which AP-1 function was diminished by reducing expression of its μ1A subunit. Copper levels were unchanged when AP-1 function was impaired, but cellular levels of Atp7a declined slightly. The ability of PAM to function was assessed by monitoring 18-kDa fragment-NH2 production from proopiomelanocortin. Reduced AP-1 function made 18-kDa fragment amidation more sensitive to inhibition by bathocuproine disulfonate, a cell-impermeant Cu(I) chelator. The endocytic trafficking of PAM was altered, and PAM-1 accumulated on the cell surface when AP-1 levels were reduced. Reduced AP-1 function increased the Atp7a presence in early/recycling endosomes but did not alter the ability of copper to stimulate its appearance on the plasma membrane. Co-immunoprecipitation of a small fraction of PAM and Atp7a supports the suggestion that copper can be transferred directly from Atp7a to PAM, a process that can occur only when both proteins are present in the same subcellular compartment. Altered luminal cuproenzyme function may contribute to deficits observed when the AP-1 function is compromised. PMID:26170456

Mitochondrial Bioenergetics Is Altered in Fibroblasts from Patients with Sporadic Alzheimer's Disease.

PubMed

Pérez, María J; Ponce, Daniela P; Osorio-Fuentealba, Cesar; Behrens, Maria I; Quintanilla, Rodrigo A

2017-01-01

The identification of an early biomarker to diagnose Alzheimer's disease (AD) remains a challenge. Neuropathological studies in animal and AD patients have shown that mitochondrial dysfunction is a hallmark of the development of the disease. Current studies suggest the use of peripheral tissues, like skin fibroblasts as a possibility to detect the early pathological alterations present in the AD brain. In this context, we studied mitochondrial function properties (bioenergetics and morphology) in cultured fibroblasts obtained from AD, aged-match and young healthy patients. We observed that AD fibroblasts presented a significant reduction in mitochondrial length with important changes in the expression of proteins that control mitochondrial fusion. Moreover, AD fibroblasts showed a distinct alteration in proteolytic processing of OPA1, a master regulator of mitochondrial fusion, compared to control fibroblasts. Complementary to these changes AD fibroblasts showed a dysfunctional mitochondrial bioenergetics profile that differentiates these cells from aged-matched and young patient fibroblasts. Our findings suggest that the human skin fibroblasts obtained from AD patients could replicate mitochondrial impairment observed in the AD brain. These promising observations suggest that the analysis of mitochondrial bioenergetics could represent a promising strategy to develop new diagnostic methods in peripheral tissues of AD patients.

Mitochondrial Bioenergetics Is Altered in Fibroblasts from Patients with Sporadic Alzheimer's Disease

PubMed Central

Pérez, María J.; Ponce, Daniela P.; Osorio-Fuentealba, Cesar; Behrens, Maria I.; Quintanilla, Rodrigo A.

2017-01-01

The identification of an early biomarker to diagnose Alzheimer's disease (AD) remains a challenge. Neuropathological studies in animal and AD patients have shown that mitochondrial dysfunction is a hallmark of the development of the disease. Current studies suggest the use of peripheral tissues, like skin fibroblasts as a possibility to detect the early pathological alterations present in the AD brain. In this context, we studied mitochondrial function properties (bioenergetics and morphology) in cultured fibroblasts obtained from AD, aged-match and young healthy patients. We observed that AD fibroblasts presented a significant reduction in mitochondrial length with important changes in the expression of proteins that control mitochondrial fusion. Moreover, AD fibroblasts showed a distinct alteration in proteolytic processing of OPA1, a master regulator of mitochondrial fusion, compared to control fibroblasts. Complementary to these changes AD fibroblasts showed a dysfunctional mitochondrial bioenergetics profile that differentiates these cells from aged-matched and young patient fibroblasts. Our findings suggest that the human skin fibroblasts obtained from AD patients could replicate mitochondrial impairment observed in the AD brain. These promising observations suggest that the analysis of mitochondrial bioenergetics could represent a promising strategy to develop new diagnostic methods in peripheral tissues of AD patients. PMID:29056898

Alterations in cerebral metabolism observed in living rodents using fluorescence lifetime microscopy of intrinsic NADH (Conference Presentation)

NASA Astrophysics Data System (ADS)

Yaseen, Mohammad A.; Sakadžić, Sava; Sutin, Jason; Wu, Weicheng; Fu, Buyin; Boas, David A.

2017-02-01

Monitoring cerebral energy metabolism at a cellular level is essential to improve our understanding of healthy brain function and its pathological alterations. In this study, we resolve specific alterations in cerebral metabolism utilizing minimally-invasive 2-Photon fluorescence lifetime imaging (2P-FLIM) measurements of reduced nicotinamide adenine dinucleotide (NADH) fluorescence, collected in vivo from anesthetized rats and mice. Time-resolved lifetime measurements enables distinction of different components contributing to NADH autofluorescence. These components reportedly represent different enzyme-bound formulations of NADH. Our observations from this study confirm the hypothesis that NADH FLIM can identify specific alterations in cerebral metabolism. Using time-correlated single photon counting (TCSPC) equipment and a custom-built multimodal imaging system, 2-photon fluorescence lifetime imaging (FLIM) was performed in cerebral tissue with high spatial and temporal resolution. Multi-exponential fits for NADH fluorescence lifetimes indicate 4 distinct components, or 'species.' We observed distinct variations in the relative proportions of these components before and after pharmacological-induced impairments to several reactions involved in anaerobic glycolysis and aerobic oxidative metabolism. Classification models developed with experimental data correctly predict the metabolic impairments associated with bicuculline-induced focal seizures in separate experiments. Compared to traditional intensity-based NADH measurements, lifetime imaging of NADH is less susceptible to the adverse effects of overlying blood vessels. Evaluating NADH measurements will ultimately lead to a deeper understanding of cerebral energetics and its pathology-related alterations. Such knowledge will likely aid development of therapeutic strategies for neurodegenerative diseases such as Alzheimer's Disease, Parkinson's disease, and stroke.

A genome-wide analysis of putative functional and exonic variation associated with extremely high intelligence

PubMed Central

Spain, S L; Pedroso, I; Kadeva, N; Miller, M B; Iacono, W G; McGue, M; Stergiakouli, E; Smith, G D; Putallaz, M; Lubinski, D; Meaburn, E L; Plomin, R; Simpson, M A

2016-01-01

Although individual differences in intelligence (general cognitive ability) are highly heritable, molecular genetic analyses to date have had limited success in identifying specific loci responsible for its heritability. This study is the first to investigate exome variation in individuals of extremely high intelligence. Under the quantitative genetic model, sampling from the high extreme of the distribution should provide increased power to detect associations. We therefore performed a case–control association analysis with 1409 individuals drawn from the top 0.0003 (IQ >170) of the population distribution of intelligence and 3253 unselected population-based controls. Our analysis focused on putative functional exonic variants assayed on the Illumina HumanExome BeadChip. We did not observe any individual protein-altering variants that are reproducibly associated with extremely high intelligence and within the entire distribution of intelligence. Moreover, no significant associations were found for multiple rare alleles within individual genes. However, analyses using genome-wide similarity between unrelated individuals (genome-wide complex trait analysis) indicate that the genotyped functional protein-altering variation yields a heritability estimate of 17.4% (s.e. 1.7%) based on a liability model. In addition, investigation of nominally significant associations revealed fewer rare alleles associated with extremely high intelligence than would be expected under the null hypothesis. This observation is consistent with the hypothesis that rare functional alleles are more frequently detrimental than beneficial to intelligence. PMID:26239293

A genome-wide analysis of putative functional and exonic variation associated with extremely high intelligence.

PubMed

Spain, S L; Pedroso, I; Kadeva, N; Miller, M B; Iacono, W G; McGue, M; Stergiakouli, E; Davey Smith, G; Putallaz, M; Lubinski, D; Meaburn, E L; Plomin, R; Simpson, M A

2016-08-01

Although individual differences in intelligence (general cognitive ability) are highly heritable, molecular genetic analyses to date have had limited success in identifying specific loci responsible for its heritability. This study is the first to investigate exome variation in individuals of extremely high intelligence. Under the quantitative genetic model, sampling from the high extreme of the distribution should provide increased power to detect associations. We therefore performed a case-control association analysis with 1409 individuals drawn from the top 0.0003 (IQ >170) of the population distribution of intelligence and 3253 unselected population-based controls. Our analysis focused on putative functional exonic variants assayed on the Illumina HumanExome BeadChip. We did not observe any individual protein-altering variants that are reproducibly associated with extremely high intelligence and within the entire distribution of intelligence. Moreover, no significant associations were found for multiple rare alleles within individual genes. However, analyses using genome-wide similarity between unrelated individuals (genome-wide complex trait analysis) indicate that the genotyped functional protein-altering variation yields a heritability estimate of 17.4% (s.e. 1.7%) based on a liability model. In addition, investigation of nominally significant associations revealed fewer rare alleles associated with extremely high intelligence than would be expected under the null hypothesis. This observation is consistent with the hypothesis that rare functional alleles are more frequently detrimental than beneficial to intelligence.

Evolution or Entropy? Changing Reference/User Culture and the Future of Reference Librarians.

ERIC Educational Resources Information Center

Wilson, Myoung C.

2000-01-01

This article addresses issues that relate to the changing functional relationship between the reference librarian and the user, based on the observation that the advance of information technology, particularly the Internet, has altered the values, attitudes, and beliefs of library users, and, as a consequence, their micro-culture. (Author/LRW)

Deletion of ultraconserved elements yields viable mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ahituv, Nadav; Zhu, Yiwen; Visel, Axel

2007-07-15

Ultraconserved elements have been suggested to retainextended perfect sequence identity between the human, mouse, and ratgenomes due to essential functional properties. To investigate thenecessities of these elements in vivo, we removed four non-codingultraconserved elements (ranging in length from 222 to 731 base pairs)from the mouse genome. To maximize the likelihood of observing aphenotype, we chose to delete elements that function as enhancers in amouse transgenic assay and that are near genes that exhibit markedphenotypes both when completely inactivated in the mouse as well as whentheir expression is altered due to other genomic modifications.Remarkably, all four resulting lines of mice lackingmore » these ultraconservedelements were viable and fertile, and failed to reveal any criticalabnormalities when assayed for a variety of phenotypes including growth,longevity, pathology and metabolism. In addition more targeted screens,informed by the abnormalities observed in mice where genes in proximityto the investigated elements had been altered, also failed to revealnotable abnormalities. These results, while not inclusive of all thepossible phenotypic impact of the deleted sequences, indicate thatextreme sequence constraint does not necessarily reflect crucialfunctions required for viability.« less

Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans.

PubMed

Driesen, N R; McCarthy, G; Bhagwagar, Z; Bloch, M; Calhoun, V; D'Souza, D C; Gueorguieva, R; He, G; Ramachandran, R; Suckow, R F; Anticevic, A; Morgan, P T; Krystal, J H

2013-11-01

N-methyl-D-aspartate glutamate receptor (NMDA-R) antagonists produce schizophrenia-like positive and negative symptoms in healthy human subjects. Preclinical research suggests that NMDA-R antagonists interfere with the function of gamma-aminobutyric acid (GABA) neurons and alter the brain oscillations. These changes have been hypothesized to contribute to psychosis. In this investigation, we evaluated the hypothesis that the NMDA-R antagonist ketamine produces alterations in cortical functional connectivity during rest that are related to symptoms. We administered ketamine to a primary sample of 22 subjects and to an additional, partially overlapping, sample of 12 subjects. Symptoms before and after the experimental session were rated with the Positive and Negative Syndrome Scale (PANSS). In the primary sample, functional connectivity was measured via functional magnetic resonance imaging almost immediately after infusion began. In the additional sample, this assessment was repeated after 45 min of continuous ketamine infusion. Global, enhanced functional connectivity was observed at both timepoints, and this hyperconnectivity was related to symptoms in a region-specific manner. This study supports the hypothesis that pathological increases in resting brain functional connectivity contribute to the emergence of positive and negative symptoms associated with schizophrenia.

Relationship of Resting Brain Hyperconnectivity and Schizophrenia-like Symptoms Produced by the NMDA receptor Antagonist Ketamine in Humans

PubMed Central

Driesen, Naomi R.; McCarthy, Gregory; Bhagwagar, Zubin; Bloch, Michael; Calhoun, Vincent; D’Souza, Deepak C.; Gueorguieva, Ralitza; He, George; Ramachandran, Ramani; Suckow, Raymond F.; Anticevic, Alan; Morgan, Peter T.; Krystal, John H.

2012-01-01

N-methyl-D-aspartate glutamate receptor (NMDA-R) antagonists produce schizophrenia-like positive and negative symptoms in healthy human subjects. Preclinical research suggests that NMDA-R antagonists interfere with the function of gamma-aminobutyric acid (GABA) neurons and alter brain oscillations. These changes have been hypothesized to contribute to psychosis. In this investigation, we evaluated the hypothesis that the NMDA-R antagonist ketamine produces alterations in cortical functional connectivity during rest that are related to symptoms. We administered ketamine to a primary sample of twenty-two subjects and to an additional, partially overlapping, sample of twelve subjects. Symptoms before and after the experimental session were rated with the Positive and Negative Symptom Scale (PANSS). In the primary sample, functional connectivity was measured via functional magnetic resonance imaging almost immediately after infusion began. In the additional sample, this assessment was repeated after 45 minutes of continuous ketamine infusion. Global, enhanced functional connectivity was observed at both timepoints and this hyperconnectivity was related to symptoms in a region-specific manner. This study supports the hypothesis that pathological increases in resting brain functional connectivity contribute to the emergence of positive and negative symptoms associated with schizophrenia. PMID:23337947

Changes of intranetwork and internetwork functional connectivity in Alzheimer’s disease and mild cognitive impairment

NASA Astrophysics Data System (ADS)

Zhu, Haoze; Zhou, Peng; Alcauter, Sarael; Chen, Yuanyuan; Cao, Hongbao; Tian, Miao; Ming, Dong; Qi, Hongzhi; Wang, Xuemin; Zhao, Xin; He, Feng; Ni, Hongyan; Gao, Wei

2016-08-01

Objective. Alzheimer’s disease (AD) is a serious neurodegenerative disorder characterized by deficits of working memory, attention, language and many other cognitive functions. Although different stages of the disease are relatively well characterized by clinical criteria, stage-specific pathological changes in the brain remain relatively poorly understood, especially at the level of large-scale functional networks. In this study, we aimed to characterize the potential disruptions of large-scale functional brain networks based on a sample including amnestic mild cognition impairment (aMCI) and AD patients to help delineate the underlying stage-dependent AD pathology. Approach. We sought to identify the neural connectivity mechanisms of aMCI and AD through examination of both intranetwork and internetwork interactions among four of the brain’s key networks, namely dorsal attention network (DAN), default mode network (DMN), executive control network (ECN) and salience network (SAL). We analyzed functional connectivity based on resting-state functional magnetic resonance imaging (rs-fMRI) data from 25 Alzheimer’s disease patients, 20 aMCI patients and 35 elderly normal controls (NC). Main results. Intranetwork functional disruptions within the DAN and ECN were detected in both aMCI and AD patients. Disrupted intranetwork connectivity of DMN and anti-correlation between DAN and DMN were observed in AD patients. Moreover, aMCI-specific alterations in the internetwork functional connectivity of SAL were observed. Significance. Our results confirmed previous findings that AD pathology was related to dysconnectivity both within and between resting-state networks but revealed more spatial details. Moreover, the SAL network, reportedly flexibly coupling either with the DAN or DMN networks during different brain states, demonstrated interesting alterations specifically in the early stage of the disease.

Environmentally Induced Transgenerational Epigenetic Reprogramming of Primordial Germ Cells and the Subsequent Germ Line

PubMed Central

Skinner, Michael K.; Haque, Carlos Guerrero-Bosagna M.; Nilsson, Eric; Bhandari, Ramji; McCarrey, John R.

2013-01-01

A number of environmental factors (e.g. toxicants) have been shown to promote the epigenetic transgenerational inheritance of disease and phenotypic variation. Transgenerational inheritance requires the germline transmission of altered epigenetic information between generations in the absence of direct environmental exposures. The primary periods for epigenetic programming of the germ line are those associated with primordial germ cell development and subsequent fetal germline development. The current study examined the actions of an agricultural fungicide vinclozolin on gestating female (F0 generation) progeny in regards to the primordial germ cell (PGC) epigenetic reprogramming of the F3 generation (i.e. great-grandchildren). The F3 generation germline transcriptome and epigenome (DNA methylation) were altered transgenerationally. Interestingly, disruptions in DNA methylation patterns and altered transcriptomes were distinct between germ cells at the onset of gonadal sex determination at embryonic day 13 (E13) and after cord formation in the testis at embryonic day 16 (E16). A larger number of DNA methylation abnormalities (epimutations) and transcriptional alterations were observed in the E13 germ cells than in the E16 germ cells. These observations indicate that altered transgenerational epigenetic reprogramming and function of the male germline is a component of vinclozolin induced epigenetic transgenerational inheritance of disease. Insights into the molecular control of germline transmitted epigenetic inheritance are provided. PMID:23869203

'Tagging' along memories in aging: Synaptic tagging and capture mechanisms in the aged hippocampus.

PubMed

Shivarama Shetty, Mahesh; Sajikumar, Sreedharan

2017-05-01

Aging is accompanied by a general decline in the physiological functions of the body with the deteriorating organ systems. Brain is no exception to this and deficits in cognitive functions are quite common in advanced aging. Though a variety of age-related alterations are observed in the structure and function throughout the brain, certain regions show selective vulnerability. Medial temporal lobe, especially the hippocampus, is one such preferentially vulnerable region and is a crucial structure involved in the learning and long-term memory functions. Hippocampal synaptic plasticity, such as long-term potentiation (LTP) and depression (LTD), are candidate cellular correlates of learning and memory and alterations in these properties have been well documented in aging. A related phenomenon called synaptic tagging and capture (STC) has been proposed as a mechanism for cellular memory consolidation and to account for temporal association of memories. Mounting evidences from behavioral settings suggest that STC could be a physiological phenomenon. In this article, we review the recent data concerning STC and provide a framework for how alterations in STC-related mechanisms could contribute to the age-associated memory impairments. The enormity of impairment in learning and memory functions demands an understanding of age-associated memory deficits at the fundamental level given its impact in the everyday tasks, thereby in the quality of life. Such an understanding is also crucial for designing interventions and preventive measures for successful brain aging. Copyright © 2017 National University of Singapore. Published by Elsevier B.V. All rights reserved.

Altered Expression of ZO-1 and ZO-2 in Sertoli Cells and Loss of Blood-Testis Barrier Integrity in Testicular Carcinoma In Situ1

PubMed Central

Fink, Cornelia; Weigel, Roswitha; Hembes, Tanja; Lauke-Wettwer, Heidrun; Kliesch, Sabine; Bergmann, Martin; Brehm, Ralph H

2006-01-01

Abstract Carcinoma in situ (CIS) is the noninvasive precursor of most human testicular germ cell tumors. In normal seminiferous epithelium, specialized tight junctions between Sertoli cells constitute the major component of the blood-testis barrier. Sertoli cells associated with CIS exhibit impaired maturation status, but their functional significance remains unknown. The aim was to determine whether the blood-testis barrier is morphologically and/or functionally altered. We investigated the expression and distribution pattern of the tight junction proteins zonula occludens (ZO) 1 and 2 in normal seminiferous tubules compared to tubules showing CIS. In normal tubules, ZO-1 and ZO-2 immunostaining was observed at the blood-testis barrier region of adjacent Sertoli cells. Within CIS tubules, ZO-1 and ZO-2 immunoreactivity was reduced at the blood-testis barrier region, but spread to stain the Sertoli cell cytoplasm. Western blot analysis confirmed ZO-1 and ZO-2, and their respective mRNA were shown by RT-PCR. Additionally, we assessed the functional integrity of the blood-testis barrier by lanthanum tracer study. Lanthanum permeated tight junctions in CIS tubules, indicating disruption of the blood-testis barrier. In conclusion, Sertoli cells associated with CIS show an altered distribution of ZO-1 and ZO-2 and lose their blood-testis barrier function. PMID:17217619

New Insights into the Effects of Chronic Kidney Failure and Dialysate Exposure on the Peritoneum.

PubMed

Vlahu, Carmen A; Aten, Jan; de Graaff, Marijke; van Veen, Henk; Everts, Vincent; de Waart, Dirk R; Struijk, Dirk G; Krediet, Raymond T

♦ INTRODUCTION: Chronic uremia and the exposure to dialysis solutions during peritoneal dialysis (PD) induce peritoneal alterations. Using a long-term peritoneal exposure model, we compared the effects of chronic kidney failure (CKD) itself and exposure to either a 'conventional' or a 'biocompatible' dialysis solution on peritoneal morphology and function. ♦ METHODS: Wistar rats (Harlan, Zeist, the Netherlands) were grouped into: normal kidney function (NKF), CKD induced by 70% nephrectomy, CKD receiving daily peritoneal infusions with 3.86% glucose Dianeal (CKDD), or Physioneal (both solutions from Baxter Healthcare, Castlebar, Ireland) (CKDP). At 16 weeks, a peritoneal function test was performed, and histology, ultrastructure, and hydroxyproline content of peritoneal tissue were assessed. ♦ RESULTS: Comparing CKD with NKF, peritoneal transport rates were higher, mesothelial cells (MC) displayed increased number of microvilli, blood and lymph vasculature expanded, vascular basal lamina appeared thicker, with limited areas of duplication, and fibrosis had developed. All alterations, except lymphangiogenesis, were enhanced by exposure to both dialysis fluids. Distinct MC alterations were observed in CKDD and CKDP, the latter displaying prominent basolateral protrusions. In addition, CKDP was associated with a trend towards less fibrosis compared to CKDD. ♦ CONCLUSIONS: Chronic kidney failure itself induced peritoneal alterations, which were in part augmented by exposure to glucose-based dialysis solutions. Overall, the conventional and biocompatible solutions had similar long-term effects on the peritoneum. Importantly, the latter may attenuate the development of fibrosis. Copyright © 2016 International Society for Peritoneal Dialysis.

Anesthesia, brain changes, and behavior: Insights from neural systems biology.

PubMed

Colon, Elisabeth; Bittner, Edward A; Kussman, Barry; McCann, Mary Ellen; Soriano, Sulpicio; Borsook, David

2017-06-01

Long-term consequences of anesthetic exposure in humans are not well understood. It is possible that alterations in brain function occur beyond the initial anesthetic administration. Research in children and adults has reported cognitive and/or behavioral changes after surgery and general anesthesia that may be short lived in some patients, while in others, such changes may persist. The changes observed in humans are corroborated by a large body of evidence from animal studies that support a role for alterations in neuronal survival (neuroapoptosis) or structure (altered dendritic and glial morphology) and later behavioral deficits at older age after exposure to various anesthetic agents during fetal or early life. The potential of anesthetics to induce long-term alterations in brain function, particularly in vulnerable populations, warrants investigation. In this review, we critically evaluate the available preclinical and clinical data on the developing and aging brain, and in known vulnerable populations to provide insights into potential changes that may affect the general population of patients in a more, subtle manner. In addition this review summarizes underlying processes of how general anesthetics produce changes in the brain at the cellular and systems level and the current understanding underlying mechanisms of anesthetics agents on brain systems. Finally, we present how neuroimaging techniques currently emerge as promising approaches to evaluate and define changes in brain function resulting from anesthesia, both in the short and the long-term. Copyright © 2017 Elsevier Ltd. All rights reserved.

Oral administration of liquid iron preparation containing excess iron induces intestine and liver injury, impairs intestinal barrier function and alters the gut microbiota in rats.

PubMed

Fang, Shenglin; Zhuo, Zhao; Yu, Xiaonan; Wang, Haichao; Feng, Jie

2018-05-01

The aim of this study was to determine the toxicological effects of excess iron in a liquid iron preparation (especially on intestinal barrier function) and the possible etiology of side effects or diseases caused by the excess iron. In study 1, forty male Sprague-Dawley rats (4-5 wk old) were subjected to oral gavage with 1 ml vehicle (0.01 mol/L HCl) or 1 ml liquid iron preparation containing 8 mg, 16 mg or 24 mg of iron for 30 d. Iron status, oxidative stress, histology (H&E staining), ultrastructure (electron microscopy) and apoptosis (TUNEL assay) in the intestines and liver were assessed. The cecal microbiota was evaluated by 16S rRNA sequencing. In study 2, twenty rats with the same profile as above were subjected to oral gavage with 1 ml vehicle or 24 mg Fe for 30 d. The intestinal barrier function was determined by in vivo studies and an Ussing chamber assay; tight junction proteins and serum pro-inflammatory cytokines were observed by enzyme-linked immunosorbent assay. In study 1, the intestinal mucosa and liver showed apparent oxidative stress. In addition, iron concentration-dependent ultrastructural alterations to duodenal enterocytes and hepatocytes and histological damage to the colonic mucosa were detected. Notably, apoptosis was increased in duodenal enterocytes and hepatocytes. Impaired intestinal barrier function and lower expression of intestinal tight junction proteins were observed, and the phenotype was more severe in the colon than in the duodenum. A trend toward higher expression of serum pro-inflammatory cytokines might indicate systemic inflammation. Furthermore, the caecal microbiota showed a significant change, with increased Defluviitaleaceae, Ruminococcaceae, and Coprococcus and reduced Lachnospiraceae and Allobaculum, which could mediate the detrimental effects of excess iron on gut health. We concluded that excessive iron exposure from liquid iron preparation induces oxidative stress and histopathological alterations in the intestine and liver. Impaired intestinal barrier function could increase iron transportation, and inflammation along with oxidative stress-enhanced liver iron deposition may cause further liver injury in a vicious circle. These effects were accompanied by lower intestinal segment damage and altered gut microbial composition of rats toward a profile with an increased risk of gut disease. Copyright © 2018 Elsevier GmbH. All rights reserved.

Experimental 'jet lag' inhibits adult neurogenesis and produces long-term cognitive deficits in female hamsters.

PubMed

Gibson, Erin M; Wang, Connie; Tjho, Stephanie; Khattar, Neera; Kriegsfeld, Lance J

2010-12-01

Circadian disruptions through frequent transmeridian travel, rotating shift work, and poor sleep hygiene are associated with an array of physical and mental health maladies, including marked deficits in human cognitive function. Despite anecdotal and correlational reports suggesting a negative impact of circadian disruptions on brain function, this possibility has not been experimentally examined. In the present study, we investigated whether experimental 'jet lag' (i.e., phase advances of the light:dark cycle) negatively impacts learning and memory and whether any deficits observed are associated with reductions in hippocampal cell proliferation and neurogenesis. Because insults to circadian timing alter circulating glucocorticoid and sex steroid concentrations, both of which influence neurogenesis and learning/memory, we assessed the contribution of these endocrine factors to any observed alterations. Circadian disruption resulted in pronounced deficits in learning and memory paralleled by marked reductions in hippocampal cell proliferation and neurogenesis. Significantly, deficits in hippocampal-dependent learning and memory were not only seen during the period of the circadian disruption, but also persisted well after the cessation of jet lag, suggesting long-lasting negative consequences on brain function. Together, these findings support the view that circadian disruptions suppress hippocampal neurogenesis via a glucocorticoid-independent mechanism, imposing pronounced and persistent impairments on learning and memory.

Psychological stress has a higher rate of developing addictive behaviors compared to physical stress in rat offspring

PubMed Central

Nazeri, Masoud; Ebrahimi, Arezoo; Aghaei, Iraj; Ghotbi Ravandi, Samaneh; Shabani, Mohammad

2017-01-01

Prenatal stress could have great influence on development of offspring and might alter cognitive function and other physiological processes of children. The current study was conducted to study the effect of physical or psychological prenatal stress on addictive and anxiety-like behavior of male and female offspring during their adolescence period (postnatal day (PND) 40). Adult female rats were exposed to physical (swimming) or psychological (observing another female rat swimming) stress from day six of gestation for 10 days. Male and female offspring were assayed for anxiety-like behavior, motor and balance function and morphine conditioned place preference using the open field, elevated plus maze (EPM), rotarod and wire grip assay and conditioned place preference. Offspring in both physical and psychological prenatal stress groups demonstrated significant increase in anxiety-like behavior in EPM paradigm, but no alterations were observed in motor and balance function of animals. Offspring in the psychological prenatal stress group had an increased preference for morphine in comparison to control and physical prenatal stress groups. Results of the current study demonstrated that animals exposed to psychological stress during fetal development are at a higher risk of developing addictive behaviors. Further research might elucidate the exact mechanisms involved to provide better preventive and therapeutic interventions. PMID:28900372

Study on the short-term effects of increased alcohol and cigarette consumption in healthy young men’s seminal quality

PubMed Central

Silva, Joana Vieira; Cruz, Daniel; Gomes, Mariana; Correia, Bárbara Regadas; Freitas, Maria João; Sousa, Luís; Silva, Vladimiro; Fardilha, Margarida

2017-01-01

Many studies have reported a negative impact of lifestyle factors on testicular function, spermatozoa parameters and pituitary-gonadal axis. However, conclusions are difficult to draw, since studies in the general population are rare. In this study we intended to address the early and late short-term impact of acute lifestyle alterations on young men’s reproductive function. Thirty-six healthy male students, who attended the Portuguese academic festivities, provided semen samples and answered questionnaires at three time-points. The consumption of alcohol and cigarette increased more than 8 and 2 times, respectively, during the academic festivities and resulted in deleterious effects on semen quality: one week after the festivities, a decrease on semen volume, spermatozoa motility and normal morphology was observed, in parallel with an increase on immotile spermatozoa, head and midpiece defects and spermatozoa oxidative stress. Additionally, three months after the academic festivities, besides the detrimental effect on volume, motility and morphology, a negative impact on spermatozoa concentration was observed, along with a decrease on epididymal, seminal vesicles and prostate function. This study contributed to understanding the pathophysiology underlying semen quality degradation induced by acute lifestyle alterations, suggesting that high alcohol and cigarette consumption are associated with decreased semen quality in healthy young men. PMID:28367956

Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Muscle Cells

PubMed Central

Fontes-Oliveira, Cibely C.; Steinz, Maarten; Schneiderat, Peter; Mulder, Hindrik; Durbeej, Madeleine

2017-01-01

Skeletal muscle has high energy requirement and alterations in metabolism are associated with pathological conditions causing muscle wasting and impaired regeneration. Congenital muscular dystrophy type 1A (MDC1A) is a severe muscle disorder caused by mutations in the LAMA2 gene. Leigh syndrome (LS) is a neurometabolic disease caused by mutations in genes related to mitochondrial function. Skeletal muscle is severely affected in both diseases and a common feature is muscle weakness that leads to hypotonia and respiratory problems. Here, we have investigated the bioenergetic profile in myogenic cells from MDC1A and LS patients. We found dysregulated expression of genes related to energy production, apoptosis and proteasome in myoblasts and myotubes. Moreover, impaired mitochondrial function and a compensatory upregulation of glycolysis were observed when monitored in real-time. Also, alterations in cell cycle populations in myoblasts and enhanced caspase-3 activity in myotubes were observed. Thus, we have for the first time demonstrated an impairment of the bioenergetic status in human MDC1A and LS muscle cells, which could contribute to cell cycle disturbance and increased apoptosis. Our findings suggest that skeletal muscle metabolism might be a promising pharmacological target in order to improve muscle function, energy efficiency and tissue maintenance of MDC1A and LS patients. PMID:28367954

Similarities and differences between helminth parasites and cancer cell lines in shaping human monocytes: Insights into parallel mechanisms of immune evasion.

PubMed

Narasimhan, Prakash Babu; Akabas, Leor; Tariq, Sameha; Huda, Naureen; Bennuru, Sasisekhar; Sabzevari, Helen; Hofmeister, Robert; Nutman, Thomas B; Tolouei Semnani, Roshanak

2018-04-01

A number of features at the host-parasite interface are reminiscent of those that are also observed at the host-tumor interface. Both cancer cells and parasites establish a tissue microenvironment that allows for immune evasion and may reflect functional alterations of various innate cells. Here, we investigated how the phenotype and function of human monocytes is altered by exposure to cancer cell lines and if these functional and phenotypic alterations parallel those induced by exposure to helminth parasites. Thus, human monocytes were exposed to three different cancer cell lines (breast, ovarian, or glioblastoma) or to live microfilariae (mf) of Brugia malayi-a causative agent of lymphatic filariasis. After 2 days of co-culture, monocytes exposed to cancer cell lines showed markedly upregulated expression of M1-associated (TNF-α, IL-1β), M2-associated (CCL13, CD206), Mreg-associated (IL-10, TGF-β), and angiogenesis associated (MMP9, VEGF) genes. Similar to cancer cell lines, but less dramatically, mf altered the mRNA expression of IL-1β, CCL13, TGM2 and MMP9. When surface expression of the inhibitory ligands PDL1 and PDL2 was assessed, monocytes exposed to both cancer cell lines and to live mf significantly upregulated PDL1 and PDL2 expression. In contrast to exposure to mf, exposure to cancer cell lines increased the phagocytic ability of monocytes and reduced their ability to induce T cell proliferation and to expand Granzyme A+ CD8+ T cells. Our data suggest that despite the fact that helminth parasites and cancer cell lines are extraordinarily disparate, they share the ability to alter the phenotype of human monocytes.

Insight and psychosis: Functional and anatomical brain connectivity and self-reflection in Schizophrenia.

PubMed

Ćurčić-Blake, Branislava; van der Meer, Lisette; Pijnenborg, Gerdina H M; David, Anthony S; Aleman, André

2015-12-01

Impaired insight into illness, associated with worse treatment outcome, is common in schizophrenia. Insight has been related to the self-reflective processing, centred on the medial frontal cortex. We hypothesized that anatomical and functional routes to and from the ventromedial prefrontal cortex (vmPFC) would differ in patients according to their degree of impaired insight. Forty-five schizophrenia patients and 19 healthy subjects performed a self-reflection task during fMRI, and underwent diffusion tensor imaging. Using dynamic causal modelling we observed increased effective connectivity from the posterior cingulate cortex (PCC), inferior parietal lobule (IPL), and dorsal mPFC (dmPFC) towards the vmPFC with poorer insight and decrease from vmPFC to the IPL. Stronger connectivity from the PCC to vmPFC during judgment of traits related to self was associated with poorer insight. We found small-scale significant changes in white matter integrity associated with clinical insight. Self-reflection may be influenced by synaptic changes that lead to the observed alterations in functional connectivity accompanied by the small-scale but measurable alterations in anatomical connections. Our findings may point to a neural compensatory response to an impairment of connectivity between self-processing regions. Similarly, the observed hyper-connectivity might be a primary deficit linked to inefficiency in the component cognitive processes that lead to impaired insight. We suggest that the stronger cognitive demands placed on patients with poor insight is reflected in increased effective connectivity during the task in this study. © 2015 Wiley Periodicals, Inc.

Mitochondrial Optic Atrophy (OPA) 1 Processing Is Altered in Response to Neonatal Hypoxic-Ischemic Brain Injury

PubMed Central

Baburamani, Ana A.; Hurling, Chloe; Stolp, Helen; Sobotka, Kristina; Gressens, Pierre; Hagberg, Henrik; Thornton, Claire

2015-01-01

Perturbation of mitochondrial function and subsequent induction of cell death pathways are key hallmarks in neonatal hypoxic-ischemic (HI) injury, both in animal models and in term infants. Mitoprotective therapies therefore offer a new avenue for intervention for the babies who suffer life-long disabilities as a result of birth asphyxia. Here we show that after oxygen-glucose deprivation in primary neurons or in a mouse model of HI, mitochondrial protein homeostasis is altered, manifesting as a change in mitochondrial morphology and functional impairment. Furthermore we find that the mitochondrial fusion and cristae regulatory protein, OPA1, is aberrantly cleaved to shorter forms. OPA1 cleavage is normally regulated by a balanced action of the proteases Yme1L and Oma1. However, in primary neurons or after HI in vivo, protein expression of YmelL is also reduced, whereas no change is observed in Oma1 expression. Our data strongly suggest that alterations in mitochondria-shaping proteins are an early event in the pathogenesis of neonatal HI injury. PMID:26393574

Alterations of cortical GABA neurons and network oscillations in schizophrenia.

PubMed

Gonzalez-Burgos, Guillermo; Hashimoto, Takanori; Lewis, David A

2010-08-01

The hypothesis that alterations of cortical inhibitory gamma-aminobutyric acid (GABA) neurons are a central element in the pathology of schizophrenia has emerged from a series of postmortem studies. How such abnormalities may contribute to the clinical features of schizophrenia has been substantially informed by a convergence with basic neuroscience studies revealing complex details of GABA neuron function in the healthy brain. Importantly, activity of the parvalbumin-containing class of GABA neurons has been linked to the production of cortical network oscillations. Furthermore, growing knowledge supports the concept that gamma band oscillations (30-80 Hz) are an essential mechanism for cortical information transmission and processing. Herein we review recent studies further indicating that inhibition from parvalbumin-positive GABA neurons is necessary to produce gamma oscillations in cortical circuits; provide an update on postmortem studies documenting that deficits in the expression of glutamic acid decarboxylase67, which accounts for most GABA synthesis in the cortex, are widely observed in schizophrenia; and describe studies using novel, noninvasive approaches directly assessing potential relations between alterations in GABA, oscillations, and cognitive function in schizophrenia.

Chronic Alcohol Ingestion in Rats Alters Lung Metabolism, Promotes Lipid Accumulation, and Impairs Alveolar Macrophage Functions

PubMed Central

Romero, Freddy; Shah, Dilip; Duong, Michelle; Stafstrom, William; Hoek, Jan B.; Kallen, Caleb B.; Lang, Charles H.

2014-01-01

Chronic alcoholism impairs pulmonary immune homeostasis and predisposes to inflammatory lung diseases, including infectious pneumonia and acute respiratory distress syndrome. Although alcoholism has been shown to alter hepatic metabolism, leading to lipid accumulation, hepatitis, and, eventually, cirrhosis, the effects of alcohol on pulmonary metabolism remain largely unknown. Because both the lung and the liver actively engage in lipid synthesis, we hypothesized that chronic alcoholism would impair pulmonary metabolic homeostasis in ways similar to its effects in the liver. We reasoned that perturbations in lipid metabolism might contribute to the impaired pulmonary immunity observed in people who chronically consume alcohol. We studied the metabolic consequences of chronic alcohol consumption in rat lungs in vivo and in alveolar epithelial type II cells and alveolar macrophages (AMs) in vitro. We found that chronic alcohol ingestion significantly alters lung metabolic homeostasis, inhibiting AMP-activated protein kinase, increasing lipid synthesis, and suppressing the expression of genes essential to metabolizing fatty acids (FAs). Furthermore, we show that these metabolic alterations promoted a lung phenotype that is reminiscent of alcoholic fatty liver and is characterized by marked accumulation of triglycerides and free FAs within distal airspaces, AMs, and, to a lesser extent, alveolar epithelial type II cells. We provide evidence that the metabolic alterations in alcohol-exposed rats are mechanistically linked to immune impairments in the alcoholic lung: the elevations in FAs alter AM phenotypes and suppress both phagocytic functions and agonist-induced inflammatory responses. In summary, our work demonstrates that chronic alcohol ingestion impairs lung metabolic homeostasis and promotes pulmonary immune dysfunction. These findings suggest that therapies aimed at reversing alcohol-related metabolic alterations might be effective for preventing and/or treating alcohol-related pulmonary disorders. PMID:24940828

Rapamycin mitigates erythrocyte membrane transport functions and oxidative stress during aging in rats.

PubMed

Singh, Abhishek Kumar; Singh, Sandeep; Garg, Geetika; Rizvi, Syed Ibrahim

2018-02-01

Erythrocyte membrane is a suitable model to study various metabolic and physiological functions as it undergoes variety of biochemical changes during aging. An age-dependent modulatory effect of rapamycin on erythrocyte membrane functions is completely unknown. Therefore, the present study was undertaken to investigate the effect of rapamycin on age-dependent impaired activities of transporters/exchangers, altered levels of redox biomarkers, viz. protein carbonyl (PC), lipid hydroperoxides (LHs), total thiol (-SH), sialic acid (SA) and intracellular calcium ion [Ca 2+ ]i, and osmotic fragility of erythrocyte membrane. A significant reduction in membrane-bound activities of Na + /K + -ATPase (NKA) and Ca 2+ -ATPase (PMCA), and levels of -SH and SA was observed along with a simultaneous induction in Na + /H + exchanger (NHE) activity and levels of [Ca 2+ ]i, PC, LH and osmotic fragility in old-aged rats. Rapamycin was found to be a promising age-delaying drug that significantly reversed the aging-induced impaired activities of membrane-bound ATPases and altered levels of redox biomarkers.

[Executive dysfunctions in adults with attention deficit hyperactivity disorder].

PubMed

Rodriguez-Jiménez, R; Cubillo, A; Jiménez-Arriero, M A; Ponce, G; Aragüés-Figuero, M; Palomo, T

Several different follow-up studies have shown that attention deficit hyperactivity disorder (ADHD) can persist into adulthood. To review the findings in adults with ADHD related to alterations in the executive functions. Research conducted among children with ADHD has revealed the existence of alterations in different tasks that evaluate the executive functions, such as the planning test, sustained attention tasks, cognitive flexibility, verbal fluency and working memory tasks, as well as several inhibition response tasks. In adults with ADHD, despite the lower number of reports in the literature and the methodological shortcomings that exist in some studies, analogous results have also been described with respect to executive functioning, namely, disorders affecting inhibition response, the capacity for planning, difficulties in cognitive flexibility and verbal fluency, and problems with working memory, which include aspects of spatial working memory, logical or visual memory. The findings we have available at present enable us to confirm the persistence of executive dysfunctions in adult patients with ADHD that are similar to those observed in children with ADHD.

Socioeconomic disparities affect prefrontal function in children.

PubMed

Kishiyama, Mark M; Boyce, W Thomas; Jimenez, Amy M; Perry, Lee M; Knight, Robert T

2009-06-01

Social inequalities have profound effects on the physical and mental health of children. Children from low socioeconomic status (SES) backgrounds perform below children from higher SES backgrounds on tests of intelligence and academic achievement, and recent findings indicate that low SES (LSES) children are impaired on behavioral measures of prefrontal function. However, the influence of socioeconomic disparity on direct measures of neural activity is unknown. Here, we provide electrophysiological evidence indicating that prefrontal function is altered in LSES children. We found that prefrontal-dependent electrophysiological measures of attention were reduced in LSES compared to high SES (HSES) children in a pattern similar to that observed in patients with lateral prefrontal cortex (PFC) damage. These findings provide neurophysiological evidence that social inequalities are associated with alterations in PFC function in LSES children. There are a number of factors associated with LSES rearing conditions that may have contributed to these results such as greater levels of stress and lack of access to cognitively stimulating materials and experiences. Targeting specific prefrontal processes affected by socioeconomic disparity could be helpful in developing intervention programs for LSES children.

Brain correlates of hypnotic paralysis-a resting-state fMRI study.

PubMed

Pyka, M; Burgmer, M; Lenzen, T; Pioch, R; Dannlowski, U; Pfleiderer, B; Ewert, A W; Heuft, G; Arolt, V; Konrad, C

2011-06-15

Hypnotic paralysis has been used since the times of Charcot to study altered states of consciousness; however, the underlying neurobiological correlates are poorly understood. We investigated human brain function during hypnotic paralysis using resting-state functional magnetic resonance imaging (fMRI), focussing on two core regions of the default mode network and the representation of the paralysed hand in the primary motor cortex. Hypnotic suggestion induced an observable left-hand paralysis in 19 participants. Resting-state fMRI at 3T was performed in pseudo-randomised order awake and in the hypnotic condition. Functional connectivity analyses revealed increased connectivity of the precuneus with the right dorsolateral prefrontal cortex, angular gyrus, and a dorsal part of the precuneus. Functional connectivity of the medial frontal cortex and the primary motor cortex remained unchanged. Our results reveal that the precuneus plays a pivotal role during maintenance of an altered state of consciousness. The increased coupling of selective cortical areas with the precuneus supports the concept that hypnotic paralysis may be mediated by a modified representation of the self which impacts motor abilities. Copyright © 2011 Elsevier Inc. All rights reserved.

Proteome-wide quantitative multiplexed profiling of protein expression: carbon-source dependency in Saccharomyces cerevisiae

PubMed Central

Paulo, Joao A.; O’Connell, Jeremy D.; Gaun, Aleksandr; Gygi, Steven P.

2015-01-01

The global proteomic alterations in the budding yeast Saccharomyces cerevisiae due to differences in carbon sources can be comprehensively examined using mass spectrometry–based multiplexing strategies. In this study, we investigate changes in the S. cerevisiae proteome resulting from cultures grown in minimal media using galactose, glucose, or raffinose as the carbon source. We used a tandem mass tag 9-plex strategy to determine alterations in relative protein abundance due to a particular carbon source, in triplicate, thereby permitting subsequent statistical analyses. We quantified more than 4700 proteins across all nine samples; 1003 proteins demonstrated statistically significant differences in abundance in at least one condition. The majority of altered proteins were classified as functioning in metabolic processes and as having cellular origins of plasma membrane and mitochondria. In contrast, proteins remaining relatively unchanged in abundance included those having nucleic acid–related processes, such as transcription and RNA processing. In addition, the comprehensiveness of the data set enabled the analysis of subsets of functionally related proteins, such as phosphatases, kinases, and transcription factors. As a resource, these data can be mined further in efforts to understand better the roles of carbon source fermentation in yeast metabolic pathways and the alterations observed therein, potentially for industrial applications, such as biofuel feedstock production. PMID:26399295

Neural and behavioural changes in male periadolescent mice after prolonged nicotine-MDMA treatment.

PubMed

Adeniyi, Philip A; Ishola, Azeez O; Laoye, Babafemi J; Olatunji, Babawale P; Bankole, Oluwamolakun O; Shallie, Philemon D; Ogundele, Olalekan M

2016-02-01

The interaction between MDMA and Nicotine affects multiple brain centres and neurotransmitter systems (serotonin, dopamine and glutamate) involved in motor coordination and cognition. In this study, we have elucidated the effect of prolonged (10 days) MDMA, Nicotine and a combined Nicotine-MDMA treatment on motor-cognitive neural functions. In addition, we have shown the correlation between the observed behavioural change and neural structural changes induced by these treatments in BALB/c mice. We observed that MDMA (2 mg/Kg body weight; subcutaneous) induced a decline in motor function, while Nicotine (2 mg/Kg body weight; subcutaneous) improved motor function in male periadolescent mice. In combined treatment, Nicotine reduced the motor function decline observed in MDMA treatment, thus no significant change in motor function for the combined treatment versus the control. Nicotine or MDMA treatment reduced memory function and altered hippocampal structure. Similarly, a combined Nicotine-MDMA treatment reduced memory function when compared with the control. Ultimately, the metabolic and structural changes in these neural systems were seen to vary for the various forms of treatment. It is noteworthy to mention that a combined treatment increased the rate of lipid peroxidation in brain tissue.

Probiotics Improve Inflammation-Associated Sickness Behavior by Altering Communication between the Peripheral Immune System and the Brain.

PubMed

D'Mello, Charlotte; Ronaghan, Natalie; Zaheer, Raza; Dicay, Michael; Le, Tai; MacNaughton, Wallace K; Surrette, Michael G; Swain, Mark G

2015-07-29

Patients with systemic inflammatory diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, chronic liver disease) commonly develop debilitating symptoms (i.e., sickness behaviors) that arise from changes in brain function. The microbiota-gut-brain axis alters brain function and probiotic ingestion can influence behavior. However, how probiotics do this remains unclear. We have previously described a novel periphery-to-brain communication pathway in the setting of peripheral organ inflammation whereby monocytes are recruited to the brain in response to systemic TNF-α signaling, leading to microglial activation and subsequently driving sickness behavior development. Therefore, we investigated whether probiotic ingestion (i.e., probiotic mixture VSL#3) alters this periphery-to-brain communication pathway, thereby reducing subsequent sickness behavior development. Using a well characterized mouse model of liver inflammation, we now show that probiotic (VSL#3) treatment attenuates sickness behavior development in mice with liver inflammation without affecting disease severity, gut microbiota composition, or gut permeability. Attenuation of sickness behavior development was associated with reductions in microglial activation and cerebral monocyte infiltration. These events were paralleled by changes in markers of systemic immune activation, including decreased circulating TNF-α levels. Our observations highlight a novel pathway through which probiotics mediate cerebral changes and alter behavior. These findings allow for the potential development of novel therapeutic interventions targeted at the gut microbiome to treat inflammation-associated sickness behaviors in patients with systemic inflammatory diseases. This research shows that probiotics, when eaten, can improve the abnormal behaviors (including social withdrawal and immobility) that are commonly associated with inflammation. Probiotics are able to cause this effect within the body by changing how the immune system signals the brain to alter brain function. These findings broaden our understanding of how probiotics may beneficially affect brain function in the context of inflammation occurring within the body and may open potential new therapeutic alternatives for the treatment of these alterations in behavior that can greatly affect patient quality of life. Copyright © 2015 the authors 0270-6474/15/3510822-10$15.00/0.

Exposure to radio-frequency electromagnetic waves alters acetylcholinesterase gene expression, exploratory and motor coordination-linked behaviour in male rats.

PubMed

Obajuluwa, Adejoke Olukayode; Akinyemi, Ayodele Jacob; Afolabi, Olakunle Bamikole; Adekoya, Khalid; Sanya, Joseph Olurotimi; Ishola, Azeez Olakunle

2017-01-01

Humans in modern society are exposed to an ever-increasing number of electromagnetic fields (EMFs) and some studies have demonstrated that these waves can alter brain function but the mechanism still remains unclear. Hence, this study sought to investigate the effect of 2.5 Ghz band radio-frequency electromagnetic waves (RF-EMF) exposure on cerebral cortex acetylcholinesterase (AChE) activity and their mRNA expression level as well as locomotor function and anxiety-linked behaviour in male rats. Animals were divided into four groups namely; group 1 was control (without exposure), group 2-4 were exposed to 2.5 Ghz radiofrequency waves from an installed WI-FI device for a period of 4, 6 and 8 weeks respectively. The results revealed that WiFi exposure caused a significant increase in anxiety level and affect locomotor function. Furthermore, there was a significant decrease in AChE activity with a concomitant increase in AChE mRNA expression level in WiFi exposed rats when compared with control. In conclusions, these data showed that long term exposure to WiFi may lead to adverse effects such as neurodegenerative diseases as observed by a significant alteration on AChE gene expression and some neurobehavioral parameters associated with brain damage.

Altered emotion regulation capacity in social phobia as a function of comorbidity

PubMed Central

Craske, Michelle G.; Taylor, Shelley E.; Lieberman, Matthew D.

2015-01-01

Social phobia (SP) has been associated with amygdala hyperreactivity to fear-relevant stimuli. However, little is known about the neural basis of SP individuals’ capacity to downregulate their responses to such stimuli and how such regulation varies as a function of comorbid depression and anxiety. We completed an functional magnetic resonance imaging (fMRI) study wherein SP participants without comorbidity (n = 30), with comorbid depression (n = 18) and with comorbid anxiety (n = 19) and healthy controls (n = 15) were scanned while completing an affect labeling emotion regulation task. Individuals with SP as a whole exhibited a reversal of the pattern observed in healthy controls in that they showed upregulation of amygdala activity during affect labeling. However, subsequent analyses revealed a more complex picture based on comorbidity type. Although none of the SP subgroups showed the normative pattern of amygdala downregulation, it was those with comorbid depression specifically who showed significant upregulation. Effects could not be attributed to differences in task performance, amygdala reactivity or right ventral lateral prefrontal cortex (RVLPFC) engagement, but may stem from dysfunctional communication between amygdala and RVLPFC. Furthermore, the particularly altered emotion regulation seen in those with comorbid depression could not be fully explained by symptom severity or state anxiety. Results reveal altered emotion regulation in SP, especially when comorbid with depression. PMID:24813437

Altered Methylation Profile of Lymphocytes Is Concordant with Perturbation of Lipids Metabolism and Inflammatory Response in Obesity

PubMed Central

Jacobsen, Mette J.; Mentzel, Caroline M. Junker; Olesen, Ann Sofie; Huby, Thierry; Jørgensen, Claus B.; Barrès, Romain; Fredholm, Merete

2016-01-01

Obesity is associated with immunological perturbations that contribute to insulin resistance. Epigenetic mechanisms can control immune functions and have been linked to metabolic complications, although their contribution to insulin resistance still remains unclear. In this study, we investigated the link between metabolic dysfunction and immune alterations with the epigenetic signature in leukocytes in a porcine model of obesity. Global DNA methylation of circulating leukocytes, adipose tissue leukocyte trafficking, and macrophage polarisation were established by flow cytometry. Adipose tissue inflammation and metabolic function were further characterised by quantification of metabolites and expression levels of genes associated with obesity and inflammation. Here we show that obese pigs showed bigger visceral fat pads, higher levels of circulating LDL cholesterol, and impaired glucose tolerance. These changes coincided with impaired metabolism, sustained macrophages infiltration, and increased inflammation in the adipose tissue. Those immune alterations were linked to global DNA hypermethylation in both B-cells and T-cells. Our results provide novel insight into the possible contribution of immune cell epigenetics into the immunological disturbances observed in obesity. The dramatic changes in the transcriptomic and epigenetic signature of circulating lymphocytes reinforce the concept that epigenetic processes participate in the increased immune cell activation and impaired metabolic functions in obesity. PMID:26798656

Epithelial Permeability Alterations in an In Vitro Air-Liquid Interface Model of Allergic Fungal Rhinosinusitis

PubMed Central

Den Beste, Kyle A.; Hoddeson, Elizabeth K.; Parkos, Charles A.; Nusrat, Asma; Wise, Sarah K.

2012-01-01

Background Chronic rhinosinusitis (CRS) is an inflammatory upper-airway disease with numerous etiologies. Patients with a characteristic subtype of CRS, allergic fungal rhinosinusitis (AFRS), display increased expression of Th2 cytokines and antigen-specific IgE. Various sinonasal inflammatory conditions are associated with alterations in epithelial barrier function. The aim of this study was to compare epithelial permeability and intercellular junctional protein expression amongst cultured primary sinonasal cells from AFRS patients versus non-inflammatory controls. Methods Epithelial cells isolated from paranasal sinus mucosa of AFRS and non-inflammatory control patients were grown to confluence on permeable supports and transitioned to air-liquid interface (ALI). Trans-epithelial resistance (TER) was measured with a horizontal Ussing chamber to characterize the functional permeability of each cell type. After TER recordings were complete, a panel of intercellular junctional proteins was assessed by Western blot and immunofluorescence labeling followed by confocal microscopy. Results After 12 samples were measured from each group, we observed a 41% mean decrease in TER in AFRS cells (296±89 ohms × cm2) compared to control (503±134 ohms × cm2, P=0.006). TER deficits observed in AFRS were associated with decreased expression of the tight junction proteins occludin and Junctional Adhesion Molecule-A (JAM-A), and increased expression of a leaky tight junction protein claudin-2. Conclusions Cultured sinonasal epithelium from AFRS patients displayed increased epithelial permeability and altered expression of intercellular junctional proteins. Given that these cells were not incubated with inflammatory cytokines in vitro, the cultured AFRS epithelial alterations may represent a retained modification in protein expression from the in vivo phenotype. PMID:22927233

Electrophysiologic alterations in the excitability of the sciatic and vagus nerves during early stages of sepsis

PubMed Central

Diniz, Lúcio Ricardo Leite; Portella, Viviane Gomes; da Silva Alves, Kerly Shamira; Araújo, Pâmella Cristina da Costa; de Albuquerque Júnior, Ricardo Luiz Cavalcanti; Cavalcante de Albuquerque, Aline Alice; Coelho-de-Souza, Andrelina Noronha; Leal-Cardoso, José Henrique

2018-01-01

Background Nonspecific and delayed diagnosis of neurologic damage contributes to the development of neuropathies in patients with severe sepsis. The present study assessed the electrophysiologic parameters related to the excitability and conductibility of sciatic and vagus nerves during early stages of sepsis. Materials and methods Twenty-four hours after sepsis induced by cecal ligation and puncture (CLP) model, sciatic and vagus nerves of septic (CLP group) and control (sham group) rats were removed, and selected electric stimulations were applied to measure the parameters of the first and second components of the compound action potential. The first component originated from fibers with motor and sensory functions (Types Aα and Aβ fibers) with a large conduction velocity (70–120 m/s), and the second component originated from fibers (Type Aγ) with sensorial function. To evaluate the presence of sensorial alterations, the sensitivity to non-noxious mechanical stimuli was measured by using the von Frey test. Hematoxylin and eosin staining of the nerves was performed. Results We observed an increase of rheobase followed by a decrease in the first component amplitude and a higher paw withdrawal threshold in response to the application of von Frey filaments in sciatic nerves from the CLP group compared to the sham group. Differently, a decrease in rheobase and an increase in the first component amplitude of vagal C fibers from CLP group were registered. No significant morphologic alteration was observed. Conclusion Our data showed that the electrophysiologic alterations in peripheral nerves vary with the fiber type and might be identified in the first 24 h of sepsis, before clinical signs of neuromuscular disorders. PMID:29731661

41 CFR 102-76.80 - What is required if the costs of alterations to provide an accessible path of travel to an...

Code of Federal Regulations, 2010 CFR

2010-07-01

... to provide an accessible path of travel to an altered area containing a primary function are... accessible path of travel to an altered area containing a primary function are disproportionate to the costs... exceeding 20 percent of the costs of the alterations to the primary function area. Priority should be given...

41 CFR 102-76.80 - What is required if the costs of alterations to provide an accessible path of travel to an...

Code of Federal Regulations, 2012 CFR

2012-01-01

... to provide an accessible path of travel to an altered area containing a primary function are... accessible path of travel to an altered area containing a primary function are disproportionate to the costs... exceeding 20 percent of the costs of the alterations to the primary function area. Priority should be given...

41 CFR 102-76.80 - What is required if the costs of alterations to provide an accessible path of travel to an...

Code of Federal Regulations, 2013 CFR

2013-07-01

... to provide an accessible path of travel to an altered area containing a primary function are... accessible path of travel to an altered area containing a primary function are disproportionate to the costs... exceeding 20 percent of the costs of the alterations to the primary function area. Priority should be given...

41 CFR 102-76.80 - What is required if the costs of alterations to provide an accessible path of travel to an...

Code of Federal Regulations, 2011 CFR

2011-01-01

... to provide an accessible path of travel to an altered area containing a primary function are... accessible path of travel to an altered area containing a primary function are disproportionate to the costs... exceeding 20 percent of the costs of the alterations to the primary function area. Priority should be given...

41 CFR 102-76.80 - What is required if the costs of alterations to provide an accessible path of travel to an...

Code of Federal Regulations, 2014 CFR

2014-01-01

... to provide an accessible path of travel to an altered area containing a primary function are... accessible path of travel to an altered area containing a primary function are disproportionate to the costs... exceeding 20 percent of the costs of the alterations to the primary function area. Priority should be given...

Altered Spontaneous Brain Activity in Betel Quid Dependence: A Resting-state Functional Magnetic Resonance Imaging Study.

PubMed

Liu, Tao; Li, Jian-Jun; Zhao, Zhong-Yan; Yang, Guo-Shuai; Pan, Meng-Jie; Li, Chang-Qing; Pan, Su-Yue; Chen, Feng

2016-02-01

It has been suggested by the first voxel-based morphometry investigation that betel quid dependence (BQD) individuals are presented with brain structural changes in previous reports, and there may be a neurobiological basis for BQD individuals related to an increased risk of executive dysfunction and disinhibition, subjected to the reward system, cognitive system, and emotion system. However, the effects of BQD on neural activity remain largely unknown. Individuals with impaired cognitive control of behavior often reveal altered spontaneous cerebral activity in resting-state functional magnetic resonance imaging and those changes are usually earlier than structural alteration.Here, we examined BQD individuals (n = 33) and age-, sex-, and education-matched healthy control participants (n = 32) in an resting-state functional magnetic resonance imaging study to observe brain function alterations associated with the severity of BQD. Amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) values were both evaluated to stand for spontaneous cerebral activity. Gray matter volumes of these participants were also calculated for covariate.In comparison with healthy controls, BQD individuals demonstrated dramatically decreased ALFF and ReHo values in the prefrontal gurus along with left fusiform, and increased ALFF and ReHo values in the primary motor cortex area, temporal lobe as well as some regions of occipital lobe. The betel quid dependence scores (BQDS) were negatively related to decreased activity in the right anterior cingulate.The abnormal spontaneous cerebral activity revealed by ALFF and ReHo calculation excluding the structural differences in patients with BQD may help us probe into the neurological pathophysiology underlying BQD-related executive dysfunction and disinhibition. Diminished spontaneous brain activity in the right anterior cingulate cortex may, therefore, represent a biomarker of BQD individuals.

Skeletal muscle tissue transcriptome differences in lean and obese female beagle dogs.

PubMed

Grant, R W; Vester Boler, B M; Ridge, T K; Graves, T K; Swanson, K S

2013-08-01

Skeletal muscle is a large and insulin-sensitive tissue that is an important contributor to metabolic homeostasis and energy expenditure. Many metabolic processes are altered with obesity, but the contribution of muscle tissue in this regard is unclear. A limited number of studies have compared skeletal muscle gene expression of lean and obese dogs. Using microarray technology, our objective was to identify genes and functional classes differentially expressed in skeletal muscle of obese (14.6 kg; 8.2 body condition score; 44.5% body fat) vs. lean (8.6 kg; 4.1 body condition score; 22.9% body fat) female beagle adult dogs. Alterations in 77 transcripts was observed in genes pertaining to the functional classes of signaling, transport, protein catabolism and proteolysis, protein modification, development, transcription and apoptosis, cell cycle and differentiation. Genes differentially expressed in obese vs. lean dog skeletal muscle indicate oxidative stress and altered skeletal muscle cell differentiation. Many genes traditionally associated with lipid, protein and carbohydrate metabolism were not altered in obese vs. lean dogs, but genes pertaining to endocannabinoid metabolism, insulin signaling, type II diabetes mellitus and carnitine transport were differentially expressed. The relatively small response of skeletal muscle could indicate that changes are occurring at a post-transcriptional level, that other tissues (e.g., adipose tissue) were buffering skeletal muscle from metabolic dysfunction or that obesity-induced changes in skeletal muscle require a longer period of time and that the length of our study was not sufficient to detect them. Although only a limited number of differentially expressed genes were detected, these results highlight genes and functional classes that may be important in determining the etiology of obesity-induced derangement of skeletal muscle function. © 2013 The Authors, Animal Genetics © 2013 Stichting International Foundation for Animal Genetics.

Different alterations in brain functional networks according to direct and indirect topological connections in patients with schizophrenia.

PubMed

Park, Chang-Hyun; Lee, Seungyup; Kim, Taewon; Won, Wang Yeon; Lee, Kyoung-Uk

2017-10-01

Schizophrenia displays connectivity deficits in the brain, but the literature has shown inconsistent findings about alterations in global efficiency of brain functional networks. We supposed that such inconsistency at the whole brain level may be due to a mixture of different portions of global efficiency at sub-brain levels. Accordingly, we considered measuring portions of global efficiency in two aspects: spatial portions by considering sub-brain networks and topological portions by considering contributions to global efficiency according to direct and indirect topological connections. We proposed adjacency and indirect adjacency as new network parameters attributable to direct and indirect topological connections, respectively, and applied them to graph-theoretical analysis of brain functional networks constructed from resting state fMRI data of 22 patients with schizophrenia and 22 healthy controls. Group differences in the network parameters were observed not for whole brain and hemispheric networks, but for regional networks. Alterations in adjacency and indirect adjacency were in opposite directions, such that adjacency increased, but indirect adjacency decreased in patients with schizophrenia. Furthermore, over connections in frontal and parietal regions, increased adjacency was associated with more severe negative symptoms, while decreased adjacency was associated with more severe positive symptoms of schizophrenia. This finding indicates that connectivity deficits associated with positive and negative symptoms of schizophrenia may involve topologically different paths in the brain. In patients with schizophrenia, although changes in global efficiency may not be clearly shown, different alterations in brain functional networks according to direct and indirect topological connections could be revealed at the regional level. Copyright © 2017 Elsevier B.V. All rights reserved.

Stress and sodium intake in neural control of renal function in hypertension.

PubMed

DiBona, G F

1991-04-01

The interaction between genetic and environmental factors is important in the pathophysiology of hypertension. By examining the effects of two environmental factors--acute psychoemotional stress and dietary sodium intake--in rats with genetic hypertension, an important influence on central neural mechanisms governing the renal sympathetic neural control of renal function has been demonstrated. Additional studies of the central opioid systems have demonstrated an important role of opioid peptides in modulating the renal functional responses to acute psychoemotional stress. The observed renal functional alterations--antidiuresis, antinatriuresis, and renal vasoconstriction--are known to be capable of contributing to the initiation, development, and maintenance of the hypertensive process.

Variants of Transient Receptor Potential Melastatin Member 4 in Childhood Atrioventricular Block.

PubMed

Syam, Ninda; Chatel, Stéphanie; Ozhathil, Lijo Cherian; Sottas, Valentin; Rougier, Jean-Sébastien; Baruteau, Alban; Baron, Estelle; Amarouch, Mohamed-Yassine; Daumy, Xavier; Probst, Vincent; Schott, Jean-Jacques; Abriel, Hugues

2016-05-20

Transient receptor potential melastatin member 4 (TRPM4) is a nonselective cation channel. TRPM4 mutations have been linked to cardiac conduction disease and Brugada syndrome. The mechanisms underlying TRPM4-dependent conduction slowing are not fully understood. The aim of this study was to characterize TRPM4 genetic variants found in patients with congenital or childhood atrioventricular block. Ninety-one patients with congenital or childhood atrioventricular block were screened for candidate genes. Five rare TRPM4 genetic variants were identified and investigated. The variants were expressed heterologously in HEK293 cells. Two of the variants, A432T and A432T/G582S, showed decreased expression of the protein at the cell membrane; inversely, the G582S variant showed increased expression. Further functional characterization of these variants using whole-cell patch-clamp configuration showed a loss of function and a gain of function, respectively. We hypothesized that the observed decrease in expression was caused by a folding and trafficking defect. This was supported by the observation that incubation of these variants at lower temperature partially rescued their expression and function. Previous studies have suggested that altered SUMOylation of TRPM4 may cause a gain of function; however, we did not find any evidence that supports SUMOylation as being directly involved for the gain-of-function variant. This study underpins the role of TRPM4 in the cardiac conduction system. The loss-of-function variants A432T/G582S found in 2 unrelated patients with atrioventricular block are most likely caused by misfolding-dependent altered trafficking. The ability to rescue this variant with lower temperature may provide a novel use of pharmacological chaperones in treatment strategies. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Intestinal microbiota in primary sclerosing cholangitis.

PubMed

Hov, Johannes R; Kummen, Martin

2017-03-01

Alterations of the gut-liver axis have been linked to the pathogenesis of primary sclerosing cholangitis (PSC) since the disease was first described. The purpose of this review is to discuss multiple recent studies on the intestinal microbiota in human PSC and experimental models of this disease. Data are available from eight cross-sectional studies of human PSC, which include a variable number of patients (n = 11-85), material (mucosal or fecal), and microbiota profiling methodology. Despite the heterogeneity of the studies, a pattern of differences is observed that could represent a theme or signature of the PSC gut microbiota, characterized by low diversity and with alterations in multiple bacterial taxa. In experimental models of PSC, re-derivation of animals into germ-free facilities may either aggravate or attenuate the disease, depending on host genetics and putative disease mechanisms (e.g., fibrotic or immune-driven processes, respectively). The present data provide a strong rationale to explore the functional consequences of the observed gut microbial alterations and their influence on the pathogenesis in PSC. Studies of gut microbiota as biomarker and treatment target may potentially also lead to early translation into clinical practice.

Impaired brain energy metabolism in the BACHD mouse model of Huntington's disease: critical role of astrocyte–neuron interactions

PubMed Central

Boussicault, Lydie; Hérard, Anne-Sophie; Calingasan, Noel; Petit, Fanny; Malgorn, Carole; Merienne, Nicolas; Jan, Caroline; Gaillard, Marie-Claude; Lerchundi, Rodrigo; Barros, Luis F; Escartin, Carole; Delzescaux, Thierry; Mariani, Jean; Hantraye, Philippe; Flint Beal, M; Brouillet, Emmanuel; Véga, Céline; Bonvento, Gilles

2014-01-01

Huntington's disease (HD) is caused by cytosine-adenine-guanine (CAG) repeat expansions in the huntingtin (Htt) gene. Although early energy metabolic alterations in HD are likely to contribute to later neurodegenerative processes, the cellular and molecular mechanisms responsible for these metabolic alterations are not well characterized. Using the BACHD mice that express the full-length mutant huntingtin (mHtt) protein with 97 glutamine repeats, we first demonstrated localized in vivo changes in brain glucose use reminiscent of what is observed in premanifest HD carriers. Using biochemical, molecular, and functional analyses on different primary cell culture models from BACHD mice, we observed that mHtt does not directly affect metabolic activity in a cell autonomous manner. However, coculture of neurons with astrocytes from wild-type or BACHD mice identified mutant astrocytes as a source of adverse non-cell autonomous effects on neuron energy metabolism possibly by increasing oxidative stress. These results suggest that astrocyte-to-neuron signaling is involved in early energy metabolic alterations in HD. PMID:24938402

Behavioral impairments in animal models for zinc deficiency

PubMed Central

Hagmeyer, Simone; Haderspeck, Jasmin Carmen; Grabrucker, Andreas Martin

2015-01-01

Apart from teratogenic and pathological effects of zinc deficiency such as the occurrence of skin lesions, anorexia, growth retardation, depressed wound healing, altered immune function, impaired night vision, and alterations in taste and smell acuity, characteristic behavioral changes in animal models and human patients suffering from zinc deficiency have been observed. Given that it is estimated that about 17% of the worldwide population are at risk for zinc deficiency and that zinc deficiency is associated with a variety of brain disorders and disease states in humans, it is of major interest to investigate, how these behavioral changes will affect the individual and a putative course of a disease. Thus, here, we provide a state of the art overview about the behavioral phenotypes observed in various models of zinc deficiency, among them environmentally produced zinc deficient animals as well as animal models based on a genetic alteration of a particular zinc homeostasis gene. Finally, we compare the behavioral phenotypes to the human condition of mild to severe zinc deficiency and provide a model, how zinc deficiency that is associated with many neurodegenerative and neuropsychological disorders might modify the disease pathologies. PMID:25610379

Non-verbal emotion communication training induces specific changes in brain function and structure

PubMed Central

Kreifelts, Benjamin; Jacob, Heike; Brück, Carolin; Erb, Michael; Ethofer, Thomas; Wildgruber, Dirk

2013-01-01

The perception of emotional cues from voice and face is essential for social interaction. However, this process is altered in various psychiatric conditions along with impaired social functioning. Emotion communication trainings have been demonstrated to improve social interaction in healthy individuals and to reduce emotional communication deficits in psychiatric patients. Here, we investigated the impact of a non-verbal emotion communication training (NECT) on cerebral activation and brain structure in a controlled and combined functional magnetic resonance imaging (fMRI) and voxel-based morphometry study. NECT-specific reductions in brain activity occurred in a distributed set of brain regions including face and voice processing regions as well as emotion processing- and motor-related regions presumably reflecting training-induced familiarization with the evaluation of face/voice stimuli. Training-induced changes in non-verbal emotion sensitivity at the behavioral level and the respective cerebral activation patterns were correlated in the face-selective cortical areas in the posterior superior temporal sulcus and fusiform gyrus for valence ratings and in the temporal pole, lateral prefrontal cortex and midbrain/thalamus for the response times. A NECT-induced increase in gray matter (GM) volume was observed in the fusiform face area. Thus, NECT induces both functional and structural plasticity in the face processing system as well as functional plasticity in the emotion perception and evaluation system. We propose that functional alterations are presumably related to changes in sensory tuning in the decoding of emotional expressions. Taken together, these findings highlight that the present experimental design may serve as a valuable tool to investigate the altered behavioral and neuronal processing of emotional cues in psychiatric disorders as well as the impact of therapeutic interventions on brain function and structure. PMID:24146641

Non-verbal emotion communication training induces specific changes in brain function and structure.

PubMed

Kreifelts, Benjamin; Jacob, Heike; Brück, Carolin; Erb, Michael; Ethofer, Thomas; Wildgruber, Dirk

2013-01-01

The perception of emotional cues from voice and face is essential for social interaction. However, this process is altered in various psychiatric conditions along with impaired social functioning. Emotion communication trainings have been demonstrated to improve social interaction in healthy individuals and to reduce emotional communication deficits in psychiatric patients. Here, we investigated the impact of a non-verbal emotion communication training (NECT) on cerebral activation and brain structure in a controlled and combined functional magnetic resonance imaging (fMRI) and voxel-based morphometry study. NECT-specific reductions in brain activity occurred in a distributed set of brain regions including face and voice processing regions as well as emotion processing- and motor-related regions presumably reflecting training-induced familiarization with the evaluation of face/voice stimuli. Training-induced changes in non-verbal emotion sensitivity at the behavioral level and the respective cerebral activation patterns were correlated in the face-selective cortical areas in the posterior superior temporal sulcus and fusiform gyrus for valence ratings and in the temporal pole, lateral prefrontal cortex and midbrain/thalamus for the response times. A NECT-induced increase in gray matter (GM) volume was observed in the fusiform face area. Thus, NECT induces both functional and structural plasticity in the face processing system as well as functional plasticity in the emotion perception and evaluation system. We propose that functional alterations are presumably related to changes in sensory tuning in the decoding of emotional expressions. Taken together, these findings highlight that the present experimental design may serve as a valuable tool to investigate the altered behavioral and neuronal processing of emotional cues in psychiatric disorders as well as the impact of therapeutic interventions on brain function and structure.

An imidazole functionalized pentameric thiophene displays different staining patterns in normal and malignant cells

NASA Astrophysics Data System (ADS)

Nilsson, Peter; Magnusson, Karin; Appelqvist, Hanna; Cieslar-Pobuda, Artur; Bäck, Marcus; Kågedal, Bertil; Jonasson, Jon; Los, Marek

2015-10-01

Molecular tools for fluorescent imaging of cells and their components are vital for understanding the function and activity of cells. Here, we report an imidazole functionalized pentameric oligothiophene, p-HTIm, that can be utilized for fluorescent imaging of cells. p-HTIm fluorescence in normal cells appeared in a peripheral punctate pattern partially co-localized with lysosomes, whereas a one-sided perinuclear Golgi associated localization of the dye was observed in malignant cells. The uptake of p-HTIm was temperature dependent and the intracellular target was reached within 1 h after staining. The ability of p-HTIm to stain cells was reduced when the imidazole side chain was chemically altered, verifying that specific imidazole side-chain functionalities are necessary for achieving the observed cellular staining. Our findings confirm that properly functionalized oligothiophenes can be utilized as fluorescent tools for vital staining of cells and that the selectivity towards distinct intracellular targets are highly dependent on the side-chain functionalities along the conjugated thiophene backbone.

Altered Cingulate Sub-Region Activation Accounts for Task-Related Dissociation in ERN Amplitude as a Function of Obsessive-Compulsive Symptoms

ERIC Educational Resources Information Center

Cavanagh, James F.; Grundler, Theo O. J.; Frank, Michael J.; Allen, John J. B.

2010-01-01

Larger error-related negativities (ERNs) have been consistently found in obsessive-compulsive disorder (OCD) patients, and are thought to reflect the activities of a hyperactive cortico-striatal circuit during action monitoring. We previously observed that obsessive-compulsive (OC) symptomatic students (non-patients) have larger ERNs during errors…

Glutamatergic plasticity and alcohol dependence-induced alterations in reward, affect and cognition.

PubMed

Burnett, Elizabeth J; Chandler, L Judson; Trantham-Davidson, Heather

2016-02-04

Alcohol dependence is characterized by a reduction in reward threshold, development of a negative affective state, and significant cognitive impairments. Dependence-induced glutamatergic neuroadaptations in the neurocircuitry mediating reward, affect and cognitive function are thought to underlie the neural mechanism for these alterations. These changes serve to promote increased craving for alcohol and facilitate the development of maladaptive behaviors that promote relapse to alcohol drinking during periods of abstinence. To review the extant literature on the effects of chronic alcohol exposure on glutamatergic neurotransmission and its impact on reward, affect and cognition. Evidence from a diverse set of studies demonstrates significant enhancement of glutamatergic activity following chronic alcohol exposure. In particular, up-regulation of GluN2B-containing NMDA receptor expression and function is a commonly observed phenomenon that likely reflects activity-dependent adaptive homeostatic plasticity. However, this observation as well as other glutamatergic neuroadaptations are often circuit and cell-type specific. Dependence-induced alterations in glutamate signaling contribute to many of the symptoms experienced in addicted individuals and can persist well into abstinence. This suggests that they play an important role in the development of behaviors that increase the probability for relapse. As our understanding of the complexity of the neurocircuitry involved in the addictive process has advanced, it has become increasingly clear that investigations of cell-type and circuit-specific effects are required to gain a more comprehensive understanding of the glutamatergic adaptations and their functional consequences in alcohol addiction. While pharmacological treatments for alcohol dependence and relapse targeting the glutamatergic system have shown great promise in preclinical models, more research is needed to uncover novel, possibly circuit-specific, therapeutic targets that exhibit improved efficacy and reduced side effects. Copyright © 2015 Elsevier Inc. All rights reserved.

Connectopathy in Autism Spectrum Disorders: A Review of Evidence from Visual Evoked Potentials and Diffusion Magnetic Resonance Imaging

PubMed Central

Yamasaki, Takao; Maekawa, Toshihiko; Fujita, Takako; Tobimatsu, Shozo

2017-01-01

Individuals with autism spectrum disorder (ASD) show superior performance in processing fine details; however, they often exhibit impairments of gestalt face, global motion perception, and visual attention as well as core social deficits. Increasing evidence has suggested that social deficits in ASD arise from abnormal functional and structural connectivities between and within distributed cortical networks that are recruited during social information processing. Because the human visual system is characterized by a set of parallel, hierarchical, multistage network systems, we hypothesized that the altered connectivity of visual networks contributes to social cognition impairment in ASD. In the present review, we focused on studies of altered connectivity of visual and attention networks in ASD using visual evoked potentials (VEPs), event-related potentials (ERPs), and diffusion tensor imaging (DTI). A series of VEP, ERP, and DTI studies conducted in our laboratory have demonstrated complex alterations (impairment and enhancement) of visual and attention networks in ASD. Recent data have suggested that the atypical visual perception observed in ASD is caused by altered connectivity within parallel visual pathways and attention networks, thereby contributing to the impaired social communication observed in ASD. Therefore, we conclude that the underlying pathophysiological mechanism of ASD constitutes a “connectopathy.” PMID:29170625

Chromatographic analysis of age-related changes in mucosal serotonin transmission in the murine distal ileum

PubMed Central

2012-01-01

Background In the upper bowel, alterations in motility and absorption of key nutrients have been observed as part of the normal ageing process. Serotonin (5-HT) is a key signalling molecule in the gastrointestinal tract and is known to influence motility, however little is known of how the ageing process alters 5-HT signalling processes in the bowel. Results An isocratic chromatographic method was able to detect all 5-HT precursors and metabolites. Using extracellular and intracellular sampling approaches, we were able to monitor all key parameters associated with the transmission process. There was no alteration in the levels of tryptophan and 5-HTP between 3 and 18 month old animals. There was a significant increase in the ratio of 5-HT:5-HTP and an increase in intracellular 5-HT between 3 and 18 month old animals suggesting an increase in 5-HT synthesis. There was also a significant increase in extracellular 5-HT with age, suggesting increased 5-HT release. There was an age-related decrease in the ratio of intracellular 5-HIAA:extracellular 5-HT, whilst the amount of 5-HIAA did not change with age. In the presence of an increase in extracellular 5-HT, the lack of an age-related change in 5-HIAA is suggestive of a decrease in re-uptake via the serotonin transporter (SERT). Conclusions We have used intracellular and extracellular sampling to provide more insight into alterations in the neurotransmission process of 5-HT during normal ageing. We observed elevated 5-HT synthesis and release and a possible decrease in the activity of SERT. Taken together these changes lead to increased 5-HT availability and may alter motility function and could lead to the changes in adsorption observed in the elderly. PMID:22494644

Altered Distribution of RNA Polymerase Lacking the Omega Subunit within the Prophages along the Escherichia coli K-12 Genome.

PubMed

Yamamoto, Kaneyoshi; Yamanaka, Yuki; Shimada, Tomohiro; Sarkar, Paramita; Yoshida, Myu; Bhardwaj, Neerupma; Watanabe, Hiroki; Taira, Yuki; Chatterji, Dipankar; Ishihama, Akira

2018-01-01

The RNA polymerase (RNAP) of Escherichia coli K-12 is a complex enzyme consisting of the core enzyme with the subunit structure α 2 ββ'ω and one of the σ subunits with promoter recognition properties. The smallest subunit, omega (the rpoZ gene product), participates in subunit assembly by supporting the folding of the largest subunit, β', but its functional role remains unsolved except for its involvement in ppGpp binding and stringent response. As an initial approach for elucidation of its functional role, we performed in this study ChIP-chip (chromatin immunoprecipitation with microarray technology) analysis of wild-type and rpoZ -defective mutant strains. The altered distribution of RpoZ-defective RNAP was identified mostly within open reading frames, in particular, of the genes inside prophages. For the genes that exhibited increased or decreased distribution of RpoZ-defective RNAP, the level of transcripts increased or decreased, respectively, as detected by reverse transcription-quantitative PCR (qRT-PCR). In parallel, we analyzed, using genomic SELEX (systemic evolution of ligands by exponential enrichment), the distribution of constitutive promoters that are recognized by RNAP RpoD holoenzyme alone and of general silencer H-NS within prophages. Since all 10 prophages in E. coli K-12 carry only a small number of promoters, the altered occupancy of RpoZ-defective RNAP and of transcripts might represent transcription initiated from as-yet-unidentified host promoters. The genes that exhibited transcription enhanced by RpoZ-defective RNAP are located in the regions of low-level H-NS binding. By using phenotype microarray (PM) assay, alterations of some phenotypes were detected for the rpoZ -deleted mutant, indicating the involvement of RpoZ in regulation of some genes. Possible mechanisms of altered distribution of RNAP inside prophages are discussed. IMPORTANCE The 91-amino-acid-residue small-subunit omega (the rpoZ gene product) of Escherichia coli RNA polymerase plays a structural role in the formation of RNA polymerase (RNAP) as a chaperone in folding the largest subunit (β', of 1,407 residues in length), but except for binding of the stringent signal ppGpp, little is known of its role in the control of RNAP function. After analysis of genomewide distribution of wild-type and RpoZ-defective RNAP by the ChIP-chip method, we found alteration of the RpoZ-defective RNAP inside open reading frames, in particular, of the genes within prophages. For a set of the genes that exhibited altered occupancy of the RpoZ-defective RNAP, transcription was found to be altered as observed by qRT-PCR assay. All the observations here described indicate the involvement of RpoZ in recognition of some of the prophage genes. This study advances understanding of not only the regulatory role of omega subunit in the functions of RNAP but also the regulatory interplay between prophages and the host E. coli for adjustment of cellular physiology to a variety of environments in nature.

Altered Distribution of RNA Polymerase Lacking the Omega Subunit within the Prophages along the Escherichia coli K-12 Genome

PubMed Central

Yamamoto, Kaneyoshi; Yamanaka, Yuki; Shimada, Tomohiro; Sarkar, Paramita; Yoshida, Myu; Bhardwaj, Neerupma; Watanabe, Hiroki; Taira, Yuki

2018-01-01

ABSTRACT The RNA polymerase (RNAP) of Escherichia coli K-12 is a complex enzyme consisting of the core enzyme with the subunit structure α2ββ′ω and one of the σ subunits with promoter recognition properties. The smallest subunit, omega (the rpoZ gene product), participates in subunit assembly by supporting the folding of the largest subunit, β′, but its functional role remains unsolved except for its involvement in ppGpp binding and stringent response. As an initial approach for elucidation of its functional role, we performed in this study ChIP-chip (chromatin immunoprecipitation with microarray technology) analysis of wild-type and rpoZ-defective mutant strains. The altered distribution of RpoZ-defective RNAP was identified mostly within open reading frames, in particular, of the genes inside prophages. For the genes that exhibited increased or decreased distribution of RpoZ-defective RNAP, the level of transcripts increased or decreased, respectively, as detected by reverse transcription-quantitative PCR (qRT-PCR). In parallel, we analyzed, using genomic SELEX (systemic evolution of ligands by exponential enrichment), the distribution of constitutive promoters that are recognized by RNAP RpoD holoenzyme alone and of general silencer H-NS within prophages. Since all 10 prophages in E. coli K-12 carry only a small number of promoters, the altered occupancy of RpoZ-defective RNAP and of transcripts might represent transcription initiated from as-yet-unidentified host promoters. The genes that exhibited transcription enhanced by RpoZ-defective RNAP are located in the regions of low-level H-NS binding. By using phenotype microarray (PM) assay, alterations of some phenotypes were detected for the rpoZ-deleted mutant, indicating the involvement of RpoZ in regulation of some genes. Possible mechanisms of altered distribution of RNAP inside prophages are discussed. IMPORTANCE The 91-amino-acid-residue small-subunit omega (the rpoZ gene product) of Escherichia coli RNA polymerase plays a structural role in the formation of RNA polymerase (RNAP) as a chaperone in folding the largest subunit (β′, of 1,407 residues in length), but except for binding of the stringent signal ppGpp, little is known of its role in the control of RNAP function. After analysis of genomewide distribution of wild-type and RpoZ-defective RNAP by the ChIP-chip method, we found alteration of the RpoZ-defective RNAP inside open reading frames, in particular, of the genes within prophages. For a set of the genes that exhibited altered occupancy of the RpoZ-defective RNAP, transcription was found to be altered as observed by qRT-PCR assay. All the observations here described indicate the involvement of RpoZ in recognition of some of the prophage genes. This study advances understanding of not only the regulatory role of omega subunit in the functions of RNAP but also the regulatory interplay between prophages and the host E. coli for adjustment of cellular physiology to a variety of environments in nature. PMID:29468196

Dorso-Lateral Prefrontal Cortex MRI Measurements and Cognitive Performance in Autism

PubMed Central

Griebling, Jessica; Minshew, Nancy J.; Bodner, Kimberly; Libove, Robin; Bansal, Rahul; Konasale, Prasad; Keshavan, Matcheri S.; Hardan, Antonio

2012-01-01

This study examined the relationships between volumetric measurements of frontal lobe structures and performance on executive function tasks in individuals with autism. MRI scans were obtained from 38 individuals with autism and 40 matched controls between the ages of 8 and 45 years. Executive function was assessed using neuropsychological measures including the Wisconsin Card Sorting Test and Tower of Hanoi. Differences in performance on the neuropsychological tests were found between the two groups. However, no differences in dorsolateral prefrontal cortex volumes were observed between groups. No correlations between volumetric measurements and performance on the neuropsychological tests were found. Findings from this study suggest that executive function deficits observed in autism are related to functional but not anatomical abnormalities of the frontal lobe. The absence of correlations suggests that executive dysfunction is not the result of focal brain alterations but, rather, is the result of a distributed neural network dysfunction. PMID:20097663

A Toll-Like Receptor 9 Antagonist Improves Bladder Function and White Matter Sparing in Spinal Cord Injury

PubMed Central

David, Brian T.; Sampath, Sujitha; Dong, Wei; Heiman, Adee; Rella, Courtney E.; Elkabes, Stella

2014-01-01

Abstract Spinal cord injury (SCI) affects motor, sensory, and autonomic functions. As current therapies do not adequately alleviate functional deficits, the development of new and more effective approaches is of critical importance. Our earlier investigations indicated that intrathecal administration of a toll-like receptor 9 (TLR9) antagonist, cytidine-phosphate-guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), to mice sustaining a severe, mid-thoracic contusion injury diminished neuropathic pain but did not alter locomotor deficits. These changes were paralleled by a decrease in the pro-inflammatory response at the injury epicenter. Using the same SCI paradigm and treatment regimen, the current studies investigated the effects of the TLR9 antagonist on bladder function. We report that the TLR9 antagonist decreases SCI-elicited urinary retention and ameliorates bladder morphopathology without affecting kidney function. A significant improvement in white matter sparing was also observed, most likely due to alterations in the inflammatory milieu. These findings indicate that the TLR9 antagonist has beneficial effects not only in reducing sensory deficits, but also on bladder dysfunction and tissue preservation. Thus, modulation of innate immune receptor signaling in the spinal cord can impact the effects of SCI. PMID:24936867

A toll-like receptor 9 antagonist improves bladder function and white matter sparing in spinal cord injury.

PubMed

David, Brian T; Sampath, Sujitha; Dong, Wei; Heiman, Adee; Rella, Courtney E; Elkabes, Stella; Heary, Robert F

2014-11-01

Spinal cord injury (SCI) affects motor, sensory, and autonomic functions. As current therapies do not adequately alleviate functional deficits, the development of new and more effective approaches is of critical importance. Our earlier investigations indicated that intrathecal administration of a toll-like receptor 9 (TLR9) antagonist, cytidine-phosphate-guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), to mice sustaining a severe, mid-thoracic contusion injury diminished neuropathic pain but did not alter locomotor deficits. These changes were paralleled by a decrease in the pro-inflammatory response at the injury epicenter. Using the same SCI paradigm and treatment regimen, the current studies investigated the effects of the TLR9 antagonist on bladder function. We report that the TLR9 antagonist decreases SCI-elicited urinary retention and ameliorates bladder morphopathology without affecting kidney function. A significant improvement in white matter sparing was also observed, most likely due to alterations in the inflammatory milieu. These findings indicate that the TLR9 antagonist has beneficial effects not only in reducing sensory deficits, but also on bladder dysfunction and tissue preservation. Thus, modulation of innate immune receptor signaling in the spinal cord can impact the effects of SCI.

Streptozotocin alters glucose transport, connexin expression and endoplasmic reticulum functions in neurons and astrocytes.

PubMed

Biswas, Joyshree; Gupta, Sonam; Verma, Dinesh Kumar; Singh, Sarika

2017-07-25

The study was undertaken to explore the cell-specific streptozotocin (STZ)-induced mechanistic alterations. STZ-induced rodent model is a well-established experimental model of Alzheimer's disease (AD) and in our previous studies we have established it as an in vitro screening model of AD by employing N2A neuronal cells. Therefore, STZ was selected in the present study to understand the STZ-induced cell-specific alterations by utilizing neuronal N2A and astrocytes C6 cells. Both neuronal and astrocyte cells were treated with STZ at 10, 50, 100 and 1000μM concentrations for 48h. STZ exposure caused significant decline in cellular viability and augmented cytotoxicity of cells involving astrocytes activation. STZ treatment also disrupted the energy metabolism by altered glucose uptake and its transport in both cells as reflected with decreased expression of glucose transporters (GLUT) 1/3. The consequent decrease in ATP level and decreased mitochondrial membrane potential was also observed in both the cells. STZ caused increased intracellular calcium which could cause the initiation of endoplasmic reticulum (ER) stress. Significant upregulation of ER stress-related markers were observed in both cells after STZ treatment. The cellular communication of astrocytes and neurons was altered as reflected by increased expression of connexin 43 along with DNA fragmentation. STZ-induced apoptotic death was evaluated by elevated expression of caspase-3 and PI/Hoechst staining of cells. In conclusion, study showed that STZ exert alike biochemical alterations, ER stress and cellular apoptosis in both neuronal and astrocyte cells. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Ultra-structural hair alterations in Friedreich's ataxia: A scanning electron microscopic investigation.

PubMed

Turkmenoglu, F Pinar; Kasirga, U Baran; Celik, H Hamdi

2015-08-01

Friedreich's ataxia (FRDA) is an autosomal recessive inherited disorder involving progressive damage to the central and peripheral nervous systems and cardiomyopathy. FRDA is caused by the silencing of the FXN gene and reduced levels of the encoded protein, frataxin. Frataxin is a mitochondrial protein that functions primarily in iron-sulfur cluster synthesis. Skin disorders including hair abnormalities have previously been reported in patients with mitochondrial disorders. However, to our knowledge, ultra-structural hair alterations in FRDA were not demonstrated. The purpose of this study was to determine ultra-structural alterations in the hairs of FRDA patients as well as carriers. Hair specimen from four patients, who are in different stages of the disease, and two carriers were examined by scanning electron microscope. Thin and weak hair follicles with absence of homogeneities on the cuticular surface, local damages of the cuticular layer, cuticular fractures were detected in both carriers and patients, but these alterations were much more prominent in the hair follicles of patients. In addition, erosions on the surface of the cuticle and local deep cavities just under the cuticular level were observed only in patients. Indistinct cuticular pattern, pores on the cuticular surface, and presence of concavities on the hair follicle were also detected in patients in later stages of the disease. According to our results, progression of the disease increased the alterations on hair structure. We suggest that ultra-structural alterations observed in hair samples might be due to oxidative stress caused by deficient frataxin expression in mitochondria. © 2015 Wiley Periodicals, Inc.

Connectivity and functional profiling of abnormal brain structures in pedophilia

PubMed Central

Poeppl, Timm B.; Eickhoff, Simon B.; Fox, Peter T.; Laird, Angela R.; Rupprecht, Rainer; Langguth, Berthold; Bzdok, Danilo

2015-01-01

Despite its 0.5–1% lifetime prevalence in men and its general societal relevance, neuroimaging investigations in pedophilia are scarce. Preliminary findings indicate abnormal brain structure and function. However, no study has yet linked structural alterations in pedophiles to both connectional and functional properties of the aberrant hotspots. The relationship between morphological alterations and brain function in pedophilia as well as their contribution to its psychopathology thus remain unclear. First, we assessed bimodal connectivity of structurally altered candidate regions using meta-analytic connectivity modeling (MACM) and resting-state correlations employing openly accessible data. We compared the ensuing connectivity maps to the activation likelihood estimation (ALE) maps of a recent quantitative meta-analysis of brain activity during processing of sexual stimuli. Second, we functionally characterized the structurally altered regions employing meta-data of a large-scale neuroimaging database. Candidate regions were functionally connected to key areas for processing of sexual stimuli. Moreover, we found that the functional role of structurally altered brain regions in pedophilia relates to nonsexual emotional as well as neurocognitive and executive functions, previously reported to be impaired in pedophiles. Our results suggest that structural brain alterations affect neural networks for sexual processing by way of disrupted functional connectivity, which may entail abnormal sexual arousal patterns. The findings moreover indicate that structural alterations account for common affective and neurocognitive impairments in pedophilia. The present multi-modal integration of brain structure and function analyses links sexual and nonsexual psychopathology in pedophilia. PMID:25733379

Connectivity and functional profiling of abnormal brain structures in pedophilia.

PubMed

Poeppl, Timm B; Eickhoff, Simon B; Fox, Peter T; Laird, Angela R; Rupprecht, Rainer; Langguth, Berthold; Bzdok, Danilo

2015-06-01

Despite its 0.5-1% lifetime prevalence in men and its general societal relevance, neuroimaging investigations in pedophilia are scarce. Preliminary findings indicate abnormal brain structure and function. However, no study has yet linked structural alterations in pedophiles to both connectional and functional properties of the aberrant hotspots. The relationship between morphological alterations and brain function in pedophilia as well as their contribution to its psychopathology thus remain unclear. First, we assessed bimodal connectivity of structurally altered candidate regions using meta-analytic connectivity modeling (MACM) and resting-state correlations employing openly accessible data. We compared the ensuing connectivity maps to the activation likelihood estimation (ALE) maps of a recent quantitative meta-analysis of brain activity during processing of sexual stimuli. Second, we functionally characterized the structurally altered regions employing meta-data of a large-scale neuroimaging database. Candidate regions were functionally connected to key areas for processing of sexual stimuli. Moreover, we found that the functional role of structurally altered brain regions in pedophilia relates to nonsexual emotional as well as neurocognitive and executive functions, previously reported to be impaired in pedophiles. Our results suggest that structural brain alterations affect neural networks for sexual processing by way of disrupted functional connectivity, which may entail abnormal sexual arousal patterns. The findings moreover indicate that structural alterations account for common affective and neurocognitive impairments in pedophilia. The present multimodal integration of brain structure and function analyses links sexual and nonsexual psychopathology in pedophilia. © 2015 Wiley Periodicals, Inc.

Preliminary investigation of the relationships between sleep duration, reward circuitry function, and mood dysregulation in youth offspring of parents with bipolar disorder.

PubMed

Soehner, Adriane M; Bertocci, Michele A; Manelis, Anna; Bebko, Genna; Ladouceur, Cecile D; Graur, Simona; Monk, Kelly; Bonar, Lisa K; Hickey, Mary Beth; Axelson, David; Goldstein, Benjamin I; Goldstein, Tina R; Birmaher, Boris; Phillips, Mary L

2016-11-15

Altered reward circuitry function is observed in individuals with bipolar disorder (BD) and their unaffected offspring (OBP). While OBP are at elevated risk for BD, modifiable risk factors that may exacerbate neural vulnerabilities in OBP remain under-characterized. As sleep loss is strongly linked to mania in BD, this study tested associations between sleep duration, reward circuitry function, and mood dysregulation in OBP. Two groups of youth unaffected with BD (9-17yr) completed a number-guessing fMRI reward paradigm: 25 OBP and 21 age-sex-IQ-matched offspring of control parents with non-BD psychopathology (OCP), to differentiate risk for BD from risk for psychopathology more broadly. Regressions tested effects of group status, self-reported past-week sleep duration, and their interaction on neural activity and bilateral ventral striatum (VS) functional connectivity to win>control. Correlations with parent-reported mood dysregulation were assessed. Group effects were observed for right posterior insula activity (OCP>OBP) and VS-left posterior insula connectivity (OBP>OCP). Group ⁎ sleep duration interactions were observed for left dorsal anterior-mid-cingulate (daMCC) activity and VS-left anterior insula/ventrolateral prefrontal cortex (VLPFC) connectivity. Specifically, sleep duration and daMCC activity were positively related in OBP, but negatively related in OCP and sleep duration and VS-left anterior insula/VLPFC connectivity were negatively related in OBP, but positively in OCP. Additionally, increased VS-left posterior insula connectivity and VS-left anterior insula/VLPFC connectivity were associated with greater mood dysregulation in OBP only. Cross-sectional design and small sample size. Altered reward-related VS-insula connectivity could represent a neural pathway underpinning mood dysregulation in OBP, and may be modulated by shortened sleep duration. Copyright © 2016 Elsevier B.V. All rights reserved.

Brain Gut Microbiome Interactions and Functional Bowel Disorders

PubMed Central

Mayer, Emeran A.; Savidge, Tor; Shulman, Robert J.

2014-01-01

Alterations in the bidirectional interactions between the gut and the nervous system play an important role in IBS pathophysiology and symptom generation. A body of largely preclinical evidence suggests that the gut microbiota can modulate these interactions. Characterizations of alterations of gut microbiota in unselected IBS patients, and assessment of changes in subjective symptoms associated with manipulations of the gut microbiota with prebiotics, probiotics and antibiotics support a small, but poorly defined role of dybiosis in overall IBS symptoms. It remains to be determined if the observed abnormalities are a consequence of altered top down signaling from the brain to the gut and microbiota, if they are secondary to a primary perturbation of the microbiota, and if they play a role in the development of altered brain gut interactions early in life. Different mechanisms may play role in subsets of patients. Characterization of gut microbiome alterations in large cohorts of well phenotyped patients as well as evidence correlating gut metabolites with specific abnormalities in the gut brain axis are required to answer these questions. PMID:24583088

Short-term sleep deprivation leads to decreased systemic redox metabolites and altered epigenetic status.

PubMed

Trivedi, Malav S; Holger, Dana; Bui, Anh Tuyet; Craddock, Travis J A; Tartar, Jaime L

2017-01-01

Sleep is critical for repair as well as the rejuvenation processes in the body and many of these functions are regulated via underlying cellular metabolic homeostasis. Changes in sleep pattern are reported to alter such metabolic function resulting in altered disease susceptibility or behavior. Here, we measured the extent to which overnight total sleep deprivation (SD) in young adult humans can influence systemic (plasma-derived) redox-metabolism including the major antioxidant, glutathione as well as DNA methylation levels. Nineteen participants (n = 19, μ age = 21, SD = 3.09) underwent morning testing before and after overnight total SD. Biochemical measures before and after SD revealed that glutathione, ATP, cysteine, and homocysteine levels were significantly reduced following one night of sleep deprivation (all p's < 0.01). Parallel to the well-recognized fact that sleep deprivation (maintaining wakefulness) uses up metabolic reserves, we observed that morning cortisol levels were blunted after sleep deprivation. There were no significant correlations between self-reported or actigraphy-measured sleep and the biochemical measurements, strongly indicating that prior sleep behavior did not have any direct influence on the biochemical measures taken at baseline or after sleep deprivation. Results from the current investigation supports the previous literature implicating the induction of oxidative stress and ATP depletion with sleep deprivation. Furthermore, such altered antioxidant status can also induce downstream epigenetic changes. Although we did not measure the specific genes that were altered under the influence of such sleep deprivation, such epigenetic changes could potentially contribute towards disease predisposition.

[The child's brain: normal (unaltered) development and development altered by perinatal injury].

PubMed

Marín-Padilla, Miguel

2013-09-06

In this study we analyse some of the morphological and functional aspects of normal and altered development (the latter due to perinatal injury) in the child's brain. Both normal and altered development are developmental processes that progressively interconnect the different regions. The neuropathological development of subpial and periventricular haemorrhages, as well as that of white matter infarct, are analysed in detail. Any kind of brain damage causes a local lesion with possible remote repercussions. All the components (neurons, fibres, blood capillaries and neuroglias) of the affected region undergo alterations. Those that are destroyed are eliminated by the inflammatory process and those that survive are transformed. The pyramidal neurons with amputated apical dendrites are transformed and become stellate cells, the axonal terminals and those of the radial glial cells are regenerated and the region involved is reinnervated and revascularised with an altered morphology and function (altered local corticogenesis). The specific microvascular system of the grey matter protects its neurons from infarction of the white matter. Although it survives, the grey matter is left disconnected from the afferent and efferent fibres, amputated by the infarct with alterations affecting its morphology and possibly its functioning (altered local corticogenesis). Any local lesion can modify the morphological and functional development of remote regions that are functionally interconnected with it (altered remote corticogenesis). We suggest that any local brain injury can alter the morphology and functioning of the regions that are morphologically and functionally interconnected with it and thus end up affecting the child's neurological and psychological development. These changes can cross different regions of the brain (epileptic auras) and, if they eventually reach the motor region, will give rise to the motor storm that characterises epilepsy.

Cancer metabolism: fatty acid oxidation in the limelight

PubMed Central

Carracedo, Arkaitz; Cantley, Lewis C.; Pandolfi, Pier Paolo

2013-01-01

Warburg suggested that the alterations in metabolism that he observed in cancer cells were due to the malfunction of mitochondria. In the past decade, we have revisited this idea and reached a better understanding of the ‘metabolic switch’ in cancer cells, including the intimate and causal relationship between cancer genes and metabolic alterations, and their potential to be targeted for cancer treatment. However, the vast majority of the research into cancer metabolism has been limited to a handful of metabolic pathways, while other pathways have remained in the dark. This Progress article brings to light the important contribution of fatty acid oxidation to cancer cell function. PMID:23446547

The "intoxication state of consciousness": a model for alcohol and drug abuse.

PubMed

Galanter, M

1976-06-01

The author describes a model of intoxicant use based on altered states of consciousness and reviews his own and others' research on marijuana to illustrate the utility of this model, which is derived from both introspective reports and observed data. The relationship of social behavior and cognitive functioning to the "intoxication state of consciousness" is discussed. This state of consciousness may have an adaptive value in engendering and stabilizing social cohesion. Possible treatment implications include cognitive labeling of cues that precipitate episodes of abuse, training for moderated drug use while patients are intoxicated, and providing abusers with altered consciousness through other means, such as meditation.

Quantification of mutation-derived bias for alternate mating functionalities of the Saccharomyces cerevisiae Ste2p pheromone receptor.

PubMed

Choudhary, Pooja; Loewen, Michele C

2016-01-01

Although well documented for mammalian G-protein-coupled receptors, alternate functionalities and associated alternate signalling remain to be unequivocally established for the Saccharomyces cerevisiae pheromone Ste2p receptor. Here, evidence supporting alternate functionalities for Ste2p is re-evaluated, extended and quantified. In particular, strong mating and constitutive signalling mutations, focusing on residues S254, P258 and S259 in TM6 of Ste2p, are stacked and investigated in terms of their effects on classical G-protein-mediated signal transduction associated with cell cycle arrest, and alternatively, their impact on downstream mating projection and zygote formation events. In relative dose response experiments, accounting for systemic and observational bias, mutational-derived functional differences were observed, validating the S254L-derived bias for downstream mating responses and highlighting complex relationships between TM6-mutation derived constitutive signalling and ligand-induced functionalities. Mechanistically, localization studies suggest that alterations to receptor trafficking may contribute to mutational bias, in addition to expected receptor conformational stabilization effects. Overall, these results extend previous observations and quantify the contributions of Ste2p variants to mediating cell cycle arrest versus downstream mating functionalities. © Crown copyright 2015.

GAB2 amplifications refine molecular classification of melanoma.

PubMed

Chernoff, Karen A; Bordone, Lindsey; Horst, Basil; Simon, Katherine; Twadell, William; Lee, Keagan; Cohen, Jason A; Wang, Shuang; Silvers, David N; Brunner, Georg; Celebi, Julide Tok

2009-07-01

Gain-of-function mutations in BRAF, NRAS, or KIT are associated with distinct melanoma subtypes with KIT mutations and/or copy number changes frequently observed among melanomas arising from sun-protected sites, such as acral skin (palms, soles, and nail bed) and mucous membranes. GAB2 has recently been implicated in melanoma pathogenesis, and increased copy numbers are found in a subset of melanomas. We sought to determine the association of increased copy numbers of GAB2 among melanoma subtypes in the context of genetic alterations in BRAF, NRAS, and KIT. A total of 85 melanomas arising from sun-protected (n = 23) and sun-exposed sites (n = 62) were analyzed for copy number changes using array-based comparative genomic hybridization and for gain-of-function mutations in BRAF, NRAS, and KIT. GAB2 amplifications were found in 9% of the cases and were associated with melanomas arising from acral and mucosal sites (P = 0.005). Increased copy numbers of the KIT locus were observed in 6% of the cases. The overall mutation frequencies for BRAF and NRAS were 43.5% and 14%, respectively, and were mutually exclusive. Among the acral and mucosal melanomas studied, the genetic alteration frequency was 26% for GAB2, 13% for KIT, 30% for BRAF, and 4% for NRAS. Importantly, the majority of GAB2 amplifications occurred independent from genetic events in BRAF, NRAS, and KIT. GAB2 amplification is critical for melanomas arising from sun-protected sites. Genetic alterations in GAB2 will help refine the molecular classification of melanomas.

Brain and Bone Damage in KARAP/DAP12 Loss-of-Function Mice Correlate with Alterations in Microglia and Osteoclast Lineages

PubMed Central

Nataf, Serge; Anginot, Adrienne; Vuaillat, Carine; Malaval, Luc; Fodil, Nassima; Chereul¶, Emmanuel; Langlois¶, Jean-Baptiste; Dumontel, Christiane; Cavillon, Gaelle; Confavreux, Christian; Mazzorana, Marlène; Vico, Laurence; Belin, Marie-Franaçoise; Vivier, Eric; Tomasello, Elena; Jurdic, Pierre

2005-01-01

Human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy, also known as Nasu-Hakola disease, has been described to be associated with mutations affecting the immunoreceptor tyrosine-based activation motif-bearing KARAP/DAP12 immunoreceptor gene. Patients present bone fragilities and severe neurological alterations leading to presenile dementia. Here we investigated whether the absence of KARAP/DAP12-mediated signals in loss-of-function (KΔ75) mice also leads to bone and central nervous system pathological features. Histological analysis of adult KΔ75 mice brains revealed a diffuse hypomyelination predominating in anterior brain regions. As this was not accompanied by oligodendrocyte degeneration or microglial cell activation it suggests a developmental defect of myelin formation. Interestingly, in postnatal KΔ75 mice, we observed a dramatic reduction in microglial cell numbers similar to in vitro microglial cell differentiation impairment. Our results raise the intriguing possibility that defective microglial cell differentiation might be responsible for abnormal myelin development. Histomorphometry revealed that bone remodeling is also altered, because of a resorption defect, associated with a severe block of in vitro osteoclast differentiation. In addition, we show that, among monocytic lineages, KARAP/DAP12 specifically controls microglial and osteoclast differentiation. Our results confirm that KARAP/DAP12-mediated signals play an important role in the regulation of both brain and bone homeostasis. Yet, important differences exist between the symptoms observed in Nasu-Hakola patients and KΔ75 mice. PMID:15632019

Alterations in bladder function associated with urothelial defects in uroplakin II and IIIa knockout mice.

PubMed

Aboushwareb, Tamer; Zhou, Ge; Deng, Fang-Ming; Turner, Chanda; Andersson, Karl-Erik; Tar, Moses; Zhao, Weixin; Melman, Arnold; D'Agostino, Ralph; Sun, Tung-Tien; Christ, George J

2009-01-01

The effects of deleting genes encoding uroplakins II (UPII) and III (UPIIIa) on mouse bladder physiology/dysfunction were studied in male and female wild type and knockout (KO) mice. UPII, UPIIIa, and WT mice were catheterized using previously described techniques. Continuous cystometry was conducted in conscious, freely moving animals. Bladder strips were harvested after animal sacrifice and pharmacological studies and EFS were conducted in an organ chamber. Histological studies were also carried on with H&E staining to identify differences among the three mouse types. These studies have revealed numerous alterations, some of which were apparently gender-specific. Nonvoiding contractions were common in both UPII and UPIIIa KO mice, although more severe in the former. In particular, the increased bladder capacity, micturition pressure and demonstrable nonvoiding contractions observed in the male UPII KO's, were reminiscent of an obstruction-like syndrome accompanied by evidence of emerging bladder decompensation, as reflected by an increased residual volume. Pharmacological studies revealed a modest, gender-specific reduction in sensitivity of isolated detrusor strips from UPII KO female mice to carbachol-induced contractions. A similar reduction was observed in UPIIIa KO female mice. Histological investigation showed urothelial hyperplasia in both UPII KO and UPIIIa KO mice, although again, apparently more severe in the former. These results confirm and extend previous work to indicate that urothelial defects due to uroplakin deficiency are associated with significant alterations in bladder function and further highlight the importance of the urothelium to bladder physiology/dysfunction.

Supporting women with advanced breast cancer: the impact of altered functional status on their social roles.

PubMed

Chen, Bai Qi Peggy; Parmar, Monica P; Gartshore, Kimberley

2014-01-01

Despite early detection of breast cancer and the progress of treatment modalities, metastasis-specific symptoms continue to impact women's functional status and daily living. The aim of this study was to explore the experience of altered functional status and social roles of women with advanced breast cancer. Using qualitative descriptive methodology, semi-structured interviews were conducted with 10 women diagnosed with advanced breast cancer and altered functional status attending a tertiary care cancer centre. Results illustrated the adaptive experience of women living with their illness as they reshaped their social roles to fit with their altered functional status and advanced disease. These findings highlight the opportunity for supportive care nursing interventions to facilitate the behavioural and cognitive transitions that are experienced by women with advanced breast cancer and altered functional status. These results may have implications for women with other advanced chronic diseases, though more research is required.

Selective alterations of NMDAR function and plasticity in D1 and D2 medium spiny neurons in the nucleus accumbens shell following chronic intermittent ethanol exposure.

PubMed

Renteria, Rafael; Maier, Esther Y; Buske, Tavanna R; Morrisett, Richard A

2017-01-01

A major mouse model widely adopted in recent years to induce pronounced ethanol intake is the ethanol vapor model known as "CIE" or "Chronic Intermittent Ethanol." One critical question concerning this model is whether the rapid induction of high blood ethanol levels for such short time periods is sufficient to induce alterations in N-methyl-d-aspartate receptor (NMDAR) function which may contribute to excessive ethanol intake. In this study, we determined whether such short term intermittent ethanol exposure modulates NMDAR function as well as other prominent electrophysiological properties and the expression of plasticity in both D1 (D1+) and D2 (D1-) dopamine receptor expressing medium spiny neurons (MSNs) in the nucleus accumbens (NAc) shell. To distinguish between the two subtypes of MSNs in the NAc we treated Drd1a-TdTomato transgenic mice with CIE vapor and electrophysiological recordings were conducted 24 h after the last vapor exposure. To investigate CIE induced alterations in plasticity, long-term depression (LTD) was induced by pairing low frequency stimulation (LFS) with post synaptic depolarization. In ethanol naïve mice, LFS induced synaptic depression (LTD) was apparent exclusively in D1+ MSNs. Whereas in slices prepared from CIE treated mice, LFS induced synaptic potentiation (LTP) in D1+ MSNs. Furthermore, following CIE exposure, LFS now produced LTD in D1- MSNs. We found that CIE exposure induced an increase in excitability in D1+ MSNs with no change in D1- MSNs. After CIE, we found a significant increase in spontaneous EPSCs (sEPSCs) frequency in D1+ but not D1- MSNs suggesting alterations in baseline α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) mediated signaling. CIE induced changes in NMDAR function were measured using the NMDA/AMPA ratio and input-output curves of isolated NMDAR currents. We observed a significant increase in NMDAR function in D1+ MSNs and a decrease in D1- MSNs after ethanol vapor exposure. The reversal of NMDAR function may account for the CIE induced alterations in the expression of plasticity. The cell type specific alterations in excitatory signaling in the NAc shell may constitute an important neuroadaptation necessary for the expression of increased ethanol consumption induced by intermittent ethanol vapor exposure. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'. Copyright © 2016 Elsevier Ltd. All rights reserved.

A multivariate analysis of age-related differences in functional networks supporting conflict resolution.

PubMed

Salami, Alireza; Rieckmann, Anna; Fischer, Håkan; Bäckman, Lars

2014-02-01

Functional neuroimaging studies demonstrate age-related differences in recruitment of a large-scale attentional network during interference resolution, especially within dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). These alterations in functional responses have been frequently observed despite equivalent task performance, suggesting age-related reallocation of neural resources, although direct evidence for a facilitating effect in aging is sparse. We used the multi-source interference task and multivariate partial-least-squares to investigate age-related differences in the neuronal signature of conflict resolution, and their behavioral implications in younger and older adults. There were interference-related increases in activity, involving fronto-parietal and basal ganglia networks that generalized across age. In addition an age-by-task interaction was observed within a distributed network, including DLPFC and ACC, with greater activity during interference in the old. Next, we combined brain-behavior and functional connectivity analyses to investigate whether compensatory brain changes were present in older adults, using DLPFC and ACC as regions of interest (i.e. seed regions). This analysis revealed two networks differentially related to performance across age groups. A structural analysis revealed age-related gray-matter losses in regions facilitating performance in the young, suggesting that functional reorganization may partly reflect structural alterations in aging. Collectively, these findings suggest that age-related structural changes contribute to reductions in the efficient recruitment of a youth-like interference network, which cascades into instantiation of a different network facilitating conflict resolution in elderly people. © 2013. Published by Elsevier Inc. All rights reserved.

Gut microbiome may contribute to insulin resistance and systemic inflammation in obese rodents: a meta-analysis.

PubMed

Jiao, Na; Baker, Susan S; Nugent, Colleen A; Tsompana, Maria; Cai, Liting; Wang, Yong; Buck, Michael J; Genco, Robert J; Baker, Robert D; Zhu, Ruixin; Zhu, Lixin

2018-04-01

A number of studies have associated obesity with altered gut microbiota, although results are discordant regarding compositional changes in the gut microbiota of obese animals. Herein we used a meta-analysis to obtain an unbiased evaluation of structural and functional changes of the gut microbiota in diet-induced obese rodents. The raw sequencing data of nine studies generated from high-fat diet (HFD)-induced obese rodent models were processed with QIIME to obtain gut microbiota compositions. Biological functions were predicted and annotated with KEGG pathways with PICRUSt. No significant difference was observed for alpha diversity and Bacteroidetes-to-Firmicutes ratio between obese and lean rodents. Bacteroidia, Clostridia, Bacilli, and Erysipelotrichi were dominant classes, but gut microbiota compositions varied among studies. Meta-analysis of the nine microbiome data sets identified 15 differential taxa and 57 differential pathways between obese and lean rodents. In obese rodents, increased abundance was observed for Dorea, Oscillospira, and Ruminococcus, known for fermenting polysaccharide into short chain fatty acids (SCFAs). Decreased Turicibacter and increased Lactococcus are consistent with elevated inflammation in the obese status. Differential functional pathways of the gut microbiome in obese rodents included enriched pyruvate metabolism, butanoate metabolism, propanoate metabolism, pentose phosphate pathway, fatty acid biosynthesis, and glycerolipid metabolism pathways. These pathways converge in the function of carbohydrate metabolism, SCFA metabolism, and biosynthesis of lipid. HFD-induced obesity results in structural and functional dysbiosis of gut microbiota. The altered gut microbiome may contribute to obesity development by promoting insulin resistance and systemic inflammation.

Default Mode Network Interference in Mild Traumatic Brain Injury – A Pilot Resting State Study

PubMed Central

Sours, Chandler; Zhuo, Jiachen; Janowich, Jacqueline; Aarabi, Bizhan; Shanmuganathan, Kathirkamanthan; Gullapalli, Rao P

2013-01-01

In this study we investigated the functional connectivity in 23 Mild TBI (mTBI) patients with and without memory complaints using resting state fMRI in the sub-acute stage of injury as well as a group of control participants. Results indicate that mTBI patients with memory complaints performed significantly worse than patients without memory complaints on tests assessing memory from the Automated Neuropsychological Assessment Metrics (ANAM). Altered functional connectivity was observed between the three groups between the default mode network (DMN) and the nodes of the task positive network (TPN). Altered functional connectivity was also observed between both the TPN and DMN and nodes associated with the Salience Network (SN). Following mTBI there is a reduction in anti-correlated networks for both those with and without memory complaints for the DMN, but only a reduction in the anti-correlated network in mTBI patients with memory complaints for the TPN. Furthermore, an increased functional connectivity between the TPN and SN appears to be associated with reduced performance on memory assessments. Overall the results suggest that a disruption in the segregation of the DMN and the TPN at rest may be mediated through both a direct pathway of increased FC between various nodes of the TPN and DMN, and through an indirect pathway that links the TPN and DMN through nodes of the SN. This disruption between networks may cause a detrimental impact on memory functioning following mTBI, supporting the Default Mode Interference Hypothesis in the context of mTBI related memory deficits. PMID:23994210

Default mode network interference in mild traumatic brain injury - a pilot resting state study.

PubMed

Sours, Chandler; Zhuo, Jiachen; Janowich, Jacqueline; Aarabi, Bizhan; Shanmuganathan, Kathirkamanthan; Gullapalli, Rao P

2013-11-06

In this study we investigated the functional connectivity in 23 Mild TBI (mTBI) patients with and without memory complaints using resting state fMRI in the sub-acute stage of injury as well as a group of control participants. Results indicate that mTBI patients with memory complaints performed significantly worse than patients without memory complaints on tests assessing memory from the Automated Neuropsychological Assessment Metrics (ANAM). Altered functional connectivity was observed between the three groups between the default mode network (DMN) and the nodes of the task positive network (TPN). Altered functional connectivity was also observed between both the TPN and DMN and nodes associated with the Salience Network (SN). Following mTBI there is a reduction in anti-correlated networks for both those with and without memory complaints for the DMN, but only a reduction in the anti-correlated network in mTBI patients with memory complaints for the TPN. Furthermore, an increased functional connectivity between the TPN and SN appears to be associated with reduced performance on memory assessments. Overall the results suggest that a disruption in the segregation of the DMN and the TPN at rest may be mediated through both a direct pathway of increased FC between various nodes of the TPN and DMN, and through an indirect pathway that links the TPN and DMN through nodes of the SN. This disruption between networks may cause a detrimental impact on memory functioning following mTBI, supporting the Default Mode Interference Hypothesis in the context of mTBI related memory deficits. © 2013 Elsevier B.V. All rights reserved.

Gestational exposure to perfluorooctanoic acid (PFOA): alterations in motor related behaviors

PubMed Central

Goulding, David R.; White, Sally S.; McBride, Sandra J.; Fenton, Suzanne E.; Harry, G. Jean

2016-01-01

Perfluoroalkyl and polyfluoroalkyl substances are used in commercial applications and developmental exposure has been implicated in alterations in neurobehavioral functioning. While associations between developmental perfluorooctanoic acid (PFOA) exposure and human outcomes have been inconsistent, studies in experimental animals suggest alterations in motor related behaviors. To examine a dose-response pattern of neurobehavioral effects following gestational exposure to PFOA, pregnant CD-1 mice received PFOA (0, 0.1, 0.3, 1.0 mg/kg/day) via oral gavage from gestational day 1–17 and the male offspring examined. Motor activity assessments on postnatal day (PND)18, 19, and 20 indicated a shift in the developmental pattern with an elevated activity level observed in the 1.0 mg/kg/day dose group on PND18. In the adult, no alterations were observed in body weights, activity levels, diurnal pattern of running wheel activity, startle response, or pre-pulse startle inhibition. In response to a subcutaneous injection of saline or nicotine (80 µg/kg), all animals displayed a transient increase in activity likely associated with handling with no differences observed across dose groups. Inhibition of motor activity over 18 days of 400µg/kg nicotine injection was not significantly different across dose groups. Hyperactivity induced by 2mg/kg (+)-methamphetamine hydrochloride intraperitoneal injection was significantly lower in the 1.0 mg/kg/day PFOA dose group as compared to controls. Taken together, these data suggest that the effects on motor-related behaviors with gestational PFOA exposure do not mimic those reported for acute postnatal exposure. Changes were not observed at dose level under 1.0 mg/kg/day PFOA. Further examination of pathways associated with methamphetamine-induced activity is warranted. PMID:27888120

Phencyclidine administration during neurodevelopment alters network activity in prefrontal cortex and hippocampus in adult rats.

PubMed

Kjaerby, Celia; Hovelsø, Nanna; Dalby, Nils Ole; Sotty, Florence

2017-08-01

Symptoms of schizophrenia have been linked to insults during neurodevelopment such as NMDA receptor (NMDAR) antagonist exposure. In animal models, this leads to schizophrenia-like behavioral symptoms as well as molecular and functional changes within hippocampal and prefrontal regions. The aim of this study was to determine how administration of the NMDAR antagonist phencyclidine (PCP) during neurodevelopment affects functional network activity within the hippocampus and medial prefrontal cortex (mPFC). We recorded field potentials in vivo after electrical brain stem stimulation and observed a suppression of evoked theta power in ventral hippocampus, while evoked gamma power in mPFC was enhanced in rats administered with PCP neonatally. In addition, increased gamma synchrony elicited by acute administration of the NMDAR antagonist MK-801 was exaggerated in neonatal PCP animals. These data suggest that NMDAR antagonist exposure during brain development alters functional networks within hippocampus and mPFC possibly contributing to the reported behavioral symptoms of this animal model of schizophrenia. NEW & NOTEWORTHY We show that insults with a NMDA receptor antagonist during neurodevelopment lead to suppressed evoked theta oscillations in ventral hippocampus in adult rats, while evoked gamma oscillations are enhanced and hypersensitive to an acute challenge with a NMDA receptor antagonist in prefrontal cortex. These observations reveal the significance of neurodevelopmental disturbances in the evolvement of schizophrenia-like symptoms and contribute to the understanding of the functional deficits underlying aberrant behavior in this disease. Copyright © 2017 the American Physiological Society.

Structural alterations of faecal and mucosa-associated bacterial communities in irritable bowel syndrome.

PubMed

Durbán, Ana; Abellán, Juan J; Jiménez-Hernández, Nuria; Salgado, Patricia; Ponce, Marta; Ponce, Julio; Garrigues, Vicente; Latorre, Amparo; Moya, Andrés

2012-04-01

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder in western countries. Previous studies on IBS, mostly based on faecal samples, suggest alterations in the intestinal microbiota. However, no consensus has been reached regarding the association between specific bacteria and IBS. We explore the alterations of intestinal bacterial communities in IBS using massive sequencing of amplified 16S rRNA genes. Mucosal biopsies of the ascending and descending colon and faeces from 16 IBS patients and 9 healthy controls were analysed. Strong inter-individual variation was observed in the composition of the bacterial communities in both patients and controls. These communities showed less diversity in IBS cases. There were larger differences in the microbiota composition between biopsies and faeces than between patients and controls. We found a few over-represented and under-represented taxa in IBS cases with respect to controls. The detected alterations varied by site, with no changes being consistent across sample types. © 2012 Society for Applied Microbiology and Blackwell Publishing Ltd.

Bisphenol A exposure leads to specific microRNA alterations in placental cells.

PubMed

Avissar-Whiting, Michele; Veiga, Keila R; Uhl, Kristen M; Maccani, Matthew A; Gagne, Luc A; Moen, Erika L; Marsit, Carmen J

2010-07-01

Exposure to bisphenol A (BPA) has been observed to alter developmental pathways and cell processes, at least in part, through epigenetic mechanisms. This study sought to investigate the effect of BPA on microRNAs (miRNAs) in human placental cells. miRNA microarray was performed following BPA treatment in three immortalized cytotrophoblast cell lines and the results validated using quantitative real-time PCR. For functional analysis, overexpression constructs were stably transfected into cells that were then assayed for changes in proliferation and response to toxicants. Microarray analysis revealed several miRNAs to be significantly altered in response to BPA treatment in two cell lines. Real-time PCR results confirmed that miR-146a was particularly strongly induced and its overexpression in cells led to slower proliferation as well as higher sensitivity to the DNA damaging agent, bleomycin. Overall, these results suggest that BPA can alter miRNA expression in placental cells, a potentially novel mode of BPA toxicity.

Bisphenol A Exposure Leads to Specific MicroRNA Alterations in Placental Cells

PubMed Central

Avissar-Whiting, Michele; Veiga, Keila; Uhl, Kristen; Maccani, Matthew; Gagne, Luc; Moen, Erika; Marsit, Carmen J.

2010-01-01

Exposure to bisphenol-A (BPA) has been observed to alter developmental pathways and cell processes, at least in part, through epigenetic mechanisms. This study sought to investigate the effect of BPA on microRNAs (miRNAs) in human placental cells. miRNA microarray was performed following BPA treatment in three immortalized cytotrophoblast cell lines and the results validated using quantitative real-time PCR. For functional analysis, overexpression constructs were stably transfected into cells that were then assayed for changes in proliferation and response to toxicants. Microarray analysis revealed several miRNAs to be significantly altered in response to BPA treatment in two cell lines. Real-time PCR results confirmed that miR-146a was particularly strongly induced and its overexpression in cells led to slower proliferation as well as higher sensitivity to the DNA damaging agent, bleomycin. Overall, these results suggest that BPA can alter miRNA expression in placental cells, a potentially novel mode of BPA toxicity. PMID:20417706

Testing a structural model for viral DNA packaging motor function by optical tweezers measurements, site directed mutagenesis, and molecular dynamics calculations

NASA Astrophysics Data System (ADS)

Keller, Nicholas A.; Migliori, Amy D.; Arya, Gaurav; Rao, Venigalla B.; Smith, Douglas E.

2013-09-01

Many double-stranded DNA viruses employ a molecular motor to package DNA into preformed capsid shells. Based on structures of phage T4 motor proteins determined by X-ray crystallography and cryo-electron microscopy, Rao, Rossmann and coworkers recently proposed a structural model for motor function. They proposed that DNA is ratcheted by a large conformational change driven by electrostatic interactions between charged residues at an interface between two globular domains of the motor protein. We have conducted experiments to test this model by studying the effect on packaging under applied load of site-directed changes altering these residues. We observe significant impairment of packaging activity including reductions in packaging rate, percent time packaging, and time active under high load. We show that these measured impairments correlate well with alterations in free energies associated with the conformational change predicted by molecular dynamics simulations.

Intrauterine growth restriction: impact on cardiovascular development and function throughout infancy.

PubMed

Cohen, Emily; Wong, Flora Y; Horne, Rosemary S C; Yiallourou, Stephanie R

2016-06-01

Intrauterine growth restriction (IUGR) refers to the situation where a fetus does not grow according to its genetic growth potential. One of the main causes of IUGR is uteroplacental vascular insufficiency. Under these circumstances of chronic oxygen and nutrient deprivation, the growth-restricted fetus often displays typical circulatory changes, which in part represent adaptations to the suboptimal intrauterine environment. These fetal adaptations aim to preserve oxygen and nutrient supply to vital organs such as the brain, the heart, and the adrenals. These prenatal circulatory adaptations are thought to lead to an altered development of the cardiovascular system and "program" the fetus for life long cardiovascular morbidities. In this review, we discuss the alterations to cardiovascular structure, function, and control that have been observed in growth-restricted fetuses, neonates, and infants following uteroplacental vascular insufficiency. We also discuss the current knowledge on early life surveillance and interventions to prevent progression into chronic disease.

Chronic Sleep Restriction during Pregnancy - Repercussion on Cardiovascular and Renal Functioning of Male Offspring

PubMed Central

Lima, Ingrid L. B.; Rodrigues, Aline F. A. C.; Bergamaschi, Cássia T.; Campos, Ruy R.; Hirata, Aparecida E.; Tufik, Sergio; Xylaras, Beatriz D. P.; Visniauskas, Bruna; Chagas, Jair R.; Gomes, Guiomar N.

2014-01-01

Changes in the maternal environment can induce fetal adaptations that result in the progression of chronic diseases in the offspring. The objective of the present study was to evaluate the effects of maternal chronic sleep restriction on blood pressure, renal function and cardiac baroreflex response on male offspring at adult age. Female 3-month-old Wistar rats were divided in two experimental groups: control (C) and chronic sleep restricted (CSR). Pregnancy was confirmed by vaginal smear. Chronic sleep restricted females were subjected to sleep restriction by the multiple platform technique for 20 h daily, between the 1st and 20th day of pregnancy. After birth, the litters were reduced to 6 rats per mother, and were designated as offspring from control (OC) and offspring from chronic sleep restricted (OCSR). Indirect blood pressure (BPi – tail cuff) was measured by plethysmography in male offspring at 3 months old. Following, the renal function and cardiac baroreflex response were analyzed. Values of BPi in OCSR were significantly higher compared to OC [OC: 127±2.6 (19); OCSR: 144±2.5 (17) mmHg]. The baroreflex sensitivity to the increase of blood pressure was reduced in OCSR [Slope: OC: −2.6±0.15 (9); OCRS: −1.6±0.13 (9)]. Hypothalamic activity of ACE2 was significantly reduced in OCSR compared to OC [OC: 97.4±15 (18); OSR: 60.2±3.6 (16) UAF/min/protein mg]. Renal function alteration was noticed by the increase in glomerular filtration rate (GFR) observed in OCSR [OC: 6.4±0.2 (10); OCSR: 7.4±0.3 (7)]. Chronic sleep restriction during pregnancy caused in the offspring hypertension, altered cardiac baroreflex response, reduced ACE-2 activity in the hypothalamus and renal alterations. Our data suggest that the reduction of sleeping time along the pregnancy is able to modify maternal homeostasis leading to functional alterations in offspring. PMID:25405471

Chronic sleep restriction during pregnancy--repercussion on cardiovascular and renal functioning of male offspring.

PubMed

Lima, Ingrid L B; Rodrigues, Aline F A C; Bergamaschi, Cássia T; Campos, Ruy R; Hirata, Aparecida E; Tufik, Sergio; Xylaras, Beatriz D P; Visniauskas, Bruna; Chagas, Jair R; Gomes, Guiomar N

2014-01-01

Changes in the maternal environment can induce fetal adaptations that result in the progression of chronic diseases in the offspring. The objective of the present study was to evaluate the effects of maternal chronic sleep restriction on blood pressure, renal function and cardiac baroreflex response on male offspring at adult age. Female 3-month-old Wistar rats were divided in two experimental groups: control (C) and chronic sleep restricted (CSR). Pregnancy was confirmed by vaginal smear. Chronic sleep restricted females were subjected to sleep restriction by the multiple platform technique for 20 h daily, between the 1st and 20th day of pregnancy. After birth, the litters were reduced to 6 rats per mother, and were designated as offspring from control (OC) and offspring from chronic sleep restricted (OCSR). Indirect blood pressure (BPi - tail cuff) was measured by plethysmography in male offspring at 3 months old. Following, the renal function and cardiac baroreflex response were analyzed. Values of BPi in OCSR were significantly higher compared to OC [OC: 127 ± 2.6 (19); OCSR: 144 ± 2.5 (17) mmHg]. The baroreflex sensitivity to the increase of blood pressure was reduced in OCSR [Slope: OC: -2.6 ± 0.15 (9); OCRS: -1.6 ± 0.13 (9)]. Hypothalamic activity of ACE2 was significantly reduced in OCSR compared to OC [OC: 97.4 ± 15 (18); OSR: 60.2 ± 3.6 (16) UAF/min/protein mg]. Renal function alteration was noticed by the increase in glomerular filtration rate (GFR) observed in OCSR [OC: 6.4 ± 0.2 (10); OCSR: 7.4 ± 0.3 (7)]. Chronic sleep restriction during pregnancy caused in the offspring hypertension, altered cardiac baroreflex response, reduced ACE-2 activity in the hypothalamus and renal alterations. Our data suggest that the reduction of sleeping time along the pregnancy is able to modify maternal homeostasis leading to functional alterations in offspring.

EEG sensorimotor rhythms' variation and functional connectivity measures during motor imagery: linear relations and classification approaches.

PubMed

Stefano Filho, Carlos A; Attux, Romis; Castellano, Gabriela

2017-01-01

Hands motor imagery (MI) has been reported to alter synchronization patterns amongst neurons, yielding variations in the mu and beta bands' power spectral density (PSD) of the electroencephalography (EEG) signal. These alterations have been used in the field of brain-computer interfaces (BCI), in an attempt to assign distinct MI tasks to commands of such a system. Recent studies have highlighted that information may be missing if knowledge about brain functional connectivity is not considered. In this work, we modeled the brain as a graph in which each EEG electrode represents a node. Our goal was to understand if there exists any linear correlation between variations in the synchronization patterns-that is, variations in the PSD of mu and beta bands-induced by MI and alterations in the corresponding functional networks. Moreover, we (1) explored the feasibility of using functional connectivity parameters as features for a classifier in the context of an MI-BCI; (2) investigated three different types of feature selection (FS) techniques; and (3) compared our approach to a more traditional method using the signal PSD as classifier inputs. Ten healthy subjects participated in this study. We observed significant correlations ( p  < 0.05) with values ranging from 0.4 to 0.9 between PSD variations and functional network alterations for some electrodes, prominently in the beta band. The PSD method performed better for data classification, with mean accuracies of (90 ± 8)% and (87 ± 7)% for the mu and beta band, respectively, versus (83 ± 8)% and (83 ± 7)% for the same bands for the graph method. Moreover, the number of features for the graph method was considerably larger. However, results for both methods were relatively close, and even overlapped when the uncertainties of the accuracy rates were considered. Further investigation regarding a careful exploration of other graph metrics may provide better alternatives.

Semen Quality and Sperm Function Loss by Hypercholesterolemic Diet Was Recovered by Addition of Olive Oil to Diet in Rabbit

PubMed Central

Romero, Aida A.; Funes, Abi K.; Cid-Barria, Macarena; Cabrillana, María E.; Monclus, María A.; Simón, Layla; Vicenti, Amanda E.; Fornés, Miguel W.

2013-01-01

Fat increment (0.05% cholesterol, chol) in standard diet promoted a significant increase in serum and sperm membrane chol, which ultimately altered membrane-coupled sperm specific functions: osmotic resistance, acrosomal reaction, and sperm capacitation in White New Zealand rabbits. These changes were also associated with a reduction in motility percentage and appearance of abnormal sperm morphology. The present study was carried out to evaluate the effect of dietary olive oil (OO, 7% v/w) administration to several male hypercholesterolemic rabbits (hypercholesterolemic rabbits, HCR) with altered fertility parameters. These HCR males were achieved by feeding normal rabbits with a high-fat diet (0.05% chol). HCR were associated with a modest non-significant increase in body weight (standard diet, 4.08±0.17 Kg, versus high-fat diet, 4.37±0.24 Kg). Hypercholesterolemic rabbits presented a marked decrease in semen volume, sperm cell count, and percentage of sperm motility, associated with a significant increase in sperm cell abnormalities. Moreover, sperm capacitation measured by the characteristic phosphorylated protein pattern in and induced acrosomal reaction were also altered suggesting sperm dysfunction. However, the administration of OO (for 16 weeks) to rabbits that were fed with 50% of the high-fat diet normalized serum chol. Curiously, OO supply succeeded to attenuate the seminal and sperm alterations observed in HCR group. Administration of OO alone did not cause any significant changes in above mentioned parameters. These data suggest that OO administration to HCR male rabbits recovers the loss of semen quality and sperm functionality. PMID:23326331

Differential proteomics study of platelets in asymptomatic constitutional macrothrombocytopenia: altered levels of cytoskeletal proteins.

PubMed

Karmakar, Shilpita; Saha, Sutapa; Banerjee, Debasis; Chakrabarti, Abhijit

2015-01-01

Harris platelet syndrome (HPS), also known as asymptomatic constitutional macrothrombocytopenia (ACMT), is an autosomal dominant platelet disorder characterized by mild-to-severe thrombocytopenia and giant platelets with normal platelet aggregation and absence of bleeding symptoms. We have attempted a comparative proteomics study for profiling of platelet proteins in healthy vs. pathological states to discover characteristic protein expression changes in macrothrombocytes and decipher the factors responsible for the functionally active yet morphologically distinct platelets. We have used 2-D gel-based protein separation techniques coupled with MALDI-ToF/ToF-based mass spectrometric identification and characterization of the proteins to investigate the differential proteome profiling of platelet proteins isolated from the peripheral blood samples of patients and normal volunteers. Our study revealed altered levels of actin-binding proteins such as myosin light chain, coactosin-like protein, actin-related protein 2/3 complex, and transgelin2 that hint toward the cytoskeletal changes necessary to maintain the structural and functional integrity of macrothrombocytes. We have also observed over expressed levels of peroxiredoxin2 that signifies the prevailing oxidative stress in these cells. Additionally, altered levels of protein disulfide isomerase and transthyretin provide insights into the measures adapted by the macrothrombocytes to maintain their normal functional activity. This first proteomics study of platelets from ACMT may provide an understanding of the structural stability and normal functioning of these platelets in spite of their large size. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Deleterious effects of tributyltin on porcine vascular stem cells physiology.

PubMed

Bernardini, Chiara; Zannoni, Augusta; Bertocchi, Martina; Bianchi, Francesca; Salaroli, Roberta; Botelho, Giuliana; Bacci, Maria Laura; Ventrella, Vittoria; Forni, Monica

2016-01-01

The vascular functional and structural integrity is essential for the maintenance of the whole organism and it has been demonstrated that different types of vascular progenitor cells resident in the vessel wall play an important role in this process. The purpose of the present research was to observe the effect of tributyltin (TBT), a risk factor for vascular disorders, on porcine Aortic Vascular Precursor Cells (pAVPCs) in term of cytotoxicity, gene expression profile, functionality and differentiation potential. We have demonstrated that pAVPCs morphology deeply changed following TBT treatment. After 48h a cytotoxic effect has been detected and Annexin binding assay demonstrated that TBT induced apoptosis. The transcriptional profile of characteristic pericyte markers has been altered: TBT 10nM substantially induced alpha-SMA, while, TBT 500nM determined a significant reduction of all pericyte markers. IL-6 protein detected in the medium of pAVPCs treated with TBT at both doses studied and with a dose response. TBT has interfered with normal pAVPC functionality preventing their ability to support a capillary-like network. In addition TBT has determined an increase of pAVPC adipogenic differentiation. In conclusion in the present paper we have demonstrated that TBT alters the vascular stem cells in terms of structure, functionality and differentiating capability, therefore effects of TBT in blood should be deeply explored to understand the potential vascular risk associated with the alteration of vascular stem cell physiology. Copyright © 2016 Elsevier Inc. All rights reserved.

Increasing protein production rates can decrease the rate at which functional protein is produced

NASA Astrophysics Data System (ADS)

Sharma, Ajeet; O'Brien, Edward

The rate at which soluble, functional protein is produced by the ribosome has recently been found to vary in complex and unexplained ways as various translation-associated rates are altered through synonymous codon substitutions. We combine a well-established ribosome-traffic model with a master-equation model of co-translational domain folding to explore the scenarios that are possible for the protein production rate, J, and the functional-nascent protein production rate, F, as the rates associated with translation are altered. We find that while J monotonically increases as the rates of translation-initiation, -elongation and -termination increase, F can either increase or decrease. F exhibits non-monotonic behavior because increasing these rates can cause a protein to be synthesized more rapidly but provide less time for nascent-protein domains to co-translationally fold thereby producing less functional nascent protein immediately after synthesis. We further demonstrate that these non-monotonic changes in Faffect the post-translational, steady-state levels of functional protein in a similar manner. Our results provide a possible explanation for recent experimental observations that the specific activity of enzymatic proteins can decrease with increased synthesis rates and can in principle be used to rationally-design transcripts to maximize the production of functional nascent protein.

Impact of early childhood caries and its treatment under general anesthesia on orofacial function and quality of life : A prospective comparative study.

PubMed

Collado, V; Pichot, H; Delfosse, C; Eschevins, C; Nicolas, E; Hennequin, M

2017-05-01

Early Childhood Caries (ECC) has become a major public health concern worldwide, mostly affecting children from disadvantaged families in increasingly severe forms. This condition has been frequently reported to alter children's nutrition, growth and general development. It negatively impacts their quality of life, through painful episodes and severe eating difficulties. While this period is crucial for oral praxes development, the impact of dental state on oro-facial functions is poorly documented. This study evaluated the impact of ECC and its treatment under general anesthesia on oro-facial functions and quality of life in pre-school children. The dysfunction and quality of life scores from 25 children with ECC were evaluated before treatment (T0), one month (T1) and three months after treatment (T2), using the Nordic Orofacial Test-Screening (NOT-S) and the Early Childhood Oral Health Impact Scale (ECOHIS), respectively, in comparison with 16 caries-free children. The number and extent of inter-arch dental contacts were also observed. The pre-operative higher NOT-S score observed in children with ECC decreased to reach the control level at T2. The mastication item was the most affected in the ECC group throughout the study. Their mean ECOHIS score also significantly decreased post-operatively and differences remaining between both groups were no longer clinically relevant. In addition, in children with ECC, values of functional inter-arch surfaces tended to increase over the follow-up period. Oro-facial functions and quality of life, altered by ECC, could be restored through a conservative treatment approach. Relations between dental state, orofacial functions and particularly chewing, and nutrition should be investigated further.

Chronic alcohol disrupts dopamine receptor activity and the cognitive function of the medial prefrontal cortex.

PubMed

Trantham-Davidson, Heather; Burnett, Elizabeth J; Gass, Justin T; Lopez, Marcelo F; Mulholland, Patrick J; Centanni, Samuel W; Floresco, Stan B; Chandler, L Judson

2014-03-05

Dopamine (DA) receptors in the medial prefrontal cortex (mPFC) exert powerful effects on cognition by modulating the balance between excitatory and inhibitory neurotransmission. The present study examined the impact of chronic intermittent ethanol (CIE) exposure on cognitive function and DA receptor-mediated neurotransmission in the rat mPFC. Consistent with alterations in executive function in alcoholics, CIE-exposed rats exhibited deficits in behavioral flexibility in an operant set-shifting task. Since alterations in dopaminergic neurotransmission in the mPFC have been implicated in a number of behavioral disorders including addiction, studies were then performed in the adult acute slice preparation to examine changes in DA receptor function in the mPFC following CIE exposure. In slices obtained from control rats, DA receptor stimulation was observed to exert complex actions on neuronal firing and synaptic neurotransmission that were not only dependent upon the particular receptor subtype but also whether it was a pyramidal cell or a fast-spiking interneuron. In contrast to slices from control rats, there was a near complete loss of the modulatory actions of D2/D4 receptors on cell firing and neurotransmission in slices obtained immediately, 1 and 4 weeks after the last day of CIE exposure. This loss did not appear to be associated with changes in receptor expression. In contrast, CIE exposure did not alter D1 receptor function or mGluR1 modulation of firing. These studies are consistent with the suggestion that chronic alcohol exposure disrupts cognitive function at least in part through disruption of D2 and D4 receptor signaling in mPFC.

Sex and disease-related alterations of anterior insula functional connectivity in chronic abdominal pain.

PubMed

Hong, Jui-Yang; Kilpatrick, Lisa A; Labus, Jennifer S; Gupta, Arpana; Katibian, David; Ashe-McNalley, Cody; Stains, Jean; Heendeniya, Nuwanthi; Smith, Suzanne R; Tillisch, Kirsten; Naliboff, Bruce; Mayer, Emeran A

2014-10-22

Resting-state functional magnetic resonance imaging has been used to investigate intrinsic brain connectivity in healthy subjects and patients with chronic pain. Sex-related differences in the frequency power distribution within the human insula (INS), a brain region involved in the integration of interoceptive, affective, and cognitive influences, have been reported. Here we aimed to test sex and disease-related alterations in the intrinsic functional connectivity of the dorsal anterior INS. The anterior INS is engaged during goal-directed tasks and modulates the default mode and executive control networks. By comparing functional connectivity of the dorsal anterior INS in age-matched female and male healthy subjects and patients with irritable bowel syndrome (IBS), a common chronic abdominal pain condition, we show evidence for sex and disease-related alterations in the functional connectivity of this region: (1) male patients compared with female patients had increased positive connectivity of the dorsal anterior INS bilaterally with the medial prefrontal cortex (PFC) and dorsal posterior INS; (2) female patients compared with male patients had greater negative connectivity of the left dorsal anterior INS with the left precuneus; (3) disease-related differences in the connectivity between the bilateral dorsal anterior INS and the dorsal medial PFC were observed in female subjects; and (4) clinical characteristics were significantly correlated to the insular connectivity with the dorsal medial PFC in male IBS subjects and with the precuneus in female IBS subjects. These findings are consistent with the INS playing an important role in modulating the intrinsic functional connectivity of major networks in the resting brain and show that this role is influenced by sex and diagnosis. Copyright © 2014 the authors 0270-6474/14/3414252-08$15.00/0.

Differential Functional Connectivity Alterations of Two Subdivisions within the Right dlPFC in Parkinson's Disease

PubMed Central

Caspers, Julian; Mathys, Christian; Hoffstaedter, Felix; Südmeyer, Martin; Cieslik, Edna C.; Rubbert, Christian; Hartmann, Christian J.; Eickhoff, Claudia R.; Reetz, Kathrin; Grefkes, Christian; Michely, Jochen; Turowski, Bernd; Schnitzler, Alfons; Eickhoff, Simon B.

2017-01-01

Patients suffering from Parkinson's disease (PD) often show impairments in executive function (EF) like decision-making and action control. The right dorsolateral prefrontal cortex (dlPFC) has been strongly implicated in EF in healthy subjects and has repeatedly been reported to show alterations related to EF impairment in PD. Recently, two key regions for cognitive action control have been identified within the right dlPFC by co-activation based parcellation. While the posterior region is engaged in rather basal EF like stimulus integration and working memory, the anterior region has a more abstract, supervisory function. To investigate whether these functionally distinct subdivisions of right dlPFC are differentially affected in PD, we analyzed resting-state functional connectivity (FC) in 39 PD patients and 44 age- and gender-matched healthy controls. Patients were examined both after at least 12 h withdrawal of dopaminergic drugs (OFF) and under their regular dopaminergic medication (ON). We found that only the posterior right dlPFC subdivision shows FC alterations in PD, while the anterior part remains unaffected. PD-related decreased FC with posterior right dlPFC was found in the bilateral medial posterior parietal cortex (mPPC) and left dorsal premotor region (PMd) in the OFF state. In the medical ON, FC with left PMd normalized, while decoupling with bilateral mPPC remained. Furthermore, we observed increased FC between posterior right dlPFC and the bilateral dorsomedial prefrontal cortex (dmPFC) in PD in the ON state. Our findings point to differential disturbances of right dlPFC connectivity in PD, which relate to its hierarchical organization of EF processing by stronger affecting the functionally basal posterior aspect than the hierarchically higher anterior part. PMID:28611616

Obesity Determines the Immunophenotypic Profile and Functional Characteristics of Human Mesenchymal Stem Cells From Adipose Tissue

PubMed Central

Pachón-Peña, Gisela; Serena, Carolina; Ejarque, Miriam; Petriz, Jordi; Duran, Xevi; Oliva-Olivera, W.; Simó, Rafael; Tinahones, Francisco J.

2016-01-01

Adipose tissue is a major source of mesenchymal stem cells (MSCs), which possess a variety of properties that make them ideal candidates for regenerative and immunomodulatory therapies. Here, we compared the immunophenotypic profile of human adipose-derived stem cells (hASCs) from lean and obese individuals, and explored its relationship with the apparent altered plasticity of hASCs. We also hypothesized that persistent hypoxia treatment of cultured hASCs may be necessary but not sufficient to drive significant changes in mature adipocytes. hASCs were obtained from subcutaneous adipose tissue of healthy, adult, female donors undergoing abdominal plastic surgery: lean (n = 8; body mass index [BMI]: 23 ± 1 kg/m2) and obese (n = 8; BMI: 35 ± 5 kg/m2). Cell surface marker expression, proliferation and migration capacity, and adipogenic differentiation potential of cultured hASCs at two different oxygen conditions were studied. Compared with lean-derived hASCs, obese-derived hASCs demonstrated increased proliferation and migration capacity but decreased lipid droplet accumulation, correlating with a higher expression of human leukocyte antigen (HLA)-II and cluster of differentiation (CD) 106 and lower expression of CD29. Of interest, adipogenic differentiation modified CD106, CD49b, HLA-ABC surface protein expression, which was dependent on the donor’s BMI. Additionally, low oxygen tension increased proliferation and migration of lean but not obese hASCs, which correlated with an altered CD36 and CD49b immunophenotypic profile. In summary, the differences observed in proliferation, migration, and differentiation capacity in obese hASCs occurred in parallel with changes in cell surface markers, both under basal conditions and during differentiation. Therefore, obesity is an important determinant of stem cell function independent of oxygen tension. Significance The obesity-related hypoxic environment may have latent effects on human adipose tissue-derived mesenchymal stem cells (hASCs) with potential consequences in mature cells. This study explores the immunophenotypic profile of hASCs obtained from lean and obese individuals and its potential relationship with the altered plasticity of hASCs observed in obesity. In this context, an altered pattern of cell surface marker expression in obese-derived hASCs in both undifferentiated and differentiated stages is demonstrated. Differences in proliferation, migration, and differentiation capacity of hASCs from obese adipose tissue correlated with alterations in cell surface expression. Remarkably, altered plasticity observed in obese-derived hASCs was maintained in the absence of hypoxia, suggesting that these cells might be obesity conditioned. PMID:26956208

Physiologic and biochemical aspects of skeletal muscle denervation and reinnervation

NASA Technical Reports Server (NTRS)

Max, S. R.; Mayer, R. F.

1984-01-01

Some of the physiologic and biochemical changes that occur in mammalian skeletal muscle following denervation and reinnervation are considered and some comparisons are made with changes observed following altered motor function. The nature of the trophic influence by which nerves control muscle properties are discussed, including the effects of choline acetyltransferase and acetylcholinesterase and the role of the acetylcholine receptor.

Duration of breast feeding and arterial distensibility in early adult life: population based study.

PubMed

Leeson, C P; Kattenhorn, M; Deanfield, J E; Lucas, A

2001-03-17

To test the hypothesis that duration of breast feeding is related to changes in vascular function relevant to the development of cardiovascular disease. Population based observational study. Cambridge. 331 adults (171 women, 160 men) aged between 20 and 28 years, born in Cambridge Maternity Hospital. Distensibility of brachial artery, type and duration of infant feeding, current lipid profile, and other cardiovascular risk factors. The longer the period of breast feeding the less distensible the artery wall in early adult life, with no sex differences (regression coefficient = -3.93 micrometer/month, 95% confidence interval -7.29 to -0.57, P=0.02). However, in those breast fed for less than four months, arterial distensibility was not significantly reduced compared with an exclusively formula fed group. The vascular changes observed were not explained by alterations in plasma cholesterol concentration in adult life. Breast feeding in infancy is related to reduced arterial function 20 years later. These data should not alter current recommendations in favour of breast feeding, which has several benefits for infant health. Further work is needed, however, to explore the optimal duration of breast feeding in relation to cardiovascular outcomes.

Functional Implications of the IL-23/IL-17 Immune Axis in Schizophrenia.

PubMed

Debnath, Monojit; Berk, Michael

2017-12-01

The aetiology of schizophrenia seems to stem from complex interactions amongst environmental, genetic, metabolic, immunologic and oxidative components. Chronic low-grade inflammation has been persistently linked to schizophrenia, and this has primarily been based on the findings derived from Th1/Th2 cytokine balance. While the IL-23/IL-17 axis plays crucial role in the pathogenesis of several immune-mediated disorders, it has remained relatively unexplored in neuropsychiatric disorders. Altered levels of cytokines related to IL-23/IL-17 axis have been observed in schizophrenia patients in a few studies. In addition, other indirect factors known to confer schizophrenia risk like complement activation and altered gut microbiota are shown to modulate the IL-23/IL-17 axis. These preliminary observations provide crucial clues about the functional implications of IL-23/IL-17 axis in schizophrenia. In this review, an attempt has been made to highlight the biology of IL-23/IL-17 axis and its relevance to schizophrenia risk and pathogenesis. Given the pathogenic potential of the IL-23/IL-17 axis, therapeutic targeting of this axis may be a promising approach to benefit patients suffering from this devastating disorder.

Characterizing genomic alterations in cancer by complementary functional associations.

PubMed

Kim, Jong Wook; Botvinnik, Olga B; Abudayyeh, Omar; Birger, Chet; Rosenbluh, Joseph; Shrestha, Yashaswi; Abazeed, Mohamed E; Hammerman, Peter S; DiCara, Daniel; Konieczkowski, David J; Johannessen, Cory M; Liberzon, Arthur; Alizad-Rahvar, Amir Reza; Alexe, Gabriela; Aguirre, Andrew; Ghandi, Mahmoud; Greulich, Heidi; Vazquez, Francisca; Weir, Barbara A; Van Allen, Eliezer M; Tsherniak, Aviad; Shao, Diane D; Zack, Travis I; Noble, Michael; Getz, Gad; Beroukhim, Rameen; Garraway, Levi A; Ardakani, Masoud; Romualdi, Chiara; Sales, Gabriele; Barbie, David A; Boehm, Jesse S; Hahn, William C; Mesirov, Jill P; Tamayo, Pablo

2016-05-01

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes.

Functions of Huntingtin in Germ Layer Specification and Organogenesis

PubMed Central

Nguyen, Giang D.; Molero, Aldrin E.; Gokhan, Solen; Mehler, Mark F.

2013-01-01

Huntington’s disease (HD) is a neurodegenerative disease caused by abnormal polyglutamine expansion in the huntingtin protein (Htt). Although both Htt and the HD pathogenic mutation (mHtt) are implicated in early developmental events, their individual involvement has not been adequately explored. In order to better define the developmental functions and pathological consequences of the normal and mutant proteins, respectively, we employed embryonic stem cell (ESC) expansion, differentiation and induction experiments using huntingtin knock-out (KO) and mutant huntingtin knock-in (Q111) mouse ESC lines. In KO ESCs, we observed impairments in the spontaneous specification and survival of ectodermal and mesodermal lineages during embryoid body formation and under inductive conditions using retinoic acid and Wnt3A, respectively. Ablation of BAX improves cell survival, but failed to correct defects in germ layer specification. In addition, we observed ensuing impairments in the specification and maturation of neural, hepatic, pancreatic and cardiomyocyte lineages. These developmental deficits occurred in concert with alterations in Notch, Hes1 and STAT3 signaling pathways. Moreover, in Q111 ESCs, we observed differential developmental stage-specific alterations in lineage specification and maturation. We also observed changes in Notch/STAT3 expression and activation. Our observations underscore essential roles of Htt in the specification of ectoderm, endoderm and mesoderm, in the specification of neural and non-neural organ-specific lineages, as well as cell survival during early embryogenesis. Remarkably, these developmental events are differentially deregulated by mHtt, raising the possibility that HD-associated early developmental impairments may contribute not only to region-specific neurodegeneration, but also to non-neural co-morbidities. PMID:23967334

Functional diversification and specialization of cytosolic 70-kDa heat shock proteins.

PubMed

McCallister, Chelsea; Siracusa, Matthew C; Shirazi, Farzaneh; Chalkia, Dimitra; Nikolaidis, Nikolas

2015-03-20

A fundamental question in molecular evolution is how protein functional differentiation alters the ability of cells and organisms to cope with stress and survive. To answer this question we used two paralogous Hsp70s from mouse and explored whether these highly similar cytosolic molecular chaperones, which apart their temporal expression have been considered functionally interchangeable, are differentiated with respect to their lipid-binding function. We demonstrate that the two proteins bind to diverse lipids with different affinities and therefore are functionally specialized. The observed lipid-binding patterns may be related with the ability of both Hsp70s to induce cell death by binding to a particular plasma-membrane lipid, and the potential of only one of them to promote cell survival by binding to a specific lysosomal-membrane lipid. These observations reveal that two seemingly identical proteins differentially modulate cellular adaptation and survival by having acquired specialized functions via sequence divergence. Therefore, this study provides an evolutionary paradigm, where promiscuity, specificity, sub- and neo-functionalization orchestrate one of the most conserved systems in nature, the cellular stress-response.

Altered resting brain function and structure in professional badminton players.

PubMed

Di, Xin; Zhu, Senhua; Jin, Hua; Wang, Pin; Ye, Zhuoer; Zhou, Ke; Zhuo, Yan; Rao, Hengyi

2012-01-01

Neuroimaging studies of professional athletic or musical training have demonstrated considerable practice-dependent plasticity in various brain structures, which may reflect distinct training demands. In the present study, structural and functional brain alterations were examined in professional badminton players and compared with healthy controls using magnetic resonance imaging (MRI) and resting-state functional MRI. Gray matter concentration (GMC) was assessed using voxel-based morphometry (VBM), and resting-brain functions were measured by amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity. Results showed that the athlete group had greater GMC and ALFF in the right and medial cerebellar regions, respectively. The athlete group also demonstrated smaller ALFF in the left superior parietal lobule and altered functional connectivity between the left superior parietal and frontal regions. These findings indicate that badminton expertise is associated with not only plastic structural changes in terms of enlarged gray matter density in the cerebellum, but also functional alterations in fronto-parietal connectivity. Such structural and functional alterations may reflect specific experiences of badminton training and practice, including high-capacity visuo-spatial processing and hand-eye coordination in addition to refined motor skills.

Congenital ureteropelvic junction obstruction: human disease and animal models

PubMed Central

Klein, Julie; Gonzalez, Julien; Miravete, Mathieu; Caubet, Cécile; Chaaya, Rana; Decramer, Stéphane; Bandin, Flavio; Bascands, Jean-Loup; Buffin-Meyer, Bénédicte; Schanstra, Joost P

2011-01-01

Ureteropelvic junction (UPJ) obstruction is the most frequently observed cause of obstructive nephropathy in children. Neonatal and foetal animal models have been developed that mimic closely what is observed in human disease. The purpose of this review is to discuss how obstructive nephropathy alters kidney histology and function and describe the molecular mechanisms involved in the progression of the lesions, including inflammation, proliferation/apoptosis, renin–angiotensin system activation and fibrosis, based on both human and animal data. Also we propose that during obstructive nephropathy, hydrodynamic modifications are early inducers of the tubular lesions, which are potentially at the origin of the pathology. Finally, an important observation in animal models is that relief of obstruction during kidney development has important effects on renal function later in adult life. A major short-coming is the absence of data on the impact of UPJ obstruction on long-term adult renal function to elucidate whether these animal data are also valid in humans. PMID:20681980

Longitudinal assessment of chemotherapy-induced changes in brain and cognitive functioning: A systematic review.

PubMed

Li, Mingmei; Caeyenberghs, Karen

2018-05-20

In addition to the burden of a life-threatening diagnosis, cancer patients are struggling with adverse side-effects from cancer treatment. Chemotherapy has been linked to an array of cognitive impairments and alterations in brain structure and function ("chemobrain"). In this review, we summarized the existing evidence that evaluate the changes in cognitive functioning and brain with chemotherapy, as assessed using structural and functional MRI-based techniques in a longitudinal design. This review followed the latest PRISMA guidelines using Embase, Medline, PsychINFO, Scopus, and Web of Science databases with date restrictions from 2012-2017. Fourteen research articles met the key inclusion criteria: (i) the studies involved adult cancer patients (mean age≥18); (ii) the use of chemotherapy in the treatment of cancer; (iii) pre-post assessment of behavioral and brain-based outcomes; and (iv) abstracts written in English. Effect sizes of subjective and objective cognitive impairments from the reviewed studies were estimated using Cohen's d or z-scores. We calculated percentage of mean change or effect sizes for main neuroimaging findings when data were available. Strength of the correlations between brain alterations and cognitive changes was obtained using squared correlation coefficients. We showed small to medium effect sizes on individual tests of attention, processing speed, verbal memory, and executive control; and medium effect sizes on self-report questionnaires. Neuroimaging data showed reduced grey matter density in cancer patients in frontal, parietal, and temporal regions. Changes in brain function (brain activation and cerebral blood flow) were observed with cancer across functional networks involving (pre)frontal, parietal, occipital, temporal, and cerebellar regions. Data from diffusion-weighted MRI suggested reduced white matter integrity involving the superior longitudinal fasciculus, corpus callosum, forceps major, and corona radiate, and altered structural connectivity across the whole brain network. Finally, we observed moderate-to-strong correlations between worsening cognitive function and morphological changes in frontal brain regions. While MRI is a powerful tool for detection of longitudinal brain changes in the 'chemobrain', the underlying biological mechanisms are still unclear. Continued work in this field will hopefully detect MRI metrics to be used as biomarkers to help guide cognitive treatment at the individual cancer patient level. Copyright © 2018. Published by Elsevier Ltd.

Human land-use and soil change

USGS Publications Warehouse

Wills, Skye A.; Williams, Candiss O.; Duniway, Michael C.; Veenstra, Jessica; Seybold, Cathy; Pressley, DeAnn

2017-01-01

Soil change refers to the alteration of soil and soil properties over time in one location, as opposed to soil variability across space. Although soils change with pedogensis, this chapter focuses on human caused soil change. Soil change can occur with human use and management over long or short time periods and small or large scales. While change can be negative or positive; often soil change is observed when short-term or narrow goals overshadow the other soil’s ecosystem services. Many soils have been changed in their chemical, physical or biological properties through agricultural activities, including cultivation, tillage, weeding, terracing, subsoiling, deep plowing, manure and fertilizer addition, liming, draining, and irrigation. Assessing soil change depends upon the ecosystem services and soil functions being evaluated. The interaction of soil properties with the type and intensity of management and disturbance determines the changes that will be observed. Tillage of cropland disrupts aggregates and decreases soil organic carbon content which can lead to decreased infiltration, increased erosion, and reduced biological function. Improved agricultural management systems can increase soil functions including crop productivity and sustainability. Forest management is most intensive during harvesting and seedling establishment. Most active management in forests causes disturbance of the soil surface which may include loss of forest floor organic materials, increases in bulk density, and increased risk of erosion. In grazing lands, pasture management often includes periods of biological, chemical and physical disturbance in addition to the grazing management imposed on rangelands. Grazing animals have both direct and indirect impacts on soil change. Hoof action can lead to the disturbance of biological crusts and other surface features impairing the soil’s physical, biological and hydrological function. There are clear feedbacks between vegetative systems and soil properties; when vegetation is altered because of grazing or other disturbances, soil property changes often follow. Some soils are very sensitive to management and disturbance and can undergo rapid change: cropping led to massive gully formation in the southeastern USA, exposure of acid-sulfate soils led to irreversible changes in soil minerology and thawing of cold soils has created thermokarst features. These soil changes alter soil properties and functions and may impact soil ecosystem services far into the future.

Non-invasive imaging of flow and vascular function in disease of the aorta

PubMed Central

Whitlock, Matthew C.; Hundley, W. Gregory

2015-01-01

With advancements in technology and a better understanding of human cardiovascular physiology, research as well as clinical care can go beyond dimensional anatomy offered by traditional imaging and investigate aortic functional properties and the impact disease has on this function. Linking the knowledge of the histopathological changes with the alterations in aortic function observed on noninvasive imaging results in a better understanding of disease pathophysiology. Translating this to clinical medicine, these noninvasive imaging assessments of aortic function are proving to be able to diagnosis disease, better predict risk, and assess response to therapies. This review is designed to summarize the various hemodynamic measures that can characterize the aorta, the various non-invasive techniques, and applications for various disease states. PMID:26381770

Clinical evaluation of patients with moderate to severe Alzheimer disease.

PubMed

Varandas, Paulo Rogério Borges Rosmaninho; Funari, Rossana Russo

2007-01-01

Today, Alzheimer disease has become a serious risk to individual and public health, due to the significant incapacity it causes patients, its influence on family members and caregivers, along with the ensuing direct and indirect costs. To build the profile of patients with moderate/severe AD, in the Geriatric Clinic Service of Cognitive Alterations of the Medical School at Universidade de São Paulo, by studying demential and comorbidity conditions and the degree of effectiveness of the therapies applied. 30 patients with moderate or severe AD were selected, (77.8±7.29 years). Age, sex, schooling, prevalent comorbidities/treatments and respective clinical-laboratorial effectiveness were analyzed. Instruments were applied to evaluate the cognitive and behavioral condition and dementia control therapies. Most frequent comorbidities were arterial hypertension (80%) and diabetes (43.3%). A maximum dose of rivastigmine was observed in 43% of the patients, where 76% experienced adverse effects. Severe patients presented more cases of uncontrolled comorbidities, such as hypertension (P<0.001), as well as more behavioral alterations (P<0.001) and functional loss (P=0.004). Patients with greater behavioral alterations proved to be more functionally dependent (P=0.002), having less comorbidity control (P=0.004). In this population, a high incidence of comorbidities, frequent behavioral alterations and difficulties in therapy management were noted due to the severity of the dementia condition. New therapies for more adequate control of severe dementia should be studied.

High-salt diets during pregnancy affected fetal and offspring renal renin-angiotensin system.

PubMed

Mao, Caiping; Liu, Rong; Bo, Le; Chen, Ningjing; Li, Shigang; Xia, Shuixiu; Chen, Jie; Li, Dawei; Zhang, Lubo; Xu, Zhice

2013-07-01

Intrauterine environments are related to fetal renal development and postnatal health. Influence of salty diets during pregnancy on renal functions and renin-angiotensin system (RAS) was determined in the ovine fetuses and offspring. Pregnant ewes were fed high-salt diet (HSD) or normal-salt diet (NSD) for 2 months during middle-to-late gestation. Fetal renal functions, plasma hormones, and mRNA and protein expressions of the key elements of renal RAS were measured in the fetuses and offspring. Fetal renal excretion of sodium was increased while urine volume decreased in the HSD group. Fetal blood urea nitrogen was increased, while kidney weight:body weight ratio decreased in the HSD group. The altered ratio was also observed in the offspring aged 15 and 90 days. Maternal and fetal plasma antidiuretic hormone was elevated without changes in plasma renin activity and Ang I levels, while plasma Ang II was decreased. The key elements of local renal RAS, including angiotensinogen, angiotensin converting enzyme (ACE), ACE2, AT1, and AT2 receptor expression in both mRNA and protein, except renin, were altered following maternal high salt intake. The results suggest that high intake of salt during pregnancy affected fetal renal development associated with an altered expression of the renal key elements of RAS, some alterations of fetal origins remained after birth as possible risks in developing renal or cardiovascular diseases.

Visual impairment in FOXG1-mutated individuals and mice.

PubMed

Boggio, E M; Pancrazi, L; Gennaro, M; Lo Rizzo, C; Mari, F; Meloni, I; Ariani, F; Panighini, A; Novelli, E; Biagioni, M; Strettoi, E; Hayek, J; Rufa, A; Pizzorusso, T; Renieri, A; Costa, M

2016-06-02

The Forkead Box G1 (FOXG1 in humans, Foxg1 in mice) gene encodes for a DNA-binding transcription factor, essential for the development of the telencephalon in mammalian forebrain. Mutations in FOXG1 have been reported to be involved in the onset of Rett Syndrome, for which sequence alterations of MECP2 and CDKL5 are known. While visual alterations are not classical hallmarks of Rett syndrome, an increasing body of evidence shows visual impairment in patients and in MeCP2 and CDKL5 animal models. Herein we focused on the functional role of FOXG1 in the visual system of animal models (Foxg1(+/Cre) mice) and of a cohort of subjects carrying FOXG1 mutations or deletions. Visual physiology of Foxg1(+/Cre) mice was assessed by visually evoked potentials, which revealed a significant reduction in response amplitude and visual acuity with respect to wild-type littermates. Morphological investigation showed abnormalities in the organization of excitatory/inhibitory circuits in the visual cortex. No alterations were observed in retinal structure. By examining a cohort of FOXG1-mutated individuals with a panel of neuro-ophthalmological assessments, we found that all of them exhibited visual alterations compatible with high-level visual dysfunctions. In conclusion our data show that Foxg1 haploinsufficiency results in an impairment of mouse and human visual cortical function. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Airway structure and function in Eisenmenger's syndrome.

PubMed

McKay, K O; Johnson, P R; Black, J L; Glanville, A R; Armour, C L

1998-10-01

The responsiveness of airways from patients with Eisenmenger's syndrome (n = 5) was compared with that in airways from organ donors (n = 10). Enhanced contractile responses to cholinergic stimulation were found in airways from patients with Eisenmenger's syndrome. The maximal responses to acetylcholine, carbachol, and parasympathetic nerve stimulation in airway tissue from these patients were 221%, 139%, and 152%, respectively, of the maximal responses obtained in donor tissue. Further, relaxation responses to isoproterenol and levocromakalim were absent (n = 2) or markedly impaired (n = 3) in airways from patients with Eisenmenger's syndrome. This attenuated relaxation response was nonspecific in that it was also absent after vasoactive intestinal peptide, sodium nitroprusside, papaverine, and electrical field application. These observations can most likely be explained by a decrease in intrinsic smooth muscle tone, as precontraction of airways revealed relaxation responses that were equivalent to those obtained in donor tissues. Morphometric analysis of tissues used for the functional studies revealed no differences in the airway dimensions (internal perimeter) or airway wall components (e.g., smooth muscle, cartilage) or total area to explain these observations. Although the mechanism for this observed decrease in intrinsic airway smooth muscle tone is not certain, it may be due to alteration in the substructure of the airway wall or, alternatively, may result from the continued release of depressant factors in the vicinity of the smooth muscle which permanently alters smooth muscle responsiveness.

Bipolar disorder: a neural network perspective on a disorder of emotion and motivation.

PubMed

Wessa, Michèle; Kanske, Philipp; Linke, Julia

2014-01-01

Bipolar disorder (BD) is a severe, chronic disease with a heritability of 60-80%. BD is frequently misdiagnosed due to phenomenological overlap with other psychopathologies, an important issue that calls for the identification of biological and psychological vulnerability and disease markers. Altered structural and functional connectivity, mainly between limbic and prefrontal brain areas, have been proposed to underlie emotional and motivational dysregulation in BD and might represent relevant vulnerability and disease markers. In the present laboratory review we discuss functional and structural neuroimaging findings on emotional and motivational dysregulation from our research group in BD patients and healthy individuals at risk to develop BD. As a main result of our studies, we observed altered orbitofrontal and limbic activity and reduced connectivity between dorsal prefrontal and limbic brain regions, as well as reduced integrity of fiber tracts connecting prefrontal and subcortical brain structures in BD patients and high-risk individuals. Our results provide novel insights into pathophysiological mechanisms of bipolar disorder. The current laboratory review provides a specific view of our group on altered brain connectivity and underlying psychological processes in bipolar disorder based on our own work, integrating relevant findings from others. Thereby we attempt to advance neuropsychobiological models of BD.

The CD20 homologue MS4A4 directs trafficking of KIT toward clathrin-independent endocytosis pathways and thus regulates receptor signaling and recycling

PubMed Central

Cruse, Glenn; Beaven, Michael A.; Music, Stephen C.; Bradding, Peter; Gilfillan, Alasdair M.; Metcalfe, Dean D.

2015-01-01

MS4A family members differentially regulate the cell cycle, and aberrant, or loss of, expression of MS4A family proteins has been observed in colon and lung cancer. However, the precise functions of MS4A family proteins and their mechanistic interactions remain unsolved. Here we report that MS4A4 facilitates trafficking of the receptor tyrosine kinase KIT through endocytic recycling rather than degradation pathways by a mechanism that involves recruitment of KIT to caveolin-1–enriched microdomains. Silencing of MS4A4 in human mast cells altered ligand-induced KIT endocytosis pathways and reduced receptor recycling to the cell surface, thus promoting KIT signaling in the endosomes while reducing that in the plasma membrane, as exemplified by Akt and PLCγ1 phosphorylation, respectively. The altered endocytic trafficking of KIT also resulted in an increase in SCF-induced mast cell proliferation and migration, which may reflect altered signaling in these cells. Our data reveal a novel function for MS4A family proteins in regulating trafficking and signaling, which could have implications in both proliferative and immunological diseases. PMID:25717186

CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands.

PubMed

Lamas, Bruno; Richard, Mathias L; Leducq, Valentin; Pham, Hang-Phuong; Michel, Marie-Laure; Da Costa, Gregory; Bridonneau, Chantal; Jegou, Sarah; Hoffmann, Thomas W; Natividad, Jane M; Brot, Loic; Taleb, Soraya; Couturier-Maillard, Aurélie; Nion-Larmurier, Isabelle; Merabtene, Fatiha; Seksik, Philippe; Bourrier, Anne; Cosnes, Jacques; Ryffel, Bernhard; Beaugerie, Laurent; Launay, Jean-Marie; Langella, Philippe; Xavier, Ramnik J; Sokol, Harry

2016-06-01

Complex interactions between the host and the gut microbiota govern intestinal homeostasis but remain poorly understood. Here we reveal a relationship between gut microbiota and caspase recruitment domain family member 9 (CARD9), a susceptibility gene for inflammatory bowel disease (IBD) that functions in the immune response against microorganisms. CARD9 promotes recovery from colitis by promoting interleukin (IL)-22 production, and Card9(-/-) mice are more susceptible to colitis. The microbiota is altered in Card9(-/-) mice, and transfer of the microbiota from Card9(-/-) to wild-type, germ-free recipients increases their susceptibility to colitis. The microbiota from Card9(-/-) mice fails to metabolize tryptophan into metabolites that act as aryl hydrocarbon receptor (AHR) ligands. Intestinal inflammation is attenuated after inoculation of mice with three Lactobacillus strains capable of metabolizing tryptophan or by treatment with an AHR agonist. Reduced production of AHR ligands is also observed in the microbiota from individuals with IBD, particularly in those with CARD9 risk alleles associated with IBD. Our findings reveal that host genes affect the composition and function of the gut microbiota, altering the production of microbial metabolites and intestinal inflammation.

Perflurooctanoic Acid Induces Developmental Cardiotoxicity in ...

EPA Pesticide Factsheets

Perfluorooctanoic acid (PFOA) is a widespread environmental contaminant that is detectable in serum of the general U.S. population. PFOA is a known developmental toxicant that induces mortality in mammalian embryos and is thought to induce toxicity via interaction with the peroxisome proliferator activated receptor alpha (PPAR_). As the cardiovascular system is crucial for embryonic survival, PFOA-induced effects on the heart may partially explain embryonic mortality. To assess impacts of PFOA exposure on the developing heart in an avian model, we used histopathology and immunohistochemical staining for myosin to assess morphological alterations in 19-day-old chicken embryo hearts after PFOA exposure. Additionally, echocardiography and cardiac myofibril ATPase activity assays were used to assess functional alterations in 1-day-old hatchling chickens following developmental PFOA exposure. Overall thinning and thinning of a dense layer of myosin in the right ventricular wall were observed in PFOA-exposed chicken embryo hearts. Alteration of multiple cardiac structural and functional parameters, including left ventricular wall thickness, left ventricular volume, heart rate, stroke volume, and ejection fraction were detected with echocardiography in the exposed hatchling chickens. Assessment of ATPase activity indicated that the ratio of cardiac myofibril calcium-independent ATPase activity to calcium-dependent ATPase activity was not affected, which suggests that d

Recent findings in cardiovascular physiology with space travel.

PubMed

Hughson, Richard L

2009-10-01

The cardiovascular system undergoes major changes in stress with space flight primarily related to the elimination of the head-to-foot gravitational force. A major observation has been that the central venous pressure is not elevated early in space flight yet stroke volume is increased at least early in flight. Recent observations demonstrate that heart rate remains lower during the normal daily activities of space flight compared to Earth-based conditions. Structural and functional adaptations occur in the vascular system that could result in impaired response with demands of physical exertion and return to Earth. Cardiac muscle mass is reduced after flight and contractile function may be altered. Regular and specific countermeasures are essential to maintain cardiovascular health during long-duration space flight.

Altered emotion regulation capacity in social phobia as a function of comorbidity.

PubMed

Burklund, Lisa J; Craske, Michelle G; Taylor, Shelley E; Lieberman, Matthew D

2015-02-01

Social phobia (SP) has been associated with amygdala hyperreactivity to fear-relevant stimuli. However, little is known about the neural basis of SP individuals' capacity to downregulate their responses to such stimuli and how such regulation varies as a function of comorbid depression and anxiety. We completed an functional magnetic resonance imaging (fMRI) study wherein SP participants without comorbidity (n = 30), with comorbid depression (n = 18) and with comorbid anxiety (n = 19) and healthy controls (n = 15) were scanned while completing an affect labeling emotion regulation task. Individuals with SP as a whole exhibited a reversal of the pattern observed in healthy controls in that they showed upregulation of amygdala activity during affect labeling. However, subsequent analyses revealed a more complex picture based on comorbidity type. Although none of the SP subgroups showed the normative pattern of amygdala downregulation, it was those with comorbid depression specifically who showed significant upregulation. Effects could not be attributed to differences in task performance, amygdala reactivity or right ventral lateral prefrontal cortex (RVLPFC) engagement, but may stem from dysfunctional communication between amygdala and RVLPFC. Furthermore, the particularly altered emotion regulation seen in those with comorbid depression could not be fully explained by symptom severity or state anxiety. Results reveal altered emotion regulation in SP, especially when comorbid with depression. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Resting-state networks associated with cognitive processing show more age-related decline than those associated with emotional processing.

PubMed

Nashiro, Kaoru; Sakaki, Michiko; Braskie, Meredith N; Mather, Mara

2017-06-01

Correlations in activity across disparate brain regions during rest reveal functional networks in the brain. Although previous studies largely agree that there is an age-related decline in the "default mode network," how age affects other resting-state networks, such as emotion-related networks, is still controversial. Here we used a dual-regression approach to investigate age-related alterations in resting-state networks. The results revealed age-related disruptions in functional connectivity in all 5 identified cognitive networks, namely the default mode network, cognitive-auditory, cognitive-speech (or speech-related somatosensory), and right and left frontoparietal networks, whereas such age effects were not observed in the 3 identified emotion networks. In addition, we observed age-related decline in functional connectivity in 3 visual and 3 motor/visuospatial networks. Older adults showed greater functional connectivity in regions outside 4 out of the 5 identified cognitive networks, consistent with the dedifferentiation effect previously observed in task-based functional magnetic resonance imaging studies. Both reduced within-network connectivity and increased out-of-network connectivity were correlated with poor cognitive performance, providing potential biomarkers for cognitive aging. Copyright © 2017 Elsevier Inc. All rights reserved.

[Fragile X syndrome with Dandy-Walker variant: a clinical study of oral and written communicative manifestations].

PubMed

Lamônica, Dionísia Aparecida Cusin; Ferraz, Plínio Marcos Duarte Pinto; Ferreira, Amanda Tragueta; Prado, Lívia Maria do; Abramides, Dagma Venturini Marquez; Gejão, Mariana Germano

2011-01-01

The Fragile X syndrome is the most frequent cause of inherited intellectual disability. The Dandy-Walker variant is a specific constellation of neuroradiological findings. The present study reports oral and written communication findings in a 15-year-old boy with clinical and molecular diagnosis of Fragile X syndrome and neuroimaging findings consistent with Dandy-Walker variant. The speech-language pathology and audiology evaluation was carried out using the Communicative Behavior Observation, the Phonology assessment of the ABFW - Child Language Test, the Phonological Abilities Profile, the Test of School Performance, and the Illinois Test of Psycholinguistic Abilities. Stomatognathic system and hearing assessments were also performed. It was observed: phonological, semantic, pragmatic and morphosyntactic deficits in oral language; deficits in psycholinguistic abilities (auditory reception, verbal expression, combination of sounds, auditory and visual sequential memory, auditory closure, auditory and visual association); and morphological and functional alterations in the stomatognathic system. Difficulties in decoding the graphical symbols were observed in reading. In writing, the subject presented omissions, agglutinations and multiple representations with the predominant use of vowels, besides difficulties in visuo-spatial organization. In mathematics, in spite of the numeric recognition, the participant didn't accomplish arithmetic operations. No alterations were observed in the peripheral hearing evaluation. The constellation of behavioral, cognitive, linguistic and perceptual symptoms described for Fragile X syndrome, in addition to the structural central nervous alterations observed in the Dandy-Walker variant, caused outstanding interferences in the development of communicative abilities, in reading and writing learning, and in the individual's social integration.

Agrin in Alzheimer's Disease: Altered Solubility and Abnormal Distribution within Microvasculature and Brain Parenchyma

NASA Astrophysics Data System (ADS)

Donahue, John E.; Berzin, Tyler M.; Rafii, Michael S.; Glass, David J.; Yancopoulos, George D.; Fallon, Justin R.; Stopa, Edward G.

1999-05-01

Agrin is a heparan sulfate proteoglycan that is widely expressed in neurons and microvascular basal lamina in the rodent and avian central nervous system. Agrin induces the differentiation of nerve-muscle synapses, but its function in either normal or diseased brains is not known. Alzheimer's disease (AD) is characterized by loss of synapses, changes in microvascular architecture, and formation of neurofibrillary tangles and senile plaques. Here we have asked whether AD causes changes in the distribution and biochemical properties of agrin. Immunostaining of normal, aged human central nervous system revealed that agrin is expressed in neurons in multiple brain areas. Robust agrin immunoreactivity was observed uniformly in the microvascular basal lamina. In AD brains, agrin is highly concentrated in both diffuse and neuritic plaques as well as neurofibrillary tangles; neuronal expression of agrin also was observed. Furthermore, patients with AD had microvascular alterations characterized by thinning and fragmentation of the basal lamina. Detergent extraction and Western blotting showed that virtually all the agrin in normal brain is soluble in 1% SDS. In contrast, a large fraction of the agrin in AD brains is insoluble under these conditions, suggesting that it is tightly associated with β -amyloid. Together, these data indicate that the agrin abnormalities observed in AD are closely linked to β -amyloid deposition. These observations suggest that altered agrin expression in the microvasculature and the brain parenchyma contribute to the pathogenesis of AD.

Gentamicin treatment in exercised mdx mice: Identification of dystrophin-sensitive pathways and evaluation of efficacy in work-loaded dystrophic muscle.

PubMed

De Luca, Annamaria; Nico, Beatrice; Rolland, Jean-François; Cozzoli, Anna; Burdi, Rosa; Mangieri, Domenica; Giannuzzi, Viviana; Liantonio, Antonella; Cippone, Valentina; De Bellis, Michela; Nicchia, Grazia Paola; Camerino, Giulia Maria; Frigeri, Antonio; Svelto, Maria; Camerino, Diana Conte

2008-11-01

Aminoglycosides force read through of premature stop codon mutations and introduce new mutation-specific gene-corrective strategies in Duchenne muscular dystrophy. A chronic treatment with gentamicin (32 mg/kg/daily i.p., 8-12 weeks) was performed in exercised mdx mice with the dual aim to clarify the dependence on dystrophin of the functional, biochemical and histological alterations present in dystrophic muscle and to verify the long term efficiency of small molecule gene-corrective strategies in work-loaded dystrophic muscle. The treatment counteracted the exercise-induced impairment of in vivo forelimb strength after 6-8 weeks. We observed an increase in dystrophin expression level in all the fibers, although lower than that observed in normal fibers, and found a concomitant recovery of aquaporin-4 at sarcolemma. A significant reduction in centronucleated fibers, in the area of necrosis and in the percentage of nuclear factor-kB-positive nuclei was observed in gastrocnemious muscle of treated animals. Plasma creatine kinase was reduced by 70%. Ex vivo, gentamicin restored membrane ionic conductance in mdx diaphragm and limb muscle fibers. No effects were observed on the altered calcium homeostasis and sarcolemmal calcium permeability, detected by electrophysiological and microspectrofluorimetric approaches. Thus, the maintenance of a partial level of dystrophin is sufficient to reinforce sarcolemmal stability, reducing leakiness, inflammation and fiber damage, while correction of altered calcium homeostasis needs greater expression of dystrophin or direct interventions on the channels involved.

MicroRNA miR-23a cluster promotes osteocyte differentiation by regulating TGF-β signalling in osteoblasts

PubMed Central

Zeng, Huan-Chang; Bae, Yangjin; Dawson, Brian C.; Chen, Yuqing; Bertin, Terry; Munivez, Elda; Campeau, Philippe M.; Tao, Jianning; Chen, Rui; Lee, Brendan H.

2017-01-01

Osteocytes are the terminally differentiated cell type of the osteoblastic lineage and have important functions in skeletal homeostasis. Although the transcriptional regulation of osteoblast differentiation has been well characterized, the factors that regulate differentiation of osteocytes from mature osteoblasts are poorly understood. Here we show that miR-23a∼27a∼24-2 (miR-23a cluster) promotes osteocyte differentiation. Osteoblast-specific miR-23a cluster gain-of-function mice have low bone mass associated with decreased osteoblast but increased osteocyte numbers. By contrast, loss-of-function transgenic mice overexpressing microRNA decoys for either miR-23a or miR-27a, but not miR24-2, show decreased osteocyte numbers. Moreover, RNA-sequencing analysis shows altered transforming growth factor-β (TGF-β) signalling. Prdm16, a negative regulator of the TGF-β pathway, is directly repressed by miR-27a with concomitant alteration of sclerostin expression, and pharmacological inhibition of TGF-β rescues the phenotypes observed in the gain-of-function transgenic mice. Taken together, the miR-23a cluster regulates osteocyte differentiation by modulating the TGF-β signalling pathway through targeting of Prdm16. PMID:28397831

A mouse neurodegenerative dynein heavy chain mutation alters dynein motility and localization in Neurospora crassa.

PubMed

Sivagurunathan, Senthilkumar; Schnittker, Robert R; Nandini, Swaran; Plamann, Michael D; King, Stephen J

2012-09-01

Cytoplasmic dynein is responsible for the transport and delivery of cargoes in organisms ranging from humans to fungi. Dysfunction of dynein motor machinery due to mutations in dynein or its activating complex dynactin can result in one of several neurological diseases in mammals. The mouse Legs at odd angles (Loa) mutation in the tail domain of the dynein heavy chain has been shown to lead to progressive neurodegeneration in mice. The mechanism by which the Loa mutation affects dynein function is just beginning to be understood. In this work, we generated the dynein tail mutation observed in Loa mice into the Neurospora crassa genome and utilized cell biological and complementing biochemical approaches to characterize how that tail mutation affected dynein function. We determined that the Loa mutation exhibits several subtle defects upon dynein function in N. crassa that were not seen in mice, including alterations in dynein localization, impaired velocity of vesicle transport, and in the biochemical properties of purified motors. Our work provides new information on the role of the tail domain on dynein function and points out areas of future research that will be of interest to pursue in mammalian systems. 2012 Wiley Periodicals, Inc

A Mouse Neurodegenerative Dynein Heavy Chain Mutation Alters Dynein Motility and Localization in Neurospora crassa

PubMed Central

Sivagurunathan, Senthilkumar; Schnittker, Robert R.; Nandini, Swaran; Plamann, Michael D.; King, Stephen J.

2013-01-01

Cytoplasmic dynein is responsible for the transport and delivery of cargoes in organisms ranging from humans to fungi. Dysfunction of dynein motor machinery due to mutations in dynein or its activating complex dynactin can result in one of several neurological diseases in mammals. The mouse Legs at odd angles (Loa) mutation in the tail domain of the dynein heavy chain has been shown to lead to progressive neurodegeneration in mice. The mechanism by which the Loa mutation affects dynein function is just beginning to be understood. In this work, we generated the dynein tail mutation observed in Loa mice into the Neurospora crassa genome and utilized cell biological and complementing biochemical approaches to characterize how that tail mutation affected dynein function. We determined that the Loa mutation exhibits several subtle defects upon dynein function in N. crassa that were not seen in mice, including alterations in dynein localization, impaired velocity of vesicle transport, and in the biochemical properties of purified motors. Our work provides new information on the role of the tail domain on dynein function and points out areas of future research that will be of interest to pursue in mammalian systems. PMID:22991199

Alteration of Endothelins: A Common Pathogenetic Mechanism in Chronic Diabetic Complications

PubMed Central

Khan, Zia Ali; Cukiernik, Mark; Fukuda, Gen; Chen, Shali; Mukherjee, Suranjana

2002-01-01

Endothelin (ET) peptides perform several physiological, vascular, and nonvascular functions and are widely distributed in a number of tissues. They are altered in several disease processes including diabetes. Alteration of ETs have been demonstrated in organs of chronic diabetic complications in both experimental and clinical studies. The majority of the effects of ET alteration in diabetes are due to altered vascular function. Furthermore, ET antagonists have been shown to prevent structural and functional changes induced by diabetes in animal models. This review discusses the contribution of ETs in the pathogenesis and the potential role of ET antagonism in the treatment of chronic diabetic complications. PMID:12546275

Orofacial functions and oral health associated with Treacher Collins syndrome.

PubMed

Asten, Pamela; Skogedal, Nina; Nordgarden, Hilde; Axelsson, Stefan; Akre, Harriet; Sjögreen, Lotta

2013-01-01

The aim of this study was to describe orofacial features and functions and oral health associated with Treacher Collins syndrome (TCS) in relation to the variable phenotypic expression of the condition. The Nordic Orofacial Test-Screening (NOT-S), MHC Questionnaire, MHC Observation chart and clinical examinations of nasal and pharyngeal conditions and chewing and swallowing function were used to assess 19 individuals aged 5-74 years (median 34 years). TCS severity scores were calculated by a clinical geneticist. Orofacial features characterizing the study group were altered profile, increased mandibular angle, narrow hypopharynx and facial asymmetry. Basic orofacial functions such as breathing, eating, facial expression and speech were affected in all subjects demonstrating orofacial dysfunction in at least two NOT-S domains (median NOT-S total score 4/12, range 2-7). Significant correlation was found between the TCS severity scores reflecting phenotypic expression and the NOT-S total scores reflecting orofacial function. Self-reported experience of dry oral mucosa was common. Overall, dental health was good with few carious lesions diagnosed, but considerable need for orthodontic treatment was documented. Altered orofacial features and functions in TCS are common and often persist into late adolescence and adulthood. The functional level was correlated with the phenotypic variability of the condition. The standard of oral health was satisfactory. The findings indicated that individuals with TCS are likely to require lifelong health services related to their oral condition.

Emotion and Theory of Mind in Schizophrenia-Investigating the Role of the Cerebellum.

PubMed

Mothersill, Omar; Knee-Zaska, Charlotte; Donohoe, Gary

2016-06-01

Social cognitive dysfunction, including deficits in facial emotion recognition and theory of mind, is a core feature of schizophrenia and more strongly predicts functional outcome than neurocognition alone. Although traditionally considered to play an important role in motor coordination, the cerebellum has been suggested to play a role in emotion processing and theory of mind, and also shows structural and functional abnormalities in schizophrenia. The aim of this systematic review was to investigate the specific role of the cerebellum in emotion and theory of mind deficits in schizophrenia using previously published functional neuroimaging studies. PubMed and PsycINFO were used to search for all functional neuroimaging studies reporting altered cerebellum activity in schizophrenia patients during emotion processing or theory of mind tasks, published until December 2014. Overall, 14 functional neuroimaging studies were retrieved. Most emotion studies reported lower cerebellum activity in schizophrenia patients relative to healthy controls. In contrast, the theory of mind studies reported mixed findings. Altered activity was observed across several posterior cerebellar regions involved in emotion and cognition. Weaker cerebellum activity in schizophrenia patients relative to healthy controls during emotion processing may contribute to blunted affect and reduced ability to recognise emotion in others. This research could be expanded by examining the relationship between cerebellum function, symptomatology and behaviour, and examining cerebellum functional connectivity in patients during emotion and theory of mind tasks.

A Focus on Reward Prediction and the Lateral Habenula: Functional Alterations and the Behavioral Outcomes Induced by Drugs of Abuse.

PubMed

Graziane, Nicholas M; Neumann, Peter A; Dong, Yan

2018-01-01

The lateral habenula (LHb) regulates reward learning and controls the updating of reward-related information. Drugs of abuse have the capacity to hijack the cellular and neurocircuit mechanisms mediating reward learning, forming non-adaptable, compulsive behaviors geared toward obtaining illicit substances. Here, we discuss current findings demonstrating how drugs of abuse alter intrinsic and synaptic LHb neuronal function. Additionally, we discuss evidence for how drug-induced LHb alterations may affect the ability to predict reward, potentially facilitating an addiction-like state. Altogether, we combine ex vivo and in vivo results for an overview of how drugs of abuse alter LHb function and how these functional alterations affect the ability to learn and update behavioral responses to hedonic external stimuli.

Physical exercise prevents motor disorders and striatal oxidative imbalance after cerebral ischemia-reperfusion.

PubMed

Sosa, P M; Schimidt, H L; Altermann, C; Vieira, A S; Cibin, F W S; Carpes, F P; Mello-Carpes, P B

2015-09-01

Stroke is the third most common cause of death worldwide, and most stroke survivors present some functional impairment. We assessed the striatal oxidative balance and motor alterations resulting from stroke in a rat model to investigate the neuroprotective role of physical exercise. Forty male Wistar rats were assigned to 4 groups: a) control, b) ischemia, c) physical exercise, and d) physical exercise and ischemia. Physical exercise was conducted using a treadmill for 8 weeks. Ischemia-reperfusion surgery involved transient bilateral occlusion of the common carotid arteries for 30 min. Neuromotor performance (open-field and rotarod performance tests) and pain sensitivity were evaluated beginning at 24 h after the surgery. Rats were euthanized and the corpora striata was removed for assay of reactive oxygen species, lipoperoxidation activity, and antioxidant markers. Ischemia-reperfusion caused changes in motor activity. The ischemia-induced alterations observed in the open-field test were fully reversed, and those observed in the rotarod test were partially reversed, by physical exercise. Pain sensitivity was similar among all groups. Levels of reactive oxygen species and lipoperoxidation increased after ischemia; physical exercise decreased reactive oxygen species levels. None of the treatments altered the levels of antioxidant markers. In summary, ischemia-reperfusion resulted in motor impairment and altered striatal oxidative balance in this animal model, but those changes were moderated by physical exercise.

Maternal hyperthyroidism alters the pattern of expression of cardiac renin-angiotensin system components in rat offspring.

PubMed

Lino, Caroline A; Shibata, Caroline E R; Barreto-Chaves, Maria Luiza M

2014-03-01

Changes in perinatal environment can lead to physiological, morphological, or metabolic alterations in adult life. It is well known that thyroid hormones (TH) are critical for the development, growth, and maturation of organs and systems. In addition, TH interact with the renin-angiotensin system (RAS), and both play a critical role in adult cardiovascular function. The objective of this study was to evaluate the effect of maternal hyperthyroidism on cardiac RAS components in pups during development. From gestational day nine (GD9), pregnant Wistar rats received thyroxine (T4, 12 mg/l in tap water; Hyper group) or vehicle (control group). Dams and pups were killed on GD18 and GD20. Serum concentrations of triiodothyronine (T3) and T4 were higher in the Hyper group than in the control group dams. Cardiac hypertrophy was observed in Hyper pups on GD20. Cardiac angiotensin-converting enzyme (ACE) activity was significantly lower in Hyper pups on both GD18 and GD20, but there was no difference in Ang I/Ang II levels. Ang II receptors expression was higher in the Hyper pup heart on GD18. Maternal hyperthyroidism is associated with alterations in fetal development and altered pattern of expression in RAS components, which in addition to cardiac hypertrophy observed on GD20 may represent an important predisposing factor to cardiovascular diseases in adult life.

Effect of altered reproductive function and lowered testosterone levels on bone density in male endurance athletes.

PubMed

Bennell, K L; Brukner, P D; Malcolm, S A

1996-09-01

It is apparent that bone density in male athletes can be reduced without a concomitant decrease in testosterone, suggesting that bone density and testosterone concentrations in the normal range are not closely related in male athletes. Further research is necessary to monitor concurrent changes in bone density and testosterone over a period of time in exercising males. In any case, the effect of exercise on the male reproductive system does not appear as extreme as that which can occur in female athletes, and any impact on bone density is not nearly as evident. These results imply that factors apart from testosterone concentrations must be responsible for the observed osteopenia in some male athletes. Many factors have the potential to adversely affect bone density, independently of alterations in reproductive function. These include low calcium intake, energy deficit, weight loss, psychological stress, and low body fat, all of which may be associated with intense endurance training. Future research investigating skeletal health in male athletes should include a thorough assessment of reproductive function in addition to these other factors.

Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sirvent, P., E-mail: pascal.sirvent@univ-bpclermont.fr; CHRU Montpellier, 34295 Montpellier; Clermont Université, Université Blaise Pascal, EA 3533, Laboratoire des Adaptations Métaboliques à l'Exercice en conditions Physiologiques et Pathologiques

2012-03-01

The most common and problematic side effect of statins is myopathy. To date, the patho-physiological mechanisms of statin myotoxicity are still not clearly understood. In previous studies, we showed that acute application in vitro of simvastatin caused impairment of mitochondrial function and dysfunction of calcium homeostasis in human and rat healthy muscle samples. We thus evaluated in the present study, mitochondrial function and calcium signaling in muscles of patients treated with statins, who present or not muscle symptoms, by oxygraphy and recording of calcium sparks, respectively. Patients treated with statins showed impairment of mitochondrial respiration that involved mainly the complexmore » I of the respiratory chain and altered frequency and amplitude of calcium sparks. The muscle problems observed in statin-treated patients appear thus to be related to impairment of mitochondrial function and muscle calcium homeostasis, confirming the results we previously reported in vitro. -- Highlights: ► The most common and problematic side effect of statins is myopathy. ► Patients treated with statins showed impairment of mitochondrial respiration. ► Statins-treated patients showed altered frequency and amplitude of calcium sparks.« less

Mechanisms of cross-talk between the diet, the intestinal microbiome, and the undernourished host

PubMed Central

Velly, Helene; Britton, Robert A.; Preidis, Geoffrey A.

2017-01-01

ABSTRACT Undernutrition remains one of the most pressing global health challenges today, contributing to nearly half of all deaths in children under five years of age. Although insufficient dietary intake and environmental enteric dysfunction are often inciting factors, evidence now suggests that unhealthy gut microbial populations perpetuate the vicious cycle of pathophysiology that results in persistent growth impairment in children. The metagenomics era has facilitated new research identifying an altered microbiome in undernourished hosts and has provided insight into a number of mechanisms by which these alterations may affect growth. This article summarizes a range of observational studies that highlight differences in the composition and function of gut microbiota between undernourished and healthy children; discusses dietary, environmental and host factors that shape this altered microbiome; examines the consequences of these changes on host physiology; and considers opportunities for microbiome-targeting therapies to combat the global challenge of child undernutrition. PMID:27918230

Acidification and γ-aminobutyric acid independently alter kairomone-induced behaviour

PubMed Central

Cohen, Jonathan H.

2016-01-01

Exposure to high pCO2 or low pH alters sensation and behaviour in many marine animals. We show that crab larvae lose their ability to detect and/or process predator kairomones after exposure to low pH over a time scale relevant to diel pH cycles in coastal environments. Previous work suggests that acidification affects sensation and behaviour through altered neural function, specifically the action of γ-aminobutyric acid (GABA), because a GABA antagonist, gabazine, restores the original behaviour. Here, however, gabazine resulted in a loss of kairomone detection/processing, regardless of pH. Our results also suggest that GABAergic signalling is necessary for kairomone identification in these larvae. Hence, the mechanism for the observed pH effect varies from the original GABA hypothesis. Furthermore, we suggest that this pH effect is adaptive under diel-cycling pH. PMID:27703697

Compositional differences in simulated root exudates elicit a limited functional and compositional response in soil microbial communities.

PubMed

Strickland, Michael S; McCulley, Rebecca L; Nelson, Jim A; Bradford, Mark A

2015-01-01

Inputs of low molecular weight carbon (LMW-C) to soil - primarily via root exudates- are expected to be a major driver of microbial activity and source of stable soil organic carbon. It is expected that variation in the type and composition of LMW-C entering soil will influence microbial community composition and function. If this is the case then short-term changes in LMW-C inputs may alter processes regulated by these communities. To determine if change in the composition of LMW-C inputs influences microbial community function and composition, we conducted a 90 day microcosm experiment whereby soils sourced from three different land covers (meadows, deciduous forests, and white pine stands) were amended, at low concentrations, with one of eight simulated root exudate treatments. Treatments included no addition of LMW-C, and the full factorial combination of glucose, glycine, and oxalic acid. After 90 days, we conducted a functional response assay and determined microbial composition via phospholipid fatty acid analysis. Whereas we noted a statistically significant effect of exudate treatments, this only accounted for ∼3% of the variation observed in function. In comparison, land cover and site explained ∼46 and ∼41% of the variation, respectively. This suggests that exudate composition has little influence on function compared to site/land cover specific factors. Supporting the finding that exudate effects were minor, we found that an absence of LMW-C elicited the greatest difference in function compared to those treatments receiving any LMW-C. Additionally, exudate treatments did not alter microbial community composition and observable differences were instead due to land cover. These results confirm the strong effects of land cover/site legacies on soil microbial communities. In contrast, short-term changes in exudate composition, at meaningful concentrations, may have little impact on microbial function and composition.

Alterations in protein phosphorylation in the amygdala of the 5XFamilial Alzheimer's disease animal model.

PubMed

Yang, Eun-Jeong; Mahmood, Usman; Kim, Hyunju; Choi, Moonseok; Choi, Yunjung; Lee, Jean-Pyo; Chang, Moon-Jeong; Kim, Hye-Sun

2017-04-01

Alzheimer's disease is the most common disease underlying dementia in humans. Two major neuropathological hallmarks of AD are neuritic plaques primarily composed of amyloid beta peptide and neurofibrillary tangles primarily composed of hyperphosphorylated tau. In addition to impaired memory function, AD patients often display neuropsychiatric symptoms and abnormal emotional states such as confusion, delusion, manic/depressive episodes and altered fear status. Brains from AD patients show atrophy of the amygdala which is involved in fear expression and emotional processing as well as hippocampal atrophy. However, which molecular changes are responsible for the altered emotional states observed in AD remains to be elucidated. Here, we observed that the fear response as assessed by evaluating fear memory via a cued fear conditioning test was impaired in 5XFamilial AD (5XFAD) mice, an animal model of AD. Compared to wild-type mice, 5XFAD mice showed changes in the phosphorylation of twelve proteins in the amygdala. Thus, our study provides twelve potential protein targets in the amygdala that may be responsible for the impairment in fear memory in AD. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

An autism-associated serotonin transporter variant disrupts multisensory processing.

PubMed

Siemann, J K; Muller, C L; Forsberg, C G; Blakely, R D; Veenstra-VanderWeele, J; Wallace, M T

2017-03-21

Altered sensory processing is observed in many children with autism spectrum disorder (ASD), with growing evidence that these impairments extend to the integration of information across the different senses (that is, multisensory function). The serotonin system has an important role in sensory development and function, and alterations of serotonergic signaling have been suggested to have a role in ASD. A gain-of-function coding variant in the serotonin transporter (SERT) associates with sensory aversion in humans, and when expressed in mice produces traits associated with ASD, including disruptions in social and communicative function and repetitive behaviors. The current study set out to test whether these mice also exhibit changes in multisensory function when compared with wild-type (WT) animals on the same genetic background. Mice were trained to respond to auditory and visual stimuli independently before being tested under visual, auditory and paired audiovisual (multisensory) conditions. WT mice exhibited significant gains in response accuracy under audiovisual conditions. In contrast, although the SERT mutant animals learned the auditory and visual tasks comparably to WT littermates, they failed to show behavioral gains under multisensory conditions. We believe these results provide the first behavioral evidence of multisensory deficits in a genetic mouse model related to ASD and implicate the serotonin system in multisensory processing and in the multisensory changes seen in ASD.

Synaptic plasticity and spatial working memory are impaired in the CD mouse model of Williams-Beuren syndrome.

PubMed

Borralleras, Cristina; Mato, Susana; Amédée, Thierry; Matute, Carlos; Mulle, Christophe; Pérez-Jurado, Luis A; Campuzano, Victoria

2016-08-02

Mice heterozygous for a complete deletion (CD) equivalent to the most common deletion found in individuals with Williams-Beuren syndrome (WBS) recapitulate relevant features of the neurocognitive phenotype, such as hypersociability, along with some neuroanatomical alterations in specific brain areas. However, the pathophysiological mechanisms underlying these phenotypes still remain largely unknown. We have studied the synaptic function and cognition in CD mice using hippocampal slices and a behavioral test sensitive to hippocampal function. We have found that long-term potentiation (LTP) elicited by theta burst stimulation (TBS) was significantly impaired in hippocampal field CA1 of CD animals. This deficit might be associated with the observed alterations in spatial working memory. However, we did not detect changes in presynaptic function, LTP induction mechanisms or AMPA and NMDA receptor function. Reduced levels of Brain-derived neurotrophic factor (BDNF) were present in the CA1-CA3 hippocampal region of CD mice, which could account for LTP deficits in these mice. Taken together, these results suggest a defect of CA1 synapses in CD mice to sustain synaptic strength after stimulation. These data represent the first description of synaptic functional deficits in CD mice and further highlights the utility of the CD model to study the mechanisms underlying the WBS neurocognitive profile.

Neuromuscular fatigue in racquet sports.

PubMed

Girard, Olivier; Millet, Grégoire P

2008-02-01

This article describes the physiologic and neural mechanisms that cause neuromuscular fatigue in racquet sports: table tennis, tennis, squash, and badminton. In these intermittent and dual activities, performance may be limited as a match progresses because of a reduced central activation, linked to changes in neurotransmitter concentration or in response to afferent sensory feedback. Alternatively, modulation of spinal loop properties may occur because of changes in metabolic or mechanical properties within the muscle. Finally, increased fatigue manifested by mistimed strokes, lower speed, and altered on-court movements may be caused by ionic disturbances and impairments in excitation-contraction coupling properties. These alterations in neuromuscular function contribute to decrease in racquet sports performance observed under fatigue.

Neuromuscular fatigue in racquet sports.

PubMed

Girard, Olivier; Millet, Grégoire P

2009-02-01

This article describes the physiologic and neural mechanisms that cause neuromuscular fatigue in racquet sports: table tennis, tennis, squash, and badminton. In these intermittent and dual activities, performance may be limited as a match progresses because of a reduced central activation, linked to changes in neurotransmitter concentration or in response to afferent sensory feedback. Alternatively, modulation of spinal loop properties may occur because of changes in metabolic or mechanical properties within the muscle. Finally, increased fatigue manifested by mistimed strokes, lower speed, and altered on-court movements may be caused by ionic disturbances and impairments in excitation-contraction coupling properties. These alterations in neuromuscular function contribute to decrease in racquet sports performance observed under fatigue.

Collective cell migration during inflammatory response

NASA Astrophysics Data System (ADS)

Wu, Di; Stroka, Kimberly; Aranda-Espinoza, Helim

2012-02-01

Wound scratch healing assays of endothelial cell monolayers is a simple model to study collective cell migration as a function of biological signals. A signal of particular interest is the immune response, which after initial wounding in vivo causes the release of various inflammatory factors such as tumor necrosis alpha (TNF-α). TNF-α is an innate inflammatory cytokine that can induce cell growth, cell necrosis, and change cell morphology. We studied the effects of TNF-α on collective cell migration using the wound healing assays and measured several migration metrics, such as rate of scratch closure, velocities of leading edge and bulk cells, closure index, and velocity correlation functions between migrating cells. We observed that TNF-α alters all migratory metrics as a function of the size of the scratch and TNF-α content. The changes observed in migration correlate with actin reorganization upon TNF-α exposure.

Resting state brain network function in major depression - Depression symptomatology, antidepressant treatment effects, future research.

PubMed

Brakowski, Janis; Spinelli, Simona; Dörig, Nadja; Bosch, Oliver Gero; Manoliu, Andrei; Holtforth, Martin Grosse; Seifritz, Erich

2017-09-01

The alterations of functional connectivity brain networks in major depressive disorder (MDD) have been subject of a large number of studies. Using different methodologies and focusing on diverse aspects of the disease, research shows heterogeneous results lacking integration. Disrupted network connectivity has been found in core MDD networks like the default mode network (DMN), the central executive network (CEN), and the salience network, but also in cerebellar and thalamic circuitries. Here we review literature published on resting state brain network function in MDD focusing on methodology, and clinical characteristics including symptomatology and antidepressant treatment related findings. There are relatively few investigations concerning the qualitative aspects of symptomatology of MDD, whereas most studies associate quantitative aspects with distinct resting state functional connectivity alterations. Such depression severity associated alterations are found in the DMN, frontal, cerebellar and thalamic brain regions as well as the insula and the subgenual anterior cingulate cortex. Similarly, different therapeutical options in MDD and their effects on brain function showed patchy results. Herein, pharmaceutical treatments reveal functional connectivity alterations throughout multiple brain regions notably the DMN, fronto-limbic, and parieto-temporal regions. Psychotherapeutical interventions show significant functional connectivity alterations in fronto-limbic networks, whereas electroconvulsive therapy and repetitive transcranial magnetic stimulation result in alterations of the subgenual anterior cingulate cortex, the DMN, the CEN and the dorsal lateral prefrontal cortex. While it appears clear that functional connectivity alterations are associated with the pathophysiology and treatment of MDD, future research should also generate a common strategy for data acquisition and analysis, as a least common denominator, to set the basis for comparability across studies and implementation of functional connectivity as a scientifically and clinically useful biomarker. Copyright © 2017 Elsevier Ltd. All rights reserved.

A longitudinal study of altered taste and smell perception and change in blood pressure.

PubMed

Liu, Y-H; Huang, Z; Vaidya, A; Li, J; Curhan, G C; Wu, S; Gao, X

2018-05-29

Previous studies suggest that olfactory receptors, which mediate smell chemosensation, are located in the kidney and involved in blood pressure regulation. Mammalian epithelial sodium channels located in taste receptor cells are also found to participate in blood pressure regulation. However, there is currently no human study that has examined the association between taste and smell function and blood pressure. We thus conducted a longitudinal study to examine whether participants with altered taste and smell perception had larger increases in blood pressure compared with those without altered perception in a community-based cohort. The study included 5190 Chinese adults (4058 men and 1132 women) who were normotensive at baseline. Taste and smell perception were assessed via questionnaire in 2012 (baseline). Blood pressure was measured in 2012 and 2014 to determine relative change in blood pressure. Mean differences of 2-year blood pressure change and 95% confidence intervals (CIs) across four categories of taste and smell perception were calculated after adjusting for known risk factors for hypertension. After adjusting for potential confounders, individuals with altered taste and smell perception had larger increases in systolic blood pressure (adjusted mean difference = 5.1 mmHg, 95% CI: 0.1-10.0, p-value: 0.04) and mean arterial pressure (adjusted mean difference = 3.8 mmHg, 95% CI: 0.4-7.1, p-value: 0.03) after two years of follow-up compared with those having neither altered taste nor altered smell perception. No significant association was observed in individuals with altered taste or smell perception only. Our results suggest an association between chemosensory function and blood pressure. Copyright © 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

PRENATAL ALCOHOL EXPOSURE ALTERS STEADY-STATE AND ACTIVATED GENE EXPRESSION IN THE ADULT RAT BRAIN

PubMed Central

Stepien, Katarzyna A.; Lussier, Alexandre A.; Neumann, Sarah M.; Pavlidis, Paul; Kobor, Michael S.; Weinberg, Joanne

2016-01-01

Background Prenatal alcohol exposure (PAE) is associated with alterations in numerous physiological systems, including the stress and immune systems . We have previously shown that PAE increases the course and severity of arthritis in an adjuvant-induced arthritis (AA) model. While the molecular mechanisms underlying these effects are not fully known, changes in neural gene expression are emerging as important factors in the etiology of PAE effects. As the prefrontal cortex (PFC) and hippocampus (HPC) play key roles in neuroimmune function, PAE-induced alterations to their transcriptome may underlie abnormal steady-state functions and responses to immune challenge. The current study examined brains from adult PAE and control females from our recent AA study to determine whether PAE causes long-term alterations in gene expression and whether these mediate the altered severity and course of arthritis in PAE females Methods Adult females from PAE, pair-fed [PF], and ad libitum-fed control [C]) groups were injected with either saline or complete Freund’s adjuvant. Animals were terminated at the peak of inflammation or during resolution (days 16 and 39 post-injection, respectively); cohorts of saline-injected PAE, PF and C females were terminated in parallel. Gene expression was analyzed in the PFC and HPC using whole genome mRNA expression microarrays. Results Significant changes in gene expression in both the PFC and HPC were found in PAE compared to controls in response to ethanol exposure alone (saline-injected females), including genes involved in neurodevelopment, apoptosis, and energy metabolism. Moreover, in response to inflammation (adjuvant-injected females), PAE animals showed unique expression patterns, while failing to exhibit the activation of genes and regulators involved in the immune response observed in control and pair-fed animals. Conclusions These results support the hypothesis that PAE affects neuroimmune function at the level of gene expression, demonstrating long-term effects of PAE on the CNS response under steady-state conditions and following an inflammatory insult. PMID:25684047

Altered interregional molecular associations of the serotonin transporter in attention deficit/hyperactivity disorder assessed with PET.

PubMed

Vanicek, Thomas; Kutzelnigg, Alexandra; Philippe, Cecile; Sigurdardottir, Helen L; James, Gregory M; Hahn, Andreas; Kranz, Georg S; Höflich, Anna; Kautzky, Alexander; Traub-Weidinger, Tatjana; Hacker, Marcus; Wadsak, Wolfgang; Mitterhauser, Markus; Kasper, Siegfried; Lanzenberger, Rupert

2017-02-01

Altered serotonergic neurotransmission has been found to cause impulsive and aggressive behavior, as well as increased motor activity, all exemplifying key symptoms of ADHD. The main objectives of this positron emission tomography (PET) study were to investigate the serotonin transporter binding potential (SERT BP ND ) in patients with ADHD and to assess associations of SERT BP ND between the brain regions. 25 medication-free patients with ADHD (age ± SD; 32.39 ± 10.15; 10 females) without any psychiatric comorbidity and 25 age and sex matched healthy control subjects (33.74 ± 10.20) were measured once with PET and the highly selective and specific radioligand [ 11 C]DASB. SERT BP ND maps in nine a priori defined ROIs exhibiting high SERT binding were compared between groups by means of a linear mixed model. Finally, adopted from structural and functional connectivity analyses, we performed correlational analyses using regional SERT binding potentials to examine molecular interregional associations between all selected ROIs. We observed significant differences in the interregional correlations between the precuneus and the hippocampus in patients with ADHD compared to healthy controls, using SERT BP ND of the investigated ROIs (P < 0.05; Bonferroni corrected). When correlating SERT BP ND and age in the ADHD and the healthy control group, we confirmed an age-related decline in brain SERT binding in the thalamus and insula (R 2  = 0.284, R 2  = 0.167, Ps < 0.05; Bonferroni corrected). The results show significantly different interregional molecular associations of the SERT expression for the precuneus with hippocampus in patients with ADHD, indicating presumably altered functional coupling. Altered interregional coupling between brain regions might be a sensitive approach to demonstrate functional and molecular alterations in psychiatric conditions. Hum Brain Mapp 38:792-802, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Altered Resting Brain Function and Structure in Professional Badminton Players

PubMed Central

Di, Xin; Zhu, Senhua; Wang, Pin; Ye, Zhuoer; Zhou, Ke; Zhuo, Yan

2012-01-01

Abstract Neuroimaging studies of professional athletic or musical training have demonstrated considerable practice-dependent plasticity in various brain structures, which may reflect distinct training demands. In the present study, structural and functional brain alterations were examined in professional badminton players and compared with healthy controls using magnetic resonance imaging (MRI) and resting-state functional MRI. Gray matter concentration (GMC) was assessed using voxel-based morphometry (VBM), and resting-brain functions were measured by amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity. Results showed that the athlete group had greater GMC and ALFF in the right and medial cerebellar regions, respectively. The athlete group also demonstrated smaller ALFF in the left superior parietal lobule and altered functional connectivity between the left superior parietal and frontal regions. These findings indicate that badminton expertise is associated with not only plastic structural changes in terms of enlarged gray matter density in the cerebellum, but also functional alterations in fronto-parietal connectivity. Such structural and functional alterations may reflect specific experiences of badminton training and practice, including high-capacity visuo-spatial processing and hand-eye coordination in addition to refined motor skills. PMID:22840241

Alterations of resting state networks and structural connectivity in relation to the prefrontal and anterior cingulate cortices in late prematurity.

PubMed

Degnan, Andrew J; Wisnowski, Jessica L; Choi, SoYoung; Ceschin, Rafael; Bhushan, Chitresh; Leahy, Richard M; Corby, Patricia; Schmithorst, Vincent J; Panigrahy, Ashok

2015-01-07

Late preterm birth is increasingly recognized as a risk factor for cognitive and social deficits. The prefrontal cortex is particularly vulnerable to injury in late prematurity because of its protracted development and extensive cortical connections. Our study examined children born late preterm without access to advanced postnatal care to assess structural and functional connectivity related to the prefrontal cortex. Thirty-eight preadolescents [19 born late preterm (34-36 /7 weeks gestational age) and 19 at term] were recruited from a developing community in Brazil. Participants underwent neuropsychological testing. Individuals underwent three-dimensional T1-weighted, diffusion-weighted, and resting state functional MRI. Probabilistic tractography and functional connectivity analyses were carried out using unilateral seeds combining the medial prefrontal cortex and the anterior cingulate cortex. Late preterm children showed increased functional connectivity within regions of the default mode, salience, and central-executive networks from both right and left frontal cortex seeds. Decreased functional connectivity was observed within the right parahippocampal region from left frontal seeding. Probabilistic tractography showed a pattern of decreased streamlines in frontal white matter pathways and the corpus callosum, but also increased streamlines in the left orbitofrontal white matter and the right frontal white matter when seeded from the right. Late preterm children and term control children scored similarly on neuropsychological testing. Prefrontal cortical connectivity is altered in late prematurity, with hyperconnectivity observed in key resting state networks in the absence of neuropsychological deficits. Abnormal structural connectivity indicated by probabilistic tractography suggests subtle changes in white matter development, implying disruption of normal maturation during the late gestational period.

Parkin Modulates Endosomal Organization and Function of the Endo-Lysosomal Pathway.

PubMed

Song, Pingping; Trajkovic, Katarina; Tsunemi, Taiji; Krainc, Dimitri

2016-02-24

Mutations in PARK2 (parkin), which encodes Parkin protein, an E3 ubiquitin ligase, are associated with autosomal recessive early-onset Parkinson's disease (PD). While several studies implicated Parkin in the regulation of mitophagy and proteasomal degradation, the precise mechanism leading to neurodegeneration upon Parkin loss of function remains incompletely understood. In this study, we found that Parkin modulates the endocytic pathway through the regulation of endosomal structure and function. We showed that loss of Parkin function led to decreased endosomal tubulation and membrane association of vesicle protein sorting 35 (VPS35) and sorting nexin 1 (SNX1), as well as decreased mannose 6 phosphate receptor (M6PR), suggesting the impairment of retromer pathway in Parkin-deficient cells. We also found increased formation of intraluminal vesicles coupled with enhanced release of exosomes in the presence of mutant Parkin. To elucidate the molecular mechanism of these alterations in the endocytic pathway in Parkin-deficient cells, we found that Parkin regulates the levels and activity of Rab7 by promoting its ubiquitination on lysine 38 residue. Both endogenous Rab7 in Parkin-deficient cells and overexpressed K38 R-Rab7 mutant displayed decreased effector binding and membrane association. Furthermore, overexpression of K38R-Rab7 in HEK293 cells phenocopied the increased secretion of exosomes observed in Parkin-deficient cells, suggesting that Rab7 deregulation may be at least partially responsible for the endocytic phenotype observed in Parkin-deficient cells. These findings establish a role for Parkin in regulating the endo-lysosomal pathway and retromer function and raise the possibility that alterations in these pathways contribute to the development of pathology in Parkin-linked Parkinson's disease. Copyright © 2016 the authors 0270-6474/16/362425-13$15.00/0.

Functional Connectivity Changes in Systemic Lupus Erythematosus: A Resting-State Study.

PubMed

Nystedt, Jessika; Mannfolk, Peter; Jönsen, Andreas; Bengtsson, Anders; Nilsson, Petra; Sundgren, Pia C; Strandberg, Tor O

2018-05-01

To investigate resting-state functional connectivity of lupus patients and associated subgroups according to the ACR NPSLE case definitions (ACR ad hoc). In addition, we investigated whether or not the observed alterations correlated with disease duration, the systemic lupus erythematosus (SLE)-Disease Activity Index-2000 (SLEDAI-2k), and Systemic Lupus International Collaborating Clinical/ACR organ damage index (SDI)-scores. Anatomical 3T magnetic resonance imaging (MRI) and resting-state functional MRI were performed in 61 female lupus patients (mean age = 37.0 years, range = 18.2-52.0 years) and 20 gender- and age-matched controls (mean age = 36.2 years, range = 23.3-52.2 years) in conjunction with clinical examination and laboratory testing. Whole-brain voxelwise functional connectivity analysis with permutation testing was performed to extract network components that differed in lupus patients relative to healthy controls (HCs). Lupus patients exhibited both inter- and intranetwork hypo- and hyperconnectivity involving several crucial networks. We found reduced connectivity within the default mode network (DMN), the central executive network (CEN), and in-between the DMN and CEN in lupus patients. Increased connectivity was primarily observed within and between the sensory motor network in lupus patients when compared to HCs. Comparing lupus patients with and without neuropsychiatric symptoms, hypoconnectivity was more pronounced in the group with neuropsychiatric complaints. The functional connectivity of SLE patients was both positively and negatively correlated to duration of disease. We conclude that SLE patients in general and neuropsychiatric SLE patients in particular experience altered brain connectivity. These patterns may be due both to direct neuronal damage and compensatory mechanisms through neuronal rewiring and recruitment and may partly explain neuropsychiatric symptoms in SLE patients.

Studies of peripheral thyroxine distribution in thyrotoxicosis and hypothyroidism.

PubMed

Nicoloff, J T; Dowling, J T

1968-09-01

Compartmental analysis of the peripheral distribution of labeled thyroxine was applied to various groups of subjects with thyrotoxicosis and hypothyroidism. It was observed that the hepatic incorporation of thyroxine was augmented in subjects with Graves' disease when compared to non-Graves' disease control groups at all levels of thyroid function. Decreased values of hepatic incorporation occurred in primary hypothyroid subjects. These lowered values were not acutely corrected by elevation of the serum thyroxine level, but were observed to be rectified after several months' therapy with exogenous thyroid hormone. These alterations of the hepatic thyroxine-(131)I incorporation were independently verified by direct quantitative liver scintiscan determinations. Employing a dual thyroxine tracer system, we were able to demonstrate that during the early phases of equilibration of a tracer dose of thyroxine, alterations in the rate of deiodination were observed to be present in the various thyroid disease states. Increased deiodination rates were found in subjects with Graves' disease and the reverse was noted in patients with primary hypothyroidism. Kinetic analysis of thyroxine compartmental distribution during this early phase of equilibration of a labeled thyroxine tracer indicated that the primary tissue uptake occurred in the liver. These findings supported the contention that the amount of labeled thyroxine incorporated in the liver may be directly related to the deiodination rate of thyroxine by that organ. The pathogenetic basis of these alterations is presently unknown.

Functional Connectivity of the Amygdala Is Disrupted in Preschool-Aged Children With Autism Spectrum Disorder.

PubMed

Shen, Mark D; Li, Deana D; Keown, Christopher L; Lee, Aaron; Johnson, Ryan T; Angkustsiri, Kathleen; Rogers, Sally J; Müller, Ralph-Axel; Amaral, David G; Nordahl, Christine Wu

2016-09-01

The objective of this study was to determine whether functional connectivity of the amygdala is altered in preschool-age children with autism spectrum disorder (ASD) and to assess the clinical relevance of observed alterations in amygdala connectivity. A resting-state functional connectivity magnetic resonance imaging study of the amygdala (and a parallel study of primary visual cortex) was conducted in 72 boys (mean age 3.5 years; n = 43 with ASD; n = 29 age-matched controls). The ASD group showed significantly weaker connectivity between the amygdala and several brain regions involved in social communication and repetitive behaviors, including bilateral medial prefrontal cortex, temporal lobes, and striatum (p < .05, corrected). Weaker connectivity between the amygdala and frontal and temporal lobes was significantly correlated with increased autism severity in the ASD group (p < .05). In a parallel analysis examining the functional connectivity of primary visual cortex, the ASD group showed significantly weaker connectivity between visual cortex and sensorimotor regions (p < .05, corrected). Weaker connectivity between visual cortex and sensorimotor regions was not correlated with core autism symptoms, but instead was correlated with increased sensory hypersensitivity in the visual/auditory domain (p < .05). These findings indicate that preschool-age children with ASD have disrupted functional connectivity between the amygdala and regions of the brain important for social communication and language, which might be clinically relevant because weaker connectivity was associated with increased autism severity. Moreover, although amygdala connectivity was associated with behavioral domains that are diagnostic of ASD, altered connectivity of primary visual cortex was related to sensory hypersensitivity. Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Cortical functional hyperconnectivity in a mouse model of depression and selective network effects of ketamine.

PubMed

McGirr, Alexander; LeDue, Jeffrey; Chan, Allen W; Xie, Yicheng; Murphy, Timothy H

2017-08-01

See Huang and Liston (doi:10.1093/awx166) for a scientific commentary on this article.Human depression is associated with glutamatergic dysfunction and alterations in resting state network activity. However, the indirect nature of human in vivo glutamate and activity assessments obscures mechanistic details. Using the chronic social defeat mouse model of depression, we determine how mesoscale glutamatergic networks are altered after chronic stress, and in response to the rapid acting antidepressant, ketamine. Transgenic mice (Ai85) expressing iGluSnFR (a recombinant protein sensor) permitted real-time in vivo selective characterization of extracellular glutamate and longitudinal imaging of mesoscale cortical glutamatergic functional circuits. Mice underwent chronic social defeat or a control condition, while spontaneous cortical activity was longitudinally sampled. After chronic social defeat, we observed network-wide glutamate functional hyperconnectivity in defeated animals, which was confirmed with voltage sensitive dye imaging in an independent cohort. Subanaesthetic ketamine has unique effects in defeated animals. Acutely, subanaesthetic ketamine induces large global cortical glutamate transients in defeated animals, and an elevated subanaesthetic dose resulted in sustained global increase in cortical glutamate. Local cortical inhibition of glutamate transporters in naïve mice given ketamine produced a similar extracellular glutamate phenotype, with both glutamate transients and a dose-dependent accumulation of glutamate. Twenty-four hours after ketamine, normalization of depressive-like behaviour in defeated animals was accompanied by reduced glutamate functional connectivity strength. Altered glutamate functional connectivity in this animal model confirms the central role of glutamate dynamics as well as network-wide changes after chronic stress and in response to ketamine. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Neural traces of stress: cortisol related sustained enhancement of amygdala-hippocampal functional connectivity

PubMed Central

Vaisvaser, Sharon; Lin, Tamar; Admon, Roee; Podlipsky, Ilana; Greenman, Yona; Stern, Naftali; Fruchter, Eyal; Wald, Ilan; Pine, Daniel S.; Tarrasch, Ricardo; Bar-Haim, Yair; Hendler, Talma

2013-01-01

Stressful experiences modulate neuro-circuitry function, and the temporal trajectory of these alterations, elapsing from early disturbances to late recovery, heavily influences resilience and vulnerability to stress. Such effects of stress may depend on processes that are engaged during resting-state, through active recollection of past experiences and anticipation of future events, all known to involve the default mode network (DMN). By inducing social stress and acquiring resting-state functional magnetic resonance imaging (fMRI) before stress, immediately following it, and 2 h later, we expanded the time-window for examining the trajectory of the stress response. Throughout the study repeated cortisol samplings and self-reports of stress levels were obtained from 51 healthy young males. Post-stress alterations were investigated by whole brain resting-state functional connectivity (rsFC) of two central hubs of the DMN: the posterior cingulate cortex (PCC) and hippocampus. Results indicate a ’recovery’ pattern of DMN connectivity, in which all alterations, ascribed to the intervening stress, returned to pre-stress levels. The only exception to this pattern was a stress-induced rise in amygdala-hippocampal connectivity, which was sustained for as long as 2 h following stress induction. Furthermore, this sustained enhancement of limbic connectivity was inversely correlated to individual stress-induced cortisol responsiveness (AUCi) and characterized only the group lacking such increased cortisol (i.e., non-responders). Our observations provide evidence of a prolonged post-stress response profile, characterized by both the comprehensive balance of most DMN functional connections and the distinct time and cortisol dependent ascent of intra-limbic connectivity. These novel insights into neuro-endocrine relations are another milestone in the ongoing search for individual markers in stress-related psychopathologies. PMID:23847492

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

PubMed Central

Berger, Stefan M; Weber, Tillmann; Perreau-Lenz, Stephanie; Vogt, Miriam A; Gartside, Sarah E; Maser-Gluth, Christiane; Lanfumey, Laurence; Gass, Peter; Spanagel, Rainer; Bartsch, Dusan

2012-01-01

The association of single-nucleotide polymorphisms (SNPs) in the human tryptophan hydroxylase 2 (TPH2) gene with anxiety traits and depression has been inconclusive. Observed inconsistencies might result from the fact that TPH2 polymorphisms have been studied in a genetically heterogeneous human population. A defined genetic background, control over environmental factors, and the ability to analyze the molecular and neurochemical consequences of introduced genetic alterations constitute major advantages of investigating SNPs in inbred laboratory mouse strains. To investigate the behavioral and neurochemical consequences of a functional C1473G SNP in the mouse Tph2 gene, we generated congenic C57BL/6N mice homozygous for the Tph2 1473G allele. The Arg447 substitution in the TPH2 enzyme resulted in a significant reduction of the brain serotonin (5-HT) in vivo synthesis rate. Despite decreased 5-HT synthesis, we could detect neither a reduction of brain region-specific 5-HT concentrations nor changes in baseline and stress-induced 5-HT release using a microdialysis approach. However, using a [35S]GTP-γ-S binding assay and 5-HT1A receptor autoradiography, a functional desensitization of 5-HT1A autoreceptors could be identified. Furthermore, behavioral analysis revealed a distinct anxiety phenotype in homozygous Tph2 1473G mice, which could be reversed with chronic escitalopram treatment. Alterations in depressive-like behavior could not be detected under baseline conditions or after chronic mild stress. These findings provide evidence for an involvement of functional Tph2 polymorphisms in anxiety-related behaviors, which are likely not caused directly by alterations in 5-HT content or release but are rather due to compensatory changes during development involving functional desensitization of 5-HT1A autoreceptors. PMID:22491354

The effects of noncoding aquaporin-4 single-nucleotide polymorphisms on cognition and functional progression of Alzheimer's disease.

PubMed

Burfeind, Kevin G; Murchison, Charles F; Westaway, Shawn K; Simon, Matthew J; Erten-Lyons, Deniz; Kaye, Jeffrey A; Quinn, Joseph F; Iliff, Jeffrey J

2017-09-01

The glymphatic system is a brain-wide perivascular network that facilitates clearance of proteins, including amyloid β, from the brain interstitium through the perivascular exchange of cerebrospinal fluid and interstitial fluid. The astrocytic water channel aquaporin-4 (AQP4) is required for glymphatic system function, and impairment of glymphatic function in the aging brain is associated with altered AQP4 expression and localization. In human cortical tissue, alterations in AQP4 expression and localization are associated with Alzheimer's disease (AD) status and pathology. Although this suggests a potential role for AQP4 in the development or progression of AD, the relationship between of naturally occurring variants in the human AQP4 gene and cognitive function has not yet been evaluated. Using data from several longitudinal aging cohorts, we investigated the association between five AQP4 single-nucleotide polymorphisms (SNPs) and the rate of cognitive decline in participants with a diagnosis of AD. None of the five SNPs were associated with different rates of AD diagnosis, age of dementia onset in trial subjects. No association between AQP4 SNPs with histological measures of AD pathology, including Braak stage or neuritic plaque density was observed. However, AQP4 SNPs were associated with altered rates of cognitive decline after AD diagnosis, with two SNPS (rs9951307 and rs3875089) associated with slower cognitive decline and two (rs3763040 and rs3763043) associated with more rapid cognitive decline after AD diagnosis. These results provide the first evidence that variations in the AQP4 gene, whose gene product AQP4 is vital for glymphatic pathway function, may modulate the progression of cognitive decline in AD.

Arsenic Compromises Conducting Airway Epithelial Barrier Properties in Primary Mouse and Immortalized Human Cell Cultures

PubMed Central

Sherwood, Cara L.; Liguori, Andrew E.; Olsen, Colin E.; Lantz, R. Clark; Burgess, Jefferey L.; Boitano, Scott

2013-01-01

Arsenic is a lung toxicant that can lead to respiratory illness through inhalation and ingestion, although the most common exposure is through contaminated drinking water. Lung effects reported from arsenic exposure include lung cancer and obstructive lung disease, as well as reductions in lung function and immune response. As part of their role in innate immune function, airway epithelial cells provide a barrier that protects underlying tissue from inhaled particulates, pathogens, and toxicants frequently found in inspired air. We evaluated the effects of a five-day exposure to environmentally relevant levels of arsenic {<4μM [~300 μg/L (ppb)] as NaAsO2} on airway epithelial barrier function and structure. In a primary mouse tracheal epithelial (MTE) cell model we found that both micromolar (3.9 μM) and submicromolar (0.8 μM) arsenic concentrations reduced transepithelial resistance, a measure of barrier function. Immunofluorescent staining of arsenic-treated MTE cells showed altered patterns of localization of the transmembrane tight junction proteins claudin (Cl) Cl-1, Cl-4, Cl-7 and occludin at cell-cell contacts when compared with untreated controls. To better quantify arsenic-induced changes in tight junction transmembrane proteins we conducted arsenic exposure experiments with an immortalized human bronchial epithelial cell line (16HBE14o-). We found that arsenic exposure significantly increased the protein expression of Cl-4 and occludin as well as the mRNA levels of Cl-4 and Cl-7 in these cells. Additionally, arsenic exposure resulted in altered phosphorylation of occludin. In summary, exposure to environmentally relevant levels of arsenic can alter both the function and structure of airway epithelial barrier constituents. These changes likely contribute to the observed arsenic-induced loss in basic innate immune defense and increased infection in the airway. PMID:24349408

Methyl-parathion decreases sperm function and fertilization capacity after targeting spermatocytes and maturing spermatozoa

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pina-Guzman, Belem; Sanchez-Gutierrez, M.; Marchetti, Francesco

Paternal germline exposure to organophosphorous pesticides (OP) has been associated with reproductive failures and adverse effects in the offspring. Methyl parathion (Me-Pa), a worldwide-used OP, has reproductive adverse effects and is genotoxic to sperm. Oxidative damage has been involved in the genotoxic and reproductive effects of OP. The purpose of this study was to determine the effects of Me-Pa on spermatozoa function and ability to fertilize. Male mice were exposed to Me-Pa (20 mg/kg bw, i.p.) and spermatozoa from epididymis-vas deferens were collected at 7 or 28 days post-treatment (dpt) to assess the effects on maturing spermatozoa and spermatocytes, respectively.more » DNA damage was evaluated by nick translation (NT-positive cells) and SCSA (percentDFI); lipoperoxidation (LPO) by malondialdehyde production; sperm function by spontaneous- and induced-acrosome reactions (AR); mitochondrial membrane potential (MMP) by using the JC-1 flurochrome; and, fertilization ability by an in vitro assay and in vivo mating. Results showed alterations in DNA integrity (percentDFI and NT-positive cells) at 7 and 28 dpt, in addition to decreased sperm quality and a decrease in induced-AR; reduced MMP and LPO was observed only at 7 dpt. We found negative correlations between LPO and all sperm alterations. Altered sperm functional parameters were associated with reduced fertilization rates at both times, evaluated either in vitro or in vivo. These results show that Me-Pa exposure of maturing spermatozoa and spermatocytes affects many sperm functional parameters that result in a decreased fertilizing capacity. Oxidative stress seems to be a likely mechanism ofthe detrimental effects of Me-Pa in male germ cells.« less

Effect of Gestational Exposure of Cypermethrin on Postnatal Development of Brain Cytochrome P450 2D1 and 3A1 and Neurotransmitter Receptors.

PubMed

Singh, Anshuman; Mudawal, Anubha; Shukla, Rajendra K; Yadav, Sanjay; Khanna, Vinay K; Sethumadhavan, Rao; Parmar, Devendra

2015-08-01

Oral administration of low doses (1.25, 2.5, or 5 mg/kg) of cypermethrin to pregnant Wistar rats from gestation days 5 to 21 led to dose-dependent differences in the induction of cytochrome P450 2D1 (CYP2D1) and 3A1 messenger RNA (mRNA) and protein in brain regions isolated from the offsprings postnatally at 3 weeks that persisted up to adulthood (12 weeks). Similar alterations were observed in the expression of GABAergic, muscarinic, dopaminergic, and serotonergic neurotransmitter receptors in brain regions of rat offsprings. Rechallenge of the prenatally exposed offsprings at adulthood (12 weeks old) with cypermethrin (p.o., 10 mg/kg for 6 days) led to a greater magnitude of alterations in the expression of CYPs, neurotransmitter receptors, and neurotransmitter receptor binding in the brain regions when compared to the control offsprings treated at adulthood with cypermethrin or prenatally exposed offsprings. A greater magnitude of decrease was also observed in the spontaneous locomotor activity (SLA) in prenatally exposed offsprings rechallenged with cypermethrin. The present data indicating similarities in the alterations in the expression of CYPs (2D1 and 3A1) and neurotransmitter receptors in brain has led us to suggest that endogenous function regulating CYPs is possibly associated with neurotransmission processes. A greater magnitude of alterations in CYP2D1, 3A1, neurotransmitter receptors, and SLA in rechallenged animals has further provided evidence that alterations in CYPs are possibly linked with neurotransmission processes.

Laser Capture Microdissection of Pancreatic Acinar Cells to Identify Proteomic Alterations in a Murine Model of Caerulein-Induced Pancreatitis

PubMed Central

Shapiro, John P; Komar, Hannah M; Hancioglu, Baris; Yu, Lianbo; Jin, Ming; Ogata, Yuko; Hart, Phil A; Cruz-Monserrate, Zobeida; Lesinski, Gregory B; Conwell, Darwin L

2017-01-01

Objectives: Chronic pancreatitis (CP) is characterized by inflammation and fibrosis of the pancreas, leading to pain, parenchymal damage, and loss of exocrine and endocrine function. There are currently no curative therapies; diagnosis remains difficult and aspects of pathogenesis remain unclear. Thus, there is a need to identify novel biomarkers to improve diagnosis and understand pathophysiology. We hypothesize that pancreatic acinar regions contain proteomic signatures relevant to disease processes, including secreted proteins that could be detected in biofluids. Methods: Acini from pancreata of mice injected with or without caerulein were collected using laser capture microdissection followed by mass spectrometry analysis. This protocol enabled high-throughput analysis that captured altered protein expression throughout the stages of CP. Results: Over 2,900 proteins were identified, whereas 331 were significantly changed ≥2-fold by mass spectrometry spectral count analysis. Consistent with pathogenesis, we observed increases in proteins related to fibrosis (e.g., collagen, P<0.001), several proteases (e.g., trypsin 1, P<0.001), and altered expression of proteins associated with diminished pancreas function (e.g., lipase, amylase, P<0.05). In comparison with proteomic data from a public data set of CP patients, a significant correlation was observed between proteomic changes in tissue from both the caerulein model and CP patients (r=0.725, P<0.001). CONCLUSIONS: This study illustrates the ability to characterize proteome changes of acinar cells isolated from pancreata of caerulein-treated mice and demonstrates a relationship between signatures from murine and human CP. PMID:28406494

Alterations in Bladder Function Associated With Urothelial Defects in Uroplakin II and IIIa Knockout Mice

PubMed Central

Aboushwareb, Tamer; Zhou, Ge; Deng, Fang-Ming; Turner, Chanda; Andersson, Karl-Erik; Tar, Moses; Zhao, Weixin; Melman, Arnold; D’Agostino, Ralph; Sun, Tung-Tien; Christ, George J.

2014-01-01

Aims The effects of deleting genes encoding uroplakins II (UPII) and III (UPIIIa) on mouse bladder physiology/ dysfunction were studied in male and female wild type and knockout (KO) mice. Methods UPII, UPIIIa, and WT mice were catheterized using previously described techniques. Continuous cystometry was conducted in conscious, freely moving animals. Bladder strips were harvested after animal sacrifice and pharmacological studies and EFS were conducted in an organ chamber. Histological studies were also carried on with H&E staining to identify differences among the three mouse types. Results These studies have revealed numerous alterations, some of which were apparently gender-specific. Nonvoiding contractions were common in both UPII and UPIIIa KO mice, although more severe in the former. In particular, the increased bladder capacity, micturition pressure and demonstrable nonvoiding contractions observed in the male UPII KO’s, were reminiscent of an obstruction-like syndrome accompanied by evidence of emerging bladder decompensation, as reflected by an increased residual volume. Pharmacological studies revealed a modest, gender-specific reduction in sensitivity of isolated detrusor strips from UPII KO female mice to carbachol-induced contractions. A similar reduction was observed in UPIIIa KO female mice. Histological investigation showed urothelial hyperplasia in both UPII KO and UPIIIa KO mice, although again, apparently more severe in the former. Conclusions These results confirm and extend previous work to indicate that urothelial defects due to uroplakin deficiency are associated with significant alterations in bladder function and further highlight the importance of the urothelium to bladder physiology/dysfunction. PMID:19267388

The CENP-A N-Tail Confers Epigenetic Stability to Centromeres via the CENP-T Branch of the CCAN in Fission Yeast

PubMed Central

Folco, H. Diego; Campbell, Christopher S.; May, Karen M.; Espinoza, Celso A.; Oegema, Karen; Hardwick, Kevin G.; Grewal, Shiv I. S.; Desai, Arshad

2014-01-01

Summary In most eukaryotes, centromeres are defined epigenetically by presence of the histone H3 variant CENP-A [1-3]. CENP-A containing chromatin recruits the constitutive centromere-associated network (CCAN) of proteins, which in turn directs assembly of the outer kinetochore to form microtubule attachments and ensure chromosome segregation fidelity [4-6]. While the mechanisms that load CENP-A at centromeres are being elucidated, the functions of its divergent N-terminal tail remain enigmatic [7-12]. Here, we employ the well-studied fission yeast centromere [13-16] to investigate the function of the CENP-A (Cnp1) N-tail. We show that alteration of the N-tail did not affect Cnp1 loading at centromeres, outer kinetochore formation, or spindle checkpoint signaling, but nevertheless elevated chromosome loss. N-Tail mutants exhibited synthetic lethality with an altered centromeric DNA sequence, with rare survivors harboring chromosomal fusions in which the altered centromere was epigenetically inactivated. Elevated centromere inactivation was also observed for N-tail mutants with unaltered centromeric DNA sequences. N-tail mutants specifically reduced localization of the CCAN proteins Cnp20/CENP-T and Mis6/CENP-I, but not Cnp3/CENP-C. Overexpression of Cnp20/CENP-T suppressed defects in an N-tail mutant, suggesting a link between reduced CENP-T recruitment and the observed centromere inactivation phenotype. Thus, the Cnp1 N-tail promotes epigenetic stability of centromeres in fission yeast, at least in part via recruitment of the CENP-T branch of the CCAN. PMID:25619765

MitoQ improves mitochondrial dysfunction in heart failure induced by pressure overload.

PubMed

Ribeiro Junior, Rogério Faustino; Dabkowski, Erinne Rose; Shekar, Kadambari Chandra; O Connell, Kelly A; Hecker, Peter A; Murphy, Michael P

2018-03-01

Heart failure remains a major public-health problem with an increase in the number of patients worsening from this disease. Despite current medical therapy, the condition still has a poor prognosis. Heart failure is complex but mitochondrial dysfunction seems to be an important target to improve cardiac function directly. Our goal was to analyze the effects of MitoQ (100 µM in drinking water) on the development and progression of heart failure induced by pressure overload after 14 weeks. The main findings are that pressure overload-induced heart failure in rats decreased cardiac function in vivo that was not altered by MitoQ. However, we observed a reduction in right ventricular hypertrophy and lung congestion in heart failure animals treated with MitoQ. Heart failure also decreased total mitochondrial protein content, mitochondrial membrane potential in the intermyofibrillar mitochondria. MitoQ restored membrane potential in IFM but did not restore mitochondrial protein content. These alterations are associated with the impairment of basal and stimulated mitochondrial respiration in IFM and SSM induced by heart failure. Moreover, MitoQ restored mitochondrial respiration in heart failure induced by pressure overload. We also detected higher levels of hydrogen peroxide production in heart failure and MitoQ restored the increase in ROS production. MitoQ was also able to improve mitochondrial calcium retention capacity, mainly in the SSM whereas in the IFM we observed a small alteration. In summary, MitoQ improves mitochondrial dysfunction in heart failure induced by pressure overload, by decreasing hydrogen peroxide formation, improving mitochondrial respiration and improving mPTP opening. Published by Elsevier Inc.

Mechano- and metabosensitive alterations after injection of botulinum toxin into gastrocnemius muscle.

PubMed

Caron, Guillaume; Rouzi, Talifujiang; Grelot, Laurent; Magalon, Guy; Marqueste, Tanguy; Decherchi, Patrick

2014-07-01

This study was designed to investigate effects of motor denervation by Clostridium botulinum toxin serotype A (BoNT/A) on the afferent activity of fibers originating from the gastrocnemius muscle of rats. Animals were randomized in two groups, 1) untreated animals acting as control and 2) treated animals in which the toxin was injected in the left muscle. Locomotor activity was evaluated once per day during 12 days with a test based on footprint measurements of walking rats (sciatic functional index). At the end of the functional assessment period, electrophysiological tests were used to measure muscle properties, metabosensitive afferent fiber responses to chemical (KCl and lactic acid) injections, electrically induced fatigue (EIF), and mechanosensitive responses to tendon vibrations. Additionally, ventilatory response was recorded during repetitive muscle contractions. Then, rats were sacrificed, and the BoNT/A-injected muscles were weighed. Twelve days postinjection we observed a complete motor denervation associated with a significant muscle atrophy and loss of force to direct muscle stimulation. In the BoNT/A group, the metabosensitive responses to KCl injections were unaltered. However, we observed alterations in responses to EIF and to 1 mM of lactic acid (which induces the greatest activation). The ventilatory adjustments during repetitive muscle activation were abolished, and the mechanosensitive fiber responses to tendon vibrations were reduced. These results indicate that BoNT/A alters the sensorimotor loop and may induce insufficient motor and physiological adjustments in patients in whom a motor denervation with BoNT/A was performed. Copyright © 2014 Wiley Periodicals, Inc.

Altered Spontaneous Brain Activity in Betel Quid Dependence

PubMed Central

Liu, Tao; Li, Jian-jun; Zhao, Zhong-yan; Yang, Guo-shuai; Pan, Meng-jie; Li, Chang-qing; Pan, Su-yue; Chen, Feng

2016-01-01

Abstract It has been suggested by the first voxel-based morphometry investigation that betel quid dependence (BQD) individuals are presented with brain structural changes in previous reports, and there may be a neurobiological basis for BQD individuals related to an increased risk of executive dysfunction and disinhibition, subjected to the reward system, cognitive system, and emotion system. However, the effects of BQD on neural activity remain largely unknown. Individuals with impaired cognitive control of behavior often reveal altered spontaneous cerebral activity in resting-state functional magnetic resonance imaging and those changes are usually earlier than structural alteration. Here, we examined BQD individuals (n = 33) and age-, sex-, and education-matched healthy control participants (n = 32) in an resting-state functional magnetic resonance imaging study to observe brain function alterations associated with the severity of BQD. Amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) values were both evaluated to stand for spontaneous cerebral activity. Gray matter volumes of these participants were also calculated for covariate. In comparison with healthy controls, BQD individuals demonstrated dramatically decreased ALFF and ReHo values in the prefrontal gurus along with left fusiform, and increased ALFF and ReHo values in the primary motor cortex area, temporal lobe as well as some regions of occipital lobe. The betel quid dependence scores (BQDS) were negatively related to decreased activity in the right anterior cingulate. The abnormal spontaneous cerebral activity revealed by ALFF and ReHo calculation excluding the structural differences in patients with BQD may help us probe into the neurological pathophysiology underlying BQD-related executive dysfunction and disinhibition. Diminished spontaneous brain activity in the right anterior cingulate cortex may, therefore, represent a biomarker of BQD individuals. PMID:26844480

Obesity Alters Molecular and Functional Cardiac Responses to Ischemia-Reperfusion and Glucagon-Like Peptide-1 Receptor Agonism

PubMed Central

Sassoon, Daniel J; Goodwill, Adam G; Noblet, Jillian N; Conteh, Abass M; Herring, B. Paul; McClintick, Jeanette N; Tune, Johnathan D; Mather, Kieren J

2016-01-01

This study tested the hypothesis that obesity alters the cardiac response to ischemia/reperfusion and/or glucagon like peptide-1 (GLP-1) receptor activation, and that these differences are associated with alterations in the obese cardiac proteome and microRNA (miR) transcriptome. Ossabaw swine were fed normal chow or obesogenic diet for 6 months. Cardiac function was assessed at baseline, during a 30-min coronary occlusion, and during 2 hours of reperfusion in anesthetized swine treated with saline or exendin-4 for 24 hours. Cardiac biopsies were obtained from normal and ischemia/reperfusion territories. Fat-fed animals were heavier, and exhibited hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. Plasma troponin-I concentration (index of myocardial injury) was increased following ischemia/reperfusion and decreased by exendin-4 treatment in both groups. Ischemia/reperfusion produced reductions in systolic pressure and stroke volume in lean swine. These indices were higher in obese hearts at baseline and relatively maintained throughout ischemia/reperfusion. Exendin-4 administration increased systolic pressure in lean swine but did not affect blood pressure in obese swine. End-diastolic volume was reduced by exendin-4 following ischemia/reperfusion in obese swine. These divergent physiologic responses were associated with obesity-related differences in proteins related to myocardial structure/function (e.g. titin) and calcium handling (e.g. SERCA2a, histidine-rich Ca2+ binding protein). Alterations in expression of cardiac miRs in obese hearts included miR-15, miR-27, miR-130, miR-181, and let-7. Taken together, these observations validate this discovery approach and reveal novel associations that suggest previously undiscovered mechanisms contributing to the effects of obesity on the heart and contributing to the actions of GLP-1 following ischemia/reperfusion. PMID:27234258

Effect of iron deficiency on the expression of insulin-like growth factor-II and its receptor in neuronal and glial cells.

PubMed

Morales González, E; Contreras, I; Estrada, J A

2014-09-01

Many studies have demonstrated that iron deficiency modifies the normal function of the central nervous system and alters cognitive abilities. When cellular damage occurs in the central nervous system, neuroprotective mechanisms, such as the production of neurotrophic factors, are essential in order for nervous tissue to function correctly. Insulin-like growth factor II (IGF- II) is a neurotrophic factor that was recently shown to be involved in the normal functioning of cognitive processes in animal models. However, the impact of iron deficiency on the expression and function of this molecule has not yet been clarified. Mixed primary cell cultures from the central nervous system were collected to simulate iron deficiency using deferoxamine. The expression of IGF-I, IGF-II, IGF-IR, and IGF-IIR was determined with the western blot test. We observed increased expression of IGF-II, along with a corresponding decrease in the expression of IGF-IIR, in iron-deficient mixed primary cell cultures. We did not observe alterations in the expression of these proteins in isolated microglia or neuronal cultures under the same conditions. We did not detect differences in the expression of IGF-I and IGF-IR in iron-deficient cultures. In vitro iron deficiency increases the expression of IGF-II in mixed glial cell cultures, which may have a beneficial effect on brain tissue homeostasis in a situation in which iron availability is decreased. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Noradrenergic modulation of neural erotic stimulus perception.

PubMed

Graf, Heiko; Wiegers, Maike; Metzger, Coraline Danielle; Walter, Martin; Grön, Georg; Abler, Birgit

2017-09-01

We recently investigated neuromodulatory effects of the noradrenergic agent reboxetine and the dopamine receptor affine amisulpride in healthy subjects on dynamic erotic stimulus processing. Whereas amisulpride left sexual functions and neural activations unimpaired, we observed detrimental activations under reboxetine within the caudate nucleus corresponding to motivational components of sexual behavior. However, broadly impaired subjective sexual functioning under reboxetine suggested effects on further neural components. We now investigated the same sample under these two agents with static erotic picture stimulation as alternative stimulus presentation mode to potentially observe further neural treatment effects of reboxetine. 19 healthy males were investigated under reboxetine, amisulpride and placebo for 7 days each within a double-blind cross-over design. During fMRI static erotic picture were presented with preceding anticipation periods. Subjective sexual functions were assessed by a self-reported questionnaire. Neural activations were attenuated within the caudate nucleus, putamen, ventral striatum, the pregenual and anterior midcingulate cortex and in the orbitofrontal cortex under reboxetine. Subjective diminished sexual arousal under reboxetine was correlated with attenuated neural reactivity within the posterior insula. Again, amisulpride left neural activations along with subjective sexual functioning unimpaired. Neither reboxetine nor amisulpride altered differential neural activations during anticipation of erotic stimuli. Our results verified detrimental effects of noradrenergic agents on neural motivational but also emotional and autonomic components of sexual behavior. Considering the overlap of neural network alterations with those evoked by serotonergic agents, our results suggest similar neuromodulatory effects of serotonergic and noradrenergic agents on common neural pathways relevant for sexual behavior. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

Distinct Functional Networks Associated with Improvement of Affective Symptoms and Cognitive Function During Citalopram Treatment in Geriatric Depression

PubMed Central

Diaconescu, Andreea Oliviana; Kramer, Elisse; Hermann, Carol; Ma, Yilong; Dhawan, Vijay; Chaly, Thomas; Eidelberg, David; McIntosh, Anthony Randal; Smith, Gwenn S.

2010-01-01

Variability in the affective and cognitive symptom response to antidepressant treatment has been observed in geriatric depression. The underlying neural circuitry is poorly understood. The current study evaluated the cerebral glucose metabolic effects of citalopram treatment and applied multivariate, functional connectivity analyses to identify brain networks associated with improvements in affective symptoms and cognitive function. Sixteen geriatric depressed patients underwent resting Positron Emission Tomography (PET) studies of cerebral glucose metabolism and assessment of affective symptoms and cognitive function before and after eight weeks of selective serotonin reuptake inhibitor treatment (citalopram). Voxel-wise analyses of the normalized glucose metabolic data showed decreased cerebral metabolism during citalopram treatment in the anterior cingulate gyrus, middle temporal gyrus, precuneus, amygdala, and parahippocampal gyrus. Increased metabolism was observed in the putamen, occipital cortex and cerebellum. Functional connectivity analyses revealed two networks which were uniquely associated with improvement of affective symptoms and cognitive function during treatment. A subcortical-limbic-frontal network was associated with improvement in affect (depression and anxiety), while a medial temporal-parietal-frontal network was associated with improvement in cognition (immediate verbal learning/memory and verbal fluency). The regions that comprise the cognitive network overlap with the regions that are affected in Alzheimer’s dementia. Thus, alterations in specific brain networks associated with improvement of affective symptoms and cognitive function are observed during citalopram treatment in geriatric depression. PMID:20886575

Associations between the degree of early lactation inflammation and performance, metabolism, and immune function in dairy cows.

PubMed

McCarthy, M M; Yasui, T; Felippe, M J B; Overton, T R

2016-01-01

The objective of the current study was to determine associations between the severity of systemic inflammation during the early postpartum period and performance, energy metabolism, and immune function in dairy cows. Cows were assigned to categorical quartiles (Q; Q1=0.18-0.59, Q2=0.60-1.14, Q3=1.15-2.05, and Q4=2.06-2.50 g of haptoglobin/L) based on the highest plasma haptoglobin (Hp) concentration measured during wk 1 postpartum. Although cows were assigned to different categories of inflammation during the postpartum period, we detected a quadratic relationship of inflammation on prepartum dry matter intake (DMI) and body weight (BW) such that cows in Q2 had lower prepartum DMI and cows in Q2 and Q3 had lower prepartum BW compared with cows in the other quartiles. We also detected a quadratic association of inflammation with postpartum DMI and BW such that cows in Q2 and Q3 also had generally lower postpartum DMI and BW compared with cows in Q1. There was a tendency for a Q × time interaction for milk yield and Q × time interactions for 3.5% fat-corrected milk and energy-corrected milk yields; quadratic relationships suggested decreased milk yield for Q2 and Q3 cows. We also found Q × parity and Q × time interactions for plasma glucose and insulin concentrations, suggesting alterations with differing degrees of inflammation. There was also a Q × time interaction for plasma nonesterified fatty acids concentration. In addition, alterations in liver triglyceride and glycogen contents for cows with inflammation as well as alterations in [1-(14)C]propionate oxidation in vitro were observed. Although we observed limited effects of inflammation on neutrophil and monocyte phagocytosis at d 7 postpartum, inflammation appeared to alter neutrophil and monocyte oxidative burst. Overall, cows with any degree of elevated haptoglobin in the first week after calving had alterations in both pre- and postpartum intake and postpartum metabolism. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Silicon isotopes fractionation in meteoric chemical weathering and hydrothermal alteration systems of volcanic rocks (Mayotte)

NASA Astrophysics Data System (ADS)

Basile-Doelsch, Isabelle; Puyraveau, Romain-Arnaud; Guihou, Abel; Haurine, Frederic; Deschamps, Pierre; rad, Setareh; Nehlig, Pierre

2017-04-01

Low temperature chemical weathering fractionates silicon (Si) isotopes while forming secondary silicates. The Si fractionation ranges of high temperature secondary phyllosilicates formed in hydrothermal alteration environments have not been investigated to date. Several parameters, including temperature, reaction rates, pH, ionic concentrations in solution, precipitation/dissolution series or kinetic versus equilibrium regime are not the same in hydrothermal alteration and surface weathering systems and may lead to different fractionation factors. In this work, we analyzed Si isotopes in these two types of alteration conditions in two profiles sampled on the volcanic island of Mayotte. In both profiles, Si-bearing secondary mineral was kaolinite. Both profiles showed 30Si depletion as a function of the degree of alteration but each with a distinct pattern. In the meteoric weathering profile, from the bottom to the top, a gradual decrease of the δ30Si from parent rock (-0.29 ± 0.13 ‰) towards the most weathered product (-2.05 ± 0.13 ‰) was observed. In the hydrothermal alteration profile, in which meteoric weathering was also superimposed at the top of the profile, an abrupt transition of the δ30Si was measured at the interface between parent-rock (-0.21 ± 0.11 ‰) and the altered products, with a minimum value of -3.06 ± 0.16 ‰˙ At the scale of Si-bearing secondary minerals, in the chemical weathering system, a Δ30Sikaol-parentrock of -1.9 ‰ was observed, in agreement with results in the literature. A low temperature kinetic fractionation 30ɛ of -2.29 ‰ was calculated using a simple steady state model. However, an unexpected Δ30Sikaol-parentrock of -2.85 ‰ was measured in the hydrothermal alteration site, pointing to possible mechanisms linked to dissolution/precipitation series and/or to ionic composition of the solution as the main controlling factors of fractionation in hydrothermal conditions. At the scale of the profiles, both δ30Si bulk rocks showed linear correlations with the SiO2:Al2O3 ratios, suggesting an alternative alteration index based on Si isotopic composition.

Modulation of the Hypothalamic-Pituitary-Adrenal Axis by Early Life Stress Exposure

PubMed Central

van Bodegom, Miranda; Homberg, Judith R.; Henckens, Marloes J. A. G.

2017-01-01

Exposure to stress during critical periods in development can have severe long-term consequences, increasing overall risk on psychopathology. One of the key stress response systems mediating these long-term effects of stress is the hypothalamic-pituitary-adrenal (HPA) axis; a cascade of central and peripheral events resulting in the release of corticosteroids from the adrenal glands. Activation of the HPA-axis affects brain functioning to ensure a proper behavioral response to the stressor, but stress-induced (mal)adaptation of the HPA-axis' functional maturation may provide a mechanistic basis for the altered stress susceptibility later in life. Development of the HPA-axis and the brain regions involved in its regulation starts prenatally and continues after birth, and is protected by several mechanisms preventing corticosteroid over-exposure to the maturing brain. Nevertheless, early life stress (ELS) exposure has been reported to have numerous consequences on HPA-axis function in adulthood, affecting both its basal and stress-induced activity. According to the match/mismatch theory, encountering ELS prepares an organism for similar (“matching”) adversities during adulthood, while a mismatching environment results in an increased susceptibility to psychopathology, indicating that ELS can exert either beneficial or disadvantageous effects depending on the environmental context. Here, we review studies investigating the mechanistic underpinnings of the ELS-induced alterations in the structural and functional development of the HPA-axis and its key external regulators (amygdala, hippocampus, and prefrontal cortex). The effects of ELS appear highly dependent on the developmental time window affected, the sex of the offspring, and the developmental stage at which effects are assessed. Albeit by distinct mechanisms, ELS induced by prenatal stressors, maternal separation, or the limited nesting model inducing fragmented maternal care, typically results in HPA-axis hyper-reactivity in adulthood, as also found in major depression. This hyper-activity is related to increased corticotrophin-releasing hormone signaling and impaired glucocorticoid receptor-mediated negative feedback. In contrast, initial evidence for HPA-axis hypo-reactivity is observed for early social deprivation, potentially reflecting the abnormal HPA-axis function as observed in post-traumatic stress disorder, and future studies should investigate its neural/neuroendocrine foundation in further detail. Interestingly, experiencing additional (chronic) stress in adulthood seems to normalize these alterations in HPA-axis function, supporting the match/mismatch theory. PMID:28469557

Failing to learn from negative prediction errors: Obesity is associated with alterations in a fundamental neural learning mechanism.

PubMed

Mathar, David; Neumann, Jane; Villringer, Arno; Horstmann, Annette

2017-10-01

Prediction errors (PEs) encode the difference between expected and actual action outcomes in the brain via dopaminergic modulation. Integration of these learning signals ensures efficient behavioral adaptation. Obesity has recently been linked to altered dopaminergic fronto-striatal circuits, thus implying impairments in cognitive domains that rely on its integrity. 28 obese and 30 lean human participants performed an implicit stimulus-response learning paradigm inside an fMRI scanner. Computational modeling and psycho-physiological interaction (PPI) analysis was utilized for assessing PE-related learning and associated functional connectivity. We show that human obesity is associated with insufficient incorporation of negative PEs into behavioral adaptation even in a non-food context, suggesting differences in a fundamental neural learning mechanism. Obese subjects were less efficient in using negative PEs to improve implicit learning performance, despite proper coding of PEs in striatum. We further observed lower functional coupling between ventral striatum and supplementary motor area in obese subjects subsequent to negative PEs. Importantly, strength of functional coupling predicted task performance and negative PE utilization. These findings show that obesity is linked to insufficient behavioral adaptation specifically in response to negative PEs, and to associated alterations in function and connectivity within the fronto-striatal system. Recognition of neural differences as a central characteristic of obesity hopefully paves the way to rethink established intervention strategies: Differential behavioral sensitivity to negative and positive PEs should be considered when designing intervention programs. Measures relying on penalization of unwanted behavior may prove less effective in obese subjects than alternative approaches. Copyright © 2017 Elsevier Ltd. All rights reserved.

Functional resting-state networks are differentially affected in schizophrenia

PubMed Central

Woodward, Neil D.; Rogers, Baxter; Heckers, Stephan

2011-01-01

Neurobiological theories posit that schizophrenia relates to disturbances in connectivity between brain regions. Resting-state functional magnetic resonance imaging is a powerful tool for examining functional connectivity and has revealed several canonical brain networks, including the default mode, dorsal attention, executive control, and salience networks. The purpose of this study was to examine changes in these networks in schizophrenia. 42 patients with schizophrenia and 61 healthy subjects completed a RS-fMRI scanning session. Seed-based region-of-interest correlation analysis was used to identify the default mode, dorsal attention, executive control, and salience networks. Compared to healthy subjects, individuals with schizophrenia demonstrated greater connectivity between the posterior cingulate cortex, a key hub of the default mode, and the left inferior gyrus, left middle frontal gyrus, and left middle temporal gyrus. Interestingly, these regions were more strongly connected to the executive control network in healthy control subjects. In contrast to the default mode, patients demonstrated less connectivity in the executive control and dorsal attention networks. No differences were observed in the salience network. The results indicate that resting-state networks are differentially affected in schizophrenia. The alterations are characterized by reduced segregation between the default mode and executive control networks in the prefrontal cortex and temporal lobe, and reduced connectivity in the dorsal attention and executive control networks. The changes suggest that the process of functional specialization is altered in schizophrenia. Further work is needed to determine if the alterations are related to disturbances in white matter connectivity, neurodevelopmental abnormalities, and genetic risk for schizophrenia. PMID:21458238

Abnormal GABAergic function and face processing in schizophrenia: A pharmacologic-fMRI study.

PubMed

Tso, Ivy F; Fang, Yu; Phan, K Luan; Welsh, Robert C; Taylor, Stephan F

2015-10-01

The involvement of the gamma-aminobutyric acid (GABA) system in schizophrenia is suggested by postmortem studies and the common use of GABA receptor-potentiating agents in treatment. In a recent study, we used a benzodiazepine challenge to demonstrate abnormal GABAergic function during processing of negative visual stimuli in schizophrenia. This study extended this investigation by mapping GABAergic mechanisms associated with face processing and social appraisal in schizophrenia using a benzodiazepine challenge. Fourteen stable, medicated schizophrenia/schizoaffective patients (SZ) and 13 healthy controls (HC) underwent functional MRI using the blood oxygenation level-dependent (BOLD) technique while they performed the Socio-emotional Preference Task (SePT) on emotional face stimuli ("Do you like this face?"). Participants received single-blinded intravenous saline and lorazepam (LRZ) in two separate sessions separated by 1-3weeks. Both SZ and HC recruited medial prefrontal cortex/anterior cingulate during the SePT, relative to gender identification. A significant drug by group interaction was observed in the medial occipital cortex, such that SZ showed increased BOLD signal to LRZ challenge, while HC showed an expected decrease of signal; the interaction did not vary by task. The altered BOLD response to LRZ challenge in SZ was significantly correlated with increased negative affect across multiple measures. The altered response to LRZ challenge suggests that abnormal face processing and negative affect in SZ are associated with altered GABAergic function in the visual cortex, underscoring the role of impaired visual processing in socio-emotional deficits in schizophrenia. Copyright © 2015 Elsevier B.V. All rights reserved.

Altered Reward Function in Adolescent Depression: What, When, and How?

PubMed Central

Forbes, Erika E.; Dahl, Ronald E.

2011-01-01

Background Conceptual models and recent evidence indicate that neural response to reward is altered in depression. Taking a developmental approach to investigating reward function in adolescent depression can elucidate the etiology, pathophysiology, and course of depression, a disorder that typically begins during adolescence and has high rates of recurrence. Methods This conceptual review describes the what, when, and how of altered reward function in adolescent depression. With the goal of generating new, testable hypotheses within a developmental affective neuroscience framework, we critically review findings and suggest future directions. Peer-reviewed empirical papers for inclusion in this critical review were obtained by searching PubMed, PsycInfo, and ScienceDirect for the years 1990–2010. Results A pattern of low striatal response and high medial prefrontal response to reward is evident in adolescents and adults with depression. Given the salience of social stimuli for positive affect and depression, reward function might be especially disrupted in response to social rewards. Because of changes in the dopamine system and reward function with aging, altered reward function in depression might be more evident during adolescence than later in life; however, low reward function may also be a stable characteristic of people who experience depression. Mechanisms of altered reward function in depression could include disrupted balance of corticostriatal circuit function, with disruption occurring as aberrant adolescent brain development. Conclusions Future studies should examine responses to social rewards; employ longitudinal and prospective designs; and investigate patterns of functional connectivity in reward circuits. Understanding altered reward function in depression has potential implications for treatment development. A more rigorous approach to investigating anhedonia, threat-reward interactions, and comorbid anxiety will be valuable to future progress in describing the role of reward function in the pathophysiology of depression. PMID:22117893

Alteration minerals in impact-generated hydrothermal systems - Exploring host rock variability

NASA Astrophysics Data System (ADS)

Schwenzer, Susanne P.; Kring, David A.

2013-09-01

Impact-generated hydrothermal systems have been previously linked to the alteration of Mars’ crust and the production of secondary mineral assemblages seen from orbit. The sensitivity of the resultant assemblages has not yet been evaluated as a function of precursor primary rock compositions. In this work, we use thermochemical modeling to explore the variety of minerals that could be produced by altering several known lithologies based on martian meteorite compositions. For a basaltic host rock lithology (Dhofar 378, Humphrey) the main alteration phases are feldspar, zeolite, pyroxene, chlorite, clay (nontronite, kaolinite), and hematite; for a lherzolithic host rock lithology (LEW 88516) the main alteration phases are amphibole, serpentine, chlorite, clay (nontronite, kaolinite), and hematite; and for an ultramafic host rock lithology (Chassigny) the main minerals are secondary olivine, serpentine, magnetite, quartz, and hematite. These assemblages and proportions of phases in each of those cases depend on W/R and temperature. Integrating geologic, hydrologic and alteration mineral evidence, we have developed a model to illustrate the distribution of alteration assemblages that occur in different levels of an impact structure. At the surface, hot, hydrous alteration affects the ejecta and melt sheet producing clay and chlorite. Deeper in the subsurface and depending on the permeability of the rock, a variety of minerals - smectite, chlorite, serpentine, amphiboles and hematite - are produced in a circulating hydrothermal system. These modeled mineral distributions should assist with interpretation of orbital observations and help guide surface exploration by rovers and sample return assets.

Violent Video Games Alter Brain Function in Young Men

MedlinePlus

... the RSNA Annual Meeting Violent Video Games Alter Brain Function in Young Men At A Glance Using ... video games for one week causes changes in brain function. The brain regions affected by violent video ...

Financial Exploitation Is Associated With Structural and Functional Brain Differences in Healthy Older Adults

PubMed Central

Spreng, R. Nathan; Cassidy, Benjamin N; Darboh, Bri S; DuPre, Elizabeth; Lockrow, Amber W; Setton, Roni; Turner, Gary R

2017-01-01

Abstract Background Age-related brain changes leading to altered socioemotional functioning may increase vulnerability to financial exploitation. If confirmed, this would suggest a novel mechanism leading to heightened financial exploitation risk in older adults. Development of predictive neural markers could facilitate increased vigilance and prevention. In this preliminary study, we sought to identify structural and functional brain differences associated with financial exploitation in older adults. Methods Financially exploited older adults (n = 13, 7 female) and a matched cohort of older adults who had been exposed to, but avoided, a potentially exploitative situation (n = 13, 7 female) were evaluated. Using magnetic resonance imaging, we examined cortical thickness and resting state functional connectivity. Behavioral data were collected using standardized cognitive assessments, self-report measures of mood and social functioning. Results The exploited group showed cortical thinning in anterior insula and posterior superior temporal cortices, regions associated with processing affective and social information, respectively. Functional connectivity encompassing these regions, within default and salience networks, was reduced, while between network connectivity was increased. Self-reported anger and hostility was higher for the exploited group. Conclusions We observed financial exploitation associated with brain differences in regions involved in socioemotional functioning. These exploratory and preliminary findings suggest that alterations in brain regions implicated in socioemotional functioning may be a marker of financial exploitation risk. Large-scale, prospective studies are necessary to validate this neural mechanism, and develop predictive markers for use in clinical practice. PMID:28369260

Arterial spin labeling fMRI measurements of decreased blood flow in primary visual cortex correlates with decreased visual function in human glaucoma.

PubMed

Duncan, Robert O; Sample, Pamela A; Bowd, Christopher; Weinreb, Robert N; Zangwill, Linda M

2012-05-01

Altered metabolic activity has been identified as a potential contributing factor to the neurodegeneration associated with primary open angle glaucoma (POAG). Consequently, we sought to determine whether there is a relationship between the loss of visual function in human glaucoma and resting blood perfusion within primary visual cortex (V1). Arterial spin labeling (ASL) functional magnetic resonance imaging (fMRI) was conducted in 10 participants with POAG. Resting cerebral blood flow (CBF) was measured from dorsal and ventral V1. Behavioral measurements of visual function were obtained using standard automated perimetry (SAP), short-wavelength automated perimetry (SWAP), and frequency-doubling technology perimetry (FDT). Measurements of CBF were compared to differences in visual function for the superior and inferior hemifield. Differences in CBF between ventral and dorsal V1 were correlated with differences in visual function for the superior versus inferior visual field. A statistical bootstrapping analysis indicated that the observed correlations between fMRI responses and measurements of visual function for SAP (r=0.49), SWAP (r=0.63), and FDT (r=0.43) were statistically significant (all p<0.05). Resting blood perfusion in human V1 is correlated with the loss of visual function in POAG. Altered CBF may be a contributing factor to glaucomatous optic neuropathy, or it may be an indication of post-retinal glaucomatous neurodegeneration caused by damage to the retinal ganglion cells. Copyright © 2012 Elsevier Ltd. All rights reserved.

Investigating the Temporal Patterns within and between Intrinsic Connectivity Networks under Eyes-Open and Eyes-Closed Resting States: A Dynamical Functional Connectivity Study Based on Phase Synchronization

PubMed Central

Wang, Xun-Heng; Li, Lihua; Xu, Tao; Ding, Zhongxiang

2015-01-01

The brain active patterns were organized differently under resting states of eyes open (EO) and eyes closed (EC). The altered voxel-wise and regional-wise resting state active patterns under EO/EC were found by static analysis. More importantly, dynamical spontaneous functional connectivity has been observed in the resting brain. To the best of our knowledge, the dynamical mechanisms of intrinsic connectivity networks (ICNs) under EO/EC remain largely unexplored. The goals of this paper were twofold: 1) investigating the dynamical intra-ICN and inter-ICN temporal patterns during resting state; 2) analyzing the altered dynamical temporal patterns of ICNs under EO/EC. To this end, a cohort of healthy subjects with scan conditions of EO/EC were recruited from 1000 Functional Connectomes Project. Through Hilbert transform, time-varying phase synchronization (PS) was applied to evaluate the inter-ICN synchrony. Meanwhile, time-varying amplitude was analyzed as dynamical intra-ICN temporal patterns. The results found six micro-states of inter-ICN synchrony. The medial visual network (MVN) showed decreased intra-ICN amplitude during EC relative to EO. The sensory-motor network (SMN) and auditory network (AN) exhibited enhanced intra-ICN amplitude during EC relative to EO. Altered inter-ICN PS was found between certain ICNs. Particularly, the SMN and AN exhibited enhanced PS to other ICNs during EC relative to EO. In addition, the intra-ICN amplitude might influence the inter-ICN synchrony. Moreover, default mode network (DMN) might play an important role in information processing during EO/EC. Together, the dynamical temporal patterns within and between ICNs were altered during different scan conditions of EO/EC. Overall, the dynamical intra-ICN and inter-ICN temporal patterns could benefit resting state fMRI-related research, and could be potential biomarkers for human functional connectome. PMID:26469182

The role of JAM-A in inflammatory bowel disease: unrevealing the ties that bind.

PubMed

Vetrano, Stefania; Danese, Silvio

2009-05-01

Tight junctions (TJ) are junctional proteins whose function is to maintain an intact intestinal epithelial barrier and regulate the paracellular movement of water and solutes. Altered TJ structure and epithelial permeability are observed in inflammatory bowel disease and seem to have an important role in the pathogenesis of these diseases. Junctional adhesion molecule-A (JAM-A) is a protein expressed at tight junctions of epithelial and endothelial cells, as well as on circulating leukocytes. Its function at tight junctions appears to be crucial as an extracellular adhesive molecule in the direct regulation of intestinal barrier function. This review focuses on the role of JAM-A in controlling mucosal homeostasis by regulating the integrity and permeability of epithelial barrier function.

Pathophysiology of hypertension: interactions between macro and microvascular alterations through endothelial dysfunction.

PubMed

Yannoutsos, Alexandra; Levy, Bernard I; Safar, Michel E; Slama, Gerard; Blacher, Jacques

2014-02-01

Hypertension is a multifactorial systemic chronic disorder through functional and structural macrovascular and microvascular alterations. Macrovascular alterations are featured by arterial stiffening, disturbed wave reflection and altered central to peripheral pulse pressure amplification. Microvascular alterations, including altered wall-to-lumen ratio of larger arterioles, vasomotor tone abnormalities and network rarefaction, lead to disturbed tissue perfusion and susceptibility to ischemia. Central arterial stiffness and microvascular alterations are common denominators of organ damages. Vascular alterations are intercorrelated, amplifying the haemodynamic load and causing further damage in the arterial network. A plausible precursor role of vascular alterations in incident hypertension provides new insights for preventive and therapeutic strategies targeting macro and microvasculature. Cumulative metabolic burden and oxidative stress lead to chronic endothelial injury, promoting structural and functional vascular alterations, especially in the microvascular network. Pathophysiology of hypertension may then be revisited, based on both macrovascular and microvascular alterations, with a precursor role of endothelial dysfunction for the latter.

Desensitizing the posterior interosseous nerve alters wrist proprioceptive reflexes.

PubMed

Hagert, Elisabet; Persson, Jonas K E

2010-07-01

The presence of wrist proprioceptive reflexes after stimulation of the dorsal scapholunate interosseous ligament has previously been described. Because this ligament is primarily innervated by the posterior interosseous nerve (PIN) we hypothesized altered ligamento-muscular reflex patterns following desensitization of the PIN. Eight volunteers (3 women, 5 men; mean age, 26 y; range 21-28 y) participated in the study. In the first study on wrist proprioceptive reflexes (study 1), the scapholunate interosseous ligament was stimulated through a fine-wire electrode with 4 1-ms bipolar pulses at 200 Hz, 30 times consecutively, while EMG activity was recorded from the extensor carpi radialis brevis, extensor carpi ulnaris, flexor carpi radialis, and flexor carpi ulnaris, with the wrist in extension, flexion, radial deviation, and ulnar deviation. After completion of study 1, the PIN was anesthetized in the radial aspect of the fourth extensor compartment using 2-mL lidocaine (10 mg/mL) infiltration anesthesia. Ten minutes after desensitization, the experiment was repeated as in study 1. The average EMG results from the 30 consecutive stimulations were rectified and analyzed using Student's t-test. Statistically significant changes in EMG amplitude were plotted along time lines so that the results of study 1 and 2 could be compared. Dramatic alterations in reflex patterns were observed in wrist flexion, radial deviation, and ulnar deviation following desensitization of the PIN, with an average of 72% reduction in excitatory reactions. In ulnar deviation, the inhibitory reactions of the extensor carpi ulnaris were entirely eliminated. In wrist extension, no differences in the reflex patterns were observed. Wrist proprioception through the scapholunate ligament in flexion, radial deviation, and ulnar deviation depends on an intact PIN function. The unchanged reflex patterns in wrist extension suggest an alternate proprioceptive pathway for this position. Routine excision of the PIN during wrist surgical procedures should be avoided, as it alters the proprioceptive function of the wrist. Therapeutic IV. Copyright 2010 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

Visual perception and frontal lobe in intellectual disabilities: a study with evoked potentials and neuropsychology.

PubMed

Muñoz-Ruata, J; Caro-Martínez, E; Martínez Pérez, L; Borja, M

2010-12-01

Perception disorders are frequently observed in persons with intellectual disability (ID) and their influence on cognition has been discussed. The objective of this study is to clarify the mechanisms behind these alterations by analysing the visual event related potentials early component, the N1 wave, which is related to perception alterations in several pathologies. Additionally, the relationship between N1 and neuropsychological visual tests was studied with the aim to understand its functional significance in ID persons. A group of 69 subjects, with etiologically heterogeneous mild ID, performed an odd-ball task of active discrimination of geometric figures. N1a (frontal) and N1b (post-occipital) waves were obtained from the evoked potentials. They also performed several neuropsychological tests. Only component N1a, produced by the target stimulus, showed significant correlations with the visual integration, visual semantic association, visual analogical reasoning tests, Perceptual Reasoning Index (Wechsler Intelligence Scale for Children Fourth Edition) and intelligence quotient. The systematic correlations, produced by the target stimulus in perceptual abilities tasks, with the N1a (frontal) and not with N1b (posterior), suggest that the visual perception process involves frontal participation. These correlations support the idea that the N1a and N1b are not equivalent. The relationship between frontal functions and early stages of visual perception is revised and discussed, as well as the frontal contribution with the neuropsychological tests used. A possible relationship between the frontal activity dysfunction in ID and perceptive problems is suggested. Perceptive alteration observed in persons with ID could indeed be because of altered sensory areas, but also to a failure in the frontal participation of perceptive processes conceived as elaborations inside reverberant circuits of perception-action. © 2010 The Authors. Journal of Intellectual Disability Research © 2010 Blackwell Publishing Ltd.

PCBs Alter Dopamine Mediated Function in Aging Workers

DTIC Science & Technology

2004-01-01

Do PCBs Alter Doparnine Mediated Function in Aging Workers ? Principal Investigators: Dr. Richard Seegal of the New York State Department of Health and...Award Number: DAMD17-02-1-0173 TITLE: PCBs Alter Dopamine Mediated Function in Aging Workers PRINCIPAL INVESTIGATOR: Richard F.Seegal, Ph.D...CONTRACTING ORGANIZATION: Health Research, Incorporated Rensselaer, New York 12144 REPORT DATE: January 2004 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army

Cancer cell metabolism and the modulating effects of nitric oxide.

PubMed

Chang, Ching-Fang; Diers, Anne R; Hogg, Neil

2015-02-01

Altered metabolic phenotype has been recognized as a hallmark of tumor cells for many years, but this aspect of the cancer phenotype has come into greater focus in recent years. NOS2 (inducible nitric oxide synthase of iNOS) has been implicated as a component in many aggressive tumor phenotypes, including melanoma, glioblastoma, and breast cancer. Nitric oxide has been well established as a modulator of cellular bioenergetics pathways, in many ways similar to the alteration of cellular metabolism observed in aggressive tumors. In this review we attempt to bring these concepts together with the general hypothesis that one function of NOS2 and NO in cancer is to modulate metabolic processes to facilitate increased tumor aggression. There are many mechanisms by which NO can modulate tumor metabolism, including direct inhibition of respiration, alterations in mitochondrial mass, oxidative inhibition of bioenergetic enzymes, and the stimulation of secondary signaling pathways. Here we review metabolic alterations in the context of cancer cells and discuss the role of NO as a potential mediator of these changes. Copyright © 2015. Published by Elsevier Inc.

Altered Global Signal Topography in Schizophrenia.

PubMed

Yang, Genevieve J; Murray, John D; Glasser, Matthew; Pearlson, Godfrey D; Krystal, John H; Schleifer, Charlie; Repovs, Grega; Anticevic, Alan

2017-11-01

Schizophrenia (SCZ) is a disabling neuropsychiatric disease associated with disruptions across distributed neural systems. Resting-state functional magnetic resonance imaging has identified extensive abnormalities in the blood-oxygen level-dependent signal in SCZ patients, including alterations in the average signal over the brain-i.e. the "global" signal (GS). It remains unknown, however, if these "global" alterations occur pervasively or follow a spatially preferential pattern. This study presents the first network-by-network quantification of GS topography in healthy subjects and SCZ patients. We observed a nonuniform GS contribution in healthy comparison subjects, whereby sensory areas exhibited the largest GS component. In SCZ patients, we identified preferential GS representation increases across association regions, while sensory regions showed preferential reductions. GS representation in sensory versus association cortices was strongly anti-correlated in healthy subjects. This anti-correlated relationship was markedly reduced in SCZ. Such shifts in GS topography may underlie profound alterations in neural information flow in SCZ, informing development of pharmacotherapies. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Cancer Cell Metabolism and the Modulating Effects of Nitric Oxide

PubMed Central

Chang, Ching-Fang; Diers, Anne R.; Hogg, Neil

2016-01-01

Altered metabolic phenotype has been recognized as a hallmark of tumor cells for many years, but this aspect of the cancer phenotype has come into greater focus in recent years. NOS2 (inducible nitric oxide synthase of iNOS) has been implicated as a component in many aggressive tumor phenotypes, including melanoma, glioblastoma and breast cancer. Nitric oxide has been well established as a modulator of cellular bioenergetics pathways, in many ways similar to the alteration of cellular metabolism observed in aggressive tumors. In this review we attempt to bring these concepts together with the general hypothesis that one function of NOS2 and NO in cancer is to modulate metabolic processes to facilitate increased tumor aggression. There are many mechanisms by which NO can modulate tumor metabolism, including direct inhibition of respiration, alterations in mitochondrial mass, oxidative inhibition of bioenergetic enzymes, and the stimulation of secondary signaling pathways. Here we review metabolic alterations in the context of cancer cells and discuss the role of NO as a potential mediator of these changes. PMID:25464273

Garcinia kola seeds may prevent cognitive and motor dysfunctions in a type 1 diabetes mellitus rat model partly by mitigating neuroinflammation.

PubMed

Seke Etet, Paul F; Farahna, Mohammed; Satti, Gwiria M H; Bushara, Yahia M; El-Tahir, Ahmed; Hamza, Muaawia A; Osman, Sayed Y; Dibia, Ambrose C; Vecchio, Lorella

2017-04-15

Background We reported recently that extracts of seeds of Garcinia kola, a plant with established hypoglycemic properties, prevented the loss of inflammation-sensible neuronal populations like Purkinje cells in a rat model of type 1 diabetes mellitus (T1DM). Here, we assessed G. kola extract ability to prevent the early cognitive and motor dysfunctions observed in this model. Methods Rats made diabetic by single injection of streptozotocin were treated daily with either vehicle solution (diabetic control group), insulin, or G. kola extract from the first to the 6th week post-injection. Then, cognitive and motor functions were assessed using holeboard and vertical pole behavioral tests, and animals were sacrificed. Brains were dissected out, cut, and processed for Nissl staining and immunohistochemistry. Results Hyperglycemia (209.26 %), body weight loss (-12.37 %), and T1DM-like cognitive and motor dysfunctions revealed behavioral tests in diabetic control animals were not observed in insulin and extract-treated animals. Similar, expressions of inflammation markers tumor necrosis factor (TNF), iba1 (CD68), and Glial fibrillary acidic protein (GFAP), as well as decreases of neuronal density in regions involved in cognitive and motor functions (-49.56 % motor cortex, -33.24 % medial septal nucleus, -41.8 % /-37.34 % cerebellar Purkinje /granular cell layers) were observed in diabetic controls but not in animals treated with insulin or G. kola. Conclusions Our results indicate that T1DM-like functional alterations are mediated, at least partly, by neuroinflammation and neuronal loss in this model. The prevention of the development of such alterations by early treatment with G. kola confirms the neuroprotective properties of the plant and warrant further mechanistic studies, considering the potential for human disease.

Olfactory Receptors in Non-Chemosensory Organs: The Nervous System in Health and Disease.

PubMed

Ferrer, Isidro; Garcia-Esparcia, Paula; Carmona, Margarita; Carro, Eva; Aronica, Eleonora; Kovacs, Gabor G; Grison, Alice; Gustincich, Stefano

2016-01-01

Olfactory receptors (ORs) and down-stream functional signaling molecules adenylyl cyclase 3 (AC3), olfactory G protein α subunit (Gαolf), OR transporters receptor transporter proteins 1 and 2 (RTP1 and RTP2), receptor expression enhancing protein 1 (REEP1), and UDP-glucuronosyltransferases (UGTs) are expressed in neurons of the human and murine central nervous system (CNS). In vitro studies have shown that these receptors react to external stimuli and therefore are equipped to be functional. However, ORs are not directly related to the detection of odors. Several molecules delivered from the blood, cerebrospinal fluid, neighboring local neurons and glial cells, distant cells through the extracellular space, and the cells' own self-regulating internal homeostasis can be postulated as possible ligands. Moreover, a single neuron outside the olfactory epithelium expresses more than one receptor, and the mechanism of transcriptional regulation may be different in olfactory epithelia and brain neurons. OR gene expression is altered in several neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2 with disease-, region- and subtype-specific patterns. Altered gene expression is also observed in the prefrontal cortex in schizophrenia with a major but not total influence of chlorpromazine treatment. Preliminary parallel observations have also shown the presence of taste receptors (TASRs), mainly of the bitter taste family, in the mammalian brain, whose function is not related to taste. TASRs in brain are also abnormally regulated in neurodegenerative diseases. These seminal observations point to the need for further studies on ORs and TASRs chemoreceptors in the mammalian brain.

Olfactory Receptors in Non-Chemosensory Organs: The Nervous System in Health and Disease

PubMed Central

Ferrer, Isidro; Garcia-Esparcia, Paula; Carmona, Margarita; Carro, Eva; Aronica, Eleonora; Kovacs, Gabor G.; Grison, Alice; Gustincich, Stefano

2016-01-01

Olfactory receptors (ORs) and down-stream functional signaling molecules adenylyl cyclase 3 (AC3), olfactory G protein α subunit (Gαolf), OR transporters receptor transporter proteins 1 and 2 (RTP1 and RTP2), receptor expression enhancing protein 1 (REEP1), and UDP-glucuronosyltransferases (UGTs) are expressed in neurons of the human and murine central nervous system (CNS). In vitro studies have shown that these receptors react to external stimuli and therefore are equipped to be functional. However, ORs are not directly related to the detection of odors. Several molecules delivered from the blood, cerebrospinal fluid, neighboring local neurons and glial cells, distant cells through the extracellular space, and the cells’ own self-regulating internal homeostasis can be postulated as possible ligands. Moreover, a single neuron outside the olfactory epithelium expresses more than one receptor, and the mechanism of transcriptional regulation may be different in olfactory epithelia and brain neurons. OR gene expression is altered in several neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) and sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2 with disease-, region- and subtype-specific patterns. Altered gene expression is also observed in the prefrontal cortex in schizophrenia with a major but not total influence of chlorpromazine treatment. Preliminary parallel observations have also shown the presence of taste receptors (TASRs), mainly of the bitter taste family, in the mammalian brain, whose function is not related to taste. TASRs in brain are also abnormally regulated in neurodegenerative diseases. These seminal observations point to the need for further studies on ORs and TASRs chemoreceptors in the mammalian brain. PMID:27458372

[Assessment of sexual function in men with idiopathic Parkinson's disease using the International Index of Erectile Dysfunction (IIEF-15)].

PubMed

Roumiguié, M; Guillotreau, J; Castel-Lacanal, E; Malavaud, B; De Boissezon, X; Marque, P; Rischmann, P; Gamé, X

2011-01-01

to assess the sexual function in men with idiopathic Parkinson's disease. a cross-sectional study was performed in 35 men, mean age 68 ± 9 years, with idiopathic Parkinson's disease followed in a single urological department. The 15 questions International Index of the Erectile Function was sent by postal mail. the answer's rate was 42.9% (15 patients). The mean age of the responders was 68.7 ± 10.0 years. Mean duration of the disease was 10.4 ± 6.8 years. Sexual dysfunction was the second cause for consultation in urology. Despite a sustained sexual desire, patients had an altered sexual function with low erectile function, orgasmic function, intercourse satisfaction and total satisfaction scores. According to the Cappelleri's classification, the erectile dysfunction was severe in 54% of the cases and moderate in 26.6%. Age, institutionalization and overactive bladder symptoms were associated with erectile, orgasmic function and intercourse satisfaction alteration, sexual desire alteration, intercourse and global satisfaction alteration, respectively. men with idiopathic Parkinson's disease had a severe sexual dysfunction. The sexual desire was usually maintained but all the other domains were severely altered. 2010 Elsevier Masson SAS. All rights reserved.

Increased Hippocampus–Medial Prefrontal Cortex Resting-State Functional Connectivity and Memory Function after Tai Chi Chuan Practice in Elder Adults

PubMed Central

Tao, Jing; Liu, Jiao; Egorova, Natalia; Chen, Xiangli; Sun, Sharon; Xue, Xiehua; Huang, Jia; Zheng, Guohua; Wang, Qin; Chen, Lidian; Kong, Jian

2016-01-01

Previous studies provide evidence that aging is associated with the decline of memory function and alterations in the hippocampal (HPC) function, including functional connectivity to the medial prefrontal cortex (mPFC). In this study, we investigated if longitudinal (12-week) Tai Chi Chuan and Baduanjin practice can improve memory function and modulate HPC resting-state functional connectivity (rs-FC). Memory function measurements and resting-state functional magnetic resonance imaging (rs-fMRI) were applied at the beginning and the end of the experiment. The results showed that (1) the memory quotient (MQ) measured by the Wechsler Memory Scale-Chinese Revision significantly increased after Tai Chi Chuan and Baduanjin practice as compared with the control group, and no significant difference was observed in MQ between the Tai Chi Chuan and Baduanjin groups; (2) rs-FC between the bilateral hippocampus and mPFC significantly increased in the Tai Chi Chuan group compared to the control group (also in the Baduanjin group compared to the control group, albeit at a lower threshold), and no significant difference between the Tai Chi Chuan and Baduanjin groups was observed; (3) rs-FC increases between the bilateral hippocampus and mPFC were significantly associated with corresponding memory function improvement across all subjects. Similar results were observed using the left or right hippocampus as seeds. Our results suggest that both Tai Chi Chuan and Baduanjin may be effective exercises to prevent memory decline during aging. PMID:26909038

Increased Hippocampus-Medial Prefrontal Cortex Resting-State Functional Connectivity and Memory Function after Tai Chi Chuan Practice in Elder Adults.

PubMed

Tao, Jing; Liu, Jiao; Egorova, Natalia; Chen, Xiangli; Sun, Sharon; Xue, Xiehua; Huang, Jia; Zheng, Guohua; Wang, Qin; Chen, Lidian; Kong, Jian

2016-01-01

Previous studies provide evidence that aging is associated with the decline of memory function and alterations in the hippocampal (HPC) function, including functional connectivity to the medial prefrontal cortex (mPFC). In this study, we investigated if longitudinal (12-week) Tai Chi Chuan and Baduanjin practice can improve memory function and modulate HPC resting-state functional connectivity (rs-FC). Memory function measurements and resting-state functional magnetic resonance imaging (rs-fMRI) were applied at the beginning and the end of the experiment. The results showed that (1) the memory quotient (MQ) measured by the Wechsler Memory Scale-Chinese Revision significantly increased after Tai Chi Chuan and Baduanjin practice as compared with the control group, and no significant difference was observed in MQ between the Tai Chi Chuan and Baduanjin groups; (2) rs-FC between the bilateral hippocampus and mPFC significantly increased in the Tai Chi Chuan group compared to the control group (also in the Baduanjin group compared to the control group, albeit at a lower threshold), and no significant difference between the Tai Chi Chuan and Baduanjin groups was observed; (3) rs-FC increases between the bilateral hippocampus and mPFC were significantly associated with corresponding memory function improvement across all subjects. Similar results were observed using the left or right hippocampus as seeds. Our results suggest that both Tai Chi Chuan and Baduanjin may be effective exercises to prevent memory decline during aging.

Action-based touch observation in adults with high functioning autism: Can compromised self-other distinction abilities link social and sensory everyday problems?

PubMed Central

Wiersema, Jan R.; Brass, Marcel

2017-01-01

Abstract Next to social problems, individuals with autism spectrum disorder (ASD) often report severe sensory difficulties. Altered processing of touch is however a stronger mediator of social symptoms’ severity than altered processing of for instance vision or audition. Why is this the case? We reasoned that sensory difficulties may be linked to social problems in ASD through insufficient self-other distinction centred on touch. We investigated by means of EEG whether the brain of adults with ASD adequately signals when a tactile consequence of an observed action does not match own touch, as compared to the brain of matched controls. We employed the action-based somatosensory congruency paradigm. Participants observed a human or wooden hand touching a surface, combined with a tap-like tactile sensation that either matched or mismatched the tactile consequence of the observed movement. The ASD group showed a diminished congruency effect for human hands only in the P3-complex, suggesting difficulties with signalling observed action-based touch of others that does not match own touch experiences. Crucially, this effect reliably correlated with self-reported social and sensory everyday difficulties in ASD. The findings might denote a novel theoretical link between sensory and social impairments in the autism spectrum. PMID:27613781

Application of a pore-scale reactive transport model to a natural analog for reaction-induced pore alterations

DOE PAGES

Yoon, Hongkyu; Major, Jonathan; Dewers, Thomas; ...

2017-01-05

Dissolved CO 2 in the subsurface resulting from geological CO 2 storage may react with minerals in fractured rocks, confined aquifers, or faults, resulting in mineral precipitation and dissolution. The overall rate of reaction can be affected by coupled processes including hydrodynamics, transport, and reactions at the (sub) pore-scale. In this work pore-scale modeling of coupled fluid flow, reactive transport, and heterogeneous reactions at the mineral surface is applied to account for permeability alterations caused by precipitation-induced pore-blocking. This paper is motivated by observations of CO 2 seeps from a natural CO 2 sequestration analog, Crystal Geyser, Utah. Observations alongmore » the surface exposure of the Little Grand Wash fault indicate the lateral migration of CO 2 seep sites (i.e., alteration zones) of 10–50 m width with spacing on the order of ~100 m over time. Sandstone permeability in alteration zones is reduced by 3–4 orders of magnitude by carbonate cementation compared to unaltered zones. One granular porous medium and one fracture network systems are used to conceptually represent permeable porous media and locations of conduits controlled by fault-segment intersections and/or topography, respectively. Simulation cases accounted for a range of reaction regimes characterized by the Damköhler (Da) and Peclet (Pe) numbers. Pore-scale simulation results demonstrate that combinations of transport (Pe), geochemical conditions (Da), solution chemistry, and pore and fracture configurations contributed to match key patterns observed in the field of how calcite precipitation alters flow paths by pore plugging. This comparison of simulation results with field observations reveals mechanistic explanations of the lateral migration and enhances our understanding of subsurface processes associated with the CO 2 injection. In addition, permeability and porosity relations are constructed from pore-scale simulations which account for a range of reaction regimes characterized by the Da and Pe numbers. Finally, the functional relationships obtained from pore-scale simulations can be used in a continuum scale model that may account for large-scale phenomena mimicking lateral migration of surface CO 2 seeps.« less

[The value of double contrast arthrotomography combined with cinematography in the diagnosis of functional and structural TMJ alterations].

PubMed

Engelke, W; Grossniklaus, B; Sailer, H F

1991-01-01

Double contrast arthrotomography combined with cinematography as a diagnostic instrument establishing functional and structural TMJ alterations is evaluated for its diagnostic value and reliability within the chain of diagnostic measures applied. In 131 patients double-contrast arthrotomography was followed by a comprehensive history of joint problems, and verification of the clinical findings as well as the arthrographic diagnosis and the post-arthrographic TMJ alterations. Our interest was focussed, among others, on the question whether arthrography alone would have any therapeutic effect or produce an alteration in TMJ function.

Interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in minimal hepatic encephalopathy.

PubMed

Llansola, Marta; Montoliu, Carmina; Agusti, Ana; Hernandez-Rabaza, Vicente; Cabrera-Pastor, Andrea; Gomez-Gimenez, Belen; Malaguarnera, Michele; Dadsetan, Sherry; Belghiti, Majedeline; Garcia-Garcia, Raquel; Balzano, Tiziano; Taoro, Lucas; Felipo, Vicente

2015-09-01

The cognitive and motor alterations in hepatic encephalopathy (HE) are the final result of altered neurotransmission and communication between neurons in neuronal networks and circuits. Different neurotransmitter systems cooperate to modulate cognitive and motor function, with a main role for glutamatergic and GABAergic neurotransmission in different brain areas and neuronal circuits. There is an interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in HE. This interplay may occur: (a) in different brain areas involved in specific neuronal circuits; (b) in the same brain area through cross-modulation of glutamatergic and GABAergic neurotransmission. We will summarize some examples of the (1) interplay between glutamatergic and GABAergic neurotransmission alterations in different areas in the basal ganglia-thalamus-cortex circuit in the motor alterations in minimal hepatic encephalopathy (MHE); (2) interplay between glutamatergic and GABAergic neurotransmission alterations in cerebellum in the impairment of cognitive function in MHE through altered function of the glutamate-nitric oxide-cGMP pathway. We will also comment the therapeutic implications of the above studies and the utility of modulators of glutamate and GABA receptors to restore cognitive and motor function in rats with hyperammonemia and hepatic encephalopathy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism.

PubMed

Ferris, Heather A; Perry, Rachel J; Moreira, Gabriela V; Shulman, Gerald I; Horton, Jay D; Kahn, C Ronald

2017-01-31

Cholesterol is important for normal brain function. The brain synthesizes its own cholesterol, presumably in astrocytes. We have previously shown that diabetes results in decreased brain cholesterol synthesis by a reduction in sterol regulatory element-binding protein 2 (SREBP2)-regulated transcription. Here we show that coculture of control astrocytes with neurons enhances neurite outgrowth, and this is reduced with SREBP2 knockdown astrocytes. In vivo, mice with knockout of SREBP2 in astrocytes have impaired brain development and behavioral and motor defects. These mice also have altered energy balance, altered body composition, and a shift in metabolism toward carbohydrate oxidation driven by increased glucose oxidation by the brain. Thus, SREBP2-mediated cholesterol synthesis in astrocytes plays an important role in brain and neuronal development and function, and altered brain cholesterol synthesis may contribute to the interaction between metabolic diseases, such as diabetes and altered brain function.

Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism

PubMed Central

Ferris, Heather A.; Perry, Rachel J.; Moreira, Gabriela V.; Shulman, Gerald I.; Horton, Jay D.; Kahn, C. Ronald

2017-01-01

Cholesterol is important for normal brain function. The brain synthesizes its own cholesterol, presumably in astrocytes. We have previously shown that diabetes results in decreased brain cholesterol synthesis by a reduction in sterol regulatory element-binding protein 2 (SREBP2)-regulated transcription. Here we show that coculture of control astrocytes with neurons enhances neurite outgrowth, and this is reduced with SREBP2 knockdown astrocytes. In vivo, mice with knockout of SREBP2 in astrocytes have impaired brain development and behavioral and motor defects. These mice also have altered energy balance, altered body composition, and a shift in metabolism toward carbohydrate oxidation driven by increased glucose oxidation by the brain. Thus, SREBP2-mediated cholesterol synthesis in astrocytes plays an important role in brain and neuronal development and function, and altered brain cholesterol synthesis may contribute to the interaction between metabolic diseases, such as diabetes and altered brain function. PMID:28096339

Disruption of Responding Maintained by Conditioned Reinforcement: Alterations in Response-Conditioned-Reinforcer Relations

ERIC Educational Resources Information Center

Lieving, Gregory A.; Reilly, Mark P.; Lattal, Kennon A.

2006-01-01

An observing procedure was used to investigate the effects of alterations in response-conditioned-reinforcer relations on observing. Pigeons responded to produce schedule-correlated stimuli paired with the availability of food or extinction. The contingency between observing responses and conditioned reinforcement was altered in three experiments.…

RADIOLOGICAL STUDY OF MEGACOLON IN TRYPANOSOMA CRUZI INFECTED RATS

PubMed Central

FONTES, Carlos Edmundo Rodrigues; de ABREU, Ana Paula; GASPARIM, Aretuza Zaupa

2018-01-01

ABSTRACT Background: Researches on Chagas disease still use several animals and rats, due to size and susceptibility were preferred by many authors. Aim: To develop an experimental model of megacolon in rats inoculated with the strain Y of Trypanosoma cruzi. Methods: Thirty male Wistar rats were distributed in three groups inoculated with different inoculants: Group A: 600000, Group B: 1000000 and Group C: 1500000 blood trypomastigotes of T. cruzi. Animals were sedated intramuscularly at zero inoculation time (T0) and 60 days after inoculation (T60), to perform the barium enema in order to evaluate the dilatation of the different segments of colon in a comparative study of the measurements obtained, using a digital caliper. Evidence of infection was performed by blood smear collected from the animal’s tail 18 days after inoculation with observation of blood forms. Results: Comparing the intestinal diameter of the inoculated animals with 60,0000 trypomastigotes in the T0 of infection with T60 days after the inoculation, significant dilatation was observed between the proximal, medial and distal segments (p<0.01), indicating the establishment of the megacolon model. In addition, comparing intestinal diameter between the different segments, with in the T0 of infection and the T60 after inoculation, significant alterations were observed (p<0.05). Conclusion: The proposed model was possible for in vivo studies of alterations due to infection by T. cruzi and functional alterations of the colon. In addition, the changes manifested in the colon are not directly proportional to the size of the inoculum, but to the time of infection that the animals were submitted, since the animals inoculated with 60,0000 blood forms were the ones which presented the most significant alterations. PMID:29513802

Simulated Microgravity Alters Actin Cytoskeleton and Integrin-Mediated Focal Adhesions of Cultured Human Mesenchymal Stromal Cells

NASA Astrophysics Data System (ADS)

Gershovich, P. M.; Gershovic, J. G.; Buravkova, L. B.

2008-06-01

Cytoskeletal alterations occur in several cell types including lymphocytes, glial cells, and osteoblasts, during spaceflight and under simulated microgravity (SMG) (3, 4). One potential mechanism for cytoskeletal gravisensitivity is disruption of extracellular matrix (ECM) and integrin interactions. Focal adhesions are specialized sites of cell-matrix interaction composed of integrins and the diversity of focal adhesion-associated cytoplasmic proteins including vinculin, talin, α-actinin, and actin filaments (4, 5). Integrins produce signals essential for proper cellular function, survival and differentiation. Therefore, we investigated the effects of SMG on F-actin cytoskeleton structure, vinculin focal adhesions, expression of some integrin subtypes and cellular adhesion molecules (CAMs) in mesenchymal stem cells derived from human bone marrow (hMSCs). Simulated microgravity was produced by 3D-clinostat (Dutch Space, Netherlands). Staining of actin fibers with TRITC-phalloidin showed reorganization even after 30 minutes of simulated microgravity. The increasing of cells number with abnormal F-actin was observed after subsequent terms of 3D-clinorotation (6, 24, 48, 120 hours). Randomization of gravity vector altered dimensional structure of stress fibers and resulted in remodeling of actin fibers inside the cells. In addition, we observed vinculin redistribution inside the cells after 6 hours and prolonged terms of clinorotation. Tubulin fibers in a contrast with F-actin and vinculin didn't show any reorganization even after long 3Dclinorotation (120 hours). The expression of integrin α2 increased 1,5-6-fold in clinorotated hMSCs. Also we observed decrease in number of VCAM-1-positive cells and changes in expression of ICAM-1. Taken together, our findings indicate that SMG leads to microfilament and adhesion alterations of hMSCs most probably associated with involvement of some integrin subtypes.

Intestinal Fluid Permeability in Atlantic Salmon (Salmo salar L.) Is Affected by Dietary Protein Source.

PubMed

Hu, Haibin; Kortner, Trond M; Gajardo, Karina; Chikwati, Elvis; Tinsley, John; Krogdahl, Åshild

2016-01-01

In Atlantic salmon (Salmo salar L.), and also in other fish species, certain plant protein ingredients can increase fecal water content creating a diarrhea-like condition which may impair gut function and reduce fish growth. The present study aimed to strengthen understanding of the underlying mechanisms by observing effects of various alternative plant protein sources when replacing fish meal on expression of genes encoding proteins playing key roles in regulation of water transport across the mucosa of the distal intestine (DI). A 48-day feeding trial was conducted with five diets: A reference diet (FM) in which fish meal (72%) was the only protein source; Diet SBMWG with a mix of soybean meal (30%) and wheat gluten (22%); Diet SPCPM with a mix of soy protein concentrate (30%) and poultry meal (6%); Diet GMWG with guar meal (30%) and wheat gluten (14.5%); Diet PM with 58% poultry meal. Compared to fish fed the FM reference diet, fish fed the soybean meal containing diet (SBMWG) showed signs of enteritis in the DI, increased fecal water content of DI chyme and higher plasma osmolality. Altered DI expression of a battery of genes encoding aquaporins, ion transporters, tight junction and adherens junction proteins suggested reduced transcellular transport of water as well as a tightening of the junction barrier in fish fed the SBMWG diet, which may explain the observed higher fecal water content and plasma osmolality. DI structure was not altered for fish fed the other experimental diets but alterations in target gene expression and fecal water content were observed, indicating that alterations in water transport components may take place without clear effects on intestinal structure.

Thymidine kinase 2 deficiency-induced mitochondrial DNA depletion causes abnormal development of adipose tissues and adipokine levels in mice.

PubMed

Villarroya, Joan; Dorado, Beatriz; Vilà, Maya R; Garcia-Arumí, Elena; Domingo, Pere; Giralt, Marta; Hirano, Michio; Villarroya, Francesc

2011-01-01

Mammal adipose tissues require mitochondrial activity for proper development and differentiation. The components of the mitochondrial respiratory chain/oxidative phosphorylation system (OXPHOS) are encoded by both mitochondrial and nuclear genomes. The maintenance of mitochondrial DNA (mtDNA) is a key element for a functional mitochondrial oxidative activity in mammalian cells. To ascertain the role of mtDNA levels in adipose tissue, we have analyzed the alterations in white (WAT) and brown (BAT) adipose tissues in thymidine kinase 2 (Tk2) H126N knockin mice, a model of TK2 deficiency-induced mtDNA depletion. We observed respectively severe and moderate mtDNA depletion in TK2-deficient BAT and WAT, showing both tissues moderate hypotrophy and reduced fat accumulation. Electron microscopy revealed altered mitochondrial morphology in brown but not in white adipocytes from TK2-deficient mice. Although significant reduction in mtDNA-encoded transcripts was observed both in WAT and BAT, protein levels from distinct OXPHOS complexes were significantly reduced only in TK2-deficient BAT. Accordingly, the activity of cytochrome c oxidase was significantly lowered only in BAT from TK2-deficient mice. The analysis of transcripts encoding up to fourteen components of specific adipose tissue functions revealed that, in both TK2-deficient WAT and BAT, there was a consistent reduction of thermogenesis related gene expression and a severe reduction in leptin mRNA. Reduced levels of resistin mRNA were found in BAT from TK2-deficient mice. Analysis of serum indicated a dramatic reduction in circulating levels of leptin and resistin. In summary, our present study establishes that mtDNA depletion leads to a moderate impairment in mitochondrial respiratory function, especially in BAT, causes substantial alterations in WAT and BAT development, and has a profound impact in the endocrine properties of adipose tissues. © 2011 Villarroya et al.

Thymidine Kinase 2 Deficiency-Induced Mitochondrial DNA Depletion Causes Abnormal Development of Adipose Tissues and Adipokine Levels in Mice

PubMed Central

Villarroya, Joan; Dorado, Beatriz; Vilà, Maya R.; Garcia-Arumí, Elena; Domingo, Pere; Giralt, Marta; Hirano, Michio; Villarroya, Francesc

2011-01-01

Mammal adipose tissues require mitochondrial activity for proper development and differentiation. The components of the mitochondrial respiratory chain/oxidative phosphorylation system (OXPHOS) are encoded by both mitochondrial and nuclear genomes. The maintenance of mitochondrial DNA (mtDNA) is a key element for a functional mitochondrial oxidative activity in mammalian cells. To ascertain the role of mtDNA levels in adipose tissue, we have analyzed the alterations in white (WAT) and brown (BAT) adipose tissues in thymidine kinase 2 (Tk2) H126N knockin mice, a model of TK2 deficiency-induced mtDNA depletion. We observed respectively severe and moderate mtDNA depletion in TK2-deficient BAT and WAT, showing both tissues moderate hypotrophy and reduced fat accumulation. Electron microscopy revealed altered mitochondrial morphology in brown but not in white adipocytes from TK2-deficient mice. Although significant reduction in mtDNA-encoded transcripts was observed both in WAT and BAT, protein levels from distinct OXPHOS complexes were significantly reduced only in TK2-deficient BAT. Accordingly, the activity of cytochrome c oxidase was significantly lowered only in BAT from TK2-deficient mice. The analysis of transcripts encoding up to fourteen components of specific adipose tissue functions revealed that, in both TK2-deficient WAT and BAT, there was a consistent reduction of thermogenesis related gene expression and a severe reduction in leptin mRNA. Reduced levels of resistin mRNA were found in BAT from TK2-deficient mice. Analysis of serum indicated a dramatic reduction in circulating levels of leptin and resistin. In summary, our present study establishes that mtDNA depletion leads to a moderate impairment in mitochondrial respiratory function, especially in BAT, causes substantial alterations in WAT and BAT development, and has a profound impact in the endocrine properties of adipose tissues. PMID:22216345

Microbiome and metabolome modifying effects of several cardiovascular disease interventions in apo-E-/- mice.

PubMed

Ryan, Paul M; London, Lis E E; Bjorndahl, Trent C; Mandal, Rupasri; Murphy, Kiera; Fitzgerald, Gerald F; Shanahan, Fergus; Ross, R Paul; Wishart, David S; Caplice, Noel M; Stanton, Catherine

2017-03-13

There is strong evidence indicating that gut microbiota have the potential to modify, or be modified by the drugs and nutritional interventions that we rely upon. This study aims to characterize the compositional and functional effects of several nutritional, neutraceutical, and pharmaceutical cardiovascular disease interventions on the gut microbiome, through metagenomic and metabolomic approaches. Apolipoprotein-E-deficient mice were fed for 24 weeks either high-fat/cholesterol diet alone (control, HFC) or high-fat/cholesterol in conjunction with one of three dietary interventions, as follows: plant sterol ester (PSE), oat β-glucan (OBG) and bile salt hydrolase-active Lactobacillus reuteri APC 2587 (BSH), or the drug atorvastatin (STAT). The gut microbiome composition was then investigated, in addition to the host fecal and serum metabolome. We observed major shifts in the composition of the gut microbiome of PSE mice, while OBG and BSH mice displayed more modest fluctuations, and STAT showed relatively few alterations. Interestingly, these compositional effects imparted by PSE were coupled with an increase in acetate and reduction in isovalerate (p < 0.05), while OBG promoted n-butyrate synthesis (p < 0.01). In addition, PSE significantly dampened the microbial production of the proatherogenic precursor compound, trimethylamine (p < 0.05), attenuated cholesterol accumulation, and nearly abolished atherogenesis in the model (p < 0.05). However, PSE supplementation produced the heaviest mice with the greatest degree of adiposity (p < 0.05). Finally, PSE, OBG, and STAT all appeared to have considerable impact on the host serum metabolome, including alterations in several acylcarnitines previously associated with a state of metabolic dysfunction (p < 0.05). We observed functional alterations in microbial and host-derived metabolites, which may have important implications for systemic metabolic health, suggesting that cardiovascular disease interventions may have a significant impact on the microbiome composition and functionality. This study indicates that the gut microbiome-modifying effects of novel therapeutics should be considered, in addition to the direct host effects.

Rapid Postnatal Expansion of Neural Networks Occurs in an Environment of Altered Neurovascular and Neurometabolic Coupling.

PubMed

Kozberg, Mariel G; Ma, Ying; Shaik, Mohammed A; Kim, Sharon H; Hillman, Elizabeth M C

2016-06-22

In the adult brain, increases in neural activity lead to increases in local blood flow. However, many prior measurements of functional hemodynamics in the neonatal brain, including functional magnetic resonance imaging (fMRI) in human infants, have noted altered and even inverted hemodynamic responses to stimuli. Here, we demonstrate that localized neural activity in early postnatal mice does not evoke blood flow increases as in the adult brain, and elucidate the neural and metabolic correlates of these altered functional hemodynamics as a function of developmental age. Using wide-field GCaMP imaging, the development of neural responses to somatosensory stimulus is visualized over the entire bilaterally exposed cortex. Neural responses are observed to progress from tightly localized, unilateral maps to bilateral responses as interhemispheric connectivity becomes established. Simultaneous hemodynamic imaging confirms that spatiotemporally coupled functional hyperemia is not present during these early stages of postnatal brain development, and develops gradually as cortical connectivity is established. Exploring the consequences of this lack of functional hyperemia, measurements of oxidative metabolism via flavoprotein fluorescence suggest that neural activity depletes local oxygen to below baseline levels at early developmental stages. Analysis of hemoglobin oxygenation dynamics at the same age confirms oxygen depletion for both stimulus-evoked and resting-state neural activity. This state of unmet metabolic demand during neural network development poses new questions about the mechanisms of neurovascular development and its role in both normal and abnormal brain development. These results also provide important insights for the interpretation of fMRI studies of the developing brain. This work demonstrates that the postnatal development of neuronal connectivity is accompanied by development of the mechanisms that regulate local blood flow in response to neural activity. Novel in vivo imaging reveals that, in the developing mouse brain, strong and localized GCaMP neural responses to stimulus fail to evoke local blood flow increases, leading to a state in which oxygen levels become locally depleted. These results demonstrate that the development of cortical connectivity occurs in an environment of altered energy availability that itself may play a role in shaping normal brain development. These findings have important implications for understanding the pathophysiology of abnormal developmental trajectories, and for the interpretation of functional magnetic resonance imaging data acquired in the developing brain. Copyright © 2016 the authors 0270-6474/16/366704-14$15.00/0.

Experimentally-induced hyperthyroidism is associated with activation of the rat hypothalamic-pituitary-adrenal axis.

PubMed

Johnson, Elizabeth O; Kamilaris, Themis C; Calogero, Aldo E; Gold, Philip W; Chrousos, George P

2005-07-01

Previous studies on the effects of altered thyroid function on the secretion and metabolism of adrenocortical hormones suggest a degree of adrenocortical hyperactivity in hyperthyroidism. We have previously shown that experimentally-induced hyperthyroidism is associated with significant alterations in pituitary-adrenal responsiveness to synthetic ovine corticotropin-releasing hormone (oCRH) that are contingent upon the duration of the altered thyroid function. The purpose of this study was to assess the time-dependent effects of hyperthyroidism on the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis by in vivo stimulation of the hypothalamic CRH neuron and adrenal cortex. The functional integrity of the HPA axis was examined in vivo in sham-thyroidectomized male Sprague-Dawley rats given placebo or in thyroidectomized rats given 50 mug of thyroxine every day for 7 or 60 days. Responses to insulin-induced hypoglycemia and IL-1alpha stimulation were used to assess the hypothalamic CRH neuron. Adrenocortical reserve was assessed in response to low-dose adrenocorticotropic hormone (ACTH), following suppression of the HPA axis with dexamethasone. Adrenal and thymus tissue weight, in addition to basal plasma ACTH, corticosterone and thyroid indices were also determined. Basal plasma corticosterone and corticosterone binding globulin (CBG) concentrations were significantly increased in short- and long-term hyperthyroid rats, and by 60 days, cerebrospinal fluid (CSF) corticosterone levels were significantly increased. Basal plasma ACTH levels were similar to controls. Although plasma ACTH responses to hypoglycemic stress and IL-1alpha administration in both short- and long-term hyperthyroidism were normal, corticosterone responses to the ACTH release during the administration of these stimuli were significantly increased. The adrenal reserve was significantly elevated in short-term hyperthyroidsim. Long-term hyperthyroidism, however, was associated with a significant reduction in adrenocortical reserve. A significant increase in adrenal weights and a decrease in thymus weights were observed in both short- and long-term hyperthyroidism. The available data confirms that hyperthyroidism is associated with hypercorticosteronemia, although the locus that is principally affected still remains unclear. Despite the sustained hyperactivity of the HPA axis, long-term experimentally-induced hyperthyroidism is associated with diminished adrenal functional reserve. The alterations in HPA function in states of disturbed thyroid function were found to be somewhat more pronounced as the duration of thyroid dysfunction increased.

Mechanism of choline deficiency and membrane alteration in postural orthostatic tachycardia syndrome primary skin fibroblasts

PubMed Central

Schenkel, Laila C.; Singh, Ratnesh K.; Michel, Vera; Zeisel, Steven H.; da Costa, Kerry-Ann; Johnson, Amy R.; Mudd, Harvey S.; Bakovic, Marica

2015-01-01

Fibroblasts from a patient with postural orthostatic tachycardia syndrome (POTS), who presented with low plasma choline and betaine, were studied to determine the metabolic characteristics of the choline deficiency. Choline is required for the synthesis of the phospholipid phosphatidylcholine (PC) and for betaine, an important osmoregulator. Here, choline transport, lipid homeostasis, and mitochondria function were analyzed in skin fibroblasts from POTS and compared with control cells. The choline transporter-like protein 1/solute carrier 44A1 (CTL1/SLC44A1) and mRNA expression were 2–3 times lower in POTS fibroblasts, and choline uptake was reduced 60% (P < 0.05). Disturbances of membrane homeostasis were observed by reduced ratios between PC:phosphatidylethanolamine and sphingomyelin:cholesterol, as well as by modified phospholipid fatty acid composition. Choline deficiency also impaired mitochondria function, which was observed by a reduction in oxygen consumption, mitochondrial potential, and glycolytic activity. When POTS cells were treated with choline, transporter was up-regulated, and uptake of choline increased, offering an option for patient treatment. The characteristics of the POTS fibroblasts described here represent a first model of choline and CTL1/SLC44A1 deficiency, in which choline transport, membrane homeostasis, and mitochondrial function are impaired.—Schenkel, L. C., Singh, R. K., Michel, V., Zeisel, S. H., da Costa, K.-A., Johnson, A. R., Mudd, H. S., Bakovic, M. Mechanism of choline deficiency and membrane alteration in postural orthostatic tachycardia syndrome primary skin fibroblasts. PMID:25466896

Trauma-associated Human Neutrophil Alterations Revealed by Comparative Proteomics Profiling

PubMed Central

Zhou, Jian-Ying; Krovvidi, Ravi K.; Gao, Yuqian; Gao, Hong; Petritis, Brianne O.; De, Asit; Miller-Graziano, Carol; Bankey, Paul E.; Petyuk, Vladislav A.; Nicora, Carrie D.; Clauss, Therese R; Moore, Ronald J.; Shi, Tujin; Brown, Joseph N.; Kaushal, Amit; Xiao, Wenzhong; Davis, Ronald W.; Maier, Ronald V.; Tompkins, Ronald G.; Qian, Wei-Jun; Camp, David G.; Smith, Richard D.

2013-01-01

PURPOSE Polymorphonuclear neutrophils (PMNs) play an important role in mediating the innate immune response after severe traumatic injury; however, the cellular proteome response to traumatic condition is still largely unknown. EXPERIMENTAL DESIGN We applied 2D-LC-MS/MS based shotgun proteomics to perform comparative proteome profiling of human PMNs from severe trauma patients and healthy controls. RESULTS A total of 197 out of ~2500 proteins (being identified with at least two peptides) were observed with significant abundance changes following the injury. The proteomics data were further compared with transcriptomics data for the same genes obtained from an independent patient cohort. The comparison showed that the protein abundance changes for the majority of proteins were consistent with the mRNA abundance changes in terms of directions of changes. Moreover, increased protein secretion was suggested as one of the mechanisms contributing to the observed discrepancy between protein and mRNA abundance changes. Functional analyses of the altered proteins showed that many of these proteins were involved in immune response, protein biosynthesis, protein transport, NRF2-mediated oxidative stress response, the ubiquitin-proteasome system, and apoptosis pathways. CONCLUSIONS AND CLINICAL RELEVANCE Our data suggest increased neutrophil activation and inhibited neutrophil apoptosis in response to trauma. The study not only reveals an overall picture of functional neutrophil response to trauma at the proteome level, but also provides a rich proteomics data resource of trauma-associated changes in the neutrophil that will be valuable for further studies of the functions of individual proteins in PMNs. PMID:23589343

Consumption of fermented milk product with probiotic modulates brain activity.

PubMed

Tillisch, Kirsten; Labus, Jennifer; Kilpatrick, Lisa; Jiang, Zhiguo; Stains, Jean; Ebrat, Bahar; Guyonnet, Denis; Legrain-Raspaud, Sophie; Trotin, Beatrice; Naliboff, Bruce; Mayer, Emeran A

2013-06-01

Changes in gut microbiota have been reported to alter signaling mechanisms, emotional behavior, and visceral nociceptive reflexes in rodents. However, alteration of the intestinal microbiota with antibiotics or probiotics has not been shown to produce these changes in humans. We investigated whether consumption of a fermented milk product with probiotic (FMPP) for 4 weeks by healthy women altered brain intrinsic connectivity or responses to emotional attention tasks. Healthy women with no gastrointestinal or psychiatric symptoms were randomly assigned to groups given FMPP (n = 12), a nonfermented milk product (n = 11, controls), or no intervention (n = 13) twice daily for 4 weeks. The FMPP contained Bifidobacterium animalis subsp Lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp Lactis. Participants underwent functional magnetic resonance imaging before and after the intervention to measure brain response to an emotional faces attention task and resting brain activity. Multivariate and region of interest analyses were performed. FMPP intake was associated with reduced task-related response of a distributed functional network (49% cross-block covariance; P = .004) containing affective, viscerosensory, and somatosensory cortices. Alterations in intrinsic activity of resting brain indicated that ingestion of FMPP was associated with changes in midbrain connectivity, which could explain the observed differences in activity during the task. Four-week intake of an FMPP by healthy women affected activity of brain regions that control central processing of emotion and sensation. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Influence of chronic back pain on kinematic reactions to unpredictable arm pulls.

PubMed

Götze, Martin; Ernst, Michael; Koch, Markus; Blickhan, Reinhard

2015-03-01

There is evidence that muscle reflexes are delayed in patients with chronic low back pain in response to perturbations. It is still unrevealed whether these delays accompanied by an altered kinematic or compensated by adaption of other muscle parameters. The aim of this study was to investigate whether chronic low back pain patients show an altered kinematic reaction and if such data are reliable for the classification of chronic low back pain. In an experiment involving 30 females, sudden lateral perturbations were applied to the arm of a subject in an upright, standing position. Kinematics was used to distinguish between chronic low back pain patients and healthy controls. A calculated model of a stepwise discriminant function analysis correctly predicted 100% of patients and 80% of healthy controls. The estimation of the classification error revealed a constant rate for the classification of the healthy controls and a slightly decreased rate for the patients. Observed reflex delays and identified kinematic differences inside and outside the region of pain during impaired movement indicated that chronic low back pain patients have an altered motor control that is not restricted to the lumbo-pelvic region. This applied paradigm of external perturbations can be used to detect chronic low back pain patients and also persons without chronic low back pain but with an altered motor control. Further investigations are essential to reveal whether healthy persons with changes in motor function have an increased potential to develop chronic back pain. Copyright © 2015 Elsevier Ltd. All rights reserved.

Basolateral Amygdala, Nicotinic Cholinergic Receptors, and Nicotine: pharmacological effects and addiction in animal models and humans.

PubMed

Sharp, B M

2018-05-26

The amygdala is involved in processing incoming information about rewarding stimuli and emotions that denote danger such as anxiety and fear. Bi-directional neural connections between basolateral amygdala (BLA) and brain regions such as nucleus accumbens, prefrontal cortex, hippocampus and hindbrain regions regulate motivation, cognition, and responses to stress. Altered local regulation of BLA excitability is pivotal to the behavioral disturbances characteristic of posttraumatic stress disorder (PTSD), and relapse to drug use induced by stress. Herein, we review the physiological regulation of BLA by cholinergic inputs, emphasizing the role of BLA nicotinic receptors. We review BLA-dependent effects of nicotine on cognition, motivated behaviors and emotional states, including memory, taking and seeking drugs, and anxiety and fear in humans and animal models. The alterations in BLA activity observed in animal studies inform human behavioral and brain imaging research by enabling a more exact understanding of altered BLA function. Converging evidence indicates that cholinergic signaling from basal forebrain projections to local nicotinic receptors is an important physiological regulator of BLA and that nicotine alters BLA function. In essence, BLA is necessary for: behavioral responses to stimuli that evoke anxiety and fear; reinstatement of cue-induced drug seeking; responding to second-order cues conditioned to abused drugs; reacquisition of amplified nicotine self-administration due to chronic stress during abstinence; and to promote responding for natural reward. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Intrinsic Brain Activity in Altered States of Consciousness

PubMed Central

Boly, M.; Phillips, C.; Tshibanda, L.; Vanhaudenhuyse, A.; Schabus, M.; Dang-Vu, T.T.; Moonen, G.; Hustinx, R.; Maquet, P.; Laureys, S.

2010-01-01

Spontaneous brain activity has recently received increasing interest in the neuroimaging community. However, the value of resting-state studies to a better understanding of brain–behavior relationships has been challenged. That altered states of consciousness are a privileged way to study the relationships between spontaneous brain activity and behavior is proposed, and common resting-state brain activity features observed in various states of altered consciousness are reviewed. Early positron emission tomography studies showed that states of extremely low or high brain activity are often associated with unconsciousness. However, this relationship is not absolute, and the precise link between global brain metabolism and awareness remains yet difficult to assert. In contrast, voxel-based analyses identified a systematic impairment of associative frontoparieto–cingulate areas in altered states of consciousness, such as sleep, anesthesia, coma, vegetative state, epileptic loss of consciousness, and somnambulism. In parallel, recent functional magnetic resonance imaging studies have identified structured patterns of slow neuronal oscillations in the resting human brain. Similar coherent blood oxygen level–dependent (BOLD) systemwide patterns can also be found, in particular in the default-mode network, in several states of unconsciousness, such as coma, anesthesia, and slow-wave sleep. The latter results suggest that slow coherent spontaneous BOLD fluctuations cannot be exclusively a reflection of conscious mental activity, but may reflect default brain connectivity shaping brain areas of most likely interactions in a way that transcends levels of consciousness, and whose functional significance remains largely in the dark. PMID:18591474

Out of touch with reality? Social perception in first-episode schizophrenia

PubMed Central

Salone, Anatolia; Ferri, Francesca; De Berardis, Domenico; Romani, Gian Luca; Ferro, Filippo M.; Gallese, Vittorio

2013-01-01

Social dysfunction has been recognized as an elementary feature of schizophrenia, but it remains a crucial issue whether social deficits in schizophrenia concern the inter-subjective domain or primarily have their roots in disturbances of self-experience. Social perception comprises vicarious processes grounding an experiential inter-relationship with others as well as self-regulation processes allowing to maintain a coherent sense of self. The present study investigated whether the functional neural basis underlying these processes is altered in first-episode schizophrenia (FES). Twenty-four FES patients and 22 healthy control participants underwent functional magnetic resonance imaging during a social perception task requiring them to watch videos depicting other individuals' inanimate and animate/social tactile stimulations, and a tactile localizer condition. Activation in ventral premotor cortex for observed bodily tactile stimulations was reduced in the FES group and negatively correlated with self-experience disturbances. Moreover, FES patients showed aberrant differential activation in posterior insula for first-person tactile experiences and observed affective tactile stimulations. These findings suggest that social perception in FES at a pre-reflective level is characterized by disturbances of self-experience, including impaired multisensory representations and self-other distinction. However, the results also show that social perception in FES involves more complex alterations of neural activation at multiple processing levels. PMID:22275166

Molecular characterization of insulin resistance and glycolytic metabolism in the rat uterus

PubMed Central

Zhang, Yuehui; Sun, Xue; Sun, Xiaoyan; Meng, Fanci; Hu, Min; Li, Xin; Li, Wei; Wu, Xiao-Ke; Brännström, Mats; Shao, Ruijin; Billig, Håkan

2016-01-01

Peripheral insulin resistance and hyperandrogenism are the primary features of polycystic ovary syndrome (PCOS). However, how insulin resistance and hyperandrogenism affect uterine function and contribute to the pathogenesis of PCOS are open questions. We treated rats with insulin alone or in combination with human chorionic gonadotropin (hCG) and showed that peripheral insulin resistance and hyperandrogenism alter uterine morphology, cell phenotype, and cell function, especially in glandular epithelial cells. These defects are associated with an aberration in the PI3K/Akt signaling pathway that is used as an indicator for the onset of insulin resistance in classical metabolic tissues. Concomitantly, increased GSK3β (Ser-9) phosphorylation and decreased ERK1/2 phosphorylation in rats treated with insulin and hCG were also observed. We also profiled the expression of glucose transporter (Glut) isoform genes in the uterus under conditions of insulin resistance and/or hyperandrogenism. Finally, we determined the expression pattern of glycolytic enzymes and intermediates during insulin resistance and hyperandrogenism in the uterus. These findings suggest that the PI3K/Akt and MAPK/ERK signaling pathways play a role in the onset of uterine insulin resistance, and they also suggest that changes in specific Glut isoform expression and alterations to glycolytic metabolism contribute to the endometrial dysfunction observed in PCOS patients. PMID:27461373

Association of Microvascular Function and Endothelial Biomarkers With Clinical Outcome in Dengue: An Observational Study

PubMed Central

Yacoub, Sophie; Lam, Phung Khanh; Vu, Le Hoang Mai; Le, Thi Lien; Ha, Ngo Thanh; Toan, Tran Thi; Van, Nguyen Thu; Quyen, Nguyen Than Ha; Le Duyen, Huynh Thi; Van Kinh, Nguyen; Fox, Annette; Mongkolspaya, Juthathip; Wolbers, Marcel; Simmons, Cameron Paul; Screaton, Gavin Robert; Wertheim, Heiman; Wills, Bridget

2016-01-01

Background. The hallmark of severe dengue is increased microvascular permeability, but alterations in the microcirculation and their evolution over the course of dengue are unknown. Methods. We conducted a prospective observational study to evaluate the sublingual microcirculation using side-stream dark-field imaging in patients presenting early (<72 hours after fever onset) and patients hospitalized with warning signs or severe dengue in Vietnam. Clinical findings, microvascular function, global hemodynamics assessed with echocardiography, and serological markers of endothelial activation were determined at 4 time points. Results. A total of 165 patients were enrolled. No difference was found between the microcirculatory parameters comparing dengue with other febrile illnesses. The proportion of perfused vessels (PPV) and the mean flow index (MFI) were lower in patients with dengue with plasma than those without leakage (PPV, 88.1% vs 90.6% [P = .01]; MFI, 2.1 vs 2.4 [P = .007]), most markedly during the critical phase. PPV and MFI were correlated with the endothelial activation markers vascular cell adhesion molecule 1 (P < .001 for both) and angiopoietin 2 (P < .001 for both), negatively correlated. Conclusions. Modest microcirculatory alterations occur in dengue, are associated with plasma leakage, and are correlate with molecules of endothelial activation, angiopoietin 2 and vascular cell adhesion molecule 1. PMID:27230099

Duration of breast feeding and arterial distensibility in early adult life: population based study

PubMed Central

Leeson, C P M; Kattenhorn, M; Deanfield, J E; Lucas, A

2001-01-01

Objectives To test the hypothesis that duration of breast feeding is related to changes in vascular function relevant to the development of cardiovascular disease. Design Population based observational study. Setting Cambridge. Participants 331 adults (171 women, 160 men) aged between 20 and 28 years, born in Cambridge Maternity Hospital. Main outcome measures Distensibility of brachial artery, type and duration of infant feeding, current lipid profile, and other cardiovascular risk factors. Results The longer the period of breast feeding the less distensible the artery wall in early adult life, with no sex differences (regression coefficient = −3.93 μm/month, 95% confidence interval −7.29 to −0.57, P=0.02). However, in those breast fed for less than four months, arterial distensibility was not significantly reduced compared with an exclusively formula fed group. The vascular changes observed were not explained by alterations in plasma cholesterol concentration in adult life. Conclusions Breast feeding in infancy is related to reduced arterial function 20 years later. These data should not alter current recommendations in favour of breast feeding, which has several benefits for infant health. Further work is needed, however, to explore the optimal duration of breast feeding in relation to cardiovascular outcomes. PMID:11250848

Pay attention to cardiac remodeling in cancer cachexia.

PubMed

Zheng, Yawen; Chen, Han; Li, Xiaoqing; Sun, Yuping

2016-07-01

Cancer cachexia is a complex and multifaceted disease state characterized by fatigue, weakness, and loss of skeletal muscle and adipose tissue. Recently, the profound negative effects of cancer cachexia on cardiac tissue draw much attention, which is likely to contribute to mortality in tumor-bearing animals. The mechanism of cardiac remodeling is not so clear and involved with a series of molecular alterations. In cancer cachexia model, progressive loss of left ventricular mass and decrease in myocardial function is observed and cardiac autonomic functions are altered. Levels of several emerging cardiovascular neurohormones are found elevating in patients with cancer, but it is still controversial whether the changes could reflect the heart injury accurately. The remedy for cardiac remodeling has been explored. It is showed that exercise can modulate signaling pathways activated by wasting cytokines and impact on the resulting outcomes on heart adaptation. Some drugs, such as bisoprolol, spironolactone, perindopril, tandospirone, and simvastatin, can mitigate adverse effects of the tumor on the heart and prolong survival.

PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders.

PubMed

Stijnen, Pieter; Ramos-Molina, Bruno; O'Rahilly, Stephen; Creemers, John W M

2016-08-01

Prohormone convertase 1/3, encoded by the PCSK1 gene, is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones. Humans who are homozygous or compound heterozygous for loss-of-function mutations in PCSK1 exhibit a variable and pleiotropic syndrome consisting of some or all of the following: obesity, malabsorptive diarrhea, hypogonadotropic hypogonadism, altered thyroid and adrenal function, and impaired regulation of plasma glucose levels in association with elevated circulating proinsulin-to-insulin ratio. Recently, more common variants in the PCSK1 gene have been found to be associated with alterations in body mass index, increased circulating proinsulin levels, and defects in glucose homeostasis. This review provides an overview of the endocrinopathies and other disorders observed in prohormone convertase 1/3-deficient patients, discusses the possible biochemical basis for these manifestations of the disease, and proposes a model whereby certain missense mutations in PCSK1 may result in proteins with a dominant negative action.

Mild myelin disruption elicits early alteration in behavior and proliferation in the subventricular zone.

PubMed

Gould, Elizabeth A; Busquet, Nicolas; Shepherd, Douglas; Dietz, Robert M; Herson, Paco S; Simoes de Souza, Fabio M; Li, Anan; George, Nicholas M; Restrepo, Diego; Macklin, Wendy B

2018-02-13

Myelin, the insulating sheath around axons, supports axon function. An important question is the impact of mild myelin disruption. In the absence of the myelin protein proteolipid protein (PLP1), myelin is generated but with age, axonal function/maintenance is disrupted. Axon disruption occurs in Plp1 -null mice as early as 2 months in cortical projection neurons. High-volume cellular quantification techniques revealed a region-specific increase in oligodendrocyte density in the olfactory bulb and rostral corpus callosum that increased during adulthood. A distinct proliferative response of progenitor cells was observed in the subventricular zone (SVZ), while the number and proliferation of parenchymal oligodendrocyte progenitor cells was unchanged. This SVZ proliferative response occurred prior to evidence of axonal disruption. Thus, a novel SVZ response contributes to the region-specific increase in oligodendrocytes in Plp1 -null mice. Young adult Plp1- null mice exhibited subtle but substantial behavioral alterations, indicative of an early impact of mild myelin disruption. © 2018, Gould et al.

Mild myelin disruption elicits early alteration in behavior and proliferation in the subventricular zone

PubMed Central

Gould, Elizabeth A; Busquet, Nicolas; Shepherd, Douglas; Dietz, Robert M; Herson, Paco S; Simoes de Souza, Fabio M; Li, Anan; George, Nicholas M

2018-01-01

Myelin, the insulating sheath around axons, supports axon function. An important question is the impact of mild myelin disruption. In the absence of the myelin protein proteolipid protein (PLP1), myelin is generated but with age, axonal function/maintenance is disrupted. Axon disruption occurs in Plp1-null mice as early as 2 months in cortical projection neurons. High-volume cellular quantification techniques revealed a region-specific increase in oligodendrocyte density in the olfactory bulb and rostral corpus callosum that increased during adulthood. A distinct proliferative response of progenitor cells was observed in the subventricular zone (SVZ), while the number and proliferation of parenchymal oligodendrocyte progenitor cells was unchanged. This SVZ proliferative response occurred prior to evidence of axonal disruption. Thus, a novel SVZ response contributes to the region-specific increase in oligodendrocytes in Plp1-null mice. Young adult Plp1-null mice exhibited subtle but substantial behavioral alterations, indicative of an early impact of mild myelin disruption. PMID:29436368

[The informational support of statistical observation related to children disability].

PubMed

Son, I M; Polikarpov, A V; Ogrizko, E V; Golubeva, T Yu

2016-01-01

Within the framework of the Convention on rights of the disabled the revision is specified concerning criteria of identification of disability of children and reformation of system of medical social expertise according international standards of indices of health and indices related to health. In connection with it, it is important to consider the relationship between alterations in forms of the Federal statistical monitoring in the part of registration of disabled children in the Russian Federation and classification of health indices and indices related to health applied at identification of disability. The article presents analysis of relationship between alterations in forms of the Federal statistical monitoring in the part of registration of disabled children in the Russian Federation and applied classifications used at identification of disability (International classification of impairments, disabilities and handicap (ICDH), international classification of functioning, disability and health (ICF), international classification of functioning, disability and health, version for children and youth (ICF-CY). The intersectorial interaction is considered within the framework of statistics of children disability.

General toxicity and peripheral nerve alterations induced by chronic vincristine treatment in the rabbit.

PubMed

Norido, F; Finesso, M; Fiorito, C; Marini, P; Favaro, G; Fusco, M; Tessari, F; Prosdocimi, M

1988-05-01

The effects of five 0.3 mg/kg intravenous administrations of vincristine (VCR) at weekly intervals were studied in the rabbit. Body weight gain was impaired starting from the first injection, while gross signs of motor paralysis and hair loss initiated from the third week. At the end of the observation period blood analysis revealed normocytic normochromic anemia, elevated serum creatine kinase, and low serum alkaline phosphatase, whereas all the tested parameters related to liver and kidney functions where within normal limits. The decreased number of red blood cells was the consequence of a complete, although reversible, blockade of staminal hematopoietic activity. Two important indexes of peripheral nerve function were clearly altered at the end of the treatment: (i) the sciatic nerve conduction velocity in vitro was 27% reduced and (ii) the latency between sciatic nerve stimulation and extensor digitorum longus (EDL) twitch in vivo was 34% prolonged. The usefulness of the rabbit as an animal model to study side-effects of VCR treatment is discussed.

White matter integrity in brain networks relevant to anxiety and depression: evidence from the human connectome project dataset.

PubMed

De Witte, Nele A J; Mueller, Sven C

2017-12-01

Anxiety and depression are associated with altered communication within global brain networks and between these networks and the amygdala. Functional connectivity studies demonstrate an effect of anxiety and depression on four critical brain networks involved in top-down attentional control (fronto-parietal network; FPN), salience detection and error monitoring (cingulo-opercular network; CON), bottom-up stimulus-driven attention (ventral attention network; VAN), and default mode (default mode network; DMN). However, structural evidence on the white matter (WM) connections within these networks and between these networks and the amygdala is lacking. The current study in a large healthy sample (n = 483) observed that higher trait anxiety-depression predicted lower WM integrity in the connections between amygdala and specific regions of the FPN, CON, VAN, and DMN. We discuss the possible consequences of these anatomical alterations for cognitive-affective functioning and underscore the need for further theory-driven research on individual differences in anxiety and depression on brain structure.

Alterations in melatonin and 5-HT signalling in the colonic mucosa of mice with dextran-sodium sulfate-induced colitis.

PubMed

MacEachern, Sarah J; Keenan, Catherine M; Papakonstantinou, Evangelia; Sharkey, Keith A; Patel, Bhavik Anil

2018-05-01

Inflammatory bowel disease (IBD) is characterized by pain, bleeding, cramping and altered gastrointestinal (GI) function. Changes in mucosal 5-HT (serotonin) signalling occur in animal models of colitis and in humans suffering from IBD. Melatonin is co-released with 5-HT from the mucosa and has a wide variety of actions in the GI tract. Here, we examined how melatonin signalling is affected by colitis and determined how this relates to 5-HT signalling. Using electroanalytical approaches, we investigated how 5-HT release, reuptake and availability as well as melatonin availability are altered in dextran sodium sulfate (DSS)-induced colitis in mice. Studies were conducted to explore if melatonin treatment during active colitis could reduce the severity of colitis. We observed an increase in 5-HT and a decrease in melatonin availability in DSS-induced colitis. A significant reduction in 5-HT reuptake was observed in DSS-induced colitis animals. A reduction in the content of 5-HT was observed, but no difference in tryptophan levels were observed. A reduction in deoxycholic acid-stimulated 5-HT availability and a significant reduction in mechanically-stimulated 5-HT and melatonin availability were observed in DSS-induced colitis. Orally or rectally administered melatonin once colitis was established did not significantly suppress inflammation. Our data suggest that DSS-induced colitis results in a reduction in melatonin availability and an increase in 5-HT availability, due to a reduction/loss of tryptophan hydroxylase 1 enzyme, 5-HT content and 5-HT transporters. Mechanosensory release was more susceptible to inflammation when compared with chemosensory release. © 2018 The British Pharmacological Society.

From Fly Wings to Targeted Cancer Therapies: A Centennial for Notch Signaling

PubMed Central

Ntziachristos, Panagiotis; Lim, Jing Shan; Sage, Julien; Aifantis, Iannis

2014-01-01

Since Notch phenotypes in Drosophila melanogaster were identified 100 years, Notch signaling has been extensively characterized as a regulator of cell fate decisions in a variety of organisms and tissues. However, in the past 20 years, accumulating evidence has linked alterations in the Notch pathway to tumorigenesis. In this Perspective, we discuss the pro-tumorigenic and tumor suppressive functions of Notch signaling and dissect the molecular mechanisms that underlie these functions in hematopoietic cancers and solid tumors. Finally, we link these mechanisms and observations to possible therapeutic strategies targeting the Notch pathway in human cancers. PMID:24651013

41 CFR 102-76.75 - What costs are included in the costs of alterations to provide an accessible path of travel to an...

Code of Federal Regulations, 2012 CFR

2012-01-01

... primary function for facilities subject to the standards in § 102-76.65(a)? 102-76.75 Section 102-76.75... altered area containing a primary function for facilities subject to the standards in § 102-76.65(a)? For... of travel to an altered area containing a primary function include the costs associated with— (a...

41 CFR 102-76.75 - What costs are included in the costs of alterations to provide an accessible path of travel to an...

Code of Federal Regulations, 2013 CFR

2013-07-01

... primary function for facilities subject to the standards in § 102-76.65(a)? 102-76.75 Section 102-76.75... altered area containing a primary function for facilities subject to the standards in § 102-76.65(a)? For... of travel to an altered area containing a primary function include the costs associated with— (a...

41 CFR 102-76.75 - What costs are included in the costs of alterations to provide an accessible path of travel to an...

Code of Federal Regulations, 2011 CFR

2011-01-01

... primary function for facilities subject to the standards in § 102-76.65(a)? 102-76.75 Section 102-76.75... altered area containing a primary function for facilities subject to the standards in § 102-76.65(a)? For... of travel to an altered area containing a primary function include the costs associated with— (a...

41 CFR 102-76.75 - What costs are included in the costs of alterations to provide an accessible path of travel to an...

Code of Federal Regulations, 2010 CFR

2010-07-01

... primary function for facilities subject to the standards in § 102-76.65(a)? 102-76.75 Section 102-76.75... altered area containing a primary function for facilities subject to the standards in § 102-76.65(a)? For... of travel to an altered area containing a primary function include the costs associated with— (a...

41 CFR 102-76.75 - What costs are included in the costs of alterations to provide an accessible path of travel to an...

Code of Federal Regulations, 2014 CFR

2014-01-01

... primary function for facilities subject to the standards in § 102-76.65(a)? 102-76.75 Section 102-76.75... altered area containing a primary function for facilities subject to the standards in § 102-76.65(a)? For... of travel to an altered area containing a primary function include the costs associated with— (a...

Strengthening insights into host responses to mastitis infection in ruminants by combining heterogeneous microarray data sources

PubMed Central

2011-01-01

Background Gene expression profiling studies of mastitis in ruminants have provided key but fragmented knowledge for the understanding of the disease. A systematic combination of different expression profiling studies via meta-analysis techniques has the potential to test the extensibility of conclusions based on single studies. Using the program Pointillist, we performed meta-analysis of transcription-profiling data from six independent studies of infections with mammary gland pathogens, including samples from cattle challenged in vivo with S. aureus, E. coli, and S. uberis, samples from goats challenged in vivo with S. aureus, as well as cattle macrophages and ovine dendritic cells infected in vitro with S. aureus. We combined different time points from those studies, testing different responses to mastitis infection: overall (common signature), early stage, late stage, and cattle-specific. Results Ingenuity Pathway Analysis of affected genes showed that the four meta-analysis combinations share biological functions and pathways (e.g. protein ubiquitination and polyamine regulation) which are intrinsic to the general disease response. In the overall response, pathways related to immune response and inflammation, as well as biological functions related to lipid metabolism were altered. This latter observation is consistent with the milk fat content depression commonly observed during mastitis infection. Complementarities between early and late stage responses were found, with a prominence of metabolic and stress signals in the early stage and of the immune response related to the lipid metabolism in the late stage; both mechanisms apparently modulated by few genes, including XBP1 and SREBF1. The cattle-specific response was characterized by alteration of the immune response and by modification of lipid metabolism. Comparison of E. coli and S. aureus infections in cattle in vivo revealed that affected genes showing opposite regulation had the same altered biological functions and provided evidence that E. coli caused a stronger host response. Conclusions This meta-analysis approach reinforces previous findings but also reveals several novel themes, including the involvement of genes, biological functions, and pathways that were not identified in individual studies. As such, it provides an interesting proof of principle for future studies combining information from diverse heterogeneous sources. PMID:21569310

Chemotherapy-induced long-term alteration of executive functions and hippocampal cell proliferation: role of glucose as adjuvant.

PubMed

Dubois, M; Lapinte, N; Villier, V; Lecointre, C; Roy, V; Tonon, M-C; Gandolfo, P; Joly, F; Hilber, P; Castel, H

2014-04-01

In patients, cancer and treatments provoke cognitive impairments referred to "chemofog". Here a validated neurobehavioral animal model, the unique way to explore causal direct links between chemotherapy used in clinical practices and brain disorders, allowed investigation of the direct long-term impact of colo-rectal cancer chemotherapy on cognition and cerebral plasticity. Young and aged mice received three injections every 7 days during 2 weeks of 5-fluorouracil either alone (5-FU, 37.5 mg/kg) or in combination with oxaliplatin (3 mg/kg) or with glucose (5%). The long-term effects (from day 24 to day 60) of chemotherapy were tested on emotional reactivity, learning and memory, behavioral flexibility and hippocampal cell plasticity. 5-FU (in saline)-treated aged and also young mice exhibited specific altered cognitive flexibility and behavioral hyper-reactivity to novelty, whereas the combination 5-FU (in saline)/oxaliplatin (in glucose) did not provoke any cognitive dysfunction. We thus observed that glucose counteracted 5-FU-induced altered executive functions and hippocampal cell proliferation in vivo, and protected neural stem cells in vitro from toxicity of 5-FU or oxaliplatin. In conclusion, these data suggest that the lasting chemotherapy-induced selective impairment of executive functions, whatever the age, and associated with a reduced number of hippocampal proliferating cells, can be counteracted by co-administration with glucose. Copyright © 2013 Elsevier Ltd. All rights reserved.

Interference of TRPV1 function altered the susceptibility of PTZ-induced seizures.

PubMed

Jia, Yun-Fang; Li, Ying-Chao; Tang, Yan-Ping; Cao, Jun; Wang, Li-Ping; Yang, Yue-Xiong; Xu, Lin; Mao, Rong-Rong

2015-01-01

Transient receptor potential vanilloid 1 (TRPV1) is widely distributed in the central nervous system (CNS) including hippocampus, and regulates the balance of excitation and inhibition in CNS, which imply its important role in epilepsy. We used both pharmacological manipulations and transgenic mice to disturb the function of TRPV1 and then studied the effects of these alterations on the susceptibility of pentylenetetrazol (PTZ)-induced seizures. Our results showed that systemic administration of TRPV1 agonist capsaicin (CAP, 40 mg/kg) directly induced tonic-clonic seizures (TCS) without PTZ induction. The severity of seizure was increased in lower doses of CAP groups (5 and 10 mg/kg), although the latency to TCS was delayed. On the other hand, systemic administration of TRPV1 antagonist capsazepine (CPZ, 0.05 and 0.5 mg/kg) and TRPV1 knockout mice exhibited delayed latency to TCS and reduced mortality. Furthermore, hippocampal administration of CPZ (10 and 33 nmol/μL/side) was firstly reported to increase the latency to TCS, decrease the maximal grade of seizure and mortality. It is worth noting that decreased susceptibility of PTZ-induced seizures was observed in hippocampal TRPV1 overexpression mice and hippocampal CAP administration (33 nmol/μL/side), which is opposite from results of systemic agonist CAP. Our findings suggest that the systemic administration of TRPV1 antagonist may be a novel therapeutic target for epilepsy, and alteration of hippocampal TRPV1 function exerts a critical role in seizure susceptibility.

Altering Neurospora crassa MOB2A exposes its functions in development and affects its interaction with the NDR kinase COT1.

PubMed

Aharoni-Kats, Liran; Zelinger, Einat; Chen, She; Yarden, Oded

2018-06-01

The Neurospora crassa Mps One Binder (MOB) proteins MOB2A and MOB2B physically interact with the Nuclear Dbf2 Related (NDR) kinase COT1 and have been shown to have overlapping functions in various aspects of asexual development. Here, we identified two N. crassa MOB2A residues, Tyr117 and Tyr119, which are potentially phosphorylated. Using phosphomimetic mob-2a mutants we have been able to establish that apart from their previously described roles, MOB2A/B are involved in additional developmental processes. Enhanced conidial germination, accompanied by conidial agglutination, in the phosphomimetic mutants indicated that MOB2A is a negative regulator of germination. Thick-section imaging of perithecia revealed slow maturation and a lack of asci alignment in the mutant strains demonstrating a role for MOB2A in sexual development. We demonstrate that even though MOB2A and MOB2B have some overlapping functions, MOB2B cannot compensate for the roles MOB2A has in conidiation and germination. Altering Tyr residues 117 and 119 impaired the physical interactions between MOB2A and COT1, most likely contributing to some of the observed effects. As cot-1 and the phosphomimetic mutants share an extragenic suppressor (gul-1), we concluded that at least some of the effects imposed by altering Tyr117 and Tyr119 are mediated by the NDR kinase. © 2018 John Wiley & Sons Ltd.

Increased passive stiffness promotes diastolic dysfunction despite improved Ca2+ handling during left ventricular concentric hypertrophy

PubMed Central

Røe, Åsmund T.; Aronsen, Jan Magnus; Skårdal, Kristine; Hamdani, Nazha; Linke, Wolfgang A.; Danielsen, Håvard E.; Sejersted, Ole M.; Sjaastad, Ivar; Louch, William E.

2017-01-01

Abstract Aims Concentric hypertrophy following pressure-overload is linked to preserved systolic function but impaired diastolic function, and is an important substrate for heart failure with preserved ejection fraction. While increased passive stiffness of the myocardium is a suggested mechanism underlying diastolic dysfunction in these hearts, the contribution of active diastolic Ca2+ cycling in cardiomyocytes remains unclear. In this study, we sought to dissect contributions of passive and active mechanisms to diastolic dysfunction in the concentrically hypertrophied heart following pressure-overload. Methods and results Rats were subjected to aortic banding (AB), and experiments were performed 6 weeks after surgery using sham-operated rats as controls. In vivo ejection fraction and fractional shortening were normal, confirming preservation of systolic function. Left ventricular concentric hypertrophy and diastolic dysfunction following AB were indicated by thickening of the ventricular wall, reduced peak early diastolic tissue velocity, and higher E/e’ values. Slowed relaxation was also observed in left ventricular muscle strips isolated from AB hearts, during both isometric and isotonic stimulation, and accompanied by increases in passive tension, viscosity, and extracellular collagen. An altered titin phosphorylation profile was observed with hypophosphorylation of the phosphosites S4080 and S3991 sites within the N2Bus, and S12884 within the PEVK region. Increased titin-based stiffness was confirmed by salt-extraction experiments. In contrast, isolated, unloaded cardiomyocytes exhibited accelerated relaxation in AB compared to sham, and less contracture at high pacing frequencies. Parallel enhancement of diastolic Ca2+ handling was observed, with augmented NCX and SERCA2 activity and lowered resting cytosolic [Ca2+]. Conclusion In the hypertrophied heart with preserved systolic function, in vivo diastolic dysfunction develops as cardiac fibrosis and alterations in titin phosphorylation compromise left ventricular compliance, and despite compensatory changes in cardiomyocyte Ca2+ homeostasis. PMID:28472418

Glucocorticoid-induced loss of DNA methylation in non-neuronal cells and potential involvement of DNMT1 in epigenetic regulation of Fkbp5

PubMed Central

Yang, Xiaoju; Ewald, Erin R.; Huo, Yuqing; Tamashiro, Kellie L.; Salvatori, Roberto; Sawa, Akira; Wand, Gary S.; Lee, Richard S.

2012-01-01

Glucocorticoids may play a significant role in the etiology of neuropsychiatric illnesses. Abnormalities in plasma cortisol levels, glucocorticoid sensitivity, and HPA-axis function often accompany clinical symptoms of stress-related illnesses such as PTSD and depression. Of particular interest are genetic association studies that link single nucleotide polymorphisms of HPA-axis genes with illnesses only in the context of an early-life trauma exposure such as child abuse. These studies suggest that dysregulation of HPA-axis function can have lasting repercussions in shaping mood and anxiety, long after termination of the traumatic experience. As persistent glucocorticoid-induced loss of DNA methylation in Fkbp5 was previously observed in the hippocampus and blood and in the neuronal cell line HT-22, we asked whether these epigenetic alterations occur in non-neuronal, HPA-axis relevant cells. We used the pituitary adenoma cell line AtT-20 to demonstrate that the intronic enhancer region of Fkbp5 undergoes loss of DNA methylation in response to dexamethasone treatment in a dose-dependent manner. We also focused on the mouse hippocampal dentate gyrus to test whether these changes would be enriched in a region implicated in the HPA-axis stress response, neurogenesis, and synaptic plasticity. We observed an increase in enrichment of DNA methylation loss in the dentate gyrus, as compared to whole hippocampal tissues that were similarly treated with glucocorticoids. We then asked whether Dnmt1, a methyltransferase enzyme involved in maintaining DNA methylation following cell division, is involved in the observed epigenetic alterations. We found a dose-dependent decrease of Dnmt1 expression in the AtT-20 cells following dexamethasone treatment, and a similar decrease in corticosterone-treated mouse hippocampus. Taken together, we provide evidence that these glucocorticoid-induced epigenetic alterations have a broader validity in non-neuronal cells and that they may involve the DNA methylation machinery. PMID:22445894

In vitro immune functions in thiamine-replete and -depleted lake trout (Salvelinus namaycush).

PubMed

Ottinger, Christopher A; Honeyfield, Dale C; Densmore, Christine L; Iwanowicz, Luke R

2014-05-01

In this study we examined the impacts of in vivo thiamine deficiency on lake trout leukocyte function measured in vitro. When compared outside the context of individual-specific thiamine concentrations no significant differences were observed in leukocyte bactericidal activity or in concanavalin A (Con A), and phytohemagglutinin-P (PHA-P) stimulated leukocyte proliferation. Placing immune functions into context with the ratio of in vivo liver thiamine monophosphate (TMP--biologically inactive form) to thiamine pyrophosphate (TPP--biologically active form) proved to be the best indicator of thiamine depletion impacts as determined using regression modeling. These observed relationships indicated differential effects on the immune measures with bactericidal activity exhibiting an inverse relationship with TMP to TPP ratios, Con A stimulated mitogenesis exhibiting a positive relationship with TMP to TPP ratios and PHA-P stimulated mitogenesis exhibiting no significant relationships. In addition, these relationships showed considerable complexity which included the consistent observation of a thiamine-replete subgroup with characteristics similar to those seen in the leukocytes from thiamine-depleted fish. When considered together, our observations indicate that lake trout leukocytes experience cell-type specific impacts as well as an altered physiologic environment when confronted with a thiamine-limited state. Published by Elsevier Ltd.

In vitro immune functions in thiamine-replete and -depleted lake trout (Salvelinus namaycush)

USGS Publications Warehouse

Ottinger, Christopher A.; Honeyfield, Dale C.; Densmore, Christine L.; Iwanowicz, Luke R.

2014-01-01

In this study we examined the impacts of in vivo thiamine deficiency on lake trout leukocyte function measured in vitro. When compared outside the context of individual-specific thiamine concentrations no significant differences were observed in leukocyte bactericidal activity or in concanavalin A (Con A), and phytohemagglutinin-P (PHA-P) stimulated leukocyte proliferation. Placing immune functions into context with the ratio of in vivo liver thiamine monophosphate (TMP – biologically inactive form) to thiamine pyrophosphate (TPP – biologically active form) proved to be the best indicator of thiamine depletion impacts as determined using regression modeling. These observed relationships indicated differential effects on the immune measures with bactericidal activity exhibiting an inverse relationship with TMP to TPP ratios, Con A stimulated mitogenesis exhibiting a positive relationship with TMP to TPP ratios and PHA-P stimulated mitogenesis exhibiting no significant relationships. In addition, these relationships showed considerable complexity which included the consistent observation of a thiamine-replete subgroup with characteristics similar to those seen in the leukocytes from thiamine-depleted fish. When considered together, our observations indicate that lake trout leukocytes experience cell-type specific impacts as well as an altered physiologic environment when confronted with a thiamine-limited state.

TMJ function after partial condylectomy in active mandibular condylar hyperplasia

PubMed Central

Olate, Sergio; Martinez, Felipe; Uribe, Francisca; Pozzer, Leandro; Cavalieri-Pereira, Lucas; de Moraes, Marcio

2014-01-01

Condylar hyperplasia is a frequent pathology that causes severe facial asymmetries. The partial condylectomy generally halts the disease. The aim of this research was to examine post-condylectomy TMJ function; 14 patients were included in this study, 6 male and 8 female. The average age was 21 years old. In all, the partial condylectomy was performed with preauricular or endaural access and the osteotomy were performed with drills, saw or an ultrasonic system. The patients were assessed with 3 or more time after surgery and were considering maximum mouth opening, right and left lateralities, presence of pain, noises, alterations in the facial nerve (VII) and esthetic alteration from the scar. The analysis was performed with the visual analog scale (VAS) and with a 7 cm metallic rule. Data analysis was descriptive plus chi-square test considering p value < 0.05 for statistical differences. With an average of 11 month after surgery, the results showed that the open mouth (over 35 mm) and lateralities (average 9 mm for the both right and left side) were normal and without statistical differences between the right or left side. Noise was observed in 3 patients and pain was observed in two patients with level 2 and 1 (VAS score). Scar was not related to problem with patient and the temporal branch of facial nerve was observed with limitations but without problem for patients. It can be concluded that the condylectomy is a safe and effective procedure with low morbidity for patients. PMID:24753777

Effect of ultrasound radiation force on the choroid.

PubMed

Silverman, Ronald H; Urs, Raksha; Lloyd, Harriet O

2013-01-10

While visualization of the retina and choroid has made great progress, functional imaging techniques have been lacking. Our aim was to utilize acoustic radiation force impulse (ARFI) response to probe functional properties of these tissues. A single element 18-MHz ultrasound transducer was focused upon the retina of the rabbit eye. The procedure was performed with the eye proptosed and with the eye seated normally in the orbit. The transducer was excited to emit ARFI over a 10-ms period with a 25% duty cycle. Phase resolved pulse/echo data were acquired before, during, and following ARFI. In the proptosed eye, ARFI exposure produced tissue displacements ranging from 0 to 10 μm, and an immediate increase in choroidal echo amplitude to over 6 dB, decaying to baseline after about 1 second. In the normally seated eye, ultrasound phase shifts consistent with flow were observed in the choroid, but enhanced backscatter following ARFI rarely occurred. ARFI-induced displacements of about 10 μm were observed at the choroidal margins. Larger displacements occurred within the choroid and in orbital tissues. We hypothesize that elevated intraocular pressure occurring during proptosis induced choroidal ischemia and that acoustic radiation force produced a transient local decompression and reperfusion. With the eye normally seated, choroidal flow was observed and little alteration in backscatter resulted from exposure. Clinical application of this technique may provide new insights into diseases characterized by altered choroidal hemodynamics, including maculopathies, diabetic retinopathy, and glaucoma.

Hepatitis C virus envelope components alter localization of hepatocyte tight junction-associated proteins and promote occludin retention in the endoplasmic reticulum.

PubMed

Benedicto, Ignacio; Molina-Jiménez, Francisca; Barreiro, Olga; Maldonado-Rodríguez, Alejandra; Prieto, Jesús; Moreno-Otero, Ricardo; Aldabe, Rafael; López-Cabrera, Manuel; Majano, Pedro L

2008-10-01

Hepatocyte tight junctions (TJ) play key roles in characteristic liver functions, including bile formation and secretion. Infection by hepatitis C virus (HCV) may cause alterations of the liver architecture and disruption of the bile duct, which ultimately can lead to cholestasis. Herein, we employed the HCV replicon system to analyze the effect of HCV on TJ organization. TJ-associated proteins occludin, claudin-1, and Zonula Occludens protein-1 (ZO-1) disappeared from their normal localization at the border of adjacent cells in Huh7 clones harboring genomic but not subgenomic replicons expressing only the nonstructural proteins. Furthermore, cells containing genomic replicons showed a cytoplasmic accumulation of occludin in the endoplasmic reticulum (ER). TJ-associated function, measured as FITC-dextran paracellular permeability, of genomic replicon-containing cells, was also altered. Interestingly, clearance of the HCV replicon by interferon-alpha (IFN-alpha) treatment and by short hairpin RNA (shRNA) significantly restored the localization of TJ-associated proteins. Transient expression of all HCV structural proteins, but not core protein alone, altered the localization of TJ-associated proteins in Huh7 cells and in clones with subgenomic replicons. Confocal analysis showed that accumulation of occludin in the ER partially co-localized with HCV envelope glycoprotein E2. E2/occludin association was further confirmed by co-immunoprecipitation and pull-down assays. Additionally, using a cell culture model of HCV infection, we observed the cytoplasmic dot-like accumulation of occludin in infected Huh7 cells. We propose that HCV structural proteins, most likely those of the viral envelope, promote alterations of TJ-associated proteins, which may provide new insights for HCV-related pathogenesis.

Transcriptomic alterations in the brain of painted turtles (Chrysemys picta) developmentally exposed to bisphenol A or ethinyl estradiol.

PubMed

Manshack, Lindsey K; Conard, Caroline M; Bryan, Sara J; Deem, Sharon L; Holliday, Dawn K; Bivens, Nathan J; Givan, Scott A; Rosenfeld, Cheryl S

2017-04-01

Developmental exposure of turtles and other reptiles to endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA) and ethinyl estradiol (EE), can stimulate partial to full gonadal sex-reversal in males. We have also recently shown that in ovo exposure to either EDC can induce similar sex-dependent behavioral changes typified by improved spatial learning and memory or possibly feminized brain responses. Observed behavioral changes are presumed to be due to BPA- and EE-induced brain transcriptomic alterations during development. To test this hypothesis, we treated painted turtles ( Chrysemys picta ) at developmental stage 17 , incubated at 26°C (male-inducing temperature), with 1 ) BPA (1 ng/µl), 2 ) EE (4 ng/µl), or 3 ) vehicle ethanol (control group). Ten months after hatching and completion of the behavioral tests, juvenile turtles were euthanized, brains were collected and frozen in liquid nitrogen, and RNA was isolated for RNA-Seq analysis. Turtles exposed to BPA clustered separately from EE-exposed and control individuals. More transcripts and gene pathways were altered in BPA vs. EE individuals. The one transcript upregulated in both BPA- and EE-exposed individuals was the mitochondrial-associated gene, ND5, which is involved in oxidative phosphorylation. Early exposure of turtles to BPA increases transcripts linked with ribosomal and mitochondrial functions, especially bioenergetics, which has been previously linked with improved cognitive performance. In summary, even though both BPA and EE resulted in similar behavioral alterations, they diverge in the pattern of neural transcript alterations with early BPA significantly upregulating several genes involved in oxidative phosphorylation, mitochondrial activity, and ribosomal function, which could enhance cognitive performance. Copyright © 2017 the American Physiological Society.

Does vector-free gravity simulate microgravity? Functional and morphologic attributes of clinorotated nerve and muscle grown in cell culture

NASA Technical Reports Server (NTRS)

Gruener, Raphael; Hoeger, Glenn

1988-01-01

Cocultured Xenopus neurons and myocytes were subjected to nonvectorial gravity by clinostat rotation to determine the effects of microgravity on cell development and communications. Observed effects included increases in the myocyte and its nuclear area, fragmentation of nucleoli, the appearance of neuritic aneurysms, decreased growth in the presence of trophic factors, and decreased yolk utilization. These effects were most notable at 1-10 rpm and depended on the onset and duration of rotation. It is found that, in microgravity, cell differentiation is altered by interference with cytoskeleton-related mechanisms. It is suggested that the alteration of the distribution of acetylcholine receptor aggregates on myocytes which occurs might indicate that microgravity affects brain development.

Lambda cyhalothrin induced alterations in Clarias batrachus.

PubMed

Saravanan, R; Revathi, K; Murthy, P Balakrishna

2009-03-01

The present study was undertaken to find out the toxic effect of synthetic pyrethroid lambda cyhalothrin on the functioning of endocrine glands in freshwater catfish, Clarias batrachus. The fish were exposed to the pesticide for a period of 45 days at a sublethal concentration of 5.768 ppm. Analysis of hormone profile was carried out on the 15, 30 and 45 days of exposure to find out the alteration in hormone secretion and the response of the fish to the compound. The results obtained showed a significant decline (p<0.05) in levels of thyroid hormones and testosterone while a significant increase (p<0.05) was observed in cortisol levels during the different days of exposure of the fish to lambda cyhalothrin.

Treatment of MRSA infections in an African-American male with G6PD deficiency.

PubMed

Paek, David S; Nadkarni, Milan; Singla, Manav

2009-10-01

Glucose-6-phosphate dehydrogenase (G6PD) deficiency affecting erythrocytes is the most common enzymopathy in humans. It requires caution with the intake of oxidizing substances (e.g., medications and foods) because of the threat of hemolysis. Less recognized is the threat of a deficiency in G6PD that alters neutrophil function, which can compromise the killing of microbes by the oxidative burst mechanism. This results from a secondary alteration in the NADPH oxidase pathway. Methicillin-resistant Staphylococcus aureus (MRSA) infection, which is usually observed after exposure in the hospital setting, is becoming increasingly common in a community setting. Here we show the risk of MRSA and G6PD deficiency and discuss the pitfalls of G6PD deficiency.

Changes to dryland rainfall result in rapid moss mortality and altered soil fertility

USGS Publications Warehouse

Reed, Sasha C.; Coe, Kirsten K.; Sparks, Jed P.; Housman, David C.; Zelikova, Tamara J.; Belnap, Jayne

2012-01-01

Arid and semi-arid ecosystems cover ~40% of Earth’s terrestrial surface, but we know little about how climate change will affect these widespread landscapes. Like many drylands, the Colorado Plateau in southwestern United States is predicted to experience elevated temperatures and alterations to the timing and amount of annual precipitation. We used a factorial warming and supplemental rainfall experiment on the Colorado Plateau to show that altered precipitation resulted in pronounced mortality of the widespread moss Syntrichia caninervis. Increased frequency of 1.2 mm summer rainfall events reduced moss cover from ~25% of total surface cover to <2% after only one growing season, whereas increased temperature had no effect. Laboratory measurements identified a physiological mechanism behind the mortality: small precipitation events caused a negative moss carbon balance, whereas larger events maintained net carbon uptake. Multiple metrics of nitrogen cycling were notably different with moss mortality and had significant implications for soil fertility. Mosses are important members in many dryland ecosystems and the community changes observed here reveal how subtle modifications to climate can affect ecosystem structure and function on unexpectedly short timescales. Moreover, mortality resulted from increased precipitation through smaller, more frequent events, underscoring the importance of precipitation event size and timing, and highlighting our inadequate understanding of relationships between climate and ecosystem function in drylands.

Cortical network reorganization guided by sensory input features.

PubMed

Kilgard, Michael P; Pandya, Pritesh K; Engineer, Navzer D; Moucha, Raluca

2002-12-01

Sensory experience alters the functional organization of cortical networks. Previous studies using behavioral training motivated by aversive or rewarding stimuli have demonstrated that cortical plasticity is specific to salient inputs in the sensory environment. Sensory experience associated with electrical activation of the basal forebrain (BasF) generates similar input specific plasticity. By directly engaging plasticity mechanisms and avoiding extensive behavioral training, BasF stimulation makes it possible to efficiently explore how specific sensory features contribute to cortical plasticity. This review summarizes our observations that cortical networks employ a variety of strategies to improve the representation of the sensory environment. Different combinations of receptive-field, temporal, and spectrotemporal plasticity were generated in primary auditory cortex neurons depending on the pitch, modulation rate, and order of sounds paired with BasF stimulation. Simple tones led to map expansion, while modulated tones altered the maximum cortical following rate. Exposure to complex acoustic sequences led to the development of combination-sensitive responses. This remodeling of cortical response characteristics may reflect changes in intrinsic cellular mechanisms, synaptic efficacy, and local neuronal connectivity. The intricate relationship between the pattern of sensory activation and cortical plasticity suggests that network-level rules alter the functional organization of the cortex to generate the most behaviorally useful representation of the sensory environment.

Here, there be dragons: charting autophagy-related alterations in human tumors.

PubMed

Lebovitz, Chandra B; Bortnik, Svetlana B; Gorski, Sharon M

2012-03-01

Macroautophagy (or autophagy) is a catabolic cellular process that is both homeostatic and stress adaptive. Normal cells rely on basal levels of autophagy to maintain cellular integrity (via turnover of long-lived proteins and damaged organelles) and increased levels of autophagy to buoy cell survival during various metabolic stresses (via nutrient and energy provision through lysosomal degradation of cytoplasmic components). Autophagy can function in both tumor suppression and tumor progression, and is under investigation in clinical trials as a novel target for anticancer therapy. However, its role in cancer pathogenesis has yet to be fully explored. In particular, it remains unknown whether in vitro observations will be applicable to human cancer patients. Another outstanding question is whether there exists tumor-specific selection for alterations in autophagy function. In this review, we survey reported mutations in autophagy genes and key autophagy regulators identified in human tumor samples and summarize the literature regarding expression levels of autophagy genes and proteins in various cancer tissues. Although it is too early to draw inferences from this collection of in vivo studies of autophagy-related alterations in human cancers, their results highlight the challenges that must be overcome before we can accurately assess the scope of autophagy's predicted role in tumorigenesis.

Morphofunctional and signaling molecules overlap of the pineal gland and thymus: role and significance in aging.

PubMed

Paltsev, Michael A; Polyakova, Victoria O; Kvetnoy, Igor M; Anderson, George; Kvetnaia, Tatiana V; Linkova, Natalia S; Paltseva, Ekaterina M; Rubino, Rosa; De Cosmo, Salvatore; De Cata, Angelo; Mazzoccoli, Gianluigi

2016-03-15

Deficits in neuroendocrine-immune system functioning, including alterations in pineal and thymic glands, contribute to aging-associated diseases. This study looks at ageing-associated alterations in pineal and thymic gland functioning evaluating common signaling molecules present in both human and animal pinealocytes and thymocytes: endocrine cell markers (melatonin, serotonin, pCREB, AANAT, CGRP, VIP, chromogranin А); cell renovation markers (p53, AIF, Ki67), matrix metalloproteinases (MMP2, MMP9) and lymphocytes markers (CD4, CD5, CD8, CD20). Pineal melatonin is decreased, as is one of the melatonin pathway synthesis enzymes in the thymic gland. A further similarity is the increased MMPs levels evident over age in both glands. Significant differences are evident in cell renovation processes, which deteriorate more quickly in the aged thymus versus the pineal gland. Decreases in the number of pineal B-cells and thymic T-cells were also observed over aging. Collected data indicate that cellular involution of the pineal gland and thymus show many commonalities, but also significant changes in aging-associated proteins. It is proposed that such ageing-associated alterations in these two glands provide novel pharmaceutical targets for the wide array of medical conditions that are more likely to emerge over the course of ageing.

Altered structural brain changes and neurocognitive performance in pediatric HIV.

PubMed

Yadav, Santosh K; Gupta, Rakesh K; Garg, Ravindra K; Venkatesh, Vimala; Gupta, Pradeep K; Singh, Alok K; Hashem, Sheema; Al-Sulaiti, Asma; Kaura, Deepak; Wang, Ena; Marincola, Francesco M; Haris, Mohammad

2017-01-01

Pediatric HIV patients often suffer with neurodevelopmental delay and subsequently cognitive impairment. While tissue injury in cortical and subcortical regions in the brain of adult HIV patients has been well reported there is sparse knowledge about these changes in perinatally HIV infected pediatric patients. We analyzed cortical thickness, subcortical volume, structural connectivity, and neurocognitive functions in pediatric HIV patients and compared with those of pediatric healthy controls. With informed consent, 34 perinatally infected pediatric HIV patients and 32 age and gender matched pediatric healthy controls underwent neurocognitive assessment and brain magnetic resonance imaging (MRI) on a 3 T clinical scanner. Altered cortical thickness, subcortical volumes, and abnormal neuropsychological test scores were observed in pediatric HIV patients. The structural network connectivity analysis depicted lower connection strengths, lower clustering coefficients, and higher path length in pediatric HIV patients than healthy controls. The network betweenness and network hubs in cortico-limbic regions were distorted in pediatric HIV patients. The findings suggest that altered cortical and subcortical structures and regional brain connectivity in pediatric HIV patients may contribute to deficits in their neurocognitive functions. Further, longitudinal studies are required for better understanding of the effect of HIV pathogenesis on brain structural changes throughout the brain development process under standard ART treatment.

Mismatch Negativity and P50 Sensory Gating in Abstinent Former Cannabis Users

PubMed Central

Broyd, Samantha J.; Greenwood, Lisa-marie; van Hell, Hendrika H.; Croft, Rodney J.; Coyle, Hannah; Lee-Bates, Ben; Todd, Juanita; Johnstone, Stuart J.; Michie, Patricia T.; Solowij, Nadia

2016-01-01

Prolonged heavy exposure to cannabis is associated with impaired cognition and brain functional and structural alterations. We recently reported attenuated mismatch negativity (MMN) and altered P50 sensory gating in chronic cannabis users. This study investigated the extent of brain functional recovery (indexed by MMN and P50) in chronic users after cessation of use. Eighteen ex-users (median 13.5 years prior regular use; median 3.5 years abstinence) and 18 nonusers completed (1) a multifeature oddball task with duration, frequency, and intensity deviants and (2) a P50 paired-click paradigm. Trend level smaller duration MMN amplitude and larger P50 ratios (indicative of poorer sensory gating) were observed in ex-users compared to controls. Poorer P50 gating correlated with prior duration of cannabis use. Duration of abstinence was positively correlated with duration MMN amplitude, even after controlling for age and duration of cannabis use. Impaired sensory gating and attenuated MMN amplitude tended to persist in ex-users after prolonged cessation of use, suggesting a lack of full recovery. An association with prolonged duration of prior cannabis use may indicate persistent cannabis-related alterations to P50 sensory gating. Greater reductions in MMN amplitude with increasing abstinence (positive correlation) may be related to either self-medication or an accelerated aging process. PMID:27019754

Morphofunctional and signaling molecules overlap of the pineal gland and thymus: role and significance in aging

PubMed Central

Paltsev, Michael A.; Polyakova, Victoria O.; Kvetnoy, Igor M.; Anderson, George; Kvetnaia, Tatiana V.; Linkova, Natalia S.; Paltseva, Ekaterina M.; Rubino, Rosa; De Cosmo, Salvatore; De Cata, Angelo; Mazzoccoli, Gianluigi

2016-01-01

Deficits in neuroendocrine-immune system functioning, including alterations in pineal and thymic glands, contribute to aging-associated diseases. This study looks at ageing-associated alterations in pineal and thymic gland functioning evaluating common signaling molecules present in both human and animal pinealocytes and thymocytes: endocrine cell markers (melatonin, serotonin, pCREB, AANAT, CGRP, VIP, chromogranin A); cell renovation markers (p53, AIF, Ki67), matrix metalloproteinases (MMP2, MMP9) and lymphocytes markers (CD4, CD5, CD8, CD20). Pineal melatonin is decreased, as is one of the melatonin pathway synthesis enzymes in the thymic gland. A further similarity is the increased MMPs levels evident over age in both glands. Significant differences are evident in cell renovation processes, which deteriorate more quickly in the aged thymus versus the pineal gland. Decreases in the number of pineal B-cells and thymic T-cells were also observed over aging. Collected data indicate that cellular involution of the pineal gland and thymus show many commonalities, but also significant changes in aging-associated proteins. It is proposed that such ageing-associated alterations in these two glands provide novel pharmaceutical targets for the wide array of medical conditions that are more likely to emerge over the course of ageing. PMID:26943046

Sex differences in autism: a resting-state fMRI investigation of functional brain connectivity in males and females

PubMed Central

Swinnen, Stephan P.; Wenderoth, Nicole

2016-01-01

Autism spectrum disorders (ASD) are far more prevalent in males than in females. Little is known however about the differential neural expression of ASD in males and females. We used a resting-state fMRI-dataset comprising 42 males/42 females with ASD and 75 male/75 female typical-controls to examine whether autism-related alterations in intrinsic functional connectivity are similar or different in males and females, and particularly whether alterations reflect ‘neural masculinization’, as predicted by the Extreme Male Brain theory. Males and females showed a differential neural expression of ASD, characterized by highly consistent patterns of hypo-connectivity in males with ASD (compared to typical males), and hyper-connectivity in females with ASD (compared to typical females). Interestingly, patterns of hyper-connectivity in females with ASD reflected a shift towards the (high) connectivity levels seen in typical males (neural masculinization), whereas patterns of hypo-connectivity observed in males with ASD reflected a shift towards the (low) typical feminine connectivity patterns (neural feminization). Our data support the notion that ASD is a disorder of sexual differentiation rather than a disorder characterized by masculinization in both genders. Future work is needed to identify underlying factors such as sex hormonal alterations that drive these sex-specific neural expressions of ASD. PMID:26989195

Quantitative proteomic profiling of paired cancerous and normal colon epithelial cells isolated freshly from colorectal cancer patients.

PubMed

Tu, Chengjian; Mojica, Wilfrido; Straubinger, Robert M; Li, Jun; Shen, Shichen; Qu, Miao; Nie, Lei; Roberts, Rick; An, Bo; Qu, Jun

2017-05-01

The heterogeneous structure in tumor tissues from colorectal cancer (CRC) patients excludes an informative comparison between tumors and adjacent normal tissues. Here, we develop and apply a strategy to compare paired cancerous (CEC) versus normal (NEC) epithelial cells enriched from patients and discover potential biomarkers and therapeutic targets for CRC. CEC and NEC cells are respectively isolated from five different tumor and normal locations in the resected colon tissue from each patient (N = 12 patients) using an optimized epithelial cell adhesion molecule (EpCAM)-based enrichment approach. An ion current-based quantitative method is employed to perform comparative proteomic analysis for each patient. A total of 458 altered proteins that are common among >75% of patients are observed and selected for further investigation. Besides known findings such as deregulation of mitochondrial function, tricarboxylic acid cycle, and RNA post-transcriptional modification, functional analysis further revealed RAN signaling pathway, small nucleolar ribonucleoproteins (snoRNPs), and infection by RNA viruses are altered in CEC cells. A selection of the altered proteins of interest is validated by immunohistochemistry analyses. The informative comparison between matched CEC and NEC enhances our understanding of molecular mechanisms of CRC development and provides biomarker candidates and new pathways for therapeutic intervention. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Epigenetic determinants of space radiation-induced cognitive dysfunction

PubMed Central

Acharya, Munjal M.; Baddour, Al Anoud D.; Kawashita, Takumi; Allen, Barrett D.; Syage, Amber R.; Nguyen, Thuan H.; Yoon, Nicole; Giedzinski, Erich; Yu, Liping; Parihar, Vipan K.; Baulch, Janet E.

2017-01-01

Among the dangers to astronauts engaging in deep space missions such as a Mars expedition is exposure to radiations that put them at risk for severe cognitive dysfunction. These radiation-induced cognitive impairments are accompanied by functional and structural changes including oxidative stress, neuroinflammation, and degradation of neuronal architecture. The molecular mechanisms that dictate CNS function are multifaceted and it is unclear how irradiation induces persistent alterations in the brain. Among those determinants of cognitive function are neuroepigenetic mechanisms that translate radiation responses into altered gene expression and cellular phenotype. In this study, we have demonstrated a correlation between epigenetic aberrations and adverse effects of space relevant irradiation on cognition. In cognitively impaired irradiated mice we observed increased 5-methylcytosine and 5-hydroxymethylcytosine levels in the hippocampus that coincided with increased levels of the DNA methylating enzymes DNMT3a, TET1 and TET3. By inhibiting methylation using 5-iodotubercidin, we demonstrated amelioration of the epigenetic effects of irradiation. In addition to protecting against those molecular effects of irradiation, 5-iodotubercidin restored behavioral performance to that of unirradiated animals. The findings of this study establish the possibility that neuroepigenetic mechanisms significantly contribute to the functional and structural changes that affect the irradiated brain and cognition. PMID:28220892

Altered fronto-striatal functions in the Gdi1-null mouse model of X-linked Intellectual Disability.

PubMed

Morè, Lorenzo; Künnecke, Basil; Yekhlef, Latefa; Bruns, Andreas; Marte, Antonella; Fedele, Ernesto; Bianchi, Veronica; Taverna, Stefano; Gatti, Silvia; D'Adamo, Patrizia

2017-03-06

RAB-GDP dissociation inhibitor 1 (GDI1) loss-of-function mutations are responsible for a form of non-specific X-linked Intellectual Disability (XLID) where the only clinical feature is cognitive impairment. GDI1 patients are impaired in specific aspects of executive functions and conditioned response, which are controlled by fronto-striatal circuitries. Previous molecular and behavioral characterization of the Gdi1-null mouse revealed alterations in the total number/distribution of hippocampal and cortical synaptic vesicles as well as hippocampal short-term synaptic plasticity, and memory deficits. In this study, we employed cognitive protocols with high translational validity to human condition that target the functionality of cortico-striatal circuitry such as attention and stimulus selection ability with progressive degree of complexity. We previously showed that Gdi1-null mice are impaired in some hippocampus-dependent forms of associative learning assessed by aversive procedures. Here, using appetitive-conditioning procedures we further investigated associative learning deficits sustained by the fronto-striatal system. We report that Gdi1-null mice are impaired in attention and associative learning processes, which are a key part of the cognitive impairment observed in XLID patients. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

CO2 leakage alters biogeochemical and ecological functions of submarine sands

PubMed Central

Molari, Massimiliano; Guilini, Katja; Lott, Christian; Weber, Miriam; de Beer, Dirk; Meyer, Stefanie; Ramette, Alban; Wegener, Gunter; Wenzhöfer, Frank; Martin, Daniel; Cibic, Tamara; De Vittor, Cinzia; Vanreusel, Ann; Boetius, Antje

2018-01-01

Subseabed CO2 storage is considered a future climate change mitigation technology. We investigated the ecological consequences of CO2 leakage for a marine benthic ecosystem. For the first time with a multidisciplinary integrated study, we tested hypotheses derived from a meta-analysis of previous experimental and in situ high-CO2 impact studies. For this, we compared ecological functions of naturally CO2-vented seafloor off the Mediterranean island Panarea (Tyrrhenian Sea, Italy) to those of nonvented sands, with a focus on biogeochemical processes and microbial and faunal community composition. High CO2 fluxes (up to 4 to 7 mol CO2 m−2 hour−1) dissolved all sedimentary carbonate, and comigration of silicate and iron led to local increases of microphytobenthos productivity (+450%) and standing stocks (+300%). Despite the higher food availability, faunal biomass (−80%) and trophic diversity were substantially lower compared to those at the reference site. Bacterial communities were also structurally and functionally affected, most notably in the composition of heterotrophs and microbial sulfate reduction rates (−90%). The observed ecological effects of CO2 leakage on submarine sands were reproduced with medium-term transplant experiments. This study assesses indicators of environmental impact by CO2 leakage and finds that community compositions and important ecological functions are permanently altered under high CO2. PMID:29441359

7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome.

PubMed

Balajthy, András; Somodi, Sándor; Pethő, Zoltán; Péter, Mária; Varga, Zoltán; Szabó, Gabriella P; Paragh, György; Vígh, László; Panyi, György; Hajdu, Péter

2016-08-01

In vitro manipulation of membrane sterol level affects the regulation of ion channels and consequently certain cellular functions; however, a comprehensive study that confirms the pathophysiological significance of these results is missing. The malfunction of 7-dehydrocholesterol (7DHC) reductase in Smith-Lemli-Opitz syndrome (SLOS) leads to the elevation of the 7-dehydrocholesterol level in the plasma membrane. T lymphocytes were isolated from SLOS patients to assess the effect of the in vivo altered membrane sterol composition on the operation of the voltage-gated Kv1.3 channel and the ion channel-dependent mitogenic responses. We found that the kinetic and equilibrium parameters of Kv1.3 activation changed in SLOS cells. Identical changes in Kv1.3 operation were observed when control/healthy T cells were loaded with 7DHC. Removal of the putative sterol binding sites on Kv1.3 resulted in a phenotype that was not influenced by the elevation in membrane sterol level. Functional assays exhibited impaired activation and proliferation rate of T cells probably partially due to the modified Kv1.3 operation. We concluded that the altered membrane sterol composition hindered the operation of Kv1.3 as well as the ion channel-controlled T cell functions.

CO2 leakage alters biogeochemical and ecological functions of submarine sands.

PubMed

Molari, Massimiliano; Guilini, Katja; Lott, Christian; Weber, Miriam; de Beer, Dirk; Meyer, Stefanie; Ramette, Alban; Wegener, Gunter; Wenzhöfer, Frank; Martin, Daniel; Cibic, Tamara; De Vittor, Cinzia; Vanreusel, Ann; Boetius, Antje

2018-02-01

Subseabed CO 2 storage is considered a future climate change mitigation technology. We investigated the ecological consequences of CO 2 leakage for a marine benthic ecosystem. For the first time with a multidisciplinary integrated study, we tested hypotheses derived from a meta-analysis of previous experimental and in situ high-CO 2 impact studies. For this, we compared ecological functions of naturally CO 2 -vented seafloor off the Mediterranean island Panarea (Tyrrhenian Sea, Italy) to those of nonvented sands, with a focus on biogeochemical processes and microbial and faunal community composition. High CO 2 fluxes (up to 4 to 7 mol CO 2 m -2 hour -1 ) dissolved all sedimentary carbonate, and comigration of silicate and iron led to local increases of microphytobenthos productivity (+450%) and standing stocks (+300%). Despite the higher food availability, faunal biomass (-80%) and trophic diversity were substantially lower compared to those at the reference site. Bacterial communities were also structurally and functionally affected, most notably in the composition of heterotrophs and microbial sulfate reduction rates (-90%). The observed ecological effects of CO 2 leakage on submarine sands were reproduced with medium-term transplant experiments. This study assesses indicators of environmental impact by CO 2 leakage and finds that community compositions and important ecological functions are permanently altered under high CO 2 .

Altered States of Consciousness during an Extreme Ritual

PubMed Central

Loewald, Tonio; Comber, Evelyn M.; Hanson, Sarah A.; Pruitt, Bria

2016-01-01

Extreme rituals (body-piercing, fire-walking, etc.) are anecdotally associated with altered states of consciousness—subjective alterations of ordinary mental functioning (Ward, 1984)—but empirical evidence of altered states using both direct and indirect measures during extreme rituals in naturalistic settings is limited. Participants in the “Dance of Souls”, a 3.5-hour event during which participants received temporary piercings with hooks or weights attached to the piercings and danced to music provided by drummers, responded to measures of two altered states of consciousness. Participants also completed measures of positive and negative affect, salivary cortisol (a hormone associated with stress), self-reported stress, sexual arousal, and intimacy. Both pierced participants (pierced dancers) and non-pierced participants (piercers, piercing assistants, observers, drummers, and event leaders) showed evidence of altered states aligned with transient hypofrontality (Dietrich, 2003; measured with a Stroop test) and flow (Csikszentmihalyi, 1990; Csikszentmihalyi & Csikszentmihalyi, 1990; measured with the Flow State Scale). Both pierced and non-pierced participants also reported decreases in negative affect and psychological stress and increases in intimacy from before to after the ritual. Pierced and non-pierced participants showed different physiological reactions, however, with pierced participants showing increases in cortisol and non-pierced participants showing decreases from before to during the ritual. Overall, the ritual appeared to induce different physiological effects but similar psychological effects in focal ritual participants (i.e., pierced dancers) and in participants adopting other roles. PMID:27175897

Synaptic plasticity, neural circuits, and the emerging role of altered short-term information processing in schizophrenia

PubMed Central

Crabtree, Gregg W.; Gogos, Joseph A.

2014-01-01

Synaptic plasticity alters the strength of information flow between presynaptic and postsynaptic neurons and thus modifies the likelihood that action potentials in a presynaptic neuron will lead to an action potential in a postsynaptic neuron. As such, synaptic plasticity and pathological changes in synaptic plasticity impact the synaptic computation which controls the information flow through the neural microcircuits responsible for the complex information processing necessary to drive adaptive behaviors. As current theories of neuropsychiatric disease suggest that distinct dysfunctions in neural circuit performance may critically underlie the unique symptoms of these diseases, pathological alterations in synaptic plasticity mechanisms may be fundamental to the disease process. Here we consider mechanisms of both short-term and long-term plasticity of synaptic transmission and their possible roles in information processing by neural microcircuits in both health and disease. As paradigms of neuropsychiatric diseases with strongly implicated risk genes, we discuss the findings in schizophrenia and autism and consider the alterations in synaptic plasticity and network function observed in both human studies and genetic mouse models of these diseases. Together these studies have begun to point toward a likely dominant role of short-term synaptic plasticity alterations in schizophrenia while dysfunction in autism spectrum disorders (ASDs) may be due to a combination of both short-term and long-term synaptic plasticity alterations. PMID:25505409

Functional and structural neural alterations in Internet gaming disorder: A systematic review and meta-analysis.

PubMed

Yao, Yuan-Wei; Liu, Lu; Ma, Shan-Shan; Shi, Xin-Hui; Zhou, Nan; Zhang, Jin-Tao; Potenza, Marc N

2017-12-01

This meta-analytic study aimed to identify the common and specific neural alterations in Internet gaming disorder (IGD) across different domains and modalities. Two separate meta-analyses for functional neural activation and gray-matter volume were conducted. Sub-meta-analyses for the domains of reward, cold-executive, and hot-executive functions were also performed, respectively. IGD subjects, compared with healthy controls, showed: (1) hyperactivation in the anterior and posterior cingulate cortices, caudate, posterior inferior frontal gyrus (IFG), which were mainly associated with studies measuring reward and cold-executive functions; and, (2) hypoactivation in the anterior IFG in relation to hot-executive function, the posterior insula, somatomotor and somatosensory cortices in relation to reward function. Furthermore, IGD subjects showed reduced gray-matter volume in the anterior cingulate, orbitofrontal, dorsolateral prefrontal, and premotor cortices. These findings suggest that IGD is associated with both functional and structural neural alterations in fronto-striatal and fronto-cingulate regions. Moreover, multi-domain assessments capture different aspects of neural alterations in IGD, which may be helpful for developing effective interventions targeting specific functions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Adverse Respiratory Health and Hematological Alterations among Agricultural Workers Occupationally Exposed to Organophosphate Pesticides: A Cross-Sectional Study in North India

PubMed Central

Fareed, Mohd.; Pathak, Manoj Kumar; Bihari, Vipin; Kamal, Ritul; Srivastava, Anup Kumar; Kesavachandran, Chandrasekharan Nair

2013-01-01

Background Non-protective work practices followed by farm workers during spraying of pesticides lead to occupational exposure among them. Objective This study is designed to explore the respiratory health and hematological profile of agricultural workers occupationally exposed to OP pesticides. Materials and Methods A cross sectional study was undertaken among 166 pesticide sprayers working in mango orchards of Lucknow district in North India compared with 77 controls to assess the respiratory illness, lung functions, cholinesterase levels and hematological profile. A questionnaire based survey and clinical examination for respiratory health were conducted among study subjects. Lung function test was conducted among study subjects by using spirometer. Cholinesterase level as biomarker of OP pesticides and hematological profile of study subjects were investigated in the laboratory by following the standard protocols. Results Overall respiratory morbidity observed among exposed subjects was 36.75%. Symptoms for respiratory illness like dry cough, productive cough, wheezing, irritation of throat and blood stained sputum were found to be significantly more (p<0.05) among pesticide sprayers than controls. Lung function parameters viz. PEFR, FEV1, %PEFR predicted, %FEV1 predicted and FEV1/FVC were found to be significantly decreased (p<0.05) among pesticide sprayers as compared to controls. Exposure wise distribution of respiratory illness and lung functions among pesticide sprayers show that the exposure duration significantly elevates (p<0.05) the respiratory problems and significantly decreases (p<0.001) lung functions among pesticide sprayers. Activities of acetylcholinesterase and butyrylcholinesterase were found to be significantly depleted (p<0.001) among pesticide sprayers as compared to controls which show the exposure of OP pesticides among them. The hematological profile viz. RBC, WBC, monocytes, neutrophils, MCV, MCH, MCHC and platelet count were significantly altered (p<0.001) in pesticide sprayers than controls. Conclusion This study shows that the unsafe occupational exposure of OP pesticides causes respiratory illness, decreased lung functions and hematological alterations among pesticide sprayers. PMID:23936093

Adverse respiratory health and hematological alterations among agricultural workers occupationally exposed to organophosphate pesticides: a cross-sectional study in North India.

PubMed

Fareed, Mohd; Pathak, Manoj Kumar; Bihari, Vipin; Kamal, Ritul; Srivastava, Anup Kumar; Kesavachandran, Chandrasekharan Nair

2013-01-01

Non-protective work practices followed by farm workers during spraying of pesticides lead to occupational exposure among them. This study is designed to explore the respiratory health and hematological profile of agricultural workers occupationally exposed to OP pesticides. A cross sectional study was undertaken among 166 pesticide sprayers working in mango orchards of Lucknow district in North India compared with 77 controls to assess the respiratory illness, lung functions, cholinesterase levels and hematological profile. A questionnaire based survey and clinical examination for respiratory health were conducted among study subjects. Lung function test was conducted among study subjects by using spirometer. Cholinesterase level as biomarker of OP pesticides and hematological profile of study subjects were investigated in the laboratory by following the standard protocols. Overall respiratory morbidity observed among exposed subjects was 36.75%. Symptoms for respiratory illness like dry cough, productive cough, wheezing, irritation of throat and blood stained sputum were found to be significantly more (p<0.05) among pesticide sprayers than controls. Lung function parameters viz. PEFR, FEV1, %PEFR predicted, %FEV1 predicted and FEV1/FVC were found to be significantly decreased (p<0.05) among pesticide sprayers as compared to controls. Exposure wise distribution of respiratory illness and lung functions among pesticide sprayers show that the exposure duration significantly elevates (p<0.05) the respiratory problems and significantly decreases (p<0.001) lung functions among pesticide sprayers. Activities of acetylcholinesterase and butyrylcholinesterase were found to be significantly depleted (p<0.001) among pesticide sprayers as compared to controls which show the exposure of OP pesticides among them. The hematological profile viz. RBC, WBC, monocytes, neutrophils, MCV, MCH, MCHC and platelet count were significantly altered (p<0.001) in pesticide sprayers than controls. This study shows that the unsafe occupational exposure of OP pesticides causes respiratory illness, decreased lung functions and hematological alterations among pesticide sprayers.

Lipid raft disarrangement as a result of neuropathological progresses: a novel strategy for early diagnosis?

PubMed

Marin, R; Rojo, J A; Fabelo, N; Fernandez, C E; Diaz, M

2013-08-15

Lipid rafts are the preferential site of numerous membrane signaling proteins which are involved in neuronal functioning and survival. These proteins are organized in multiprotein complexes, or signalosomes, in close contact with lipid classes particularly represented in lipid rafts (i.e. cholesterol, sphingolipids and saturated fatty acids), which may contribute to physiological responses leading to neuroprotection. Increasing evidence indicates that alteration of lipid composition in raft structures as a consequence of neuropathologies, such as Alzheimer's disease (AD) and Parkinson's disease (PD), causes a dramatic increase in lipid raft order. These phenomena may correlate with perturbation of signalosome activities, likely contributing to neurodegenerative progression. Interestingly, significant disruption of stable raft microenvironments has been already observed in the first stages of either AD or PD, suggesting that these alterations may represent early events in the neuropathological development. In this regard, the search for biochemical markers, such as specific metabolic products altered in the brain at the first steps of the disease, presently represents an important challenge for early diagnostic strategies. Alterations of these biomarkers may be reflected in either plasma or cerebrospinal fluid, thus representing a potential strategy to predict an accurate diagnosis. We propose that pathologically-linked lipid raft markers may be interesting candidates to be explored at this level, although it has not been studied so far to what extent alteration of different signalosome components may be reflected in peripheral fluids. In this mini-review, we will discuss on relevant aspects of lipid rafts that contribute to the modulation of neuropathological events related to AD and PD. An interesting hypothesis is that anomalies on raft biomarkers measured at peripheral fluids might mirror the lipid raft pathology observed in early stages of AD and PD. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Spacelab Life Sciences 1 - Dedicated life sciences mission

NASA Technical Reports Server (NTRS)

Womack, W. D.

1990-01-01

The Spacelab Life Sciences 1 (SLS-1) mission is discussed, and an overview of the SLS-1 Spacelab configuration is shown. Twenty interdisciplinary experiments, planned for this mission, are intended to explore the early stages of human and animal physiological adaptation to space flight conditions. Biomedical and gravitational biology experiments include cardiovascular and cardiopulmonary deconditioning, altered vestibular functions, altered metabolic functions (including altered fluid-electrolyte regulation), muscle atrophy, bone demineralization, decreased red blood cell mass, and altered immunologic responses.

Testing the basic assumption of the hydrogeomorphic approach to assessing wetland functions.

PubMed

Hruby, T

2001-05-01

The hydrogeomorphic (HGM) approach for developing "rapid" wetland function assessment methods stipulates that the variables used are to be scaled based on data collected at sites judged to be the best at performing the wetland functions (reference standard sites). A critical step in the process is to choose the least altered wetlands in a hydrogeomorphic subclass to use as a reference standard against which other wetlands are compared. The basic assumption made in this approach is that wetlands judged to have had the least human impact have the highest level of sustainable performance for all functions. The levels at which functions are performed in these least altered wetlands are assumed to be "characteristic" for the subclass and "sustainable." Results from data collected in wetlands in the lowlands of western Washington suggest that the assumption may not be appropriate for this region. Teams developing methods for assessing wetland functions did not find that the least altered wetlands in a subclass had a range of performance levels that could be identified as "characteristic" or "sustainable." Forty-four wetlands in four hydrogeomorphic subclasses (two depressional subclasses and two riverine subclasses) were rated by teams of experts on the severity of their human alterations and on the level of performance of 15 wetland functions. An ordinal scale of 1-5 was used to quantify alterations in water regime, soils, vegetation, buffers, and contributing basin. Performance of functions was judged on an ordinal scale of 1-7. Relatively unaltered wetlands were judged to perform individual functions at levels that spanned all of the seven possible ratings in all four subclasses. The basic assumption of the HGM approach, that the least altered wetlands represent "characteristic" and "sustainable" levels of functioning that are different from those found in altered wetlands, was not confirmed. Although the intent of the HGM approach is to use level of functioning as a metric to assess the ecological integrity or "health" of the wetland ecosystem, the metric does not seem to work in western Washington for that purpose.

Chronic social stress in pigs impairs intestinal barrier and nutrient transporter function, and alters neuro-immune mediator and receptor expression

PubMed Central

Li, Yihang; Song, Zehe; Kerr, Katelyn A.; Moeser, Adam J.

2017-01-01

Psychosocial stress is a major factor driving gastrointestinal (GI) pathophysiology and disease susceptibility in humans and animals. The mechanisms governing susceptibility to stress-induced GI disease remain poorly understood. In the present study, we investigated the influence of chronic social stress (CSS) in pigs, induced by 7 d of chronic mixing/crowding stress, on intestinal barrier and nutrient transport function, corticotropin releasing factor (CRF) signaling and immunological responses. Results from this study showed that CSS resulted in a significant impairment of ileal and colonic barrier function indicated by reduced transepithelial electrical resistance (TER) in the ileum and increased FD4 flux in the ileum (by 0.8 fold) and colon (by 0.7 fold). Ileal sodium glucose linked transporter 1 (SGLT-1) function, measured as glucose-induced changes in short-circuit current (Isc), was diminished (by 52%) in CSS pigs, associated with reduced body weight gain and feed efficiency. Although reductions in SGLT-1 function were observed in CSS pigs, mRNA expression for SGLT-1, villus heights were increased in CSS pigs. Corticotropin releasing factor (CRF) mRNA was upregulated (by 0.9 fold) in the ileum of CSS pigs but not in the colon. Urocortin 2 (Ucn2) mRNA was upregulated (by 1.5 fold) in the colon of CSS pigs, but not in the ileum. In CSS pigs, a downregulation of pro-inflammatory cytokines mRNA (IL1B, TNFA, IL8, and IL6) was observed in both ileum and colon, compared with controls. In contrast CSS induced a marked upregulation of mRNA for IL10 and mast cell chymase gene (CMA1) in the ileum and colon. Together, these data demonstrate that chronic stress in pigs results in significant alterations in intestinal barrier and nutrient transport function and neuro-immune mediator and receptor expression. PMID:28170426

Altered Structural and Functional Connectivity in Late Preterm Preadolescence: An Anatomic Seed-Based Study of Resting State Networks Related to the Posteromedial and Lateral Parietal Cortex.

PubMed

Degnan, Andrew J; Wisnowski, Jessica L; Choi, SoYoung; Ceschin, Rafael; Bhushan, Chitresh; Leahy, Richard M; Corby, Patricia; Schmithorst, Vincent J; Panigrahy, Ashok

2015-01-01

Late preterm birth confers increased risk of developmental delay, academic difficulties and social deficits. The late third trimester may represent a critical period of development of neural networks including the default mode network (DMN), which is essential to normal cognition. Our objective is to identify functional and structural connectivity differences in the posteromedial cortex related to late preterm birth. Thirty-eight preadolescents (ages 9-13; 19 born in the late preterm period (≥32 weeks gestational age) and 19 at term) without access to advanced neonatal care were recruited from a low socioeconomic status community in Brazil. Participants underwent neurocognitive testing, 3-dimensional T1-weighted imaging, diffusion-weighted imaging and resting state functional MRI (RS-fMRI). Seed-based probabilistic diffusion tractography and RS-fMRI analyses were performed using unilateral seeds within the posterior DMN (posterior cingulate cortex, precuneus) and lateral parietal DMN (superior marginal and angular gyri). Late preterm children demonstrated increased functional connectivity within the posterior default mode networks and increased anti-correlation with the central-executive network when seeded from the posteromedial cortex (PMC). Key differences were demonstrated between PMC components with increased anti-correlation with the salience network seen only with posterior cingulate cortex seeding but not with precuneus seeding. Probabilistic tractography showed increased streamlines within the right inferior longitudinal fasciculus and inferior fronto-occipital fasciculus within late preterm children while decreased intrahemispheric streamlines were also observed. No significant differences in neurocognitive testing were demonstrated between groups. Late preterm preadolescence is associated with altered functional connectivity from the PMC and lateral parietal cortex to known distributed functional cortical networks despite no significant executive neurocognitive differences. Selective increased structural connectivity was observed in the setting of decreased posterior interhemispheric connections. Future work is needed to determine if these findings represent a compensatory adaptation employing alternate neural circuitry or could reflect subtle pathology resulting in emotional processing deficits not seen with neurocognitive testing.

Stress and adolescent hippocampal neurogenesis: diet and exercise as cognitive modulators

PubMed Central

Hueston, C M; Cryan, J F; Nolan, Y M

2017-01-01

Adolescence is a critical period for brain maturation. Deciphering how disturbances to the central nervous system at this time affect structure, function and behavioural outputs is important to better understand any long-lasting effects. Hippocampal neurogenesis occurs during development and continues throughout life. In adulthood, integration of these new cells into the hippocampus is important for emotional behaviour, cognitive function and neural plasticity. During the adolescent period, maturation of the hippocampus and heightened levels of hippocampal neurogenesis are observed, making alterations to neurogenesis at this time particularly consequential. As stress negatively affects hippocampal neurogenesis, and adolescence is a particularly stressful time of life, it is important to investigate the impact of stressor exposure at this time on hippocampal neurogenesis and cognitive function. Adolescence may represent not only a time for which stress can have long-lasting effects, but is also a critical period during which interventions, such as exercise and diet, could ameliorate stress-induced changes to hippocampal function. In addition, intervention at this time may also promote life-long behavioural changes that would aid in fostering increased hippocampal neurogenesis and cognitive function. This review addresses both the acute and long-term stress-induced alterations to hippocampal neurogenesis and cognition during the adolescent period, as well as changes to the stress response and pubertal hormones at this time which may result in differential effects than are observed in adulthood. We hypothesise that adolescence may represent an optimal time for healthy lifestyle changes to have a positive and long-lasting impact on hippocampal neurogenesis, and to protect against stress-induced deficits. We conclude that future research into the mechanisms underlying the susceptibility of the adolescent hippocampus to stress, exercise and diet and the consequent effect on cognition may provide insight into why adolescence may be a vital period for correct conditioning of future hippocampal function. PMID:28375209

Stress and adolescent hippocampal neurogenesis: diet and exercise as cognitive modulators.

PubMed

Hueston, C M; Cryan, J F; Nolan, Y M

2017-04-04

Adolescence is a critical period for brain maturation. Deciphering how disturbances to the central nervous system at this time affect structure, function and behavioural outputs is important to better understand any long-lasting effects. Hippocampal neurogenesis occurs during development and continues throughout life. In adulthood, integration of these new cells into the hippocampus is important for emotional behaviour, cognitive function and neural plasticity. During the adolescent period, maturation of the hippocampus and heightened levels of hippocampal neurogenesis are observed, making alterations to neurogenesis at this time particularly consequential. As stress negatively affects hippocampal neurogenesis, and adolescence is a particularly stressful time of life, it is important to investigate the impact of stressor exposure at this time on hippocampal neurogenesis and cognitive function. Adolescence may represent not only a time for which stress can have long-lasting effects, but is also a critical period during which interventions, such as exercise and diet, could ameliorate stress-induced changes to hippocampal function. In addition, intervention at this time may also promote life-long behavioural changes that would aid in fostering increased hippocampal neurogenesis and cognitive function. This review addresses both the acute and long-term stress-induced alterations to hippocampal neurogenesis and cognition during the adolescent period, as well as changes to the stress response and pubertal hormones at this time which may result in differential effects than are observed in adulthood. We hypothesise that adolescence may represent an optimal time for healthy lifestyle changes to have a positive and long-lasting impact on hippocampal neurogenesis, and to protect against stress-induced deficits. We conclude that future research into the mechanisms underlying the susceptibility of the adolescent hippocampus to stress, exercise and diet and the consequent effect on cognition may provide insight into why adolescence may be a vital period for correct conditioning of future hippocampal function.

Alterations to Functional Analysis Methodology to Clarify the Functions of Low Rate, High Intensity Problem Behavior

PubMed Central

Davis, Barbara J; Schmidt, Jonathan; Bowman, Lynn G; Boelter, Eric W

2012-01-01

Current research provides few suggestions for modifications to functional analysis procedures to accommodate low rate, high intensity problem behavior. This study examined the results of the extended duration functional analysis procedures of Kahng, Abt, and Schonbachler (2001) with six children admitted to an inpatient hospital for the treatment of severe problem behavior. Results of initial functional analyses (Iwata, Dorsey, Slifer, Bauman, & Richman, 1982/1994) were inconclusive for all children because of low levels of responding. The altered functional analyses, which changed multiple variables including the duration of the functional analysis (i.e., 6 or 7 hrs), yielded clear behavioral functions for all six participants. These results add additional support for the utility of an altered analysis of low rate, high intensity problem behavior when standard functional analyses do not yield differentiated results. PMID:23326628

Alterations to functional analysis methodology to clarify the functions of low rate, high intensity problem behavior.

PubMed

Davis, Barbara J; Kahng, Sungwoo; Schmidt, Jonathan; Bowman, Lynn G; Boelter, Eric W

2012-01-01

Current research provides few suggestions for modifications to functional analysis procedures to accommodate low rate, high intensity problem behavior. This study examined the results of the extended duration functional analysis procedures of Kahng, Abt, and Schonbachler (2001) with six children admitted to an inpatient hospital for the treatment of severe problem behavior. Results of initial functional analyses (Iwata, Dorsey, Slifer, Bauman, & Richman, 1982/1994) were inconclusive for all children because of low levels of responding. The altered functional analyses, which changed multiple variables including the duration of the functional analysis (i.e., 6 or 7 hrs), yielded clear behavioral functions for all six participants. These results add additional support for the utility of an altered analysis of low rate, high intensity problem behavior when standard functional analyses do not yield differentiated results.

Research Review: altered reward function in adolescent depression: what, when and how?

PubMed

Forbes, Erika E; Dahl, Ronald E

2012-01-01

Conceptual models and recent evidence indicate that neural response to reward is altered in depression. Taking a developmental approach to investigating reward function in adolescent depression can elucidate the etiology, pathophysiology and course of depression, a disorder that typically begins during adolescence and has high rates of recurrence. This conceptual review describes the what, when and how of altered reward function in adolescent depression. With the goal of generating new, testable hypotheses within a developmental affective neuroscience framework, we critically review findings and suggest future directions. Peer-reviewed empirical papers for inclusion in this critical review were obtained by searching PubMed, PsycInfo and ScienceDirect for the years 1990-2010. A pattern of low striatal response and high medial prefrontal response to reward is evident in adolescents and adults with depression. Given the salience of social stimuli for positive affect and depression, reward function might be especially disrupted in response to social rewards. Because of changes in the dopamine system and reward function with aging, altered reward function in depression might be more evident during adolescence than later in life; however, low reward function may also be a stable characteristic of people who experience depression. Mechanisms of altered reward function in depression could include disrupted balance of corticostriatal circuit function, with disruption occurring as aberrant adolescent brain development. Future studies should examine responses to social rewards; employ longitudinal and prospective designs; and investigate patterns of functional connectivity in reward circuits. Understanding altered reward function in depression has potential implications for treatment development. A more rigorous approach to investigating anhedonia, threat-reward interactions and comorbid anxiety will be valuable to future progress in describing the role of reward function in the pathophysiology of depression. © 2011 The Authors. Journal of Child Psychology and Psychiatry © 2011 Association for Child and Adolescent Mental Health.

A Review of the Neuropsychological Dimensions of Tourette Syndrome

PubMed Central

Leclerc, Julie B.; Valois, Philippe; O’Connor, Kieron P.; Gauthier, Bruno

2017-01-01

Neurocognitive functioning in Tourette syndrome (TS) has been the subject of intensive research in the past 30 years. A variety of impairments, presumably related to frontal and frontostriatal dysfunctions, have been observed. These impairments were found in various domains, such as attention, memory, executive functions, language, motor and visuomotor functions, among others. In line with contemporary research, other neurocognitive domains have recently been explored in TS, bringing evidence of altered social reasoning, for instance. Therefore, the aims of this review are to give an overview of the neuropsychological dimensions of TS, to report how neuropsychological functions evolve from childhood to adulthood, and to explain how various confounding factors can affect TS patients’ performance in neuropsychological tasks. Finally, an important contribution of this review is to show how recent research has confirmed or changed our beliefs about neuropsychological functioning in TS. PMID:28820427

Spinal reflex alterations as a function of intensity and frequency of vibration applied to the feet of seated subjects.

PubMed

Martin, B J; Roll, J P; Gauthier, G M

1984-01-01

Sensorimotor system performance is known to be altered by vibration applied locally to tendons and muscles or to the whole body. The present study is an attempt to determine the influence of vibration amplitude, acceleration, and frequency on the excitability of the motoneurons as evaluated by the amplitude of electrically induced spinal reflex response in man. The results show that a vibration applied to the legs of a seated subject (S) decreased the reflex response. The effect is directly related to the vibration intensity. The reflex amplitude is minimal in the 10-30 Hz range. At constant acceleration, the depressive effect decreased beyond 20-30 Hz while, at constant displacement amplitude, the reflex inhibition was almost constant throughout the frequency range of 20-60 Hz. These observations suggest that the diminution of the reflex response is mainly related to the amplitude of the vibration, regardless of the frequency. The results are interpreted in light of current knowledge of the effect of locally applied vibration on muscle tendons. The marked inhibition observed in the 10-30 Hz range, even with moderate intensity, suggests that particular attention should be devoted to avoid vibration in that frequency range in vehicles in order to prevent alteration of the performance of sensorimotor systems.

Gemfibrozil disrupts lysophosphatidylcholine and bile acid homeostasis via PPARα and its relevance to hepatotoxicity.

PubMed

Liu, Aiming; Krausz, Kristopher W; Fang, Zhong-Ze; Brocker, Chad; Qu, Aijuan; Gonzalez, Frank J

2014-04-01

Gemfibrozil, a ligand of peroxisome proliferator-activated receptor α (PPARα), is one of the most widely prescribed anti-dyslipidemia fibrate drugs. Among the adverse reactions observed with gemfibrozil are alterations in liver function, cholestatic jaundice, and cholelithiasis. However, the mechanisms underlying these toxicities are poorly understood. In this study, wild-type and Ppara-null mice were dosed with a gemfibrozil-containing diet for 14 days. Ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry-based metabolomics and traditional approaches were used to assess the mechanism of gemfibrozil-induced hepatotoxicity. Unsupervised multivariate data analysis revealed four lysophosphatidylcholine components in wild-type mice that varied more dramatically than those in Ppara-null mice. Targeted metabolomics revealed taurocholic acid and tauro-α-muricholic acid/tauro-β-muricholic acid were significantly increased in wild-type mice, but not in Ppara-null mice. In addition to the above perturbations in metabolite homeostasis, phenotypic alterations in the liver were identified. Hepatic genes involved in metabolism and transportation of lysophosphatidylcholine and bile acid compounds were differentially regulated between wild-type and Ppara-null mice, in agreement with the observed downstream metabolic alterations. These data suggest that PPARα mediates gemfibrozil-induced hepatotoxicity in part by disrupting phospholipid and bile acid homeostasis.

Lifelong Impacts of Moderate Prenatal Alcohol Exposure on Neuroimmune Function

PubMed Central

Noor, Shahani; Milligan, Erin D.

2018-01-01

In utero alcohol exposure is emerging as a major risk factor for lifelong aberrant neuroimmune function. Fetal alcohol spectrum disorder encompasses a range of behavioral and physiological sequelae that may occur throughout life and includes cognitive developmental disabilities as well as disease susceptibility related to aberrant immune and neuroimmune actions. Emerging data from clinical studies and findings from animal models support that very low to moderate levels of fetal alcohol exposure may reprogram the developing central nervous system leading to altered neuroimmune and neuroglial signaling during adulthood. In this review, we will focus on the consequences of low to moderate prenatal alcohol exposure (PAE) on neuroimmune interactions during early life and at different stages of adulthood. Data discussed here will include recent studies suggesting that while abnormal immune function is generally minimal under basal conditions, following pathogenic stimuli or trauma, significant alterations in the neuroimmune axis occur. Evidence from published reports will be discussed with a focus on observations that PAE may bias later-life peripheral immune responses toward a proinflammatory phenotype. The propensity for proinflammatory responses to challenges in adulthood may ultimately shape neuron–glial-immune processes suspected to underlie various neuropathological outcomes including chronic pain and cognitive impairment.

Theory of mind network activity is altered in subjects with familial liability for schizophrenia

PubMed Central

Mohnke, Sebastian; Erk, Susanne; Schnell, Knut; Romanczuk-Seiferth, Nina; Schmierer, Phöbe; Romund, Lydia; Garbusow, Maria; Wackerhagen, Carolin; Ripke, Stephan; Grimm, Oliver; Haller, Leila; Witt, Stephanie H.; Degenhardt, Franziska; Tost, Heike; Heinz, Andreas; Meyer-Lindenberg, Andreas; Walter, Henrik

2016-01-01

As evidenced by a multitude of studies, abnormalities in Theory of Mind (ToM) and its neural processing might constitute an intermediate phenotype of schizophrenia. If so, neural alterations during ToM should be observable in unaffected relatives of patients as well, since they share a considerable amount of genetic risk. While behaviorally, impaired ToM function is confirmed meta-analytically in relatives, evidence on aberrant function of the neural ToM network is sparse and inconclusive. The present study therefore aimed to further explore the neural correlates of ToM in relatives of schizophrenia. About 297 controls and 63 unaffected first-degree relatives of patients with schizophrenia performed a ToM task during functional magnetic resonance imaging. Consistent with the literature relatives exhibited decreased activity of the medial prefrontal cortex. Additionally, increased recruitment of the right middle temporal gyrus and posterior cingulate cortex was found, which was related to subclinical paranoid symptoms in relatives. These results further support decreased medial prefrontal activation during ToM as an intermediate phenotype of genetic risk for schizophrenia. Enhanced recruitment of posterior ToM areas in relatives might indicate inefficiency mechanisms in the presence of genetic risk. PMID:26341902

Simulated hypogravity impairs the angiogenic response of endothelium by up-regulating apoptotic signals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morbidelli, Lucia; Monici, Monica; Marziliano, Nicola

Health hazards in astronauts are represented by cardiovascular problems and impaired bone healing. These disturbances are characterized by a common event, the loss of function by vascular endothelium, leading to impaired angiogenesis. We investigated whether the exposure of cultured endothelial cells to hypogravity condition could affect their behaviour in terms of functional activity, biochemical responses, morphology, and gene expression. Simulated hypogravity conditions for 72 h produced a reduction of cell number. Genomic analysis of endothelial cells exposed to hypogravity revealed that proapoptotic signals increased, while antiapoptotic and proliferation/survival genes were down-regulated by modelled low gravity. Activation of apoptosis was accompaniedmore » by morphological changes with mitochondrial disassembly and organelles/cytoplasmic NAD(P)H redistribution, as evidenced by autofluorescence analysis. In this condition cells were not able to respond to angiogenic stimuli in terms of migration and proliferation. Our study documents functional, morphological, and transcription alterations in vascular endothelium exposed to simulated low gravity conditions, thus providing insights on the occurrence of vascular tissue dysregulation in crewmen during prolonged space flights. Moreover, the alteration of vascular endothelium can intervene as a concause in other systemic effects, like bone remodelling, observed in weightlessness.« less

Association between cardiac autonomic function, oxidative stress and inflammatory response in impaired fasting glucose subjects: cross-sectional study.

PubMed

Thiyagarajan, Ramkumar; Subramanian, Senthil Kumar; Sampath, Nishanth; Madanmohan Trakroo; Pal, Pravati; Bobby, Zachariah; Paneerselvam, Sankar; Das, Ashok Kumar

2012-01-01

The worldwide burden of diabetes in 2030 is projected around 552 million. Diabetes leads to higher risk for cardiovascular diseases (CVD). Altered cardiac autonomic function (CAF) measured by heart rate variability (HRV) is observed in early stages of diabetes but the relationship between impaired fasting glucose (IFG) and HRV is still debatable. The aim of the study was to evaluate the association between CAF, oxidative stress, insulin resistance (IR), and inflammatory response in IFG subjects. Cross-sectional blinded study. Volunteers recruited from health awareness camps underwent CAF and biochemical tests. Based on fasting plasma glucose (FPG) participants (n = 123) were divided into two groups, normal fasting glucose (n = 76) and IFG (n = 47). The comparison of parameters between the groups was carried out using student t test and Mann-Whitney U test for parametric and non-parametric data respectively. The correlation between the parameters was analyzed by Spearman's rank correlation using SPSS 13.0. The resting cardiovagal modulation parameters, heart rate response to forced timed breathing, and orthostatic stress were reduced in IFG subjects. Fasting plasma lipid profile, coronary atherogenic lipid risk factors, IR, thiobarbituric acid reactive substance (TBARS), high sensitive C-reactive protein, and tumor necrosis factor alpha were increased and total antioxidant capacity (TAC) was decreased significantly in IFG group but no significant alteration was observed in high-density lipoprotein (HDL-c). Cardiovagal modulation parameters were negatively correlated with triglycerides, FPG, insulin, IR, TBARS, and inflammatory markers and positively with TAC. There is a continuous interplay between the altered CAF, hyperinsulinemia, IR, oxidative stress parameters, inflammatory response, and IFG in which one factor perpetuates another leading to the progression of disease.

Immune Dysregulation Following Short versus Long Duration Space Flight. Version 03

NASA Technical Reports Server (NTRS)

Crucian, Brian E.; Stowe, Raymond P.; Pierson, Duane L.; Sams, Clarence F.

2007-01-01

Immune system dysregulation has been demonstrated to occur during spaceflight and has the potential to cause serious health risks to crewmembers participating in exploration-class missions. A comprehensive immune assessment was recently performed on 13 short duration Space Shuttle crewmembers and 8 long duration International Space Station (ISS) crewmembers. Statistically significant post-flight phenotype alterations (as compared to pre-flight baseline) for the Shuttle crewmembers included: granulocytosis, increased percentage of B cells, reduced percentage of NK cells, elevated CD4/CD8 ratio, elevated levels of memory CD4+ T cells, and a CD8+ T cell shift to a less differentiated state. For the Shuttle crewmembers, T cell function was surprisingly elevated post-flight, among both the CD4+ and CD8+ subsets. This is likely an acute stress response in less-deconditioned crewmembers. The percentage of CD4+/IL-2+, CD4+/IFNg+ and CD8+/IFNg+ T cells were all decreased at landing. Culture secreted IFNg production was significantly decreased at landing, whereas production of Th2 cytokines was largely unchanged. It was found that the IFNg:IL-10 ratio was obviously declined in the Shuttle crewmembers immediately post-flight. A similar pattern of alterations were observed for the long duration ISS crewmembers. In contrast to Shuttle crewmembers, the ISS crewmembers demonstrated a dramatic reduction in T cell function immediately post-flight. This may be related to the effect of acute landing stress in conjunction with prolonged deconditioning associated with extended flight. The reduction in IFNg:IL-10 ratio (Th2 shift) was also observed post-flight in the ISS crewmembers to a much higher degree. These data indicate consistent peripheral phenotype changes and altered cytokine production profiles occur following space travel of both short and long duration.

Antibiotic-induced dysbiosis alters host-bacterial interactions and leads to colonic sensory and motor changes in mice

PubMed Central

Aguilera, M; Cerdà-Cuéllar, M; Martínez, V

2015-01-01

Alterations in the composition of the commensal microbiota (dysbiosis) seem to be a pathogenic component of functional gastrointestinal disorders, mainly irritable bowel syndrome (IBS), and might participate in the secretomotor and sensory alterations observed in these patients.We determined if a state antibiotics-induced intestinal dysbiosis is able to modify colonic pain-related and motor responses and characterized the neuro-immune mechanisms implicated in mice. A 2-week antibiotics treatment induced a colonic dysbiosis (increments in Bacteroides spp, Clostridium coccoides and Lactobacillus spp and reduction in Bifidobacterium spp). Bacterial adherence was not affected. Dysbiosis was associated with increased levels of secretory-IgA, up-regulation of the antimicrobial lectin RegIIIγ, and toll-like receptors (TLR) 4 and 7 and down-regulation of the antimicrobial-peptide Resistin-Like Molecule-β and TLR5. Dysbiotic mice showed less goblet cells, without changes in the thickness of the mucus layer. Neither macroscopical nor microscopical signs of inflammation were observed. In dysbiotic mice, expression of the cannabinoid receptor 2 was up-regulated, while the cannabinoid 1 and the mu-opioid receptors were down-regulated. In antibiotic-treated mice, visceral pain-related responses elicited by intraperitoneal acetic acid or intracolonic capsaicin were significantly attenuated. Colonic contractility was enhanced during dysbiosis. Intestinal dysbiosis induce changes in the innate intestinal immune system and modulate the expression of pain-related sensory systems, an effect associated with a reduction in visceral pain-related responses. Commensal microbiota modulates gut neuro-immune sensory systems, leading to functional changes, at least as it relates to viscerosensitivity. Similar mechanisms might explain the beneficial effects of antibiotics or certain probiotics in the treatment of IBS. PMID:25531553

Cortical thickness and VBM in young women at risk for familial depression and their depressed mothers with positive family history.

PubMed

Ozalay, Ozgun; Aksoy, Burcu; Tunay, Sebnem; Simsek, Fatma; Chandhoki, Swati; Kitis, Omer; Eker, Cagdas; Gonul, Ali Saffet

2016-06-30

It has been demonstrated that compared to low-risk subjects, high-risk subjects for depression have structural and functional alterations in their brain scans even before the disease onset. However, it is not known if these alterations are related to vulnerability to depression or epiphenomena. One way to resolve this ambiguity is to detect the structural alterations in the high-risk subjects and determine if the same alterations are present in the probands. In this study, we recruited 24 women with the diagnosis of Major Depressive Disorder (MDD) with recurrent episodes and their healthy daughters (the high-risk for familial depression group; HRFD). We compared structural brain scans of the patients and HRFG group with those of 24 age-matched healthy mothers and their healthy daughters at similar ages to the HRFD group; respectively. Both cortical gray matter (GM) volume and thickness analyses revealed that HRFD daughters and their MDD mothers had similar GM differences in two regions: the right temporoparietal region and the dorsomedial prefrontal cortex. These results suggested that the observed alterations may be related to trait clinical and neurophysiological characteristics of MDD and may present before the onset of illness. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Relationship of executive functioning deficits to N-acetyl aspartate (NAA) and gamma-aminobutyric acid (GABA) in youth with bipolar disorder.

PubMed

Huber, Rebekah S; Kondo, Douglas G; Shi, Xian-Feng; Prescot, Andrew P; Clark, Elaine; Renshaw, Perry F; Yurgelun-Todd, Deborah A

2018-01-01

Although cognitive deficits in bipolar disorder (BD) have been repeatedly observed, our understanding of these impairments at a mechanistic level remains limited. Few studies that investigated cognitive impairments in bipolar illness have examined the association with brain biochemistry. This pilot study utilized proton magnetic resonance spectroscopy ( 1 H-MRS) to evaluate the relationship between neurocognitive performance and brain metabolites in youth with BD. Thirty participants, twenty depressed BD participants and ten healthy comparison participants, ages 13-21, completed mood and executive function measures. 1 H-MRS data were also acquired from the anterior cingulate cortex (ACC) using two-dimensional (2D) J-resolved 1 H-MRS sequence. Proton metabolites including N-acetyl aspartate (NAA) and gamma-aminobutyric acid (GABA) were quantified for both groups. Participants with BD performed significantly lower on executive functioning measures than comparison participants. There were significant positive correlations between Wisconsin Card Sorting Test (WCST) performance and NAA (p < .001) and GABA (p < .01) in the ACC in bipolar youth, such that as WCST performance increased, both NAA and GABA levels increased. Small sample size and lack of control for medications. These findings build on previous observations of biochemical alterations associated with BD and indicate that executive functioning deficits in bipolar youth are correlated with NAA and GABA. These results suggest that cognitive deficits occur early in the course of illness and may reflect risk factors associated with altered neurochemistry. Further investigation of the relationship between brain metabolites and cognition in BD may lead to important information for developing novel, targeted interventions. Copyright © 2017 Elsevier B.V. All rights reserved.

Characteristics of Faecal Microbiota in Paediatric Crohn's Disease and Their Dynamic Changes During Infliximab Therapy.

PubMed

Wang, Yizhong; Gao, Xuefeng; Ghozlane, Amine; Hu, Hui; Li, Xiaolu; Xiao, Yongmei; Li, Dan; Yu, Guangjun; Zhang, Ting

2018-02-28

Crohn's disease [CD] is known to be associated with gut microbial dysbiosis. Infliximab [IFX] is increasingly used to treat paediatric CD; however, it is not clear how the gut microbiota is modified during IFX treatment. The aim of this study was to characterise the faecal microbiota community composition in paediatric CD patients and to assess its dynamic changes during IFX therapy. A 16S rRNA sequencing approach was applied to determine the compositions of microbial communities in faecal samples. The composition and function of the faecal microbiota were compared between CD patients and healthy controls. Characteristics of faecal microbiome composition in paediatric CD patients before IFX treatment were represented by a lower biodiversity, a gain in Enterococcus, and a significant loss in multiple short-chain fatty acid [SCFA]-producing bacteria, including Anaerostipes, Blautia, Coprococcus, Faecalibacterium, Lachnospira, Odoribacter, Roseburia, Ruminococcus, and Sutterella. Additionally, alterations were observed in metabolic functions of the gut microbial community in CD. IFX treatment increased the biodiversity of gut microbiota and shifted its composition as well as its functional capabilities in the paediatric CD patients toward a healthy status. However, multiple SCFA-producing taxa were not significantly expanded. The sustained response of paediatric CD patients to IFX was associated with abundance of SCFA-producing bacteria. A lower biodiversity with alterations in the composition and function of faecal microbial community, characterising gut microbial dysbiosis, was observed in Chinese paediatric CD patients. IFX diminished the CD-associated gut microbial dysbiosis but was deficient in increasing certain SCFA-producing taxa. Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

Alterations in regional shape on ipsilateral and contralateral cortex contrast in children with unilateral cerebral palsy and are predictive of multiple outcomes.

PubMed

Pagnozzi, Alex M; Dowson, Nicholas; Fiori, Simona; Doecke, James; Bradley, Andrew P; Boyd, Roslyn N; Rose, Stephen

2016-10-01

Congenital brain lesions result in a wide range of cerebral tissue alterations observed in children with cerebral palsy (CP) that are associated with a range of functional impairments. The relationship between injury severity and functional outcomes, however, remains poorly understood. This research investigates the differences in cortical shape between children with congenital brain lesions and typically developing children (TDC) and investigates the correlations between cortical shape and functional outcome in a large cohort of patients diagnosed with unilateral CP. Using 139 structural magnetic resonance images, including 95 patients with clinically diagnosed CP and 44 TDC, cortical segmentations were obtained using a modified expectation maximization algorithm. Three shape characteristics (cortical thickness, curvature, and sulcal depth) were computed within a number of cortical regions. Significant differences in these shape measures compared to the TDC were observed on both the injured hemisphere of children with CP (P < 0.004), as well as on the apparently uninjured hemisphere, illustrating potential compensatory mechanisms in these children. Furthermore, these shape measures were significantly correlated with several functional outcomes, including motor, cognition, vision, and communication (P < 0.012), with three out of these four models performing well on test set validation. This study highlights that cortical neuroplastic effects may be quantified using MR imaging, allowing morphological changes to be studied longitudinally, including any influence of treatment. Ultimately, such approaches could be used for the long term prediction of outcomes and the tailoring of treatment to individuals. Hum Brain Mapp 37:3588-3603, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Cardiovascular effects of 3 months of football training in overweight children examined by comprehensive echocardiography: a pilot study.

PubMed

Hansen, Peter Riis; Andersen, Lars Juel; Rebelo, António Natal; Brito, Joao; Hornstrup, Therese; Schmidt, Jakob Friis; Jackman, Sarah R; Mota, Jorge; Rêgo, Carla; Oliveira, Jose; Seabra, André; Krustrup, Peter

2013-01-01

We examined effects of a 3-month football training programme in overweight children using comprehensive echocardiography and peripheral arterial tonometry. Twenty preadolescent overweight children (17 boys, 3 girls aged 8-12 yrs; body mass index [BMI] ≥ 85(th) percentile) participated in a structured 3-month football training programme, consisting of 4 weekly 60-90 min sessions with mean heart rate (HR) > 80% of HRmax (football group, FG). A parallel control group (CG) included 11 children (7 boys, 4 girls) of equivalent age from an obesity clinic. After 3 months, systolic blood pressure was unchanged in FG, but had increased in CG (112 [s 6] vs. 122 [10] mmHg, P = 0.02). FG demonstrated increased left ventricular (LV) posterior wall diameter (0.60 [0.07] vs. 0.68 [0.10] cm, P < 0.001) and an improved right ventricular systolic function determined by tricuspid annular plane systolic excursion (TAPSE, 2.01 [0.29] vs. 2.27 [0.28] cm, P = 0.003). Measures of LV systolic function showed only discrete alterations and two-dimensional (2D) global strain was not changed. After 3 months, global isovolumetric relaxation time (IVRTglobal) had increased in FG (64.0 [7.5] vs. 73.9 [9.4] ms, P < 0.001) while other examined LV diastolic function variables were not altered. No echocardiographic changes were observed in CG. Between-group differences in pre-post delta values were observed for systolic blood pressure, TAPSE, and IVRTglobal (P = 0.02-0.03). We conclude that short-term football training may have positive structural and functional effects on the cardiovascular system in overweight preadolescent children.

High definition-transcranial direct current stimulation changes older adults' subjective sleep and corresponding resting-state functional connectivity.

PubMed

Sheng, Jing; Xie, Chao; Fan, Dong-Qiong; Lei, Xu; Yu, Jing

2018-07-01

With advanced age, older adults show functional deterioration in sleep. Transcranial direct current stimulation (tDCS), a noninvasive brain stimulation, modulates individuals' behavioral performance in various cognitive domains. However, the modulation effect and neural mechanisms of tDCS on sleep, especially for the elderly population are not clear. Here, we aimed to investigate whether high-definition transcranial direct current stimulation (HD-tDCS) could modulate community-dwelling older adults' subjective sleep and whether these potential improvements are associated with the large-scale brain activity alterations recorded by functional magnetic resonance imaging. Thirty-one older adults were randomly allocated to the HD-tDCS group and the control group. HD-tDCS was applied for 25 min at 1.5 mA per day for two weeks. The anode electrode was placed over the left dorsolateral prefrontal cortex, surrounded by 4 cathodes at 7 cm radius. All participants completed sleep neuropsychological assessments and fMRI scans individually before and after intervention. Behaviorally, we observed a HD-tDCS-induced enhancement of older adults' sleep duration. On the aspect of the corresponding neural alterations, we observed that HD-tDCS decreased the functional connectivity between the default mode network (DMN) and subcortical network. More importantly, the decoupling connectivity of the DMN-subcortical network was correlated with the improvements of subjective sleep in the HD-tDCS group. Our findings add novel behavioral and neural evidences about tDCS-induced sleep improvement in community-dwelling older adults. With further development, tDCS may be used as an alternative treatment for sleep disorders and alleviate the dysfunction of brain networks induced by aging. Copyright © 2018 Elsevier B.V. All rights reserved.

Neurocognitive enhancement in older adults: comparison of three cognitive training tasks to test a hypothesis of training transfer in brain connectivity.

PubMed

Strenziok, Maren; Parasuraman, Raja; Clarke, Ellen; Cisler, Dean S; Thompson, James C; Greenwood, Pamela M

2014-01-15

The ultimate goal of cognitive enhancement as an intervention for age-related cognitive decline is transfer to everyday cognitive functioning. Development of training methods that transfer broadly to untrained cognitive tasks (far transfer) requires understanding of the neural bases of training and far transfer effects. We used cognitive training to test the hypothesis that far transfer is associated with altered attentional control demands mediated by the dorsal attention network and trained sensory cortex. In an exploratory study, we randomly assigned 42 healthy older adults to six weeks of training on Brain Fitness (BF-auditory perception), Space Fortress (SF-visuomotor/working memory), or Rise of Nations (RON-strategic reasoning). Before and after training, cognitive performance, diffusion-derived white matter integrity, and functional connectivity of the superior parietal cortex (SPC) were assessed. We found the strongest effects from BF training, which transferred to everyday problem solving and reasoning and selectively changed integrity of occipito-temporal white matter associated with improvement on untrained everyday problem solving. These results show that cognitive gain from auditory perception training depends on heightened white matter integrity in the ventral attention network. In BF and SF (which also transferred positively), a decrease in functional connectivity between SPC and inferior temporal lobe (ITL) was observed compared to RON-which did not transfer to untrained cognitive function. These findings highlight the importance for cognitive training of top-down control of sensory processing by the dorsal attention network. Altered brain connectivity - observed in the two training tasks that showed far transfer effects - may be a marker for training success. © 2013 Elsevier Inc. All rights reserved.

Quadriceps Strength Asymmetry Following ACL Reconstruction Alters Knee Joint Biomechanics and Functional Performance at Time of Return to Activity

PubMed Central

Palmieri-Smith, RM; Lepley, LK

2016-01-01

Background Quadriceps strength deficits are observed clinically following anterior cruciate injury and reconstruction and are often not overcome despite rehabilitation. Given that quadriceps strength may be important for achieving symmetrical joint biomechanics and promoting long-term joint health, determining the magnitude of strength deficits that lead to altered mechanics is critical. Purpose To determine if the magnitude of quadriceps strength asymmetry alters knee and hip biomechanical symmetry, as well as functional performance and self-reported function. Study Design Cross-Sectional study. Methods Seventy-three patients were tested at the time they were cleared for return to activity following ACL reconstruction. Quadriceps strength and activation, scores on the International Knee Documentation Committee form, the hop for distance test, and sagittal plane lower extremity biomechanics were recorded while patients completed a single-legged hop. Results Patients with high and moderate quadriceps strength symmetry had larger central activation ratios as well as greater limb symmetry indices on the hop for distance compared to patients with low quadriceps strength symmetry (P<0.05). Similarly, knee flexion angle and external moment symmetry was higher in the patients with high and moderate quadriceps symmetry compared to those with low symmetry (P<0.05). Quadriceps strength was found to be associated with sagittal plane knee angle and moment symmetry (P<0.05). Conclusion Patients with low quadriceps strength displayed greater movement asymmetries at the knee in the sagittal plane. Quadriceps strength was related to movement asymmetries and functional performance. Rehabilitation following ACL reconstruction needs to focus on maximizing quadriceps strength, which likely will lead to more symmetrical knee biomechanics. PMID:25883169

RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory.

PubMed

Sinkevicius, Kerstin W; Morrison, Thomas R; Kulkarni, Praveen; Caffrey Cagliostro, Martha K; Iriah, Sade; Malmberg, Samantha; Sabrick, Julia; Honeycutt, Jennifer A; Askew, Kim L; Trivedi, Malav; Ferris, Craig F

2018-06-27

RNASET2 deficiency in humans is associated with infant cystic leukoencephalopathy, which causes psychomotor impairment, spasticity and epilepsy. A zebrafish mutant model suggests that loss of RNASET2 function leads to neurodegeneration due to the accumulation of non-degraded RNA in the lysosomes. The goal of this study was to characterize the first rodent model of RNASET2 deficiency. The brains of 3- and 12-month-old RNaseT2 knockout rats were studied using multiple magnetic resonance imaging modalities and behavioral tests. While T1- and T2-weighted images of RNaseT2 knockout rats exhibited no evidence of cystic lesions, the prefrontal cortex and hippocampal complex were enlarged in knockout animals. Diffusion-weighted imaging showed altered anisotropy and putative gray matter changes in the hippocampal complex of the RNaseT2 knockout rats. Immunohistochemistry for glial fibrillary acidic protein (GFAP) showed the presence of hippocampal neuroinflammation. Decreased levels of lysosome-associated membrane protein 2 (LAMP2) and elevated acid phosphatase and β-N-acetylglucosaminidase (NAG) activities indicated that the RNASET2 knockout rats likely had altered lysosomal function and potential defects in autophagy. Object recognition tests confirmed that RNaseT2 knockout rats exhibited memory deficits. However, the Barnes maze, and balance beam and rotarod tests indicated there were no differences in spatial memory or motor impairments, respectively. Overall, patients with RNASET2 deficiency exhibited a more severe neurodegeneration phenotype than was observed in the RNaseT2 knockout rats. However, the vulnerability of the knockout rat hippocampus as evidenced by neuroinflammation, altered lysosomal function and cognitive defects indicates that this is still a useful in vivo model to study RNASET2 function. © 2018. Published by The Company of Biologists Ltd.

Quadriceps Strength Asymmetry After Anterior Cruciate Ligament Reconstruction Alters Knee Joint Biomechanics and Functional Performance at Time of Return to Activity.

PubMed

Palmieri-Smith, Riann M; Lepley, Lindsey K

2015-07-01

Quadriceps strength deficits are observed clinically after anterior cruciate ligament (ACL) injury and reconstruction and are often not overcome despite rehabilitation. Given that quadriceps strength may be important for achieving symmetrical joint biomechanics and promoting long-term joint health, determining the magnitude of strength deficits that lead to altered mechanics is critical. To determine if the magnitude of quadriceps strength asymmetry alters knee and hip biomechanical symmetry as well as functional performance and self-reported function. Cross-sectional study; Level of evidence, 3. A total of 73 patients were tested at the time they were cleared for return to activity after ACL reconstruction. Quadriceps strength and activation, scores on the International Knee Documentation Committee form, the hop for distance test, and sagittal plane lower extremity biomechanics were recorded while patients completed a single-legged hop. Patients with high and moderate quadriceps strength symmetry had larger central activation ratios as well as greater limb symmetry indices on the hop for distance compared with patients with low quadriceps strength symmetry (P < .05). Similarly, knee flexion angle and external moment symmetry were higher in the patients with high and moderate quadriceps symmetry compared with those with low symmetry (P < .05). Quadriceps strength was found to be associated with sagittal plane knee angle and moment symmetry (P < .05). Patients with low quadriceps strength displayed greater movement asymmetries at the knee in the sagittal plane. Quadriceps strength was related to movement asymmetries and functional performance. Rehabilitation after ACL reconstruction needs to focus on maximizing quadriceps strength, which likely will lead to more symmetrical knee biomechanics. © 2015 The Author(s).

Adolescents with Classical Polycystic Ovary Syndrome Have Alterations in the Surrogate Markers of Cardiovascular Disease but Not in the Endothelial Function. The Possible Benefits of Metformin.

PubMed

Fruzzetti, Franca; Ghiadoni, Lorenzo; Virdis, Agostino; De Negri, Ferdinando; Perini, Daria; Bucci, Fiorella; Giannarelli, Chiara; Gadducci, Angiolo; Taddei, Stefano

2016-10-01

To study whether adolescents with the classical form of polycystic ovary syndrome (PCOS) have alterations in metabolic and vascular structure and function. The effect of metformin was evaluated. Controlled study. University outpatient clinic. Eighteen nonobese adolescents with PCOS were enrolled. Seventeen healthy age-matched adolescents were recruited as control subjects. The metabolic profile and the endothelial structure and function were evaluated. Hormonal and lipid profile, blood pressure (BP) measurement, fasting glucose and insulin levels, C-reactive protein (CRP), homocysteine, tissue-type plasminogen activator, plasminogen activator inhibitor-1 (PAI-1), and plasmin-antiplasmin complexes (PAP) were measured. Flow mediated dilation (FMD), central pulse wave velocity (PWV), radial artery pulse wave, and common carotid intima-media thickness (IMT) were also assessed. Girls with PCOS were also studied 6 months after treatment with metformin (850 mg twice per day). Adolescents with PCOS were insulin resistant and/or hyperinsulinemic and they had higher BP values and levels of CRP and PAI-1 than the control subjects. The levels of tissue-type plasminogen activator and PAP were similar in both groups. FMD, PWV, and IMT were also similar. Metformin significantly (P < .05) reduced insulin, BP, CRP, and PAI-1 levels. The PAP levels significantly (P < .05) increased. Radial artery pulse wave was significantly reduced after metformin treatment. No modifications in FMD, PWV, and IMT were observed. Adolescents with classical PCOS have alterations in some surrogate markers of cardiovascular risk and they are ameliorated by metformin. No deterioration of vascular structure and function has been detected, probably because of the short duration of exposure to the disease. Copyright © 2016 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

The overloaded right heart and ventricular interdependence.

PubMed

Naeije, Robert; Badagliacca, Roberto

2017-10-01

The right and the left ventricle are interdependent as both structures are nested within the pericardium, have the septum in common and are encircled with common myocardial fibres. Therefore, right ventricular volume or pressure overloading affects left ventricular function, and this in turn may affect the right ventricle. In normal subjects at rest, right ventricular function has negligible interaction with left ventricular function. However, the right ventricle contributes significantly to the normal cardiac output response to exercise. In patients with right ventricular volume overload without pulmonary hypertension, left ventricular diastolic compliance is decreased and ejection fraction depressed but without intrinsic alteration in contractility. In patients with right ventricular pressure overload, left ventricular compliance is decreased with initial preservation of left ventricular ejection fraction, but with eventual left ventricular atrophic remodelling and altered systolic function. Breathing affects ventricular interdependence, in healthy subjects during exercise and in patients with lung diseases and altered respiratory system mechanics. Inspiration increases right ventricular volumes and decreases left ventricular volumes. Expiration decreases both right and left ventricular volumes. The presence of an intact pericardium enhances ventricular diastolic interdependence but has negligible effect on ventricular systolic interdependence. On the other hand, systolic interdependence is enhanced by a stiff right ventricular free wall, and decreased by a stiff septum. Recent imaging studies have shown that both diastolic and systolic ventricular interactions are negatively affected by right ventricular regional inhomogeneity and prolongation of contraction, which occur along with an increase in pulmonary artery pressure. The clinical relevance of these observations is being explored. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Neuroimmune regulation of neurophysiology in the cerebellum.

PubMed

Gruol, Donna L

2013-06-01

Recent studies have established the existence of an innate immune system in the central nervous system (CNS) and implicated a critical role for this system in both normal and pathological processes. Astrocytes and microglia, normal components of the CNS, are the primary cell types that comprise the innate immune system of the CNS. Basic to their role during normal and adverse conditions is the production of neuroimmune factors such as cytokines and chemokines, which are signaling molecules that initiate or coordinate downstream cellular actions. During adverse conditions, cytokines and chemokines function in defensive and repair. However, if expression of these factors becomes dysregulated, abnormal CNS function can result. Both neurons and glial cells of the CNS express receptors for cytokines and chemokines, but the biological consequence of receptor activation has yet to be fully resolved. Our studies show that neuroadaptive changes are produced in primary cultures of rat cerebellar cells chronically treated with the cytokine interleukin-6 (IL-6) and in the cerebellum of transgenic mice that chronically express elevated levels of IL-6 in the CNS. In the cerebellum in culture and in vivo, the neuroadaptive changes included alterations in the level of expression of proteins involved in gene expression, signal transduction, and synaptic transmission. Associated with these changes were alterations in neuronal function. A comparison of results from the cultured cerebellar cells and cerebellum of the transgenic mice indicated that the effects of IL-6 can vary across neuronal types. However, alterations in mechanisms involved in Ca(2+) homeostasis were observed in all cell types studied. These results indicate that modifications in cerebellar function are likely to occur in disorders associated with elevated levels of IL-6 in the cerebellum.

Experimental non-alcoholic fatty liver disease results in decreased hepatic uptake transporter expression and function in rats

PubMed Central

Fisher, Craig D.; Lickteig, Andrew J.; Augustine, Lisa M.; Oude Elferink, Ronald P.J.; Besselsen, David G.; Erickson, Robert P.; Cherrington, Nathan J.

2009-01-01

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of diagnoses ranging from simple fatty liver (SFL), to non-alcoholic steatohepatitis (NASH). This study aimed to determine the effect of moderate and severe NAFLD on hepatic transporter expression and function in vivo. Rats were fed a high-fat diet (SFL model) or a methionine-choline-deficient diet (NASH model) for eight weeks. Hepatic uptake transporter function was determined by bromosulfophthalein (BSP) disposition. Transporter expression was determined by branched DNA signal amplification assay and western blotting; inflammation was identified by immunostaining of liver slices for interleukin 1 beta (IL-1β). MC- rats showed significant retention of BSP in the plasma when compared to control rats. Hepatic NTCP, OATP1a1, 1a4, 1b2 and 2b1; and OAT 2 and 3 mRNA levels were significantly decreased in high-fat and MC- diet rats when compared to control. Protein expression of OATP1a1 was significantly decreased in high-fat animals, while OATP1a1 and OATP1b2 expression was significantly lower in MC- rats when compared to control. Liver tissue from high-fat and MC- rats stained positive for IL-1β, a pro-inflammatory cytokine known to decrease expression of NTCP, OATP and OAT transporters, suggesting a plausible mechanism for the observed transporter alterations. These data suggest that different stages of NAFLD result in altered hepatic uptake transporter expression that can lead to a functional impairment of xenobiotic uptake from the blood. Furthermore, NAFLD may alter the plasma retention time of clinically relevant drugs that are reliant on these transporters and may increase the potential drug toxicity. PMID:19358839