IL-25 or IL-17E protects against high-fat diet-induced hepatic steatosis in mice dependent upon IL-13 activation of STAT6

USDA-ARS?s Scientific Manuscript database

IL-25 is a member of IL-17 cytokine family and has immune-modulating activities. The role of IL-25 in maintaining lipid metabolic homeostasis remains unknown. Here, we investigated the effects of exogenous IL-25 or deficiency of IL-25 on lipid accumulation in the liver. Mice were injected with IL-25...

Neural Activity during Encoding Predicts False Memories Created by Misinformation

ERIC Educational Resources Information Center

Okado, Yoko; Stark, Craig E. L.

2005-01-01

False memories are often demonstrated using the misinformation paradigm, in which a person's recollection of a witnessed event is altered after exposure to misinformation about the event. The neural basis of this phenomenon, however, remains unknown. The authors used fMRI to investigate encoding processes during the viewing of an event and…

Active Music Classes in Infancy Enhance Musical, Communicative and Social Development

ERIC Educational Resources Information Center

Gerry, David; Unrau, Andrea; Trainor, Laurel J.

2012-01-01

Previous studies suggest that musical training in children can positively affect various aspects of development. However, it remains unknown as to how early in development musical experience can have an effect, the nature of any such effects, and whether different types of music experience affect development differently. We found that random…

Student Engagement in Long-Term Collaborative EFL Storytelling Activities: An Analysis of Learners with English Proficiency Differences

ERIC Educational Resources Information Center

Huang, Yun-Yin; Liu, Chen-Chung; Wang, Yu; Tsai, Chin-Chung; Lin, Hung-Ming

2017-01-01

English proficiency difference among students is a challenging pedagogical issue in EFL classrooms worldwide. Collaborative digital storytelling has been adopted in language learning settings to increase motivation and engagement, especially for young learners. However, it remains unknown whether students of different proficiency levels can…

Inhibition of snowshoe hare succinate dehydrogenase activity as a mechanism of deterrence for papyriferic acid in birch

Treesearch

Jennifer Sorensen Forbey; Xinzhu Pu; Dong Xu; Knut Kielland; John Bryant

2011-01-01

The plant secondary metabolite papyriferic acid (PA) deters browsing by snowshoe hares (Lepus americanus) on the juvenile developmental stage of the Alaska paper birch (Betula neoalaskana). However, the physiological mechanism that reduces browsing remains unknown. We used pharmacological assays and molecular modeling to test the...

Apo-10'-lycopenoic acid inhibits cancer cell migration and angiogenesis and induces peroxisome proliferator-activated receptor gamma

USDA-ARS?s Scientific Manuscript database

Scope: We have previously shown that apo-10'-lycopenoic acid (ALA), a derivative of lycopene through cleavage by carotene-9',10'-oxygenase, inhibits tumor progression and metastasis in both liver and lung cancer animal models. The underlying mechanism remains unknown. We hypothesized that ALA inhibi...

Vinpocetine Attenuates the Osteoblastic Differentiation of Vascular Smooth Muscle Cells

PubMed Central

Chen, Xiu-Juan; Wang, Na; Yi, Peng-Fei; Song, Min; Zhang, Bo; Wang, Yu-Zhong; Liang, Qiu-Hua

2016-01-01

Vascular calcification is an active process of osteoblastic differentiation of vascular smooth muscle cells; however, its definite mechanism remains unknown. Vinpocetine, a derivative of the alkaloid vincamine, has been demonstrated to inhibit the high glucose-induced proliferation of vascular smooth muscle cells; however, it remains unknown whether vinpocetine can affect the osteoblastic differentiation of vascular smooth muscle cells. We hereby investigated the effect of vinpocetine on vascular calcification using a beta-glycerophosphate-induced cell model. Our results showed that vinpocetine significantly reduced the osteoblast-like phenotypes of vascular smooth muscle cells including ALP activity, osteocalcin, collagen type I, Runx2 and BMP-2 expression as well as the formation of mineralized nodule. Vinpocetine, binding to translocation protein, induced phosphorylation of extracellular signal-related kinase and Akt and thus inhibited the translocation of nuclear factor-kappa B into the nucleus. Silencing of translocator protein significantly attenuated the inhibitory effect of vinpocetine on osteoblastic differentiation of vascular smooth muscle cells. Taken together, vinpocetine may be a promising candidate for the clinical therapy of vascular calcification. PMID:27589055

Serine phosphorylation by SYK is critical for nuclear localization and transcription factor function of Ikaros

PubMed Central

Uckun, Fatih M.; Ma, Hong; Zhang, Jian; Ozer, Zahide; Dovat, Sinisa; Mao, Cheney; Ishkhanian, Rita; Goodman, Patricia; Qazi, Sanjive

2012-01-01

Ikaros is a zinc finger-containing DNA-binding protein that plays a pivotal role in immune homeostasis through transcriptional regulation of the earliest stages of lymphocyte ontogeny and differentiation. Functional deficiency of Ikaros has been implicated in the pathogenesis of acute lymphoblastic leukemia, the most common form of childhood cancer. Therefore, a stringent regulation of Ikaros activity is considered of paramount importance, but the operative molecular mechanisms responsible for its regulation remain largely unknown. Here we provide multifaceted genetic and biochemical evidence for a previously unknown function of spleen tyrosine kinase (SYK) as a partner and posttranslational regulator of Ikaros. We demonstrate that SYK phoshorylates Ikaros at unique C-terminal serine phosphorylation sites S358 and S361, thereby augmenting its nuclear localization and sequence-specific DNA binding activity. Mechanistically, we establish that SYK-induced Ikaros activation is essential for its nuclear localization and optimal transcription factor function. PMID:23071339

Predictive Movements and Human Reinforcement Learning of Sequential Action

ERIC Educational Resources Information Center

de Kleijn, Roy; Kachergis, George; Hommel, Bernhard

2018-01-01

Sequential action makes up the bulk of human daily activity, and yet much remains unknown about how people learn such actions. In one motor learning paradigm, the serial reaction time (SRT) task, people are taught a consistent sequence of button presses by cueing them with the next target response. However, the SRT task only records keypress…

Stimulation of Hippocampal Adenylyl Cyclase Activity Dissociates Memory Consolidation Processes for Response and Place Learning

ERIC Educational Resources Information Center

Martel, Guillaume; Millard, Annabelle; Jaffard, Robert; Guillou, Jean-Louis

2006-01-01

Procedural and declarative memory systems are postulated to interact in either a synergistic or a competitive manner, and memory consolidation appears to be a highly critical stage for this process. However, the precise cellular mechanisms subserving these interactions remain unknown. To investigate this issue, 24-h retention performances were…

Understanding Participation in E-Learning in Organizations: A Large-Scale Empirical Study of Employees

ERIC Educational Resources Information Center

Garavan, Thomas N.; Carbery, Ronan; O'Malley, Grace; O'Donnell, David

2010-01-01

Much remains unknown in the increasingly important field of e-learning in organizations. Drawing on a large-scale survey of employees (N = 557) who had opportunities to participate in voluntary e-learning activities, the factors influencing participation in e-learning are explored in this empirical paper. It is hypothesized that key variables…

Role of Bactericidal Peptidoglycan Recognition Proteins in Regulating Gut Microbiota and Obesity

DTIC Science & Technology

2018-03-01

s) Pglyrps have an established role in innate immunity, bactericidal activity , and inflammatory diseases. Our new data suggest that in addition...genetic cause remains unknown. We report that deletion of the innate immunity antibacterial gene Nod2 abolishes this resistance, as Nod2−/− BALB/c mice...stimula- tion of Nod2 results in the activation of NF-κB and MAP kinase-signaling cascades and production of inflam- matory molecules and anti-microbial

Structure-activity relationship of karrikin germination stimulants.

PubMed

Flematti, Gavin R; Scaffidi, Adrian; Goddard-Borger, Ethan D; Heath, Charles H; Nelson, David C; Commander, Lucy E; Stick, Robert V; Dixon, Kingsley W; Smith, Steven M; Ghisalberti, Emilio L

2010-08-11

Karrikins (2H-furo[2,3-c]pyran-2-ones) are potent smoke-derived germination promoters for a diverse range of plant species but, to date, their mode of action remains unknown. This paper reports the structure-activity relationship of numerous karrikin analogues to increase understanding of the key structural features of the molecule that are required for biological activity. The results demonstrate that modification at the C5 position is preferred over modification at the C3, C4, or C7 positions for retaining the highest bioactivity.

Memory Trace Reactivation and Behavioral Response during Retrieval Are Differentially Modulated by Amygdalar Glutamate Receptors Activity: Interaction between Amygdala and Insular Cortex

ERIC Educational Resources Information Center

Osorio-Gómez, Daniel; Guzmán-Ramos, Kioko; Bermúdez-Rattoni, Federico

2017-01-01

The insular cortex (IC) is required for conditioned taste aversion (CTA) retrieval. However, it remains unknown which cortical neurotransmitters levels are modified upon CTA retrieval. Using in vivo microdialysis, we observed that there were clear elevations in extracellular glutamate, norepinephrine, and dopamine in and around the center of the…

The Effect of Highly Scaffolded versus General Instruction on Students' Exploratory Behavior and Arousal

ERIC Educational Resources Information Center

Blikstein, Paulo; Gomes, July Silveira; Akiba, Henrique Teruo; Schneider, Bertrand

2017-01-01

Technology is changing the way students interact with knowledge, and open-ended activities are one of the main types of tasks that students engage with in technology-rich environments. However, the amount of guidance needed to promote learning in these environments remains unknown. We explore this issue by focusing on the effects of step-by-step…

CB5C affects the glucosinolate profile in Arabidopsis thaliana

PubMed Central

Vik, Daniel; Crocoll, Christoph; Andersen, Tonni Grube; Burow, Meike; Halkier, Barbara Ann

2016-01-01

ABSTRACT Cytochrome b5 (CB5) proteins are small heme-binding proteins, that influence cytochrome P450 activity. While only one CB5 isoform is found in mammals, higher plants have several isoforms of these proteins. The roles of the many CB5 isoforms in plants remain unknown. We hypothesized that CB5 proteins support the cytochrome P450 enzymes of plant specialized metabolism and found CB5C from Arabidopsis thaliana to co-express with glucosinolate biosynthetic genes. We characterized the glucosinolate profiles of 2 T-DNA insertion mutants of CB5C, and found that long-chained aliphatic glucosinolates were reduced in one of the mutant lines – a phenotype that was exaggerated upon methyl-jasmonate treatment. These results support the hypothesis, that CB5C influences glucosinolate biosynthesis, however, the mode of action remains unknown. Furthermore, the mutants differed in their biomass response to methyl jasmonate treatment. Thereby, our results highlight the varying effects of T-DNA insertion sites, as the 2 analyzed alleles show different phenotypes. PMID:27454255

Cell-specific gain modulation by synaptically released zinc in cortical circuits of audition.

PubMed

Anderson, Charles T; Kumar, Manoj; Xiong, Shanshan; Tzounopoulos, Thanos

2017-09-09

In many excitatory synapses, mobile zinc is found within glutamatergic vesicles and is coreleased with glutamate. Ex vivo studies established that synaptically released (synaptic) zinc inhibits excitatory neurotransmission at lower frequencies of synaptic activity but enhances steady state synaptic responses during higher frequencies of activity. However, it remains unknown how synaptic zinc affects neuronal processing in vivo. Here, we imaged the sound-evoked neuronal activity of the primary auditory cortex in awake mice. We discovered that synaptic zinc enhanced the gain of sound-evoked responses in CaMKII-expressing principal neurons, but it reduced the gain of parvalbumin- and somatostatin-expressing interneurons. This modulation was sound intensity-dependent and, in part, NMDA receptor-independent. By establishing a previously unknown link between synaptic zinc and gain control of auditory cortical processing, our findings advance understanding about cortical synaptic mechanisms and create a new framework for approaching and interpreting the role of the auditory cortex in sound processing.

Profilin1 activity in cerebellar granule neurons is required for radial migration in vivo

PubMed Central

Kullmann, Jan A; Wickertsheim, Ines; Minnerup, Lara; Costell, Mercedes; Friauf, Eckhard; Rust, Marco B

2015-01-01

Neuron migration defects are an important aspect of human neuropathies. The underlying molecular mechanisms of such migration defects are largely unknown. Actin dynamics has been recognized as an important determinant of neuronal migration, and we recently found that the actin-binding protein profilin1 is relevant for radial migration of cerebellar granule neurons (CGN). As the exploited brain-specific mutants lacked profilin1 in both neurons and glial cells, it remained unknown whether profilin1 activity in CGN is relevant for CGN migration in vivo. To test this, we capitalized on a transgenic mouse line that expresses a tamoxifen-inducible Cre variant in CGN, but no other cerebellar cell type. In these profilin1 mutants, the cell density was elevated in the molecular layer, and ectopic CGN occurred. Moreover, 5-bromo-2′-deoxyuridine tracing experiments revealed impaired CGN radial migration. Hence, our data demonstrate the cell autonomous role of profilin1 activity in CGN for radial migration. PMID:25495756

A store-operated current (SOC) mediates oxytocin autocontrol in the developing rat hypothalamus.

PubMed

Tobin, Vicky; Gouty, Laurie-Anne; Moos, Françoise C; Desarménien, Michel G

2006-07-01

Oxytocin (OT) and vasopressin (VP) autocontrol their secreting neurons in the supraoptic nucleus (SON) by modulating action potential firing through activation of specific metabotropic receptors. However, the mechanisms linking receptor activation to firing remain unknown. In almost all cell types, activation of plasma membrane metabotropic receptors triggers signalling cascades that induce mobilization of calcium from intracellular stores. In turn, emptying the calcium stores may evoke calcium influx through store-operated channels (SOCs), the functions of which remain largely unknown in neurons. In this study, we show that these channels play a key role in the SON, at least in the response to OT. In isolated rat SON neurons, store depletion by thapsigargin induced an influx of calcium, demonstrating the presence of SOCs in these neurons. This calcium influx was specifically inhibited by 0.2 mM 1-(2-trifluoromethylphenyl-)imidazole (TRIM). At 2 mM, this compound affected neither the resting electrophysiological properties nor the voltage-dependant inward currents. In fresh slices, TRIM (2 mM) did not affect the resting potential of SON neurons, action potential characteristics, spontaneous action potential firing or synaptic activity; this compound thus appears to be a specific blocker of SOCs in SON neurons. TRIM (0.2 mM) specifically reduced the increase in action potential firing triggered by OT but did not affect the VP-induced response. These observations demonstrate that store operated channels exist in hypothalamic neurons and specifically mediate the response to OT in the SON.

Ofuji disease: a rare dermatosis and its challenging therapeutic approach*

PubMed Central

de Brito, Fernanda Freitas; Martelli, Antonio Carlos Ceribelli; Cavalcante, Maria Lopes Lamenha Lins; Pinto, Ana Cecília Versiani Duarte; Itimura, Gabriela; Soares, Cleverson Teixeira

2016-01-01

Eosinophilic pustular folliculitis (EPF) or Ofuji disease is a rare dermatosis, prone to recurrence and chronicity. The peak incidence occurs in the third decade of life and its exact etiology remains unknown. Evidence suggests that the expression of adhesion molecules and the production of cytokines activate the follicular unit, but the stimulus that triggers these changes remains unclear. The three clinical variants reported in the literature include classic EPF, immunosuppression-associated EPF, and infancy-associated EPF. We report a case of eosinophilic pustular folliculitis with peculiar epidemiological characteristics, which represents a challenging therapeutic scenario. PMID:27828641

[Mechanism of action of antiepileptic drugs].

PubMed

Saidón, Patricia

2003-01-01

Antiepileptic drugs (DAEs) act through different mechanisms of action: increase in central inhibition, inhibition of excitatorios mechanisms and modification of the excitability through their action on the ionic channels. Epilepsy is characterized by an abnormal and hypersynchronic unloading of a neuronal population. The activity of numerous drugs is associated to increase in gabaergic activity. Another group of drugs decreases excitatory mechanisms, through the inhibition of ionic channels, or through a decrease in the activity of the excitatory neurotransmitters. There are some of antiepileptic drugs, especially within the group of drugs of recent appearance, for wich the mechanism of action remains unknown.

A simple electrostatic switch important in the activation of type I protein kinase A by cyclic AMP.

PubMed

Vigil, Dominico; Lin, Jung-Hsin; Sotriffer, Christoph A; Pennypacker, Juniper K; McCammon, J Andrew; Taylor, Susan S

2006-01-01

Cyclic AMP activates protein kinase A by binding to an inhibitory regulatory (R) subunit and releasing inhibition of the catalytic (C) subunit. Even though crystal structures of regulatory and catalytic subunits have been solved, the precise molecular mechanism by which cyclic AMP activates the kinase remains unknown. The dynamic properties of the cAMP binding domain in the absence of cAMP or C-subunit are also unknown. Here we report molecular-dynamics simulations and mutational studies of the RIalpha R-subunit that identify the C-helix as a highly dynamic switch which relays cAMP binding to the helical C-subunit binding regions. Furthermore, we identify an important salt bridge which links cAMP binding directly to the C-helix that is necessary for normal activation. Additional mutations show that a hydrophobic "hinge" region is not as critical for the cross-talk in PKA as it is in the homologous EPAC protein, illustrating how cAMP can control diverse functions using the evolutionarily conserved cAMP-binding domains.

Cultured neuronal networks as environmental biosensors.

PubMed

O'Shaughnessy, Thomas J; Gray, Samuel A; Pancrazio, Joseph J

2004-01-01

Contamination of water by toxins, either intentionally or unintentionally, is a growing concern for both military and civilian agencies and thus there is a need for systems capable of monitoring a wide range of natural and industrial toxicants. The EILATox-Oregon Workshop held in September 2002 provided an opportunity to test the capabilities of a prototype neuronal network-based biosensor with unknown contaminants in water samples. The biosensor is a portable device capable of recording the action potential activity from a network of mammalian neurons grown on glass microelectrode arrays. Changes in the action potential fi ring rate across the network are monitored to determine exposure to toxicants. A series of three neuronal networks derived from mice was used to test seven unknown samples. Two of these unknowns later were revealed to be blanks, to which the neuronal networks did not respond. Of the five remaining unknowns, a significant change in network activity was detected for four of the compounds at concentrations below a lethal level for humans: mercuric chloride, sodium arsenite, phosdrin and chlordimeform. These compounds--two heavy metals, an organophosphate and an insecticide--demonstrate the breadth of detection possible with neuronal networks. The results generated at the workshop show the promise of the neuronal network biosensor as an environmental detector but there is still considerable effort needed to produce a device suitable for routine environmental threat monitoring.

Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group TARGET Project | Office of Cancer Genomics

Cancer.gov

TARGET researchers sequenced the tyrosine kinome and downstream signaling genes in 45 high-risk pediatric ALL cases with activated kinase signaling, including Ph-like ALL, to establish the incidence of tyrosine kinase mutations in this cohort. The study confirmed previously identified somatic mutations in JAK and FLT3, but did not find novel alterations in any additional tyrosine kinases or downstream genes. The mechanism of kinase signaling activation in this high-risk subgroup of pediatric ALL remains largely unknown.

The Time Course of Verb Processing in Dutch Sentences

PubMed Central

Shapiro, Lewis P.; Wester, Femke; Swinney, David A.; Bastiaanse, Roelien

2012-01-01

The verb has traditionally been characterized as the central element in a sentence. Nevertheless, the exact role of the verb during the actual ongoing comprehension of a sentence as it unfolds in time remains largely unknown. This paper reports the results of two Cross-Modal Lexical Priming (CMLP) experiments detailing the pattern of verb priming during on-line processing of Dutch sentences. Results are contrasted with data from a third CMLP experiment on priming of nouns in similar sentences. It is demonstrated that the meaning of a matrix verb remains active throughout the entire matrix clause, while this is not the case for the meaning of a subject head noun. Activation of the meaning of the verb only dissipates upon encountering a clear signal as to the start of a new clause. PMID:19452278

What are the memory sources of dreaming?

PubMed

Nielsen, Tore A; Stenstrom, Philippe

2005-10-27

Investigators since Freud have appreciated that memories of the people, places, activities and emotions of daily life are reflected in dreams but are typically so fragmented that their predictability is nil. The mechanisms that translate such memories into dream images remain largely unknown. New research targeting relationships between dreaming, memory and the hippocampus is producing a new theory to explain how, why and when we dream of waking life events.

Active Dentate Granule Cells Encode Experience to Promote the Addition of Adult-Born Hippocampal Neurons

PubMed Central

Kirschen, Gregory W.; Shen, Jia; Wang, Jia; Man, Guoming; Wu, Song

2017-01-01

The continuous addition of new dentate granule cells (DGCs), which is regulated exquisitely by brain activity, renders the hippocampus plastic. However, how neural circuits encode experiences to affect the addition of adult-born neurons remains unknown. Here, we used endoscopic Ca2+ imaging to track the real-time activity of individual DGCs in freely behaving mice. For the first time, we found that active DGCs responded to a novel experience by increasing their Ca2+ event frequency preferentially. This elevated activity, which we found to be associated with object exploration, returned to baseline by 1 h in the same environment, but could be dishabituated via introduction to a novel environment. To transition seamlessly between environments, we next established a freely controllable virtual reality system for unrestrained mice. We again observed increased firing of active neurons in a virtual enriched environment. Interestingly, multiple novel virtual experiences increased the number of newborn neurons accumulatively compared with a single experience. Finally, optogenetic silencing of existing DGCs during novel environmental exploration perturbed experience-induced neuronal addition. Our study shows that the adult brain conveys novel, enriched experiences to increase the addition of adult-born hippocampal neurons by increasing the firing of active DGCs. SIGNIFICANCE STATEMENT Adult brains are constantly reshaping themselves from synapses to circuits as we encounter novel experiences from moment to moment. Importantly, this reshaping includes the addition of newborn hippocampal neurons. However, it remains largely unknown how our circuits encode experience-induced brain activity to govern the addition of new hippocampal neurons. By coupling in vivo Ca2+ imaging of dentate granule neurons with a novel, unrestrained virtual reality system for rodents, we discovered that a new experience increased firing of active dentate granule neurons rapidly and robustly. Exploration in multiple novel virtual environments, compared with a single environment, promoted dentate activation and enhanced the addition of new hippocampal neurons accumulatively. Finally, silencing this activation optogenetically during novel experiences perturbed experience-induced neuronal addition. PMID:28373391

The challenge of annotating protein sequences: The tale of eight domains of unknown function in Pfam.

PubMed

Goonesekere, Nalin C W; Shipely, Krysten; O'Connor, Kevin

2010-06-01

The Pfam database is an important tool in genome annotation, since it provides a collection of curated protein families. However, a subset of these families, known as domains of unknown function (DUFs), remains poorly characterized. We have related sequences from DUF404, DUF407, DUF482, DUF608, DUF810, DUF853, DUF976 and DUF1111 to homologs in PDB, within the midnight zone (9-20%) of sequence identity. These relationships were extended to provide functional annotation by sequence analysis and model building. Also described are examples of residue plasticity within enzyme active sites, and change of function within homologous sequences of a DUF. Copyright 2010 Elsevier Ltd. All rights reserved.

Separation of cordycepin from Cordyceps militaris fermentation supernatant using preparative HPLC and evaluation of its antibacterial activity as an NAD+-dependent DNA ligase inhibitor

PubMed Central

Zhou, Xiaofeng; Cai, Guoqiang; He, Yi; Tong, Guotong

2016-01-01

Cordycepin exhibits various bio-activities, including anticancer, antibacterial, antiviral and immune regulation activities, and is a significant focus of research. However, the preparation of high-purity cordycepin remains challenging. Also, the molecular target with which cordycepin interacts to cause an antibacterial effect remains unknown. In the present study, cordycepin was prepared by preparative high-performance liquid chromatography (prep-HPLC) and the purity obtained was 99.6%, indicating that this technique may be useful for the large-scale isolation of cordycepin in the future. The results of computational molecular docking analysis indicated that the interaction energy between cordycepin and NAD+-dependent DNA ligase (LigA) was lower than that between cordycepin and other common antibacterial targets. The highly pure cordycepin obtained by prep-HPLC demonstrated inhibitory activity against LigA from various bacteria in vitro. In conclusion, cordycepin may be useful as a broad-spectrum antibiotic targeting LigA in various bacteria. PMID:27588098

Glycolipids from seaweeds and their potential biotechnological applications.

PubMed

Plouguerné, Erwan; da Gama, Bernardo A P; Pereira, Renato C; Barreto-Bergter, Eliana

2014-01-01

Marine macroalgae, or seaweeds, are a formidable source of natural compounds with diverse biological activities. In the last five decades it has been estimated that more than 3000 natural compounds were discovered from these organisms. The great majority of the published works have focused on terpenoids. In comparison, glycolipids are a neglected class of macroalgal secondary metabolites therefore remaining as a largely unknown reservoir of molecular diversity. Nevertheless, the interest regarding these compounds has been growing fast in the last decades as activities of ecological or pharmaceutical interest have been highlighted. This paper will review recent work regarding isolation and structural characterization of glycolipids from seaweeds and their prospective biological activities.

Peroxisome proliferator-activated receptor {alpha}-independent peroxisome proliferation

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

Zhang Xiuguo; Tanaka, Naoki; Nakajima, Takero

2006-08-11

Hepatic peroxisome proliferation, increases in the numerical and volume density of peroxisomes, is believed to be closely related to peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) activation; however, it remains unknown whether peroxisome proliferation depends absolutely on this activation. To verify occurrence of PPAR{alpha}-independent peroxisome proliferation, fenofibrate treatment was used, which was expected to significantly enhance PPAR{alpha} dependence in the assay system. Surprisingly, a novel type of PPAR{alpha}-independent peroxisome proliferation and enlargement was uncovered in PPAR{alpha}-null mice. The increased expression of dynamin-like protein 1, but not peroxisome biogenesis factor 11{alpha}, might be associated with the PPAR{alpha}-independent peroxisome proliferation at least in part.

Mechanisms of right heart disease in pulmonary hypertension (2017 Grover Conference Series).

PubMed

Asosingh, Kewal; Erzurum, Serpil

2018-01-01

Current dogma is that pathological hypertrophy of the right ventricle is a direct consequence of pulmonary vascular remodeling. However, progression of right ventricle dysfunction is not always lung-dependent. Increased afterload caused by pulmonary vascular remodeling initiates the right ventricle hypertrophy, but determinants leading to adaptive or maladaptive hypertrophy and failure remain unknown. Ischemia in a hypertrophic right ventricle may directly contribute to right heart failure. Rapidly enlarging cardiomyocytes switch from aerobic to anaerobic energy generation resulting in cell growth under relatively hypoxic conditions. Cardiac muscle reacts to an increased afterload by over-activation of the sympathetic system and uncoupling and downregulation of β-adrenergic receptors. Recent studies suggest that β blocker therapy in PH is safe, well tolerated, and preserves right ventricle function and cardiac output by reducing right ventricular glycolysis. Fibrosis, an evolutionary conserved process in host defense and wound healing, is dysregulated in maladaptive cardiac tissue contributing directly to right ventricle failure. Despite several mechanisms having been suggested in right heart disease, the causes of maladaptive cardiac remodeling remain unknown and require further research.

Vasoactive intestinal peptide is a local mediator in a gut-brain neural axis activating intestinal gluconeogenesis.

PubMed

De Vadder, F; Plessier, F; Gautier-Stein, A; Mithieux, G

2015-03-01

Intestinal gluconeogenesis (IGN) promotes metabolic benefits through activation of a gut-brain neural axis. However, the local mediator activating gluconeogenic genes in the enterocytes remains unknown. We show that (i) vasoactive intestinal peptide (VIP) signaling through VPAC1 receptor activates the intestinal glucose-6-phosphatase gene in vivo, (ii) the activation of IGN by propionate is counteracted by VPAC1 antagonism, and (iii) VIP-positive intrinsic neurons in the submucosal plexus are increased under the action of propionate. These data support the role of VIP as a local neuromodulator released by intrinsic enteric neurons and responsible for the induction of IGN through a VPAC1 receptor-dependent mechanism in enterocytes. © 2015 John Wiley & Sons Ltd.

A new family of β-helix proteins with similarities to the polysaccharide lyases

DOE PAGES

Close, Devin W.; D'Angelo, Sara; Bradbury, Andrew R. M.

2014-09-27

Microorganisms that degrade biomass produce diverse assortments of carbohydrate-active enzymes and binding modules. Despite tremendous advances in the genomic sequencing of these organisms, many genes do not have an ascribed function owing to low sequence identity to genes that have been annotated. Consequently, biochemical and structural characterization of genes with unknown function is required to complement the rapidly growing pool of genomic sequencing data. A protein with previously unknown function (Cthe_2159) was recently isolated in a genome-wide screen using phage display to identify cellulose-binding protein domains from the biomass-degrading bacterium Clostridium thermocellum. Here, the crystal structure of Cthe_2159 is presentedmore » and it is shown that it is a unique right-handed parallel β-helix protein. Despite very low sequence identity to known β-helix or carbohydrate-active proteins, Cthe_2159 displays structural features that are very similar to those of polysaccharide lyase (PL) families 1, 3, 6 and 9. Cthe_2159 is conserved across bacteria and some archaea and is a member of the domain of unknown function family DUF4353. This suggests that Cthe_2159 is the first representative of a previously unknown family of cellulose and/or acid-sugar binding β-helix proteins that share structural similarities with PLs. More importantly, these results demonstrate how functional annotation by biochemical and structural analysis remains a critical tool in the characterization of new gene products.« less

A new family of β-helix proteins with similarities to the polysaccharide lyases

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

Close, Devin W.; D'Angelo, Sara; Bradbury, Andrew R. M.

Microorganisms that degrade biomass produce diverse assortments of carbohydrate-active enzymes and binding modules. Despite tremendous advances in the genomic sequencing of these organisms, many genes do not have an ascribed function owing to low sequence identity to genes that have been annotated. Consequently, biochemical and structural characterization of genes with unknown function is required to complement the rapidly growing pool of genomic sequencing data. A protein with previously unknown function (Cthe_2159) was recently isolated in a genome-wide screen using phage display to identify cellulose-binding protein domains from the biomass-degrading bacterium Clostridium thermocellum. Here, the crystal structure of Cthe_2159 is presentedmore » and it is shown that it is a unique right-handed parallel β-helix protein. Despite very low sequence identity to known β-helix or carbohydrate-active proteins, Cthe_2159 displays structural features that are very similar to those of polysaccharide lyase (PL) families 1, 3, 6 and 9. Cthe_2159 is conserved across bacteria and some archaea and is a member of the domain of unknown function family DUF4353. This suggests that Cthe_2159 is the first representative of a previously unknown family of cellulose and/or acid-sugar binding β-helix proteins that share structural similarities with PLs. More importantly, these results demonstrate how functional annotation by biochemical and structural analysis remains a critical tool in the characterization of new gene products.« less

Confronting the catalytic dark matter encoded by sequenced genomes

PubMed Central

Ellens, Kenneth W.; Christian, Nils; Singh, Charandeep; Satagopam, Venkata P.

2017-01-01

Abstract The post-genomic era has provided researchers with a deluge of protein sequences. However, a significant fraction of the proteins encoded by sequenced genomes remains without an identified function. Here, we aim at determining how many enzymes of uncertain or unknown function are still present in the Saccharomyces cerevisiae and human proteomes. Using information available in the Swiss-Prot, BRENDA and KEGG databases in combination with a Hidden Markov Model-based method, we estimate that >600 yeast and 2000 human proteins (>30% of their proteins of unknown function) are enzymes whose precise function(s) remain(s) to be determined. This illustrates the impressive scale of the ‘unknown enzyme problem’. We extensively review classical biochemical as well as more recent systematic experimental and computational approaches that can be used to support enzyme function discovery research. Finally, we discuss the possible roles of the elusive catalysts in light of recent developments in the fields of enzymology and metabolism as well as the significance of the unknown enzyme problem in the context of metabolic modeling, metabolic engineering and rare disease research. PMID:29059321

The mediator subunit Med23 contributes to controlling T-cell activation and prevents autoimmunity.

PubMed

Sun, Yang; Zhu, Xiaoyan; Chen, Xufeng; Liu, Haifeng; Xu, Yu; Chu, Yajing; Wang, Gang; Liu, Xiaolong

2014-10-10

T-cell activation is critical for successful immune responses and is controlled at multiple levels. Although many changes of T-cell receptor-associated signalling molecules affect T-cell activation, the transcriptional mechanisms that control this process remain largely unknown. Here we find that T cell-specific deletion of the mediator subunit Med23 leads to hyperactivation of T cells and aged Med23-deficient mice exhibit an autoimmune syndrome. Med23 specifically and consistently promotes the transcription of multiple negative regulators of T-cell activation. In the absence of Med23, the T-cell activation threshold is lower, which results in enhanced antitumour T-cell function. Cumulatively, our data suggest that Med23 contributes to controlling T-cell activation at the transcriptional level and prevents the development of autoimmunity.

Increased resin flow in mature pine trees growing under elevated CO2 and moderate soil fertility

Treesearch

K.A. Novick; G.G. Katul; H.R. McCarthy; R. Oren

2012-01-01

Warmer climates induced by elevated atmospheric CO2 (eCO2) are expected to increase damaging bark beetle activity in pine forests, yet the effect of eCO2 on resin production—the tree’s primary defense against beetle attack—remains largely unknown. Following growth-differentiation balance theory, if extra carbohydrates produced under eCO2 are not consumed by respiration...

PhcrTx2, a New Crab-Paralyzing Peptide Toxin from the Sea Anemone Phymanthus crucifer

PubMed Central

Garateix, Anoland; Salceda, Emilio; Zaharenko, André Junqueira; Pons, Tirso; Santos, Yúlica; Arreguín, Roberto; Ständker, Ludger; Forssmann, Wolf-Georg; Tytgat, Jan; Vega, Rosario

2018-01-01

Sea anemones produce proteinaceous toxins for predation and defense, including peptide toxins that act on a large variety of ion channels of pharmacological and biomedical interest. Phymanthus crucifer is commonly found in the Caribbean Sea; however, the chemical structure and biological activity of its toxins remain unknown, with the exception of PhcrTx1, an acid-sensing ion channel (ASIC) inhibitor. Therefore, in the present work, we focused on the isolation and characterization of new P. crucifer toxins by chromatographic fractionation, followed by a toxicity screening on crabs, an evaluation of ion channels, and sequence analysis. Five groups of toxic chromatographic fractions were found, and a new paralyzing toxin was purified and named PhcrTx2. The toxin inhibited glutamate-gated currents in snail neurons (maximum inhibition of 35%, IC50 4.7 µM), and displayed little or no influence on voltage-sensitive sodium/potassium channels in snail and rat dorsal root ganglion (DRG) neurons, nor on a variety of cloned voltage-gated ion channels. The toxin sequence was fully elucidated by Edman degradation. PhcrTx2 is a new β-defensin-fold peptide that shares a sequence similarity to type 3 potassium channels toxins. However, its low activity on the evaluated ion channels suggests that its molecular target remains unknown. PhcrTx2 is the first known paralyzing toxin in the family Phymanthidae. PMID:29414882

Obese individuals with more components of the metabolic syndrome and/or prediabetes demonstrate decreased activation of reward-related brain centers in response to food cues in both the fed and fasting states: A preliminary fMRI study

PubMed Central

Farr, Olivia M.; Mantzoros, Christos S.

2016-01-01

It remains unknown whether obese individuals with more components of the metabolic syndrome and/or prediabetes demonstrate altered activation of brain centers in response to food cues. We examined obese prediabetics (n=26) vs. obese nondiabetics (n=11) using fMRI. We also performed regression analyses on the basis of the number of MetS components per subject. Obese individuals with prediabetes have decreased activation of the reward-related putamen in the fasting state and decreased activation of the salience- and reward-related insula after eating. Obese individuals with more components of MetS demonstrate decreased activation of the putamen while fasting. All these activations remain significant when corrected for BMI, waist circumference (WC), HbA1c and gender. Decreased activation in reward-related brain areas between obese individuals is more pronounced in subjects with prediabetes and MetS. Prospective studies are needed to quantify their contributions to the development of prediabetes/MetS and to study whether these conditions may predispose to the exacerbation of obesity and the development of comorbidities over time. PMID:28017966

Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways

NASA Astrophysics Data System (ADS)

Chung, Won-Suk; Clarke, Laura E.; Wang, Gordon X.; Stafford, Benjamin K.; Sher, Alexander; Chakraborty, Chandrani; Joung, Julia; Foo, Lynette C.; Thompson, Andrew; Chen, Chinfei; Smith, Stephen J.; Barres, Ben A.

2013-12-01

To achieve its precise neural connectivity, the developing mammalian nervous system undergoes extensive activity-dependent synapse remodelling. Recently, microglial cells have been shown to be responsible for a portion of synaptic pruning, but the remaining mechanisms remain unknown. Here we report a new role for astrocytes in actively engulfing central nervous system synapses. This process helps to mediate synapse elimination, requires the MEGF10 and MERTK phagocytic pathways, and is strongly dependent on neuronal activity. Developing mice deficient in both astrocyte pathways fail to refine their retinogeniculate connections normally and retain excess functional synapses. Finally, we show that in the adult mouse brain, astrocytes continuously engulf both excitatory and inhibitory synapses. These studies reveal a novel role for astrocytes in mediating synapse elimination in the developing and adult brain, identify MEGF10 and MERTK as critical proteins in the synapse remodelling underlying neural circuit refinement, and have important implications for understanding learning and memory as well as neurological disease processes.

A TEST OF THE FORMATION MECHANISM OF THE BROAD LINE REGION IN ACTIVE GALACTIC NUCLEI

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

Czerny, Bozena; Du, Pu; Wang, Jian-Min

2016-11-20

The origin of the broad line region (BLR) in active galaxies remains unknown. It seems to be related to the underlying accretion disk, but an efficient mechanism is required to raise the material from the disk surface without giving signatures of the outflow that are too strong in the case of the low ionization lines. We discuss in detail two proposed mechanisms: (1) radiation pressure acting on dust in the disk atmosphere creating a failed wind and (2) the gravitational instability of the underlying disk. We compare the predicted location of the inner radius of the BLR in those two scenarios withmore » the observed position obtained from the reverberation studies of several active galaxies. The failed dusty outflow model well represents the observational data while the predictions of the self-gravitational instability are not consistent with observations. The issue that remains is why do we not see any imprints of the underlying disk instability in the BLR properties.« less

Nitric oxide is not permissive for cutaneous active vasodilatation in humans.

PubMed

Wilkins, Brad W; Holowatz, Lacy A; Wong, Brett J; Minson, Christopher T

2003-05-01

The precise role of nitric oxide (NO) in cutaneous active vasodilatation in humans is unknown. We tested the hypothesis that NO is necessary to permit the action of an unknown vasodilator. Specifically, we investigated whether a low-dose infusion of exogenous NO, in the form of sodium nitroprusside (SNP), would fully restore vasodilatation in an area of skin in which endogenous NO was inhibited during hyperthermia. This finding would suggest a 'permissive' role for NO in active vasodilatation. Eight subjects were instrumented with three microdialysis fibres in forearm skin. Sites were randomly assigned to (1) Site A: control site; (2) Site B: NO synthase (NOS) inhibition during established hyperthermia; or (3) Site C: NOS inhibition throughout the protocol. Red blood cell flux was measured using laser-Doppler flowmetry (LDF) and cutaneous vascular conductance (CVC; LDF/mean arterial pressure) was normalized to maximal vasodilatation at each site. In Site B, NG-nitro-L-arginine methyl ester (L-NAME) infusion during hyperthermia reduced CVC by approximately 32 % (65 +/- 4 % CVCmax vs. 45 +/- 4 % CVCmax; P < 0.05). Vasodilatation was not restored to pre-NOS inhibition values in this site following low-dose SNP infusion (55 +/- 4 % CVCmax vs. 65 +/- 4 % CVCmax; P < 0.05). CVC remained significantly lower than the control site with low-dose SNP infusion in Site C (P < 0.05). The rise in CVC with low-dose SNP (deltaCVC) was significantly greater in Site B and Site C during hyperthermia compared to normothermia (P < 0.05). No difference in deltaCVC was observed between hyperthermia and normothermia in the control site (Site A). Thus, NO does not act permissively in cutaneous active vasodilatation in humans but may directly mediate vasodilatation and enhance the effect of an unknown active vasodilator.

Electrical and Optical Activation of Mesoscale Neural Circuits with Implications for Coding.

PubMed

Millard, Daniel C; Whitmire, Clarissa J; Gollnick, Clare A; Rozell, Christopher J; Stanley, Garrett B

2015-11-25

Artificial activation of neural circuitry through electrical microstimulation and optogenetic techniques is important for both scientific discovery of circuit function and for engineered approaches to alleviate various disorders of the nervous system. However, evidence suggests that neural activity generated by artificial stimuli differs dramatically from normal circuit function, in terms of both the local neuronal population activity at the site of activation and the propagation to downstream brain structures. The precise nature of these differences and the implications for information processing remain unknown. Here, we used voltage-sensitive dye imaging of primary somatosensory cortex in the anesthetized rat in response to deflections of the facial vibrissae and electrical or optogenetic stimulation of thalamic neurons that project directly to the somatosensory cortex. Although the different inputs produced responses that were similar in terms of the average cortical activation, the variability of the cortical response was strikingly different for artificial versus sensory inputs. Furthermore, electrical microstimulation resulted in highly unnatural spatial activation of cortex, whereas optical input resulted in spatial cortical activation that was similar to that induced by sensory inputs. A thalamocortical network model suggested that observed differences could be explained by differences in the way in which artificial and natural inputs modulate the magnitude and synchrony of population activity. Finally, the variability structure in the response for each case strongly influenced the optimal inputs for driving the pathway from the perspective of an ideal observer of cortical activation when considered in the context of information transmission. Artificial activation of neural circuitry through electrical microstimulation and optogenetic techniques is important for both scientific discovery and clinical translation. However, neural activity generated by these artificial means differs dramatically from normal circuit function, both locally and in the propagation to downstream brain structures. The precise nature of these differences and the implications for information processing remain unknown. The significance of this work is in quantifying the differences, elucidating likely mechanisms underlying the differences, and determining the implications for information processing. Copyright © 2015 the authors 0270-6474/15/3515702-14$15.00/0.

GTSE1 tunes microtubule stability for chromosome alignment and segregation by inhibiting the microtubule depolymerase MCAK

PubMed Central

Bendre, Shweta; Hall, Conrad; Lin, Yu-Chih

2016-01-01

The dynamic regulation of microtubules (MTs) during mitosis is critical for accurate chromosome segregation and genome stability. Cancer cell lines with hyperstabilized kinetochore MTs have increased segregation errors and elevated chromosomal instability (CIN), but the genetic defects responsible remain largely unknown. The MT depolymerase MCAK (mitotic centromere-associated kinesin) can influence CIN through its impact on MT stability, but how its potent activity is controlled in cells remains unclear. In this study, we show that GTSE1, a protein found overexpressed in aneuploid cancer cell lines and tumors, regulates MT stability during mitosis by inhibiting MCAK MT depolymerase activity. Cells lacking GTSE1 have defects in chromosome alignment and spindle positioning as a result of MT instability caused by excess MCAK activity. Reducing GTSE1 levels in CIN cancer cell lines reduces chromosome missegregation defects, whereas artificially inducing GTSE1 levels in chromosomally stable cells elevates chromosome missegregation and CIN. Thus, GTSE1 inhibition of MCAK activity regulates the balance of MT stability that determines the fidelity of chromosome alignment, segregation, and chromosomal stability. PMID:27881713

Agaricus blazei Murill enhances doxorubicin-induced apoptosis in human hepatocellular carcinoma cells by NFκB-mediated increase of intracellular doxorubicin accumulation.

PubMed

Lee, Jong Seok; Hong, Eock Kee

2011-02-01

It has been demonstrated that the Agaricus blazei Murill (ABM) mushroom, which primarily consists of polysaccharides, possesses anti-tumor activities. However, the mechanisms by which ABM inhibits human hepatocellular carcinoma growth remain unknown. Our study demonstrates that ABM acts as an enhancer to sensitize doxorubicin (Dox)-mediated apoptotic signaling, and this sensitization can be achieved by enhancing intracellular Dox accumulation via the inhibition of NFκB activity. These findings suggest that ABM, when combined with low doses of Dox, has the potential to provide more efficient therapeutic effects against drug-resistant human hepatocellular carcinoma.

4 Hz oscillations synchronize prefrontal-amygdala circuits during fear behaviour

PubMed Central

Karalis, Nikolaos; Dejean, Cyril; Chaudun, Fabrice; Khoder, Suzana; Rozeske, Robert R.; Wurtz, Hélène; Bagur, Sophie; Benchenane, Karim; Sirota, Anton; Courtin, Julien; Herry, Cyril

2016-01-01

Fear expression relies on the coordinated activity of prefrontal and amygdala circuits, yet the mechanisms allowing long-range network synchronization during fear remain unknown. Using a combination of extracellular recordings, pharmacological, and optogenetic manipulations we report that freezing, a behavioural expression of fear, temporally coincides with the development of sustained, internally generated 4 Hz oscillations within prefrontal-amygdala circuits. 4 Hz oscillations predict freezing onset and offset and synchronize prefrontal-amygdala circuits. Optogenetic induction of prefrontal 4 Hz oscillations coordinates prefrontal-amygdala activity and elicits fear behaviour. These results unravel a novel sustained oscillatory mechanism mediating prefrontal-amygdala coupling during fear behaviour. PMID:26878674

Control of Hepatic Gluconeogenesis by the Promyelocytic Leukemia Zinc Finger Protein

PubMed Central

Chen, Siyu; Qian, Jinchun; Shi, Xiaoli; Gao, Tingting; Liang, Tingming

2014-01-01

The promyelocytic leukemia zinc finger (PLZF) protein is involved in major biological processes including energy metabolism, although its role remains unknown. In this study, we demonstrated that hepatic PLZF expression was induced in fasted or diabetic mice. PLZF promoted gluconeogenic gene expression and hepatic glucose output, leading to hyperglycemia. In contrast, hepatic PLZF knockdown improved glucose homeostasis in db/db mice. Mechanistically, peroxisome proliferator-activated receptor γ coactivator 1α and the glucocorticoid receptor synergistically activated PLZF expression. We conclude that PLZF is a critical regulator of hepatic gluconeogenesis. PLZF manipulation may benefit the treatment of metabolic diseases associated with gluconeogenesis. PMID:25333514

Molecular approach to annelid regeneration: cDNA subtraction cloning reveals various novel genes that are upregulated during the large-scale regeneration of the oligochaete, Enchytraeus japonensis.

PubMed

Myohara, Maroko; Niva, Cintia Carla; Lee, Jae Min

2006-08-01

To identify genes specifically activated during annelid regeneration, suppression subtractive hybridization was performed with cDNAs from regenerating and intact Enchytraeus japonensis, a terrestrial oligochaete that can regenerate a complete organism from small body fragments within 4-5 days. Filter array screening subsequently revealed that about 38% of the forward-subtracted cDNA clones contained genes that were upregulated during regeneration. Two hundred seventy-nine of these clones were sequenced and found to contain 165 different sequences (79 known and 86 unknown). Nine clones were fully sequenced and four of these sequences were matched to known genes for glutamine synthetase, glucosidase 1, retinal protein 4, and phosphoribosylaminoimidazole carboxylase, respectively. The remaining five clones encoded an unknown open-reading frame. The expression levels of these genes were highest during blastema formation. Our present results, therefore, demonstrate the great potential of annelids as a new experimental subject for the exploration of unknown genes that play critical roles in animal regeneration.

Phenformin activates the unfolded protein response in an AMP-activated protein kinase (AMPK)-dependent manner.

PubMed

Yang, Liu; Sha, Haibo; Davisson, Robin L; Qi, Ling

2013-05-10

The cross-talk between UPR activation and metabolic stress remains largely unclear. Phenformin treatment activates the IRE1α and PERK pathways in an AMPK-dependent manner. AMPK is required for phenformin-mediated IRE1α and PERK activation. Our findings demonstrate the cross-talk between UPR and metabolic signals. Activation of the unfolded protein response (UPR) is associated with the disruption of endoplasmic reticulum (ER) homeostasis and has been implicated in the pathogenesis of many human metabolic diseases, including obesity and type 2 diabetes. However, the nature of the signals activating UPR under these conditions remains largely unknown. Using a method that we recently optimized to directly measure UPR sensor activation, we screened the effect of various metabolic drugs on UPR activation and show that the anti-diabetic drug phenformin activates UPR sensors IRE1α and pancreatic endoplasmic reticulum kinase (PERK) in both an ER-dependent and ER-independent manner. Mechanistically, AMP-activated protein kinase (AMPK) activation is required but not sufficient to initiate phenformin-mediated IRE1α and PERK activation, suggesting the involvement of additional factor(s). Interestingly, activation of the IRE1α (but not PERK) pathway is partially responsible for the cytotoxic effect of phenformin. Together, our data show the existence of a non-canonical UPR whose activation requires the cytosolic kinase AMPK, adding another layer of complexity to UPR activation upon metabolic stress.

Requirement of GM2 ganglioside activator for phospholipase D activation

PubMed Central

Nakamura, Shun-ichi; Akisue, Toshihiro; Jinnai, Hitoshi; Hitomi, Tomohiro; Sarkar, Sukumar; Miwa, Noriko; Okada, Taro; Yoshida, Kimihisa; Kuroda, Shun’ichi; Kikkawa, Ushio; Nishizuka, Yasutomi

1998-01-01

Sequence analysis of a heat-stable protein necessary for the activation of ADP ribosylation factor-dependent phospholipase D (PLD) reveals that this protein has a structure highly homologous to the previously known GM2 ganglioside activator whose deficiency results in the AB-variant of GM2 gangliosidosis. The heat-stable activator protein indeed has the capacity to enhance enzymatic conversion of GM2 to GM3 ganglioside that is catalyzed by β-hexosaminidase A. Inversely, GM2 ganglioside activator purified separately from tissues as described earlier [Conzelmann, E. & Sandhoff, K. (1987) Methods Enzymol. 138, 792–815] stimulates ADP ribosylation factor-dependent PLD in a dose-dependent manner. At higher concentrations of ammonium sulfate, the PLD activator protein apparently substitutes for protein kinase C and phosphatidylinositol 4,5-bisphosphate, both of which are known as effective stimulators of the PLD reaction. The mechanism of action of the heat-stable PLD activator protein remains unknown. PMID:9770472

Fate of Carbohydrates and Lignin during Composting and Mycelium Growth of Agaricus bisporus on Wheat Straw Based Compost

PubMed Central

Jurak, Edita; Punt, Arjen M.; Arts, Wim; Kabel, Mirjam A.; Gruppen, Harry

2015-01-01

In wheat straw based composting, enabling growth of Agaricus bisporus mushrooms, it is unknown to which extent the carbohydrate-lignin matrix changes and how much is metabolized. In this paper we report yields and remaining structures of the major components. During the Phase II of composting 50% of both xylan and cellulose were metabolized by microbial activity, while lignin structures were unaltered. During A. bisporus’ mycelium growth (Phase III) carbohydrates were only slightly consumed and xylan was found to be partially degraded. At the same time, lignin was metabolized for 45% based on pyrolysis GC/MS. Remaining lignin was found to be modified by an increase in the ratio of syringyl (S) to guaiacyl (G) units from 0.5 to 0.7 during mycelium growth, while fewer decorations on the phenolic skeleton of both S and G units remained. PMID:26436656

Vibrissa motor cortex activity suppresses contralateral whisking behavior.

PubMed

Ebbesen, Christian Laut; Doron, Guy; Lenschow, Constanze; Brecht, Michael

2017-01-01

Anatomical, stimulation and lesion data implicate vibrissa motor cortex in whisker motor control. Work on motor cortex has focused on movement generation, but correlations between vibrissa motor cortex activity and whisking are weak. The exact role of vibrissa motor cortex remains unknown. We recorded vibrissa motor cortex neurons during various forms of vibrissal touch, which were invariably associated with whisker protraction and movement. Free whisking, object palpation and social touch all resulted in decreased cortical activity. To understand this activity decrease, we performed juxtacellular recordings, nanostimulation and in vivo whole-cell recordings. Social touch resulted in decreased spiking activity, decreased cell excitability and membrane hyperpolarization. Activation of vibrissa motor cortex by intracortical microstimulation elicited whisker retraction, as if to abort vibrissal touch. Various vibrissa motor cortex inactivation protocols resulted in contralateral protraction and increased whisker movements. These data collectively point to movement suppression as a prime function of vibrissa motor cortex activity.

Activation of VTA GABA neurons disrupts reward consumption

PubMed Central

van Zessen, Ruud; Phillips, Jana L.; Budygin, Evgeny A.; Stuber, Garret D.

2012-01-01

The activity of Ventral Tegmental Area (VTA) dopamine (DA) neurons promotes behavioral responses to rewards and environmental stimuli that predict them. VTA GABA inputs synapse directly onto DA neurons and may regulate DA neuronal activity to alter reward-related behaviors, however, the functional consequences of selective activation of VTA GABA neurons remains unknown. Here, we show that in vivo optogenetic activation of VTA GABA neurons disrupts reward consummatory behavior, but not conditioned anticipatory behavior in response to reward-predictive cues. In addition, direct activation of VTA GABA projections to the nucleus accumbens (NAc) resulted in detectable GABA release, but did not alter reward consumption. Furthermore, optogenetic stimulation of VTA GABA neurons directly suppressed the activity and excitability of neighboring DA neurons, as well as the release of DA in the NAc, suggesting that the dynamic interplay between VTA DA and GABA neurons can control the initiation and termination of reward-related behaviors. PMID:22445345

Genomic and genotyping characterization of haplotype-based polymorphic microsatellites in Prunus

USDA-ARS?s Scientific Manuscript database

Efficient utilization of microsatellites in genetic studies remains impeded largely due to the unknown status of their primer reliability, chromosomal location, and allele polymorphism. Discovery and characterization of microsatellite polymorphisms in a taxon will disclose the unknowns and gain new ...

Obese individuals with more components of the metabolic syndrome and/or prediabetes demonstrate decreased activation of reward-related brain centers in response to food cues in both the fed and fasting states: a preliminary fMRI study.

PubMed

Farr, O M; Mantzoros, C S

2017-03-01

It remains unknown whether obese individuals with more components of the metabolic syndrome and/or prediabetes demonstrate altered activation of brain centers in response to food cues. We examined obese individuals with prediabetes (n=26) vs obese individuals without prediabetes (n=11) using fMRI. We also performed regression analyses on the basis of the number of MetS components per subject. Obese individuals with prediabetes have decreased activation of the reward-related putamen in the fasting state and decreased activation of the salience- and reward-related insula after eating. Obese individuals with more components of MetS demonstrate decreased activation of the putamen while fasting. All these activations remain significant when corrected for BMI, waist circumference (WC), HbA1c and gender. Decreased activation in the reward-related central nervous system areas among the obese is more pronounced in subjects with prediabetes and MetS. Prospective studies are needed to quantify their contributions to the development of prediabetes/MetS and to study whether they may predispose to the exacerbation of obesity and the development of comorbidities over time.

76 FR 75907 - Notice of Inventory Completion: Minnesota Indian Affairs Council, Bemidji, MN

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-05

...''). History and Description of the Remains At an unknown date, human remains representing, at minimum, two.... SUMMARY: The Minnesota Indian Affairs Council has completed an inventory of human remains and associated... tribe that believes itself to be culturally affiliated with the human remains may contact the Minnesota...

Familial polycystic ovarian disease.

PubMed

Givens, J R

1988-12-01

Emphasis is placed on the heterogeneity of the phenotypic presentation of PCOD. It is the common expression of an unknown number of disorders and thus is a sign and not a specific diagnosis. Two essential features are arrested follicular maturation and atresia of follicles. Normal folliculogenesis is described, emphasizing that a large number of areas could be subject to derangement causing PCOD. Any interference of the finely balanced sequence of events can lead to PCOD. The genetic defect causing familial PCOD is unknown and the initiating event remains undefined. Three families are described that illustrate four features of familial PCOD. A number of associated disorders such as diabetes, hyperinsulinemia, obesity, and hypertension are described. The potential importance of agents that modulate the LH and FSH activity that may cause PCOD is emphasized. The theoretic means by which similar male and female gonadal abnormalities may be coupled in families through growth factors EGF and alpha TGF are presented.

Inverse transport calculations in optical imaging with subspace optimization algorithms

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

Ding, Tian, E-mail: tding@math.utexas.edu; Ren, Kui, E-mail: ren@math.utexas.edu

2014-09-15

Inverse boundary value problems for the radiative transport equation play an important role in optics-based medical imaging techniques such as diffuse optical tomography (DOT) and fluorescence optical tomography (FOT). Despite the rapid progress in the mathematical theory and numerical computation of these inverse problems in recent years, developing robust and efficient reconstruction algorithms remains a challenging task and an active research topic. We propose here a robust reconstruction method that is based on subspace minimization techniques. The method splits the unknown transport solution (or a functional of it) into low-frequency and high-frequency components, and uses singular value decomposition to analyticallymore » recover part of low-frequency information. Minimization is then applied to recover part of the high-frequency components of the unknowns. We present some numerical simulations with synthetic data to demonstrate the performance of the proposed algorithm.« less

Proteolytic Activation Transforms Heparin Cofactor II into a Host Defense Molecule

PubMed Central

Kalle, Martina; Papareddy, Praveen; Kasetty, Gopinath; Tollefsen, Douglas M.; Malmsten, Martin; Mörgelin, Matthias

2013-01-01

The abundant serine proteinase inhibitor heparin cofactor II (HCII) has been proposed to inhibit extravascular thrombin. However, the exact physiological role of this plasma protein remains enigmatic. In this study, we demonstrate a previously unknown role for HCII in host defense. Proteolytic cleavage of the molecule induced a conformational change, thereby inducing endotoxin-binding and antimicrobial properties. Analyses employing representative peptide epitopes mapped these effects to helices A and D. Mice deficient in HCII showed increased susceptibility to invasive infection by Pseudomonas aeruginosa, along with a significantly increased cytokine response. Correspondingly, decreased levels of HCII were observed in wild-type animals challenged with bacteria or endotoxin. In humans, proteolytically cleaved HCII forms were detected during wounding and in association with bacteria. Thus, the protease-induced uncovering of cryptic epitopes in HCII, which transforms the molecule into a host defense factor, represents a previously unknown regulatory mechanism in HCII biology and innate immunity. PMID:23656734

Proteolytic activation transforms heparin cofactor II into a host defense molecule.

PubMed

Kalle, Martina; Papareddy, Praveen; Kasetty, Gopinath; Tollefsen, Douglas M; Malmsten, Martin; Mörgelin, Matthias; Schmidtchen, Artur

2013-06-15

The abundant serine proteinase inhibitor heparin cofactor II (HCII) has been proposed to inhibit extravascular thrombin. However, the exact physiological role of this plasma protein remains enigmatic. In this study, we demonstrate a previously unknown role for HCII in host defense. Proteolytic cleavage of the molecule induced a conformational change, thereby inducing endotoxin-binding and antimicrobial properties. Analyses employing representative peptide epitopes mapped these effects to helices A and D. Mice deficient in HCII showed increased susceptibility to invasive infection by Pseudomonas aeruginosa, along with a significantly increased cytokine response. Correspondingly, decreased levels of HCII were observed in wild-type animals challenged with bacteria or endotoxin. In humans, proteolytically cleaved HCII forms were detected during wounding and in association with bacteria. Thus, the protease-induced uncovering of cryptic epitopes in HCII, which transforms the molecule into a host defense factor, represents a previously unknown regulatory mechanism in HCII biology and innate immunity.

Transferrin receptor facilitates TGF-β and BMP signaling activation to control craniofacial morphogenesis

PubMed Central

Lei, R; Zhang, K; Liu, K; Shao, X; Ding, Z; Wang, F; Hong, Y; Zhu, M; Li, H; Li, H

2016-01-01

The Pierre Robin Sequence (PRS), consisting of cleft palate, glossoptosis and micrognathia, is a common human birth defect. However, how this abnormality occurs remains largely unknown. Here we report that neural crest cell (NCC)-specific knockout of transferrin receptor (Tfrc), a well known transferrin transporter protein, caused micrognathia, cleft palate, severe respiratory distress and inability to suckle in mice, which highly resemble human PRS. Histological and anatomical analysis revealed that the cleft palate is due to the failure of palatal shelves elevation that resulted from a retarded extension of Meckel's cartilage. Interestingly, Tfrc deletion dramatically suppressed both transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling in cranial NCCs-derived mandibular tissues, suggesting that Tfrc may act as a facilitator of these two signaling pathways during craniofacial morphogenesis. Together, our study uncovers an unknown function of Tfrc in craniofacial development and provides novel insight into the etiology of PRS. PMID:27362800

The influence of spontaneous activity on stimulus processing in primary visual cortex.

PubMed

Schölvinck, M L; Friston, K J; Rees, G

2012-02-01

Spontaneous activity in the resting human brain has been studied extensively; however, how such activity affects the local processing of a sensory stimulus is relatively unknown. Here, we examined the impact of spontaneous activity in primary visual cortex on neuronal and behavioural responses to a simple visual stimulus, using functional MRI. Stimulus-evoked responses remained essentially unchanged by spontaneous fluctuations, combining with them in a largely linear fashion (i.e., with little evidence for an interaction). However, interactions between spontaneous fluctuations and stimulus-evoked responses were evident behaviourally; high levels of spontaneous activity tended to be associated with increased stimulus detection at perceptual threshold. Our results extend those found in studies of spontaneous fluctuations in motor cortex and higher order visual areas, and suggest a fundamental role for spontaneous activity in stimulus processing. Copyright © 2011. Published by Elsevier Inc.

Effects of cadmium, naphthalene, and DDVP on gut carbohydrases activity in bream (Abramis brama L. ) and Mozambique tilapia (Oreochromis mossambicus Peters)

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

Golovanova, I.L.; Chuiko, G.M.; Pavlov, D.F.

1994-03-01

Previous research has shown that sublethal concentrations of cadmium, naphthalene and dichlorvos (DDVP) decreased growth rates in bream and Mozambique tilapia. One of the factors known to affect fish growth is the activity of gut digestive enzymes such as of lipases, proteases, carbohydrases. We assumed that toxicant-induced inhibition of the digestive enzyme activity and, consequently, the impaired digestion of food may contribute to the reduction of growth in fish exposed to toxicants. However, the influence of toxicants on digestive enzyme activities is poorly studied. The contribution of toxicant-induced changes of digestive enzymes activity to growth rate retardation in exposed fishmore » remains unknown. The goal of this study was to examine the influence of an organophosphorus insecticide DDVP, a polyaromatic hydrocarbon naphthalene, and a metal cadmium on fish gut carbohydrase (CH) activity. 14 refs., 2 tabs.« less

Predictors of decreased physical activity level over time among adults: a longitudinal study.

PubMed

Dai, Sulan; Wang, Feng; Morrison, Howard

2014-08-01

Leisure-time physical activity (LTPA) plays a key role in chronic disease prevention and health promotion. The impact of life-changing events on LTPA among adults is unknown. To examine the association between life-changing events and decreased LTPA levels. Eight cycles of Canadian National Population Health Survey data were used for this study. A total of 12,901 respondents aged ≥18 years in 1994-1995 completed biannual follow-ups until 2008-2009. The association between life-changing events and decreased LTPA in any 2-year period was assessed with adjustment of potential confounding factors. Data were analyzed in 2012. From 1994-1995 to 2008-2009, nine of ten people changed their LTPA levels. Within each 2-year period, individuals were more likely to decrease their LTPA levels if they married within the 2-year period (men); became or remained overweight/obese (women); remained a regular smoker (men); became or remained unhealthy (men and women); developed or continued to have body pain (women); and acquired social support or remained without support (men). Most people change their LTPA levels or patterns, which are significantly influenced by life-changing events. An improved understanding of factors that influence LTPA may help better target those at high risk. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

The α-Secretase-derived N-terminal Product of Cellular Prion, N1, Displays Neuroprotective Function in Vitro and in Vivo*

PubMed Central

Guillot-Sestier, Marie-Victoire; Sunyach, Claire; Druon, Charlotte; Scarzello, Sabine; Checler, Frédéric

2009-01-01

Cellular prion protein (PrPc) undergoes a disintegrin-mediated physiological cleavage, generating a soluble amino-terminal fragment (N1), the function of which remained unknown. Recombinant N1 inhibits staurosporine-induced caspase-3 activation by modulating p53 transcription and activity, whereas the PrPc-derived pathological fragment (N2) remains biologically inert. Furthermore, N1 protects retinal ganglion cells from hypoxia-induced apoptosis, reduces the number of terminal deoxynucleotidyltransferase-mediated biotinylated UTP nick end labeling-positive and p53-immunoreactive neurons in a pressure-induced ischemia model of the rat retina and triggers a partial recovery of b-waves but not a-waves of rat electroretinograms. Our work is the first demonstration that the α-secretase-derived PrPc fragment N1, but not N2, displays in vivo and in vitro neuroprotective function by modulating p53 pathway. It further demonstrates that distinct N-terminal cleavage products of PrPc harbor different biological activities underlying the various phenotypes linking PrPc to cell survival. PMID:19850936

Local variance of atmospheric 14C concentrations around Fukushima Dai-ichi Nuclear Power Plant from 2010 to 2012.

PubMed

Chen, Biying; Xu, Sheng; Cook, Gordon T; Freeman, Stewart P H T; Hou, Xiaolin; Liu, Cong-Qiang; Naysmith, Philip; Yamaguchi, Katsuhiko

2017-01-01

Radiocarbon ( 14 C) has been measured in single tree ring samples collected from the southwest of the Fukushima Dai-ichi Nuclear Power Plant. Our data indicate south-westwards dispersion of radiocarbon and the highest 14 C activity observed so far in the local environment during the 2011 accident. The abnormally high 14 C activity in the late wood of 2011 ring may imply an unknown source of radiocarbon nearby after the accident. The influence of 14 C shrank from 30 km during normal reactor operation to 14 km for the accident in the northwest of FDNPP, but remains unclear in the southwest.

Remaining useful life prediction of degrading systems subjected to imperfect maintenance: Application to draught fans

NASA Astrophysics Data System (ADS)

Wang, Zhao-Qiang; Hu, Chang-Hua; Si, Xiao-Sheng; Zio, Enrico

2018-02-01

Current degradation modeling and remaining useful life prediction studies share a common assumption that the degrading systems are not maintained or maintained perfectly (i.e., to an as-good-as new state). This paper concerns the issues of how to model the degradation process and predict the remaining useful life of degrading systems subjected to imperfect maintenance activities, which can restore the health condition of a degrading system to any degradation level between as-good-as new and as-bad-as old. Toward this end, a nonlinear model driven by Wiener process is first proposed to characterize the degradation trajectory of the degrading system subjected to imperfect maintenance, where negative jumps are incorporated to quantify the influence of imperfect maintenance activities on the system's degradation. Then, the probability density function of the remaining useful life is derived analytically by a space-scale transformation, i.e., transforming the constructed degradation model with negative jumps crossing a constant threshold level to a Wiener process model crossing a random threshold level. To implement the proposed method, unknown parameters in the degradation model are estimated by the maximum likelihood estimation method. Finally, the proposed degradation modeling and remaining useful life prediction method are applied to a practical case of draught fans belonging to a kind of mechanical systems from steel mills. The results reveal that, for a degrading system subjected to imperfect maintenance, our proposed method can obtain more accurate remaining useful life predictions than those of the benchmark model in literature.

Suppression of LPS-induced inflammatory responses by the hydroxyl groups of dexamethasone

PubMed Central

Chuang, Ting-Yun; Cheng, An-Jie; Chen, I-Ting; Lan, Tien-Yun; Huang, I-Hsuan; Shiau, Chung-Wai; Hsu, Chia-Lin; Liu, Ya-Wen; Chang, Zee-Fen; Tseng, Ping-Hui; Kuo, Jean-Cheng

2017-01-01

The innate immune response is a central process that is activated during pathogenic infection in order to maintain physiological homeostasis. It is well known that dexamethasone (Dex), a synthetic glucocorticoid, is a potent immunosuppressant that inhibits the cytokine production induced by bacterial lipopolysaccharides (LPS). Nevertheless, the extent to which the functional groups of Dex control the excessive activation of inflammatory reactions remains unknown. Furthermore, importantly, the role of Dex in the innate immune response remains unclear. Here we explore the mechanism of LPS-induced TNF-α secretion and reveal p38 MAPK signaling as a target of Dex that is involved in control of tumor necrosis factor-α (TNF-α)-converting enzyme (TACE) activity; that later mediates the shedding of TNF-α that allows its secretion. We further demonstrate that the 11-hydroxyl and 21-hydroxyl groups of Dex are the main groups that are involved in reducing LPS-induced TNF-α secretion by activated macrophages. Blockage of the hydroxyl groups of Dex inhibits immunosuppressant effect of Dex during LPS-induced TNF-α secretion and mouse mortality. Our findings demonstrate Dex signaling is involved in the control of innate immunity. PMID:28537905

Choosing Money over Drugs: The Neural Underpinnings of Difficult Choice in Chronic Cocaine Users.

PubMed

Wesley, Michael J; Lohrenz, Terry; Koffarnus, Mikhail N; McClure, Samuel M; De La Garza, Richard; Salas, Ramiro; Thompson-Lake, Daisy G Y; Newton, Thomas F; Bickel, Warren K; Montague, P Read

2014-01-01

Addiction is considered a disorder that drives individuals to choose drugs at the expense of healthier alternatives. However, chronic cocaine users (CCUs) who meet addiction criteria retain the ability to choose money in the presence of the opportunity to choose cocaine. The neural mechanisms that differentiate CCUs from non-cocaine using controls (Controls) while executing these preferred choices remain unknown. Thus, therapeutic strategies aimed at shifting preferences towards healthier alternatives remain somewhat uninformed. This study used BOLD neuroimaging to examine brain activity as fifty CCUs and Controls performed single- and cross-commodity intertemporal choice tasks for money and/or cocaine. Behavioral analyses revealed preferences for each commodity type. Imaging analyses revealed the brain activity that differentiated CCUs from Controls while choosing money over cocaine. We observed that CCUs devalued future commodities more than Controls. Choices for money as opposed to cocaine correlated with greater activity in dorsal striatum of CCUs, compared to Controls. In addition, choices for future money as opposed to immediate cocaine engaged the left dorsolateral prefrontal cortex (DLPFC) of CCUs more than Controls. These data suggest that the ability of CCUs to execute choices away from cocaine relies on activity in the dorsal striatum and left DLPFC.

Neuromodulation to the Rescue: Compensation of Temperature-Induced Breakdown of Rhythmic Motor Patterns via Extrinsic Neuromodulatory Input

PubMed Central

Städele, Carola; Heigele, Stefanie; Stein, Wolfgang

2015-01-01

Stable rhythmic neural activity depends on the well-coordinated interplay of synaptic and cell-intrinsic conductances. Since all biophysical processes are temperature dependent, this interplay is challenged during temperature fluctuations. How the nervous system remains functional during temperature perturbations remains mostly unknown. We present a hitherto unknown mechanism of how temperature-induced changes in neural networks are compensated by changing their neuromodulatory state: activation of neuromodulatory pathways establishes a dynamic coregulation of synaptic and intrinsic conductances with opposing effects on neuronal activity when temperature changes, hence rescuing neuronal activity. Using the well-studied gastric mill pattern generator of the crab, we show that modest temperature increase can abolish rhythmic activity in isolated neural circuits due to increased leak currents in rhythm-generating neurons. Dynamic clamp-mediated addition of leak currents was sufficient to stop neuronal oscillations at low temperatures, and subtraction of additional leak currents at elevated temperatures was sufficient to rescue the rhythm. Despite the apparent sensitivity of the isolated nervous system to temperature fluctuations, the rhythm could be stabilized by activating extrinsic neuromodulatory inputs from descending projection neurons, a strategy that we indeed found to be implemented in intact animals. In the isolated nervous system, temperature compensation was achieved by stronger extrinsic neuromodulatory input from projection neurons or by augmenting projection neuron influence via bath application of the peptide cotransmitter Cancer borealis tachykinin-related peptide Ia (CabTRP Ia). CabTRP Ia activates the modulator-induced current IMI (a nonlinear voltage-gated inward current) that effectively acted as a negative leak current and counterbalanced the temperature-induced leak to rescue neuronal oscillations. Computational modelling revealed the ability of IMI to reduce detrimental leak-current influences on neuronal networks over a broad conductance range and indicated that leak and IMI are closely coregulated in the biological system to enable stable motor patterns. In conclusion, these results show that temperature compensation does not need to be implemented within the network itself but can be conditionally provided by extrinsic neuromodulatory input that counterbalances temperature-induced modifications of circuit-intrinsic properties. PMID:26417944

Macrophage activation induced by Brucella DNA suppresses bacterial intracellular replication via enhancing NO production.

PubMed

Liu, Ning; Wang, Lin; Sun, Changjiang; Yang, Li; Tang, Bin; Sun, Wanchun; Peng, Qisheng

2015-12-01

Brucella DNA can be sensed by TLR9 on endosomal membrane and by cytosolic AIM2-inflammasome to induce proinflammatory cytokine production that contributes to partially activate innate immunity. Additionally, Brucella DNA has been identified to be able to act as a major bacterial component to induce type I IFN. However, the role of Brucella DNA in Brucella intracellular growth remains unknown. Here, we showed that stimulation with Brucella DNA promote macrophage activation in TLR9-dependent manner. Activated macrophages can suppresses wild type Brucella intracellular replication at early stage of infection via enhancing NO production. We also reported that activated macrophage promotes bactericidal function of macrophages infected with VirB-deficient Brucella at the early or late stage of infection. This study uncovers a novel function of Brucella DNA, which can help us further elucidate the mechanism of Brucella intracellular survival. Copyright © 2015 Elsevier Ltd. All rights reserved.

Sexual attraction enhances glutamate transmission in mammalian anterior cingulate cortex

PubMed Central

Wu, Long-Jun; Kim, Susan S; Li, Xiangyao; Zhang, Fuxing; Zhuo, Min

2009-01-01

Functional human brain imaging studies have indicated the essential role of cortical regions, such as the anterior cingulate cortex (ACC), in romantic love and sex. However, the neurobiological basis of how the ACC neurons are activated and engaged in sexual attraction remains unknown. Using transgenic mice in which the expression of green fluorescent protein (GFP) is controlled by the promoter of the activity-dependent gene c-fos, we found that ACC pyramidal neurons are activated by sexual attraction. The presynaptic glutamate release to the activated neurons is increased and pharmacological inhibition of neuronal activities in the ACC reduced the interest of male mice to female mice. Our results present direct evidence of the critical role of the ACC in sexual attraction, and long-term increases in glutamate mediated excitatory transmission may contribute to sexual attraction between male and female mice. PMID:19419552

A Map of Anticipatory Activity in Mouse Motor Cortex.

PubMed

Chen, Tsai-Wen; Li, Nuo; Daie, Kayvon; Svoboda, Karel

2017-05-17

Activity in the mouse anterior lateral motor cortex (ALM) instructs directional movements, often seconds before movement initiation. It is unknown whether this preparatory activity is localized to ALM or widely distributed within motor cortex. Here we imaged activity across motor cortex while mice performed a whisker-based object localization task with a delayed, directional licking response. During tactile sensation and the delay epoch, object location was represented in motor cortex areas that are medial and posterior relative to ALM, including vibrissal motor cortex. Preparatory activity appeared first in deep layers of ALM, seconds before the behavioral response, and remained localized to ALM until the behavioral response. Later, widely distributed neurons represented the outcome of the trial. Cortical area was more predictive of neuronal selectivity than laminar location or axonal projection target. Motor cortex therefore represents sensory, motor, and outcome information in a spatially organized manner. Copyright © 2017 Elsevier Inc. All rights reserved.

RPA-Binding Protein ETAA1 Is an ATR Activator Involved in DNA Replication Stress Response.

PubMed

Lee, Yuan-Cho; Zhou, Qing; Chen, Junjie; Yuan, Jingsong

2016-12-19

ETAA1 (Ewing tumor-associated antigen 1), also known as ETAA16, was identified as a tumor-specific antigen in the Ewing family of tumors. However, the biological function of this protein remains unknown. Here, we report the identification of ETAA1 as a DNA replication stress response protein. ETAA1 specifically interacts with RPA (Replication protein A) via two conserved RPA-binding domains and is therefore recruited to stalled replication forks. Interestingly, further analysis of ETAA1 function revealed that ETAA1 participates in the activation of ATR signaling pathway via a conserved ATR-activating domain (AAD) located near its N terminus. Importantly, we demonstrate that both RPA binding and ATR activation are required for ETAA1 function at stalled replication forks to maintain genome stability. Therefore, our data suggest that ETAA1 is a new ATR activator involved in replication checkpoint control. Copyright © 2016 Elsevier Ltd. All rights reserved.

78 FR 2433 - Notice of Inventory Completion: Fort Collins Museum of Discovery, Fort Collins, CO

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-11

... Discovery). Although specific provenience of the human remains is unknown, osteological analysis conducted by physical anthropologists and by independent forensic scientists determined that the remains are of...

Activity-induced histone modifications govern Neurexin-1 mRNA splicing and memory preservation.

PubMed

Ding, Xinlu; Liu, Sanxiong; Tian, Miaomiao; Zhang, Wenhao; Zhu, Tao; Li, Dongdong; Wu, Jiawei; Deng, HaiTeng; Jia, Yichang; Xie, Wei; Xie, Hong; Guan, Ji-Song

2017-05-01

Epigenetic mechanisms regulate the formation, consolidation and reconsolidation of memories. However, the signaling path from neuronal activation to epigenetic modifications within the memory-related brain circuit remains unknown. We report that learning induces long-lasting histone modifications in hippocampal memory-activated neurons to regulate memory stability. Neuronal activity triggers a late-onset shift in Nrxn1 splice isoform choice at splicing site 4 by accumulating a repressive histone marker, H3K9me3, to modulate the splicing process. Activity-dependent phosphorylation of p66α via AMP-activated protein kinase recruits HDAC2 and Suv39h1 to establish repressive histone markers and changes the connectivity of the activated neurons. Removal of Suv39h1 abolished the activity-dependent shift in Nrxn1 splice isoform choice and reduced the stability of established memories. We uncover a cell-autonomous process for memory preservation in which memory-related neurons initiate a late-onset reduction of their rewiring capacities through activity-induced histone modifications.

Lactic acid bacterial symbionts in honeybees - an unknown key to honey's antimicrobial and therapeutic activities.

PubMed

Olofsson, Tobias C; Butler, Èile; Markowicz, Pawel; Lindholm, Christina; Larsson, Lennart; Vásquez, Alejandra

2016-10-01

Could honeybees' most valuable contribution to mankind besides pollination services be alternative tools against infections? Today, due to the emerging antibiotic-resistant pathogens, we are facing a new era of searching for alternative tools against infections. Natural products such as honey have been applied against human's infections for millennia without sufficient scientific evidence. A unique lactic acid bacterial (LAB) microbiota was discovered by us, which is in symbiosis with honeybees and present in large amounts in fresh honey across the world. This work investigates if the LAB symbionts are the source to the unknown factors contributing to honey's properties. Hence, we tested the LAB against severe wound pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa and vancomycin-resistant Enterococcus (VRE) among others. We demonstrate a strong antimicrobial activity from each symbiont and a synergistic effect, which counteracted all the tested pathogens. The mechanisms of action are partly shown by elucidating the production of active compounds such as proteins, fatty acids, anaesthetics, organic acids, volatiles and hydrogen peroxide. We show that the symbionts produce a myriad of active compounds that remain in variable amounts in mature honey. Further studies are now required to investigate if these symbionts have a potential in clinical applications as alternative tools against topical human and animal infections. © 2014 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.

Reproductive endocrinology in chondrichthyans: the present and the future.

PubMed

Awruch, C A

2013-10-01

The class Chondrichthyes, that includes Elasmobranchii and Holocephali, is a diverse group of fish occupying a key position at the base of vertebrate evolution. Their evolutionary success is greatly attributed to their wide range of reproductive strategies controlled by different endocrine mechanics. As in other vertebrates, hormonal control of reproduction in chondrichthyans is mediated by the neuropeptide gonadotropin-releasing hormone (GnRH) that regulates the brain control of gonadal activity via a hypothalamus-pituitary-gonadal (HPG) axis. Chondrichthyans lack of a direct vascular supply from the hypothalamus to the zone of the pituitary where the gonadotropic activity resides, thus transport between these two zones likely occurs via the general circulation. In the brain of elasmobranchs, two groups of GnRH, GnRH-I and GnRH-II were identified, and the presence of two immunoreactive gonadotropins similar to the luteinising (LH) and follicle stimulating (FSH) hormones was identified in the pituitary. In holocephalans, only GnRH-II has been confirmed, and while gonadotropin activity has been found in the buccal pituitary lobe, the presence of gonadotropin receptors in the gonads remains unknowns. The diversity of reproductive strategies display by chondrichthyans makes it difficult to generalize the control of gametogenesis and steroidogenesis; however, some general patterns emerge. In both sexes, androgens and estrogens are the main steroids during gonadal growth; while progestins have maturational activity. Androgens also form the precursors for estrogen steroid production. Estrogens stimulate the hepatic synthesis of yolk and stimulate the development of different part of the reproductive tract in females. The role of other gonadal steroids may play in chondrichthyan reproduction remains largely unknown. Future work should concentrate in filling the gaps into the current knowledge of the HPG axis regulation, and the use of reproductive endocrinology as a non-lethal technique for management of chondrichthyan populations. Copyright © 2013 Elsevier Inc. All rights reserved.

Salivary Alpha-Amylase Activity Levels in Catatonic Schizophrenia Decrease after Electroconvulsive Therapy.

PubMed

Kanayama, Misako; Miyaoka, Tsuyoshi; Araki, Tomoko; Hayashida, Maiko; Hashioka, Sadayuki; Horiguchi, Jun

2018-01-01

Dysfunction of the autonomic nervous system (ANS) in schizophrenia has been detected by electrophysiological methods, but the underlying mechanisms remain unknown. Several studies have suggested that measuring salivary alpha-amylase activity levels is useful for evaluating the ANS activity and that sAA levels increase in schizophrenia and correlate with Brief Psychiatric Rating Scale (BPRS) scores. However, no study has examined the relationship between sAA activity levels and symptoms of schizophrenia with catatonic state. We present the case of a 59-year-old female with persistent catatonic schizophrenia treated by electroconvulsive therapy. We evaluated the ANS activity by measuring sAA activity levels before and after ECT, and we evaluated her symptoms using the BPRS and Bush-Francis Catatonia Rating Scale (BFCRS). ECT was highly effective and BPRS and BFCRS scores substantially decreased. sAA activity levels decreased from 125 kU/l to 33 kU/l. sAA activity levels could be a potential biomarker of schizophrenia with catatonic state.

Cytoprotective signaling by activated protein C requires protease-activated receptor-3 in podocytes

PubMed Central

Madhusudhan, Thati; Wang, Hongjie; Straub, Beate K.; Gröne, Elisabeth; Zhou, Qianxing; Shahzad, Khurrum; Müller-Krebs, Sandra; Schwenger, Vedat; Gerlitz, Bruce; Grinnell, Brian W.; Griffin, John H.; Reiser, Jochen; Gröne, Hermann-Josef; Esmon, Charles T.; Nawroth, Peter P.

2012-01-01

The cytoprotective effects of activated protein C (aPC) are well established. In contrast, the receptors and signaling mechanism through which aPC conveys cytoprotection in various cell types remain incompletely defined. Thus, within the renal glomeruli, aPC preserves endothelial cells via a protease-activated receptor-1 (PAR-1) and endothelial protein C receptor-dependent mechanism. Conversely, the signaling mechanism through which aPC protects podocytes remains unknown. While exploring the latter, we identified a novel aPC/PAR-dependent cytoprotective signaling mechanism. In podocytes, aPC inhibits apoptosis through proteolytic activation of PAR-3 independent of endothelial protein C receptor. PAR-3 is not signaling competent itself as it requires aPCinduced heterodimerization with PAR-2 (human podocytes) or PAR-1 (mouse podocytes). This cytoprotective signaling mechanism depends on caveolin-1 dephosphorylation. In vivo aPC protects against lipopolysaccharide-induced podocyte injury and proteinuria. Genetic deletion of PAR-3 impairs the nephroprotective effect of aPC, demonstrating the crucial role of PAR-3 for aPC-dependent podocyte protection. This novel, aPC-mediated interaction of PARs demonstrates the plasticity and cell-specificity of cytoprotective aPC signaling. The evidence of specific, dynamic signaling complexes underlying aPC-mediated cytoprotection may allow the design of cell type specific targeted therapies. PMID:22117049

[Pseudomigraine with pleocytosis].

PubMed

Pariso, Gabriela S; Parisi, Virginia L; Persi, Gabriel G; Canto, Lucila; Rugilo, Carlos A; Gatto, Emilia M

2006-01-01

The syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis or pseudomigraine with temporary neurological symptoms and lymphocytic pleocytosis (HaNDL) is a syndrome consisting of recurrent headaches, reversible neurological deficit, lymphocytic pleocytosis in cerebrospinal fluid (CSF), variable duration over time and spontaneous resolution. Although several etiopathogenic mechanisms have been suggested (vascular, infectous, immunological and calcium channelopthy), its etiology remains unknown. We describe a 28 year old female, with recurrent migraine with pleocytosis, confusional syndrome and transient neurological deficit. The clinical remission was achieved within two months. Although its etiology remains unknown the differential diagnosis is discussed in order to keep in mind this syndrome.

Identification of signalling cascades involved in red blood cell shrinkage and vesiculation.

PubMed

Kostova, Elena B; Beuger, Boukje M; Klei, Thomas R L; Halonen, Pasi; Lieftink, Cor; Beijersbergen, Roderick; van den Berg, Timo K; van Bruggen, Robin

2015-04-16

Even though red blood cell (RBC) vesiculation is a well-documented phenomenon, notably in the context of RBC aging and blood transfusion, the exact signalling pathways and kinases involved in this process remain largely unknown. We have established a screening method for RBC vesicle shedding using the Ca(2+) ionophore ionomycin which is a rapid and efficient method to promote vesiculation. In order to identify novel pathways stimulating vesiculation in RBC, we screened two libraries: the Library of Pharmacologically Active Compounds (LOPAC) and the Selleckchem Kinase Inhibitor Library for their effects on RBC from healthy donors. We investigated compounds triggering vesiculation and compounds inhibiting vesiculation induced by ionomycin. We identified 12 LOPAC compounds, nine kinase inhibitors and one kinase activator which induced RBC shrinkage and vesiculation. Thus, we discovered several novel pathways involved in vesiculation including G protein-coupled receptor (GPCR) signalling, the phosphoinositide 3-kinase (PI3K)-Akt (protein kinase B) pathway, the Jak-STAT (Janus kinase-signal transducer and activator of transcription) pathway and the Raf-MEK (mitogen-activated protein kinase kinase)-ERK (extracellular signal-regulated kinase) pathway. Moreover, we demonstrated a link between casein kinase 2 (CK2) and RBC shrinkage via regulation of the Gardos channel activity. In addition, our data showed that inhibition of several kinases with unknown functions in mature RBC, including Alk (anaplastic lymphoma kinase) kinase and vascular endothelial growth factor receptor 2 (VEGFR-2), induced RBC shrinkage and vesiculation.

Identification of signalling cascades involved in red blood cell shrinkage and vesiculation

PubMed Central

Kostova, Elena B.; Beuger, Boukje M.; Klei, Thomas R.L.; Halonen, Pasi; Lieftink, Cor; Beijersbergen, Roderick; van den Berg, Timo K.; van Bruggen, Robin

2015-01-01

Even though red blood cell (RBC) vesiculation is a well-documented phenomenon, notably in the context of RBC aging and blood transfusion, the exact signalling pathways and kinases involved in this process remain largely unknown. We have established a screening method for RBC vesicle shedding using the Ca2+ ionophore ionomycin which is a rapid and efficient method to promote vesiculation. In order to identify novel pathways stimulating vesiculation in RBC, we screened two libraries: the Library of Pharmacologically Active Compounds (LOPAC) and the Selleckchem Kinase Inhibitor Library for their effects on RBC from healthy donors. We investigated compounds triggering vesiculation and compounds inhibiting vesiculation induced by ionomycin. We identified 12 LOPAC compounds, nine kinase inhibitors and one kinase activator which induced RBC shrinkage and vesiculation. Thus, we discovered several novel pathways involved in vesiculation including G protein-coupled receptor (GPCR) signalling, the phosphoinositide 3-kinase (PI3K)–Akt (protein kinase B) pathway, the Jak–STAT (Janus kinase–signal transducer and activator of transcription) pathway and the Raf–MEK (mitogen-activated protein kinase kinase)–ERK (extracellular signal-regulated kinase) pathway. Moreover, we demonstrated a link between casein kinase 2 (CK2) and RBC shrinkage via regulation of the Gardos channel activity. In addition, our data showed that inhibition of several kinases with unknown functions in mature RBC, including Alk (anaplastic lymphoma kinase) kinase and vascular endothelial growth factor receptor 2 (VEGFR-2), induced RBC shrinkage and vesiculation. PMID:25757360

Orally active growth hormone secretagogues: state of the art and clinical perspectives.

PubMed

Ghigo, E; Arvat, E; Camanni, F

1998-04-01

Growth hormone secretagogues (GHS) are synthetic, non-natural peptidyl and nonpeptidyl molecules with potent stimulatory effect on somatotrope secretion. They have no structural homology with growth hormone-releasing hormone (GHRH) and act via a specific receptor, which has now been cloned and is present at both the pituitary and hypothalamic level. This evidence strongly suggests the existence of a still unknown natural GHS-like ligand. Several data favour the hypothesis that GHS could counteract somatostatinergic activity at both the pituitary and hypothalamic level and/or, at least partially, via a GHRH-mediated mechanism. However, the possibility that they act via an unknown hypothalamic factor remains open. GH-releasing peptide-6 (GHRP-6) is the first hexapeptide studied extensively in humans. More recently, peptidyl superanalogues GHRP-1, GHRP-2 and hexarelin, and nonpeptidyl mimetics, such as the spiroindoline derivative MK-677, have been synthesized and their effects have been studied in humans. The GH-releasing activity of GHS is marked, dose related and reproducible after intravenous, subcutaneous, intranasal and even oral administration. The effect of GHS is partially desensitized but prolonged, intermittent oral administration increases insulin-like growth factor I (IGF-I) levels. The GH-releasing effect of GHS undergoes age-related variations; it increases from birth to puberty, remains similar in adulthood and decreases with ageing. The effect of GHS on GH release is synergistic with that of GHRH, while it is only partially refractory to inhibitory influences, which nearly abolish the effect of GHRH. GHS maintain their GH-releasing activity in some somatotrope hypersecretory states such as acromegaly, anorexia nervosa, hyperthyroidism and critical illness. The GH response to GHS has been reported clear although reduced in GH deficiency, obesity and hypothyroidism, while it is strongly reduced in patients with pituitary stalk disconnection or Cushing's syndrome. In short children, elderly subjects, critically ill patients and even in adult patients with GH deficiency an increase of IGF-I has been shown after GHS treatment. These data indicate that treatment with orally active GHS in humans enhances the activity of the GH-IGF-I axis and could be clinically useful.

Heterozygous congenital Factor VII deficiency with the 9729del4 mutation, associated with severe spontaneous intracranial bleeding in an adolescent male.

PubMed

Cramer, Thomas J; Anderson, Kristin; Navaz, Karanjia; Brown, Justin M; Mosnier, Laurent O; von Drygalski, Annette

2016-03-01

In congenital Factor (F) VII deficiency bleeding phenotype and intrinsic FVII activity levels don't always correlate. Patients with FVII activity levels <30% appear to have a higher bleeding propensity, but bleeding can also occur at higher FVII activity levels. Reasons for bleeding at higher FVII activity levels are unknown, and it remains challenging to manage such patients clinically. A 19year old male with spontaneous intracranial hemorrhage and FVII activity levels of 44%, requiring emergent surgical intervention and a strategy for FVII replacement. Genotyping showed the rare heterozygous FVII 9729del4 mutation. Bleed evacuation was complicated by epidural abscess requiring craniectomy, bone graft procedures, and prolonged administration of recombinant human (rh) activated FVII (FVIIa). The patient recovered without neurological deficits, and remains on prophylactic low dose treatment with rhFVIIa in relation to risky athletic activities. For clinicians, it is important to recognize that effects of rhFVIIa within these pathways are independent of its contribution to blood clot formation and cannot be assessed by clotting assays. Reduced FVII levels should therefore not be dismissed, as even a mild reduction may result in spontaneous bleeding. Treatment of mild FVII deficiency requires a careful case-by-case approach, based on the clinical scenario. Copyright © 2015 Elsevier Inc. All rights reserved.

Endemic Venezuelan equine encephalitis in the Americas: hidden under the dengue umbrella

PubMed Central

Aguilar, Patricia V; Estrada-Franco, Jose G; Navarro-Lopez, Roberto; Ferro, Cristina; Haddow, Andrew D; Weaver, Scott C

2011-01-01

Venezuelan equine encephalitis (VEE) is an emerging infectious disease in Latin America. Outbreaks have been recorded for decades in countries with enzootic circulation, and the recent implementation of surveillance systems has allowed the detection of additional human cases in countries and areas with previously unknown VEE activity. Clinically, VEE is indistinguishable from dengue and other arboviral diseases and confirmatory diagnosis requires the use of specialized laboratory tests that are difficult to afford in resource-limited regions. Thus, the disease burden of endemic VEE in developing countries remains largely unknown, but recent surveillance suggests that it may represent up to 10% of the dengue burden in neotropical cities, or tens-of-thousands of cases per year throughout Latin America. The potential emergence of epizootic viruses from enzootic progenitors further highlights the need to strengthen surveillance activities, identify mosquito vectors and reservoirs and develop effective strategies to control the disease. In this article, we provide an overview of the current status of endemic VEE that results from spillover of the enzootic cycles, and we discuss public health measures for disease control as well as future avenues for VEE research. PMID:21765860

Risk Assessment Using Cytochrome P450 Time-Dependent Inhibition Assays at Single Time and Concentration in the Early Stage of Drug Discovery.

PubMed

Kosaka, Mai; Kosugi, Yohei; Hirabayashi, Hideki

2017-09-01

In this article, we proposed a risk assessment strategy for CYP3A time-dependent inhibition (TDI) during drug discovery based on a thorough retrospective study of 13 reference drugs, some of which are known to have in vitro TDI potential but have unknown clinical relevance. First, the traditional parameter k inact /K I , recommended by regulatory authorities for necessity decision making in clinical drug-drug interaction (DDI) studies, was investigated as a predictive index for clinical TDI liability. The cutoff value of 1.1 for k inact /K I , established by the Food and Drug Administration, tended to produce false-positive prediction results for clinical DDI occurrence. The value of 1.25 recommended in the European Medicines Evaluation Agency draft guideline yielded better predictions with only 1 false negative for diltiazem. Second, to enable earlier risk assessment, remaining activity, defined as the residual CYP3A activity in vitro obtained in the screening conditions, was investigated as an alternative index. As a result, the ratios of unbound C max or area under the curve to remaining activity precisely predicted clinical DDI occurrence. In conclusion, we demonstrated the predictive power of k inact /K I and remaining activity values for clinical DDIs. These findings provide insights that enable TDI risk assessment, even during drug discovery. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Non-apoptotic function of BAD and BAX in long-term depression of synaptic transmission

PubMed Central

Jiao, Song; Li, Zheng

2011-01-01

Summary It has recently been found that caspases not only function in apoptosis, but are also crucial for non-apoptotic processes such as NMDA receptor-dependent long-term depression (LTD) of synaptic transmission. It remains unknown, however, how caspases are activated and how neurons escape death in LTD. Here we show that caspase-3 is activated by the BAD-BAX cascade for LTD induction. This cascade is required specifically for NMDA receptor-dependent LTD but not for mGluR-LTD, and its activation is sufficient to induce synaptic depression. In contrast to apoptosis, however, BAD is activated only moderately and transiently and BAX is not translocated to mitochondria, resulting in only modest caspase-3 activation. We further demonstrate that the intensity and duration of caspase-3 activation determin whether it leads to cell death or LTD, thus fine-tuning of caspase-3 activation is critical in distinguishing between these two pathways. PMID:21609830

"I remember thinking …": Neural activity associated with subsequent memory for stimulus-evoked internal mentations.

PubMed

Gilead, Michael; Liberman, Nira; Maril, Anat

2014-01-01

Conscious thought involves an interpretive inner monologue pertaining to our waking experiences. Previous studies focused on the mechanisms that allow us to remember externally presented stimuli, but the neurobiological basis of the ability to remember one's internal mentations remains unknown. In order to investigate this question, we presented participants with sentences and scanned their neural activity using functional magnetic resonance imaging (fMRI) as they incidentally produced spontaneous internal mentations. After the scan, we presented the sentences again and asked participants to describe the specific thoughts they had during the initial presentation of each sentence. We categorized experimental trials for each participant according to whether they resulted in subsequently reported internal mentations or not. The results show that activation within classic language processing areas was associated with participants' ability to recollect their thoughts. Activation within mostly right lateralized and medial "default-mode network" regions was associated with not reporting such thoughts.

Activation of VIP signaling enhances immunosuppressive effect of MDSCs on CMV-induced adaptive immunity.

PubMed

Forghani, Parvin; Petersen, Christopher T; Waller, Edmund K

2017-10-10

Vasoactive intestinal peptide (VIP) is recognized as a potent anti-inflammatory factor which affects both the innate and adaptive arms of the immune system. These effects include, but are not limited to, inhibition of T cell proliferation and disruption of immune homeostasis. Myeloid-derived suppressor cells (MDSC) are an immune regulatory cell type that has been described in settings of cancer and infectious disease._Here we demonstrate a reduced circulating monocytic MDSCs in the VIP -/- vs. wild type MCMV. VIP-/- MDSCs secretes less NO upon stimulation with LPS and interferon that relatively lose the ability to suppress T cells activation in vitro compared to wild type MDSCs._Considering the importance of VIP in immunomodulation, the possible effect of VIP in the suppressive function of MDSC populations following CMV infection remains unknown. We describe the possible role of VIP in the regulation of anti-CMV activity of T cells through the activation of MDSCs.

The rise and fall of a human recombination hot spot.

PubMed

Jeffreys, Alec J; Neumann, Rita

2009-05-01

Human meiotic crossovers mainly cluster into narrow hot spots that profoundly influence patterns of haplotype diversity and that may also affect genome instability and sequence evolution. Hot spots also seem to be ephemeral, but processes of hot-spot activation and their subsequent evolutionary dynamics remain unknown. We now analyze the life cycle of a recombination hot spot. Sperm typing revealed a polymorphic hot spot that was activated in cis by a single base change, providing evidence for a primary sequence determinant necessary, though not sufficient, to activate recombination. This activating mutation occurred roughly 70,000 y ago and has persisted to the present, most likely fortuitously through genetic drift despite its systematic elimination by biased gene conversion. Nonetheless, this self-destructive conversion will eventually lead to hot-spot extinction. These findings define a subclass of highly transient hot spots and highlight the importance of understanding hot-spot turnover and how it influences haplotype diversity.

Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization.

PubMed

Hernández-Tiedra, Sonia; Fabriàs, Gemma; Dávila, David; Salanueva, Íñigo J; Casas, Josefina; Montes, L Ruth; Antón, Zuriñe; García-Taboada, Elena; Salazar-Roa, María; Lorente, Mar; Nylandsted, Jesper; Armstrong, Jane; López-Valero, Israel; McKee, Christopher S; Serrano-Puebla, Ana; García-López, Roberto; González-Martínez, José; Abad, José L; Hanada, Kentaro; Boya, Patricia; Goñi, Félix; Guzmán, Manuel; Lovat, Penny; Jäättelä, Marja; Alonso, Alicia; Velasco, Guillermo

2016-11-01

Autophagy is considered primarily a cell survival process, although it can also lead to cell death. However, the factors that dictate the shift between these 2 opposite outcomes remain largely unknown. In this work, we used Δ 9 -tetrahydrocannabinol (THC, the main active component of marijuana, a compound that triggers autophagy-mediated cancer cell death) and nutrient deprivation (an autophagic stimulus that triggers cytoprotective autophagy) to investigate the precise molecular mechanisms responsible for the activation of cytotoxic autophagy in cancer cells. By using a wide array of experimental approaches we show that THC (but not nutrient deprivation) increases the dihydroceramide:ceramide ratio in the endoplasmic reticulum of glioma cells, and this alteration is directed to autophagosomes and autolysosomes to promote lysosomal membrane permeabilization, cathepsin release and the subsequent activation of apoptotic cell death. These findings pave the way to clarify the regulatory mechanisms that determine the selective activation of autophagy-mediated cancer cell death.

Mechanisms of Dendritic Cell Lysosomal Killing of Cryptococcus

NASA Astrophysics Data System (ADS)

Hole, Camaron R.; Bui, Hoang; Wormley, Floyd L.; Wozniak, Karen L.

2012-10-01

Cryptococcus neoformans is an opportunistic pulmonary fungal pathogen that disseminates to the CNS causing fatal meningitis in immunocompromised patients. Dendritic cells (DCs) phagocytose C. neoformans following inhalation. Following uptake, cryptococci translocate to the DC lysosomal compartment and are killed by oxidative and non-oxidative mechanisms. DC lysosomal extracts kill cryptococci in vitro; however, the means of antifungal activity remain unknown. Our studies determined non-oxidative antifungal activity by DC lysosomal extract. We examined DC lysosomal killing of cryptococcal strains, anti-fungal activity of purified lysosomal enzymes, and mechanisms of killing against C. neoformans. Results confirmed DC lysosome fungicidal activity against all cryptococcal serotypes. Purified lysosomal enzymes, specifically cathepsin B, inhibited cryptococcal growth. Interestingly, cathepsin B combined with its enzymatic inhibitors led to enhanced cryptococcal killing. Electron microscopy revealed structural changes and ruptured cryptococcal cell walls following treatment. Finally, additional studies demonstrated that osmotic lysis was responsible for cryptococcal death.

Activation-induced cytidine deaminase (AID) expression in human B-cell precursors is essential for central B-cell tolerance

PubMed Central

Cantaert, Tineke; Schickel, Jean-Nicolas; Bannock, Jason M.; Ng, Yen-Shing; Massad, Christopher; Oe, Tyler; Wu, Renee; Lavoie, Aubert; Walter, Jolan E.; Notarangelo, Luigi D.; Al-Herz, Waleed; Kilic, Sara Sebnem; Ochs, Hans D.; Nonoyama, Shigeaki; Durandy, Anne; Meffre, Eric

2015-01-01

SUMMARY Activation-induced cytidine deaminase (AID), the enzyme mediating class switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes, is essential for the removal of developing autoreactive B cells. How AID mediates central B-cell tolerance remains unknown. We report that AID enzymes were produced in a discrete population of immature B cells that expressed recombination-activating gene 2 (RAG2), suggesting that they undergo secondary recombination to edit autoreactive antibodies. However, most AID+ immature B cells lacked anti-apoptotic MCL-1 and were deleted by apoptosis. AID inhibition using lentiviral-encoded short hairpin (sh)RNA in B cells developing in humanized mice resulted in a failure to remove autoreactive clones. Hence, B-cell intrinsic AID expression mediates central B-cell tolerance potentially through its RAG-coupled genotoxic activity in self-reactive immature B cells. PMID:26546282

MD-2-mediated Ionic Interactions between Lipid A and TLR4 Are Essential for Receptor Activation*

PubMed Central

Meng, Jianmin; Lien, Egil; Golenbock, Douglas T.

2010-01-01

Lipopolysaccharide (LPS) activates innate immune responses through TLR4·MD-2. LPS binds to the MD-2 hydrophobic pocket and bridges the dimerization of two TLR4·MD-2 complexes to activate intracellular signaling. However, exactly how lipid A, the endotoxic moiety of LPS, activates myeloid lineage cells remains unknown. Lipid IVA, a tetra-acylated lipid A precursor, has been used widely as a model for lipid A activation. For unknown reasons, lipid IVA activates proinflammatory responses in rodent cells but inhibits the activity of LPS in human cells. Using stable TLR4-expressing cell lines and purified monomeric MD-2, as well as MD-2-deficient bone marrow-derived macrophages, we found that both mouse TLR4 and mouse MD-2 are required for lipid IVA activation. Computational studies suggested that unique ionic interactions exist between lipid IVA and TLR4 at the dimerization interface in the mouse complex only. The negatively charged 4′-phosphate on lipid IVA interacts with two positively charged residues on the opposing mouse, but not human, TLR4 (Lys367 and Arg434) at the dimerization interface. When replaced with their negatively charged human counterparts Glu369 and Gln436, mouse TLR4 was no longer responsive to lipid IVA. In contrast, human TLR4 gained lipid IVA responsiveness when ionic interactions were enabled by charge reversal at the dimerization interface, defining the basis of lipid IVA species specificity. Thus, using lipid IVA as a selective lipid A agonist, we successfully decoupled and coupled two sequential events required for intracellular signaling: receptor engagement and dimerization, underscoring the functional role of ionic interactions in receptor activation. PMID:20018893

Unraveling a mechanism of honey antibacterial action: polyphenol/H₂O₂-induced oxidative effect on bacterial cell growth and on DNA degradation.

PubMed

Brudzynski, Katrina; Abubaker, Kamal; Miotto, Danielle

2012-07-15

Several compounds with antibacterial activities were identified in honey however, a mechanism by which they lead to bacterial growth inhibition and bacterial death remains still unknown. We recently found that honeys possess DNA degrading activity mediated by honey hydrogen peroxide and an unknown honey component(s). Here we provide evidence that active honeys (MIC90 of 6.25-12.5% v/v) possessed significantly higher levels of phenolics (p<0.02) of higher radical scavenging activities (p<0.005) than honeys of average activity. Removal of H2O2 by catalase eliminated bacteriostatic activities caused by both phenolics and H2O2 suggesting that the growth inhibition resulted from the coupling chemistry between these compounds. Both phenolics and H2O2 were involved in DNA degradation by honeys. Treatment of plasmid DNA with H2O2 alone did not affect the DNA integrity but H2O2 removal from honey by catalase prevented DNA degradation. Polyphenols extracted from honeys degraded plasmid DNA in the presence of H2O2 and Cu(II) in the Fenton-type reaction. The extent of DNA degradation was inversely related to the polyphenol concentration in this system as well as in honeys. At low content, honey polyphenols exerted pro-oxidant activity damaging to DNA. In conclusion, honey phenolics with pro-oxidant activities were necessary intermediates that conferred oxidative action of H2O2. Phenolic/H2O2-induced oxidative stress constituted the mechanism of honey bacteriostatic and DNA damaging activities. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

Active faults of the Baikal depression

USGS Publications Warehouse

Levi, K.G.; Miroshnichenko, A.I.; San'kov, V. A.; Babushkin, S.M.; Larkin, G.V.; Badardinov, A.A.; Wong, H.K.; Colman, S.; Delvaux, D.

1997-01-01

The Baikal depression occupies a central position in the system of the basins of the Baikal Rift Zone and corresponds to the nucleus from which the continental lithosphere began to open. For different reasons, the internal structure of the Lake Baikal basin remained unknown for a long time. In this article, we present for the first time a synthesis of the data concerning the structure of the sedimentary section beneath Lake Baikal, which were obtained by complex seismic and structural investigations, conducted mainly from 1989 to 1992. We make a brief description of the most interesting seismic profiles which provide a rough idea of a sedimentary unit structure, present a detailed structural interpretation and show the relationship between active faults in the lake, heat flow anomalies and recent hydrothermalism.

Neuroligin 3 R451C mutation alters electroencephalography spectral activity in an animal model of autism spectrum disorders.

PubMed

Liu, Jackie J; Grace, Kevin P; Horner, Richard L; Cortez, Miguel A; Shao, Yiwen; Jia, Zhengping

2017-04-07

Human studies demonstrate that sleep impairment is a concurrent comorbidity of autism spectrum disorders (ASD), but its etiology remains largely uncertain. One of the prominent theories of ASD suggests that an imbalance in synaptic excitation/inhibition may contribute to various aspects of ASD, including sleep impairments. Following the identification of Nlgn3 R451C mutation in patients with ASD, its effects on synaptic transmission and social behaviours have been examined extensively in the mouse model. However, the contributory role of this mutation to sleep impairments in ASD remains unknown. In this study, we showed that Nlgn3 R451C knock-in mice, an established genetic model for ASD, exhibited normal duration and distribution of sleep/wake states but significantly altered electroencephalography (EEG) power spectral profiles for wake and sleep.

Phenformin Activates the Unfolded Protein Response in an AMP-activated Protein Kinase (AMPK)-dependent Manner*

PubMed Central

Yang, Liu; Sha, Haibo; Davisson, Robin L.; Qi, Ling

2013-01-01

Activation of the unfolded protein response (UPR) is associated with the disruption of endoplasmic reticulum (ER) homeostasis and has been implicated in the pathogenesis of many human metabolic diseases, including obesity and type 2 diabetes. However, the nature of the signals activating UPR under these conditions remains largely unknown. Using a method that we recently optimized to directly measure UPR sensor activation, we screened the effect of various metabolic drugs on UPR activation and show that the anti-diabetic drug phenformin activates UPR sensors IRE1α and pancreatic endoplasmic reticulum kinase (PERK) in both an ER-dependent and ER-independent manner. Mechanistically, AMP-activated protein kinase (AMPK) activation is required but not sufficient to initiate phenformin-mediated IRE1α and PERK activation, suggesting the involvement of additional factor(s). Interestingly, activation of the IRE1α (but not PERK) pathway is partially responsible for the cytotoxic effect of phenformin. Together, our data show the existence of a non-canonical UPR whose activation requires the cytosolic kinase AMPK, adding another layer of complexity to UPR activation upon metabolic stress. PMID:23548904

Cerebral activations during viewing of food stimuli in adult patients with acquired structural hypothalamic damage: a functional neuroimaging study.

PubMed

Steele, C A; Powell, J L; Kemp, G J; Halford, J C G; Wilding, J P; Harrold, J A; Kumar, S V D; Cuthbertson, D J; Cross, A A; Javadpour, M; MacFarlane, I A; Stancak, A A; Daousi, C

2015-09-01

Obesity is common following hypothalamic damage due to tumours. Homeostatic and non-homeostatic brain centres control appetite and energy balance but their interaction in the presence of hypothalamic damage remains unknown. We hypothesized that abnormal appetite in obese patients with hypothalamic damage results from aberrant brain processing of food stimuli. We sought to establish differences in activation of brain food motivation and reward neurocircuitry in patients with hypothalamic obesity (HO) compared with patients with hypothalamic damage whose weight had remained stable. In a cross-sectional study at a University Clinical Research Centre, we studied 9 patients with HO, 10 age-matched obese controls, 7 patients who remained weight-stable following hypothalamic insult (HWS) and 10 non-obese controls. Functional magnetic resonance imaging was performed in the fasted state, 1 h and 3 h after a test meal, while subjects were presented with images of high-calorie foods, low-calorie foods and non-food objects. Insulin, glucagon-like peptide-1, Peptide YY and ghrelin were measured throughout the experiment, and appetite ratings were recorded. Mean neural activation in the posterior insula and lingual gyrus (brain areas linked to food motivation and reward value of food) in HWS were significantly lower than in the other three groups (P=0.001). A significant negative correlation was found between insulin levels and posterior insula activation (P=0.002). Neural pathways associated with food motivation and reward-related behaviour, and the influence of insulin on their activation may be involved in the pathophysiology of HO.

Ecological networks to unravel the routes to horizontal transposon transfers.

PubMed

Venner, Samuel; Miele, Vincent; Terzian, Christophe; Biémont, Christian; Daubin, Vincent; Feschotte, Cédric; Pontier, Dominique

2017-02-01

Transposable elements (TEs) represent the single largest component of numerous eukaryotic genomes, and their activity and dispersal constitute an important force fostering evolutionary innovation. The horizontal transfer of TEs (HTT) between eukaryotic species is a common and widespread phenomenon that has had a profound impact on TE dynamics and, consequently, on the evolutionary trajectory of many species' lineages. However, the mechanisms promoting HTT remain largely unknown. In this article, we argue that network theory combined with functional ecology provides a robust conceptual framework and tools to delineate how complex interactions between diverse organisms may act in synergy to promote HTTs.

Beyond microbial community composition: functional activities of the oral microbiome in health and disease

PubMed Central

Duran-Pinedo, Ana E.; Frias-Lopez, Jorge

2015-01-01

The oral microbiome plays a relevant role in the health status of the host and is a key element in a variety of oral and non-oral diseases. Despite advances in our knowledge of changes in microbial composition associated with different health conditions the functional aspects of the oral microbiome that lead to dysbiosis remain for the most part unknown. In this review, we discuss the progress made towards understanding the functional role of the oral microbiome in health and disease and how novel technologies are expanding our knowledge on this subject. PMID:25862077

Diversity, cellular origin and autoreactivity of antibody-secreting cell expansions in acute Systemic Lupus Erythematosus

PubMed Central

Tipton, Christopher M; Fucile, Christopher F; Darce, Jaime; Chida, Asiya; Ichikawa, Travis; Gregoretti, Ivan; Schieferl, Sandra; Hom, Jennifer; Jenks, Scott; Feldman, Ron J; Mehr, Ramit; Wei, Chungwen; Lee, F. Eun-Hyung; Cheung, Wan Cheung; Rosenberg, Alexander F; Sanz, Iñaki

2015-01-01

Acute SLE courses with antibody-secreting cells (ASC) surges whose origin, diversity, and contribution to serum autoantibodies remain unknown. Deep sequencing, autoantibody proteome and single-cell analysis demonstrated highly diversified ASC punctuated by VH4-34 clones that produce dominant serum autoantibodies. A fraction of ASC clones contained unmutated autoantibodies, a finding consistent with differentiation outside the germinal centers. A substantial ASC segment derived from a distinct subset of newly activated naïve cells of significant clonality that persist in the circulation for several months. Thus, selection of SLE autoreactivities occurred during polyclonal activation with prolonged recruitment of recently activated naïve B cells. These findings shed light into SLE pathogenesis, help explain the benefit of anti-B cell agents and facilitate the design of future therapies. PMID:26006014

A Visual-Cue-Dependent Memory Circuit for Place Navigation.

PubMed

Qin, Han; Fu, Ling; Hu, Bo; Liao, Xiang; Lu, Jian; He, Wenjing; Liang, Shanshan; Zhang, Kuan; Li, Ruijie; Yao, Jiwei; Yan, Junan; Chen, Hao; Jia, Hongbo; Zott, Benedikt; Konnerth, Arthur; Chen, Xiaowei

2018-06-05

The ability to remember and to navigate to safe places is necessary for survival. Place navigation is known to involve medial entorhinal cortex (MEC)-hippocampal connections. However, learning-dependent changes in neuronal activity in the distinct circuits remain unknown. Here, by using optic fiber photometry in freely behaving mice, we discovered the experience-dependent induction of a persistent-task-associated (PTA) activity. This PTA activity critically depends on learned visual cues and builds up selectively in the MEC layer II-dentate gyrus, but not in the MEC layer III-CA1 pathway, and its optogenetic suppression disrupts navigation to the target location. The findings suggest that the visual system, the MEC layer II, and the dentate gyrus are essential hubs of a memory circuit for visually guided navigation. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Distinct speed dependence of entorhinal island and ocean cells, including respective grid cells

PubMed Central

Sun, Chen; Kitamura, Takashi; Yamamoto, Jun; Martin, Jared; Pignatelli, Michele; Kitch, Lacey J.; Schnitzer, Mark J.; Tonegawa, Susumu

2015-01-01

Entorhinal–hippocampal circuits in the mammalian brain are crucial for an animal’s spatial and episodic experience, but the neural basis for different spatial computations remain unknown. Medial entorhinal cortex layer II contains pyramidal island and stellate ocean cells. Here, we performed cell type-specific Ca2+ imaging in freely exploring mice using cellular markers and a miniature head-mounted fluorescence microscope. We found that both oceans and islands contain grid cells in similar proportions, but island cell activity, including activity in a proportion of grid cells, is significantly more speed modulated than ocean cell activity. We speculate that this differential property reflects island cells’ and ocean cells’ contribution to different downstream functions: island cells may contribute more to spatial path integration, whereas ocean cells may facilitate contextual representation in downstream circuits. PMID:26170279

Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics

PubMed Central

Haenisch, Britta; Nöthen, Markus M; Molderings, Gerhard J

2012-01-01

Despite increasing understanding of its pathophysiology, the aetiology of systemic mast cell activation disease (MCAD) remains largely unknown. Research has shown that somatic mutations in kinases are necessary for the establishment of a clonal mast cell population, in particular mutations in the tyrosine kinase Kit and in enzymes and receptors with crucial involvement in the regulation of mast cell activity. However, other, as yet undetermined, abnormalities are necessary for the manifestation of clinical disease. The present article reviews molecular genetic research into the identification of disease-associated genes and their mutational alterations. The authors also present novel data on familial systemic MCAD and review the associated literature. Finally, the importance of understanding the molecular basis of inherited mutations in terms of diagnostics and therapy is emphasized. PMID:22957768

Heat shock cognate 71 (HSC71) regulates cellular antiviral response by impairing formation of VISA aggregates.

PubMed

Liu, Zhigang; Wu, Shu-Wen; Lei, Cao-Qi; Zhou, Qian; Li, Shu; Shu, Hong-Bing; Wang, Yan-Yi

2013-05-01

In response to viral infection, RIG-I-like RNA helicases detect viral RNA and signal through the mitochondrial adapter protein VISA. VISA activation leads to rapid activation of transcription factors IRF3 and NF-κB, which collaborate to induce transcription of type I interferon (IFN) genes and cellular antiviral response. It has been demonstrated that VISA is activated by forming prion-like aggregates. However, how this process is regulated remains unknown. Here we show that overexpression of HSC71 resulted in potent inhibition of virus-triggered transcription of IFNB1 gene and cellular antiviral response. Consistently, knockdown of HSC71 had opposite effects. HSC71 interacted with VISA, and negatively regulated virus-triggered VISA aggregation. These findings suggest that HSC71 functions as a check against VISA-mediated antiviral response.

Fast and Famous: Looking for the Fastest Speed at Which a Face Can be Recognized

PubMed Central

Barragan-Jason, Gladys; Besson, Gabriel; Ceccaldi, Mathieu; Barbeau, Emmanuel J.

2012-01-01

Face recognition is supposed to be fast. However, the actual speed at which faces can be recognized remains unknown. To address this issue, we report two experiments run with speed constraints. In both experiments, famous faces had to be recognized among unknown ones using a large set of stimuli to prevent pre-activation of features which would speed up recognition. In the first experiment (31 participants), recognition of famous faces was investigated using a rapid go/no-go task. In the second experiment, 101 participants performed a highly time constrained recognition task using the Speed and Accuracy Boosting procedure. Results indicate that the fastest speed at which a face can be recognized is around 360–390 ms. Such latencies are about 100 ms longer than the latencies recorded in similar tasks in which subjects have to detect faces among other stimuli. We discuss which model of activation of the visual ventral stream could account for such latencies. These latencies are not consistent with a purely feed-forward pass of activity throughout the visual ventral stream. An alternative is that face recognition relies on the core network underlying face processing identified in fMRI studies (OFA, FFA, and pSTS) and reentrant loops to refine face representation. However, the model of activation favored is that of an activation of the whole visual ventral stream up to anterior areas, such as the perirhinal cortex, combined with parallel and feed-back processes. Further studies are needed to assess which of these three models of activation can best account for face recognition. PMID:23460051

Active zone density is conserved during synaptic growth but impaired in aged mice

PubMed Central

Chen, Jie; Mizushige, Takafumi; Nishimune, Hiroshi

2013-01-01

Presynaptic active zones are essential structures for synaptic vesicle release, but the developmental regulation of their number and maintenance during aging at mammalian neuromuscular junctions (NMJs) remains unknown. Here, we analyzed the distribution of active zones in developing, mature, and aged mouse NMJs by immunohistochemical detection of the active zone-specific protein Bassoon. Bassoon is a cytosolic scaffolding protein essential for the active zone assembly in ribbon synapses and some brain synapses. Bassoon staining showed a punctate pattern in nerve terminals and axons at the nascent NMJ on embryonic days 16.5–18.5. Three-dimensional reconstruction of NMJs revealed that the majority of Bassoon puncta within an NMJ were attached to the presynaptic membrane from postnatal day 0 to adulthood, and colocalized with another active zone protein Piccolo. During postnatal development, the number of Bassoon puncta increased as the size of the synapses increased. Importantly, the density of Bassoon puncta remained relatively constant from postnatal day 0 to 54 at 2.3 puncta/μm2, while the synapse size increased 3.3-fold. However, Bassoon puncta density and signal intensity were significantly attenuated at the NMJs of 27-month-old aged mice. These results suggest that synapses maintain the density of synaptic vesicle release sites while the synapse size changes, but this density becomes impaired during aging. PMID:21935939

Mps1 Phosphorylates Its N-Terminal Extension to Relieve Autoinhibition and Activate the Spindle Assembly Checkpoint.

PubMed

Combes, Guillaume; Barysz, Helena; Garand, Chantal; Gama Braga, Luciano; Alharbi, Ibrahim; Thebault, Philippe; Murakami, Luc; Bryne, Dominic P; Stankovic, Stasa; Eyers, Patrick A; Bolanos-Garcia, Victor M; Earnshaw, William C; Maciejowski, John; Jallepalli, Prasad V; Elowe, Sabine

2018-03-19

Monopolar spindle 1 (Mps1) is a conserved apical kinase in the spindle assembly checkpoint (SAC) that ensures accurate segregation of chromosomes during mitosis. Mps1 undergoes extensive auto- and transphosphorylation, but the regulatory and functional consequences of these modifications remain unclear. Recent findings highlight the importance of intermolecular interactions between the N-terminal extension (NTE) of Mps1 and the Hec1 subunit of the NDC80 complex, which control Mps1 localization at kinetochores and activation of the SAC. Whether the NTE regulates other mitotic functions of Mps1 remains unknown. Here, we report that phosphorylation within the NTE contributes to Mps1 activation through relief of catalytic autoinhibition that is mediated by the NTE itself. Moreover, we find that this regulatory NTE function is independent of its role in Mps1 kinetochore recruitment. We demonstrate that the NTE autoinhibitory mechanism impinges most strongly on Mps1-dependent SAC functions and propose that Mps1 activation likely occurs sequentially through dimerization of a "prone-to-autophosphorylate" Mps1 conformer followed by autophosphorylation of the NTE prior to maximal kinase activation segment trans-autophosphorylation. Our observations underline the importance of autoregulated Mps1 activity in generation and maintenance of a robust SAC in human cells. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Low-intensity electric fields induce two distinct response components in neocortical neuronal populations

PubMed Central

Xu, Weifeng; Wolff, Brian S.

2014-01-01

Low-intensity alternating electric fields applied to the scalp are capable of modulating cortical activity and brain functions, but the underlying mechanisms remain largely unknown. Here, we report two distinct components of voltage-sensitive dye signals induced by low-intensity, alternating electric fields in rodent cortical slices: a “passive component,” which corresponds to membrane potential changes directly induced by the electric field; and an “active component,” which is a widespread depolarization that is dependent on excitatory synaptic transmission. The passive component is stationary, with amplitude and phase accurately reflecting the cortical cytoarchitecture. In contrast, the active component is initiated from a local “hot spot” of activity and spreads to a large population as a propagating wave with rich local dynamics. The propagation of the active component may play a role in modulating large-scale cortical activity by spreading a low level of excitation from a small initiation point to a vast neuronal population. PMID:25122710

Synapse-specific astrocyte gating of amygdala-related behavior.

PubMed

Martin-Fernandez, Mario; Jamison, Stephanie; Robin, Laurie M; Zhao, Zhe; Martin, Eduardo D; Aguilar, Juan; Benneyworth, Michael A; Marsicano, Giovanni; Araque, Alfonso

2017-11-01

The amygdala plays key roles in fear and anxiety. Studies of the amygdala have largely focused on neuronal function and connectivity. Astrocytes functionally interact with neurons, but their role in the amygdala remains largely unknown. We show that astrocytes in the medial subdivision of the central amygdala (CeM) determine the synaptic and behavioral outputs of amygdala circuits. To investigate the role of astrocytes in amygdala-related behavior and identify the underlying synaptic mechanisms, we used exogenous or endogenous signaling to selectively activate CeM astrocytes. Astrocytes depressed excitatory synapses from basolateral amygdala via A 1 adenosine receptor activation and enhanced inhibitory synapses from the lateral subdivision of the central amygdala via A 2A receptor activation. Furthermore, astrocytic activation decreased the firing rate of CeM neurons and reduced fear expression in a fear-conditioning paradigm. Therefore, we conclude that astrocyte activity determines fear responses by selectively regulating specific synapses, which indicates that animal behavior results from the coordinated activity of neurons and astrocytes.

Parkin-phosphoubiquitin complex reveals a cryptic ubiquitin binding site required for RBR ligase activity

PubMed Central

Kumar, Atul; Chaugule, Viduth K; Condos, Tara E C; Barber, Kathryn R; Johnson, Clare; Toth, Rachel; Sundaramoorthy, Ramasubramanian; Knebel, Axel; Shaw, Gary S; Walden, Helen

2017-01-01

RING-BETWEENRING-RING (RBR) E3 ligases are a class of ubiquitin ligases distinct from RING or HECT E3 ligases. An important RBR is Parkin, mutations in which lead to early onset hereditary Parkinsonism. Parkin and other RBRs share a catalytic RBR module, but are usually autoinhibited and activated via distinct mechanisms. Recent insights into Parkin regulation predict large, unknown conformational changes during activation of Parkin. However, current data on active RBRs are in the absence of regulatory domains. Therefore, how individual RBRs are activated, and whether they share a common mechanism remains unclear. We now report the crystal structure of a human Parkin-phosphoubiquitin complex, which shows that phosphoubiquitin binding induces a movement in the IBR domain to reveal a cryptic ubiquitin binding site. Mutation of this site negatively impacts on Parkin’s activity. Furthermore, ubiquitin binding promotes cooperation between Parkin molecules, suggesting a role for interdomain association in RBR ligase mechanism. PMID:28414322

Activation of acid-sensing ion channels by localized proton transient reveals their role in proton signaling.

PubMed

Zeng, Wei-Zheng; Liu, Di-Shi; Liu, Lu; She, Liang; Wu, Long-Jun; Xu, Tian-Le

2015-09-15

Extracellular transients of pH alterations likely mediate signal transduction in the nervous system. Neuronal acid-sensing ion channels (ASICs) act as sensors for extracellular protons, but the mechanism underlying ASIC activation remains largely unknown. Here, we show that, following activation of a light-activated proton pump, Archaerhodopsin-3 (Arch), proton transients induced ASIC currents in both neurons and HEK293T cells co-expressing ASIC1a channels. Using chimera proteins that bridge Arch and ASIC1a by a glycine/serine linker, we found that successful coupling occurred within 15 nm distance. Furthermore, two-cell sniffer patch recording revealed that regulated release of protons through either Arch or voltage-gated proton channel Hv1 activated neighbouring cells expressing ASIC1a channels. Finally, computational modelling predicted the peak proton concentration at the intercellular interface to be at pH 6.7, which is acidic enough to activate ASICs in vivo. Our results highlight the pathophysiological role of proton signalling in the nervous system.

Parkin-phosphoubiquitin complex reveals cryptic ubiquitin-binding site required for RBR ligase activity.

PubMed

Kumar, Atul; Chaugule, Viduth K; Condos, Tara E C; Barber, Kathryn R; Johnson, Clare; Toth, Rachel; Sundaramoorthy, Ramasubramanian; Knebel, Axel; Shaw, Gary S; Walden, Helen

2017-05-01

RING-between-RING (RBR) E3 ligases are a class of ubiquitin ligases distinct from RING or HECT E3 ligases. An important RBR ligase is Parkin, mutations in which lead to early-onset hereditary Parkinsonism. Parkin and other RBR ligases share a catalytic RBR module but are usually autoinhibited and activated via distinct mechanisms. Recent insights into Parkin regulation predict large, unknown conformational changes during Parkin activation. However, current data on active RBR ligases reflect the absence of regulatory domains. Therefore, it remains unclear how individual RBR ligases are activated, and whether they share a common mechanism. We now report the crystal structure of a human Parkin-phosphoubiquitin complex, which shows that phosphoubiquitin binding induces movement in the 'in-between RING' (IBR) domain to reveal a cryptic ubiquitin-binding site. Mutation of this site negatively affects Parkin's activity. Furthermore, ubiquitin binding promotes cooperation between Parkin molecules, which suggests a role for interdomain association in the RBR ligase mechanism.

Olfactory behavior and physiology are disrupted in prion protein knockout mice.

PubMed

Le Pichon, Claire E; Valley, Matthew T; Polymenidou, Magdalini; Chesler, Alexander T; Sagdullaev, Botir T; Aguzzi, Adriano; Firestein, Stuart

2009-01-01

The prion protein PrP(C) is infamous for its role in disease, but its normal physiological function remains unknown. Here we found a previously unknown behavioral phenotype of Prnp(-/-) mice in an odor-guided task. This phenotype was manifest in three Prnp knockout lines on different genetic backgrounds, which provides strong evidence that the phenotype is caused by a lack of PrP(C) rather than by other genetic factors. Prnp(-/-) mice also showed altered behavior in a second olfactory task, suggesting that the phenotype is olfactory specific. Furthermore, PrP(C) deficiency affected oscillatory activity in the deep layers of the main olfactory bulb, as well as dendrodendritic synaptic transmission between olfactory bulb granule and mitral cells. Notably, both the behavioral and electrophysiological alterations found in Prnp(-/-) mice were rescued by transgenic neuronal-specific expression of PrP(C). These data suggest that PrP(C) is important in the normal processing of sensory information by the olfactory system.

Resveratrol protects the loss of connexin 43 induced by ethanol exposure in neonatal mouse cardiomyocytes.

PubMed

Tu, Su; Cao, Fu-Tao; Fan, Xiao-Chun; Yang, Cheng-Jian

2017-06-01

Excessive alcohol consumption provides risk to cardiomyopathy with unknown mechanisms. Resveratrol, a plant polyphenol, is widely reported for its cardiovascular benefits, while its effect on alcohol-induced impairments in cardiomyocytes largely remains unknown. Effects of resveratrol on the cardiomyocytes under ethanol insult were studied in vitro. Ethanol exposure in mouse neonatal cardiomyocytes increased cell death and induced a specific loss of tight junction protein, connexin 43. In spite of adverse effects at higher concentrations, resveratrol at 10 μM improved cell viability of cardiomyocytes in the presence of a deleterious dose of ethanol. Importantly, the co-treatment of resveratrol with ethanol exhibited the restoration of connexin 43 protein. Further assays showed that these effects were likely associated with the antioxidative actions of resveratrol, and correlated with the alleviation of MAP kinase activation in cultured cardiomyocytes in response to ethanol. Our data suggests a novel mechanism of cardiomyocyte cell loss under ethanol exposure and provides new evidence of protective effects of resveratrol in the cardiomyocytes.

Identification of a rhythmic firing pattern in the enteric nervous system that generates rhythmic electrical activity in smooth muscle.

PubMed

Spencer, Nick J; Hibberd, Timothy J; Travis, Lee; Wiklendt, Lukasz; Costa, Marcello; Hu, Hongzhen; Brookes, Simon J; Wattchow, David A; Dinning, Phil G; Keating, Damien J; Sorensen, Julian

2018-05-28

The enteric nervous system (ENS) contains millions of neurons essential for organization of motor behaviour of the intestine. It is well established the large intestine requires ENS activity to drive propulsive motor behaviours. However, the firing pattern of the ENS underlying propagating neurogenic contractions of the large intestine remains unknown. To identify this, we used high resolution neuronal imaging with electrophysiology from neighbouring smooth muscle. Myoelectric activity underlying propagating neurogenic contractions along murine large intestine (referred to as colonic migrating motor complexes, CMMCs) consisted of prolonged bursts of rhythmic depolarizations at a frequency of ∼2 Hz. Temporal coordination of this activity in the smooth muscle over large spatial fields (∼7mm, longitudinally) was dependent on the ENS. During quiescent periods between neurogenic contractions, recordings from large populations of enteric neurons, in mice of either sex, revealed ongoing activity. The onset of neurogenic contractions was characterized by the emergence of temporally synchronized activity across large populations of excitatory and inhibitory neurons. This neuronal firing pattern was rhythmic and temporally synchronized across large numbers of ganglia at ∼2 Hz. ENS activation preceded smooth muscle depolarization, indicating rhythmic depolarizations in smooth muscle were controlled by firing of enteric neurons. The cyclical emergence of temporally coordinated firing of large populations of enteric neurons represents a unique neural motor pattern outside the central nervous system. This is the first direct observation of rhythmic firing in the ENS underlying rhythmic electrical depolarizations in smooth muscle. The pattern of neuronal activity we identified underlies the generation of CMMCs. SIGNIFICANCE STATEMENT How the enteric nervous system (ENS) generates neurogenic contractions of smooth muscle in the gastrointestinal (GI) tract has been a long-standing mystery in vertebrates. It is well known that myogenic pacemaker cells exist in the GI-tract (called Interstitial cells of Cajal, ICC) that generate rhythmic myogenic contractions. However, the mechanisms underlying the generation of rhythmic neurogenic contractions of smooth muscle in the GI-tract remains unknown. We developed a high resolution neuronal imaging method with electrophysiology to address this issue. This technique revealed a novel pattern of rhythmic coordinated neuronal firing in the ENS that has never been identified. Rhythmic neuronal firing in the ENS was found to generate rhythmic neurogenic depolarizations in smooth muscle that underlie contraction of the GI-tract. Copyright © 2018 the authors.

Choosing Money over Drugs: The Neural Underpinnings of Difficult Choice in Chronic Cocaine Users

PubMed Central

Wesley, Michael J.; Lohrenz, Terry; Koffarnus, Mikhail N.; McClure, Samuel M.; De La Garza, Richard; Salas, Ramiro; Thompson-Lake, Daisy G. Y.; Newton, Thomas F.; Bickel, Warren K.; Montague, P. Read

2014-01-01

Addiction is considered a disorder that drives individuals to choose drugs at the expense of healthier alternatives. However, chronic cocaine users (CCUs) who meet addiction criteria retain the ability to choose money in the presence of the opportunity to choose cocaine. The neural mechanisms that differentiate CCUs from non-cocaine using controls (Controls) while executing these preferred choices remain unknown. Thus, therapeutic strategies aimed at shifting preferences towards healthier alternatives remain somewhat uninformed. This study used BOLD neuroimaging to examine brain activity as fifty CCUs and Controls performed single- and cross-commodity intertemporal choice tasks for money and/or cocaine. Behavioral analyses revealed preferences for each commodity type. Imaging analyses revealed the brain activity that differentiated CCUs from Controls while choosing money over cocaine. We observed that CCUs devalued future commodities more than Controls. Choices for money as opposed to cocaine correlated with greater activity in dorsal striatum of CCUs, compared to Controls. In addition, choices for future money as opposed to immediate cocaine engaged the left dorsolateral prefrontal cortex (DLPFC) of CCUs more than Controls. These data suggest that the ability of CCUs to execute choices away from cocaine relies on activity in the dorsal striatum and left DLPFC. PMID:25197609

Photoreactive “Nanorulers” Detect a Novel Conformation of Full length HDAC3-SMRT Complex in Solution

PubMed Central

Abdelkarim, Hazem; Brunsteiner, Michael; Neelarapu, Raghupathi; Bai, He; Madriaga, Antonett; van Breemen, Richard B.; Blond, Sylvie Y.; Gaponenko, Vadim; Petukhov, Pavel A.

2013-01-01

Histone deacetylase 3 (HDAC3) is a promising epigenetic drug target for multiple therapeutic applications. Direct interaction between the Deacetylase Activating Domain of the silencing mediator for retinoid or thyroid hormone receptors (SMRT-DAD) is required for activation of enzymatic activity of HDAC3. The structure of this complex and the nature of interactions with HDAC inhibitors in solution are unknown. Using novel photoreactive HDAC probes – “nanorulers”, we determined the distance between the catalytic site of the full-length HDAC3 and SMRT-DAD in solution at physiologically relevant conditions and found it to be substantially different from that predicted by the X-ray model with a Δ379-428aa truncated HDAC3. Further experiments indicated that in solution this distance might change in response to chemical stimuli, while the enzymatic activity remained unaffected. These observations were further validated by Saturation Transfer Difference (STD) NMR experiments. We propose that the observed changes in the distance are an important part of the histone code that remains to be explored. Mapping direct interactions and distances between macromolecules with such “nanorulers” as a function of cellular events facilitates better understanding of basic biology and ways for its manipulation in cell and tissue specific manner. PMID:24010878

Molecular mechanism of pH-dependent substrate transport by an arginine-agmatine antiporter.

PubMed

Wang, Sheng; Yan, Renhong; Zhang, Xi; Chu, Qi; Shi, Yigong

2014-09-02

Enteropathogenic bacteria, exemplified by Escherichia coli, rely on acid-resistance systems (ARs) to survive the acidic environment of the stomach. AR3 consumes intracellular protons through decarboxylation of arginine (Arg) in the cytoplasm and exchange of the reaction product agmatine (Agm) with extracellular Arg. The latter process is mediated by the Arg:Agm antiporter AdiC, which is activated in response to acidic pH and remains fully active at pH 6.0 and below. Despite our knowledge of structural information, the molecular mechanism by which AdiC senses acidic pH remains completely unknown. Relying on alanine-scanning mutagenesis and an in vitro proteoliposome-based transport assay, we have identified Tyr74 as a critical pH sensor in AdiC. The AdiC variant Y74A exhibited robust transport activity at all pH values examined while maintaining stringent substrate specificity for Arg:Agm. Replacement of Tyr74 by Phe, but not by any other amino acid, led to the maintenance of pH-dependent substrate transport. These observations, in conjunction with structural information, identify a working model for pH-induced activation of AdiC in which a closed conformation is disrupted by cation-π interactions between proton and the aromatic side chain of Tyr74.

Bilateral femoral neck stress fractures in a fire academy student.

PubMed

Wright, Russell C; Salzman, Garrett A; Yacoubian, Stephan V; Yacoubian, Shahan V

2010-10-11

Unilateral femoral neck stress fractures are well documented in active patients; however, the risk of a subsequent contralateral stress fracture remains unknown in patients who continue to be active. This article describes a 24-year-old male fire academy student who sustained a left femoral neck stress fracture, followed approximately 11 months later by a right femoral neck stress fracture, both of which went on to completely displace. A review of the index radiographs of each hip from outside institutions revealed femoral neck stress fractures that went undiagnosed until they displaced. The patient was referred to our institution and underwent closed reduction and internal fixation using cannulated screws in both cases. A full endocrine evaluation was performed in the following weeks and proved unremarkable. Although it is difficult to extrapolate the results from 1 patient beyond the case studied, there is cause for concern in patients who remain active following femoral neck stress fractures. Our case highlights the significance of obtaining a complete and thorough medical history on physical examination and appropriately counseling patients regarding activity level. Until further research explores this possible relationship, physicians evaluating patients with a history of a stress fracture are encouraged to be vigilant of subsequent contralateral fractures and educate patients of this potentially avoidable injury. Copyright 2010, SLACK Incorporated.

Wireless Cortical Brain-Machine Interface for Whole-Body Navigation in Primates

NASA Astrophysics Data System (ADS)

Rajangam, Sankaranarayani; Tseng, Po-He; Yin, Allen; Lehew, Gary; Schwarz, David; Lebedev, Mikhail A.; Nicolelis, Miguel A. L.

2016-03-01

Several groups have developed brain-machine-interfaces (BMIs) that allow primates to use cortical activity to control artificial limbs. Yet, it remains unknown whether cortical ensembles could represent the kinematics of whole-body navigation and be used to operate a BMI that moves a wheelchair continuously in space. Here we show that rhesus monkeys can learn to navigate a robotic wheelchair, using their cortical activity as the main control signal. Two monkeys were chronically implanted with multichannel microelectrode arrays that allowed wireless recordings from ensembles of premotor and sensorimotor cortical neurons. Initially, while monkeys remained seated in the robotic wheelchair, passive navigation was employed to train a linear decoder to extract 2D wheelchair kinematics from cortical activity. Next, monkeys employed the wireless BMI to translate their cortical activity into the robotic wheelchair’s translational and rotational velocities. Over time, monkeys improved their ability to navigate the wheelchair toward the location of a grape reward. The navigation was enacted by populations of cortical neurons tuned to whole-body displacement. During practice with the apparatus, we also noticed the presence of a cortical representation of the distance to reward location. These results demonstrate that intracranial BMIs could restore whole-body mobility to severely paralyzed patients in the future.

The cytoprotective enzyme heme oxygenase-1 suppresses Ebola virus replication.

PubMed

Hill-Batorski, Lindsay; Halfmann, Peter; Neumann, Gabriele; Kawaoka, Yoshihiro

2013-12-01

Ebola virus (EBOV) is the causative agent of a severe hemorrhagic fever in humans with reported case fatality rates as high as 90%. There are currently no licensed vaccines or antiviral therapeutics to combat EBOV infections. Heme oxygenase-1 (HO-1), an enzyme that catalyzes the rate-limiting step in heme degradation, has antioxidative properties and protects cells from various stresses. Activated HO-1 was recently shown to have antiviral activity, potently inhibiting the replication of viruses such as hepatitis C virus and human immunodeficiency virus. However, the effect of HO-1 activation on EBOV replication remains unknown. To determine whether the upregulation of HO-1 attenuates EBOV replication, we treated cells with cobalt protoporphyrin (CoPP), a selective HO-1 inducer, and assessed its effects on EBOV replication. We found that CoPP treatment, pre- and postinfection, significantly suppressed EBOV replication in a manner dependent upon HO-1 upregulation and activity. In addition, stable overexpression of HO-1 significantly attenuated EBOV growth. Although the exact mechanism behind the antiviral properties of HO-1 remains to be elucidated, our data show that HO-1 upregulation does not attenuate EBOV entry or budding but specifically targets EBOV transcription/replication. Therefore, modulation of the cellular enzyme HO-1 may represent a novel therapeutic strategy against EBOV infection.

Heterologous expression of the plant cysteine protease bromelain and its inhibitor in Pichia pastoris.

PubMed

Luniak, Nora; Meiser, Peter; Burkart, Sonja; Müller, Rolf

2017-01-01

Expression of proteases in heterologous hosts remains an ambitious challenge due to severe problems associated with digestion of host proteins. On the other hand, proteases are broadly used in industrial applications and resemble promising drug candidates. Bromelain is an herbal drug that is medicinally used for treatment of oedematous swellings and inflammatory conditions and consists in large part of proteolytic enzymes. Even though various experiments underline the requirement of active cysteine proteases for biological activity, so far no investigation succeeded to clearly clarify the pharmacological mode of action of bromelain. The potential role of proteases themselves and other molecules of this multi-component extract currently remain largely unknown or ill defined. Here, we set out to express several bromelain cysteine proteases as well as a bromelain inhibitor molecule in order to gain defined molecular entities for subsequent studies. After cloning the genes from its natural source Ananas comosus (pineapple plant) into Pichia pastoris and subsequent fermentation and purification, we obtained active protease and inhibitor molecules which were subsequently biochemically characterized. Employing purified bromelain fractions paves the way for further elucidation of pharmacological activities of this natural product. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:54-65, 2017. © 2016 American Institute of Chemical Engineers.

Amlodipine Inhibits Vascular Cell Senescence and Protects Against Atherogenesis Through the Mechanism Independent of Calcium Channel Blockade.

PubMed

Kayamori, Hiromi; Shimizu, Ippei; Yoshida, Yohko; Hayashi, Yuka; Suda, Masayoshi; Ikegami, Ryutaro; Katsuumi, Goro; Wakasugi, Takayuki; Minamino, Tohru

2018-05-30

Vascular cells have a finite lifespan and eventually enter irreversible growth arrest called cellular senescence. We have previously suggested that vascular cell senescence contributes to the pathogenesis of human atherosclerosis. Amlodipine is a mixture of two enantiomers, one of which (S- enantiomer) has L-type channel blocking activity, while the other (R+ enantiomer) shows ~1000-fold weaker channel blocking activity than S- enantiomer and has other unknown effects. It has been reported that amlodipine inhibits the progression of atherosclerosis in humans, but the molecular mechanism of this beneficial effect remains unknown. Apolipoprotein E-deficient mice on a high-fat diet were treated with amlodipine, its R+ enantiomer or vehicle for eight weeks. Compared with vehicle treatment, both amlodipine and the R+ enantiomer significantly reduced the number of senescent vascular cells and inhibited plaque formation to a similar extent. Expression of the pro-inflammatory molecule interleukin-1β was markedly upregulated in vehicle-treated mice, but was inhibited to a similar extent by treatment with amlodipine or the R+ enantiomer. Likewise, activation of p53 (a critical inducer of senescence) was markedly suppressed by treatment with amlodipine or the R+ enantiomer. These results suggest that amlodipine inhibits vascular cell senescence and protects against atherogenesis at least partly by a mechanism that is independent of calcium channel blockade.

Prevalence of unsafe sex with one's steady partner either HIV-negative or of unknown HIV status and associated determinants in Cameroon (EVAL ANRS12-116 survey).

PubMed

Dia, Aïssata; Marcellin, Fabienne; Bonono, Renée-Cécile; Boyer, Sylvie; Bouhnik, Anne-Déborah; Protopopescu, Camelia; Koulla-Shiro, Sinata; Carrieri, Maria Patrizia; Abé, Claude; Spire, Bruno

2010-04-01

Our study aimed at estimating the prevalence of inconsistent condom use and at identifying its determinants in steady partnerships among people living with HIV/AIDS (PLWHA) in Cameroon. Analyses were based on data collected during the national cross-sectional multicentre survey EVAL (ANRS 12-116), which was conducted in Cameroon between September 2006 and March 2007 among 3151 adult PLWHA diagnosed HIV-positive for at least 3 months. The study population consisted of the 907 survey participants who reported sexual activity during the previous 3 months, with a steady partner either HIV-negative or of unknown HIV status. Logistic regression was used to identify factors associated with individuals' report of inconsistent condom use during the previous 3 months. Inconsistent condom use was reported by 35.3% of sexually active PLWHA. In a multivariate analysis adjusted for socio-demographic characteristics, not receiving antiretroviral therapy (OR (95% CI): 2.28 (1.64 to 3.18)) was independently associated with inconsistent condom use. The prevalence of unsafe sex remains high among sexually active PLWHA in Cameroon. Treatment with antiretroviral therapy is identified as a factor associated with safer sex, which further encourages the continuation of the national policy for increasing access to HIV treatment and care, and underlines the need to develop counselling strategies for all patients.

Neutral Loss Scan - Based Strategy for Integrated Identification of Amorfrutin Derivatives, New Peroxisome Proliferator-Activated Receptor Gamma Agonists, from Amorpha Fruticosa by UPLC-QqQ-MS/MS and UPLC-Q-TOF-MS.

PubMed

Chen, Chu; Xue, Ying; Li, Qing-Miao; Wu, Yan; Liang, Jian; Qing, Lin-Sen

2018-04-01

Amorfrutins with a 2-hydroxybenzoic acid core structure are promising natural PPARγ agonists with potent antidiabetic activity. Owing to the complex matrix and low concentration in botanical material, the identification of unknown amorfrutins remains a challenge. In the present study, a combined application of UPLC-Q-TOF-MS and UPLC-QqQ-MS was developed to discover unknown amorfrutins from fruits of Amorpha fruticosa. First, reference compounds of amorfrutin A (AA), amorfrutin B (AB), and 2-carboxy-3,5-dihydroxy-4-geranylbibenzyl (AC) were analyzed using UPLC-Q-TOF-MS to reveal the characteristic fragment ions and the possible neutral loss. Second, the extract of A. fruticosa was separated and screened by UPLC-QqQ-MS using neutral loss scan to find out suspect compounds associated with the specified neutral fragment Δm/z 44. Third, the extract was re-analyzed by UPLC-Q-TOF-MS to obtain the exact mass of quasi-molecular ion and fragment ions of each suspect compound, and to subsequently calculate their corresponding molecular formulas. Finally, according to the molecular formula of suspect compound and its fragment ions and comparing with literature data, structure elucidation of four unidentified amorfrutins was achieved. The results indicated that the combination of QqQ-MS neutral loss scan and Q-TOF-MS molecular formula calculation was proven to be a powerful tool for unknown natural product identification, and this strategy provides an effective solution to discover natural products or metabolites of trace content. Graphical Abstract ᅟ.

Neutral Loss Scan - Based Strategy for Integrated Identification of Amorfrutin Derivatives, New Peroxisome Proliferator-Activated Receptor Gamma Agonists, from Amorpha Fruticosa by UPLC-QqQ-MS/MS and UPLC-Q-TOF-MS

NASA Astrophysics Data System (ADS)

Chen, Chu; Xue, Ying; Li, Qing-Miao; Wu, Yan; Liang, Jian; Qing, Lin-Sen

2018-02-01

Amorfrutins with a 2-hydroxybenzoic acid core structure are promising natural PPARγ agonists with potent antidiabetic activity. Owing to the complex matrix and low concentration in botanical material, the identification of unknown amorfrutins remains a challenge. In the present study, a combined application of UPLC-Q-TOF-MS and UPLC-QqQ-MS was developed to discover unknown amorfrutins from fruits of Amorpha fruticosa. First, reference compounds of amorfrutin A (AA), amorfrutin B (AB), and 2-carboxy-3,5-dihydroxy-4-geranylbibenzyl (AC) were analyzed using UPLC-Q-TOF-MS to reveal the characteristic fragment ions and the possible neutral loss. Second, the extract of A. fruticosa was separated and screened by UPLC-QqQ-MS using neutral loss scan to find out suspect compounds associated with the specified neutral fragment Δm/z 44. Third, the extract was re-analyzed by UPLC-Q-TOF-MS to obtain the exact mass of quasi-molecular ion and fragment ions of each suspect compound, and to subsequently calculate their corresponding molecular formulas. Finally, according to the molecular formula of suspect compound and its fragment ions and comparing with literature data, structure elucidation of four unidentified amorfrutins was achieved. The results indicated that the combination of QqQ-MS neutral loss scan and Q-TOF-MS molecular formula calculation was proven to be a powerful tool for unknown natural product identification, and this strategy provides an effective solution to discover natural products or metabolites of trace content.

The predictive roles of neural oscillations in speech motor adaptability.

PubMed

Sengupta, Ranit; Nasir, Sazzad M

2016-06-01

The human speech system exhibits a remarkable flexibility by adapting to alterations in speaking environments. While it is believed that speech motor adaptation under altered sensory feedback involves rapid reorganization of speech motor networks, the mechanisms by which different brain regions communicate and coordinate their activity to mediate adaptation remain unknown, and explanations of outcome differences in adaption remain largely elusive. In this study, under the paradigm of altered auditory feedback with continuous EEG recordings, the differential roles of oscillatory neural processes in motor speech adaptability were investigated. The predictive capacities of different EEG frequency bands were assessed, and it was found that theta-, beta-, and gamma-band activities during speech planning and production contained significant and reliable information about motor speech adaptability. It was further observed that these bands do not work independently but interact with each other suggesting an underlying brain network operating across hierarchically organized frequency bands to support motor speech adaptation. These results provide novel insights into both learning and disorders of speech using time frequency analysis of neural oscillations. Copyright © 2016 the American Physiological Society.

Calcium and Superoxide-Mediated Pathways Converge to Induce Nitric Oxide-Dependent Apoptosis in Mycobacterium fortuitum-Infected Fish Macrophages.

PubMed

Datta, Debika; Khatri, Preeti; Banerjee, Chaitali; Singh, Ambika; Meena, Ramavatar; Saha, Dhira Rani; Raman, Rajagopal; Rajamani, Paulraj; Mitra, Abhijit; Mazumder, Shibnath

2016-01-01

Mycobacterium fortuitum causes 'mycobacteriosis' in wide range of hosts although the mechanisms remain largely unknown. Here we demonstrate the role of calcium (Ca+2)-signalling cascade on M. fortuitum-induced apoptosis in headkidney macrophages (HKM) of Clarias sp. M. fortuitum could trigger intracellular-Ca+2 influx leading to the activation of calmodulin (CaM), protein kinase C alpha (PKCα) and Calmodulin kinase II gamma (CaMKIIg). Gene silencing and inhibitor studies established the role of CaM in M. fortuitum pathogenesis. We noted that CaMKIIg activation is regulated by CaM as well as PKCα-dependent superoxide anions. This is altogether first report of oxidised CaMKIIg in mycobacterial infections. Our studies with targeted-siRNA and pharmacological inhibitors implicate CaMKIIg to be pro-apoptotic and critical for the activation of extra-cellular signal regulated kinase 1/2 (ERK1/2). Inhibiting the ERK1/2 pathway attenuated nitric oxide synthase 2 (NOS2)-induced nitric oxide (NO) production. Conversely, inhibiting the NOS2-NO axis by specific-siRNA and inhibitors down-regulated ERK1/2 activation suggesting the crosstalk between ERK1/2 and NO is essential for pathogenesis induced by the bacterium. Silencing the NOS2-NO axis enhanced intracellular bacterial survival and attenuated caspase-8 mediated activation of caspase-3 in the infected HKM. Our findings unveil hitherto unknown mechanism of M. fortuitum pathogenesis. We propose that M. fortuitum triggers intracellular Ca+2 elevations resulting in CaM activation and PKCα-mediated superoxide generation. The cascade converges in common pathway mediated by CaMKIIg resulting in the activation of ERK1/2-NOS2 axis. The crosstalk between ERK1/2 and NO shifts the balance in favour of caspase dependent apoptosis of M. fortuitum-infected HKM.

Magnetite Equation of State: Implications for Mars' Interior and Magnetization

NASA Astrophysics Data System (ADS)

Gant, P.; Walsh, J.; Lazarz, J. D.; Jacobsen, S. D.; Jurdy, D. M.

2017-12-01

Mars once had a global magnetic field, although it no longer has an active dynamo. Mars Global Surveyor (MGS) unexpectedly measured a strongly magnetized crust. However, the magnetic carrier as well as the nature and depth of magnetization remain unknown. Downward continuation of the surface magnetization suggests the possibility of great depth of magnetization, as much as 100-200 km, far exceeding that of Earth's. The interior composition and structure of Mars remain unknown. Magnetite offers a likely candidate for Martian magnetization. Experiments with magnetite crystals - one naturally-occurring, the other a laboratory-fabricated single domain crystal, determine its equation of state. NASA's upcoming InSight (INterior Exploration using Seismic Investigations, Geodesy, and Heat Transport) mission to Mars will be the first dedicated to study of the Martian interior. It will land in the Elysium Planitia with a 3-component broadband and short period seismometer, heatflow probe, and a magnetometer to monitor the local, atmospheric, and crustal magnetic field. The planned InSight measurements of Martian heatflow will establish its current temperature gradient. The first step in understanding Mars' magnetization requires knowing both temperature and pressure conditions for its interior, along with the equation of state for magnetite - and other possible magnetic minerals. Laboratory experiments with a range of compositions for the Martian interior could provide critical comparisons with the InSight mission's seismic data.

Extracellular gentamicin reduces the activity of connexin hemichannels and interferes with purinergic Ca2+ signaling in HeLa cells

PubMed Central

Figueroa, Vania A.; Retamal, Mauricio A.; Cea, Luis A.; Salas, José D.; Vargas, Aníbal A.; Verdugo, Christian A.; Jara, Oscar; Martínez, Agustín D.; Sáez, Juan C.

2014-01-01

Gap junction channels (GJCs) and hemichannels (HCs) are composed of protein subunits termed connexins (Cxs) and are permeable to ions and small molecules. In most organs, GJCs communicate the cytoplasm of adjacent cells, while HCs communicate the intra and extracellular compartments. In this way, both channel types coordinate physiological responses of cell communities. Cx mutations explain several genetic diseases, including about 50% of autosomal recessive non-syndromic hearing loss. However, the possible involvement of Cxs in the etiology of acquired hearing loss remains virtually unknown. Factors that induce post-lingual hearing loss are diverse, exposure to gentamicin an aminoglycoside antibiotic, being the most common. Gentamicin has been proposed to block GJCs, but its effect on HCs remains unknown. In this work, the effect of gentamicin on the functional state of HCs was studied and its effect on GJCs was reevaluated in HeLa cells stably transfected with Cxs. We focused on Cx26 because it is the main Cx expressed in the cochlea of mammals where it participates in purinergic signaling pathways. We found that gentamicin applied extracellularly reduces the activity of HCs, while dye transfer across GJCs was not affected. HCs were also blocked by streptomycin, another aminoglycoside antibiotic. Gentamicin also reduced the adenosine triphosphate release and the HC-dependent oscillations of cytosolic free-Ca2+ signal. Moreover, gentamicin drastically reduced the Cx26 HC-mediated membrane currents in Xenopus laevis oocytes. Therefore, the extracellular gentamicin-induced inhibition of Cx HCs may adversely affect autocrine and paracrine signaling, including the purinergic one, which might partially explain its ototoxic effects. PMID:25237294

In vivo administration of extracellular cGMP normalizes TNF-α and membrane expression of AMPA receptors in hippocampus and spatial reference memory but not IL-1β, NMDA receptors in membrane and working memory in hyperammonemic rats.

PubMed

Cabrera-Pastor, Andrea; Hernandez-Rabaza, Vicente; Taoro-Gonzalez, Lucas; Balzano, Tiziano; Llansola, Marta; Felipo, Vicente

2016-10-01

Patients with hepatic encephalopathy (HE) show working memory and visuo-spatial orientation deficits. Hyperammonemia is a main contributor to cognitive impairment in HE. Hyperammonemic rats show impaired spatial learning and learning ability in the Y maze. Intracerebral administration of extracellular cGMP restores learning in the Y-maze. The underlying mechanisms remain unknown. It also remains unknown whether extracellular cGMP improves neuroinflammation or restores spatial learning in hyperammonemic rats and if it affects differently reference and working memory. The aims of this work were: Spatial working and reference memory were assessed using the radial and Morris water mazes and neuroinflammation by immunohistochemistry and Western blot. Membrane expression of NMDA and AMPA receptor subunits was analyzed using the BS3 crosslinker. Extracellular cGMP was administered intracerebrally using osmotic minipumps. Chronic hyperammonemia induces neuroinflammation in hippocampus, with astrocytes activation and increased IL-1β, which are associated with increased NMDA receptors membrane expression and impaired working memory. This process is not affected by extracellular cGMP. Hyperammonemia also activates microglia and increases TNF-α, alters membrane expression of AMPA receptor subunits (increased GluA1 and reduced GluA2) and impairs reference memory. All these changes are reversed by extracellular cGMP. These results show that extracellular cGMP modulates spatial reference memory but not working memory. This would be mediated by modulation of TNF-α levels and of membrane expression of GluA1 and GluA2 subunits of AMPA receptors. Copyright © 2016 Elsevier Inc. All rights reserved.

Mechanisms of action of brief alcohol interventions remain largely unknown - a narrative review.

PubMed

Gaume, Jacques; McCambridge, Jim; Bertholet, Nicolas; Daeppen, Jean-Bernard

2014-01-01

A growing body of evidence has shown the efficacy of brief intervention (BI) for hazardous and harmful alcohol use in primary health care settings. Evidence for efficacy in other settings and effectiveness when implemented at larger scale are disappointing. Indeed, BI comprises varying content; exploring BI content and mechanisms of action may be a promising way to enhance efficacy and effectiveness. Medline and PsychInfo, as well as references of retrieved publications were searched for original research or review on active ingredients (components or mechanisms) of face-to-face BIs [and its subtypes, including brief advice and brief motivational interviewing (BMI)] for alcohol. Overall, BI active ingredients have been scarcely investigated, almost only within BMI, and mostly among patients in the emergency room, young adults, and US college students. This body of research has shown that personalized feedback may be an effective component; specific MI techniques showed mixed findings; decisional balance findings tended to suggest a potential detrimental effect; while change plan exercises, advice to reduce or stop drinking, presenting alternative change options, and moderation strategies are promising but need further study. Client change talk is a potential mediator of BMI effects; change in norm perceptions and enhanced discrepancy between current behavior and broader life goals and values have received preliminary support; readiness to change was only partially supported as a mediator; while enhanced awareness of drinking, perceived risks/benefits of alcohol use, alcohol treatment seeking, and self-efficacy were seldom studied and have as yet found no significant support as such. Research is obviously limited and has provided no clear and consistent evidence on the mechanisms of alcohol BI. How BI achieves the effects seen in randomized trials remains mostly unknown and should be investigated to inform the development of more effective interventions.

76 FR 14051 - Notice of Inventory Completion: San Francisco State University, San Francisco, CA

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-15

..., pursuant to 25 U.S.C. 3001(2), that there is a relationship of shared group identity that can be reasonably... the Tubatulabals of Kern Valley, a non-Federally recognized Indian group. On an unknown date, human remains representing a minimum of one individual were removed from an unknown site (Ca-Ker-UNK (Lake...

Shotgun protein sequencing: assembly of peptide tandem mass spectra from mixtures of modified proteins.

PubMed

Bandeira, Nuno; Clauser, Karl R; Pevzner, Pavel A

2007-07-01

Despite significant advances in the identification of known proteins, the analysis of unknown proteins by MS/MS still remains a challenging open problem. Although Klaus Biemann recognized the potential of MS/MS for sequencing of unknown proteins in the 1980s, low throughput Edman degradation followed by cloning still remains the main method to sequence unknown proteins. The automated interpretation of MS/MS spectra has been limited by a focus on individual spectra and has not capitalized on the information contained in spectra of overlapping peptides. Indeed the powerful shotgun DNA sequencing strategies have not been extended to automated protein sequencing. We demonstrate, for the first time, the feasibility of automated shotgun protein sequencing of protein mixtures by utilizing MS/MS spectra of overlapping and possibly modified peptides generated via multiple proteases of different specificities. We validate this approach by generating highly accurate de novo reconstructions of multiple regions of various proteins in western diamondback rattlesnake venom. We further argue that shotgun protein sequencing has the potential to overcome the limitations of current protein sequencing approaches and thus catalyze the otherwise impractical applications of proteomics methodologies in studies of unknown proteins.

Spatiotemporal neural network dynamics for the processing of dynamic facial expressions.

PubMed

Sato, Wataru; Kochiyama, Takanori; Uono, Shota

2015-07-24

The dynamic facial expressions of emotion automatically elicit multifaceted psychological activities; however, the temporal profiles and dynamic interaction patterns of brain activities remain unknown. We investigated these issues using magnetoencephalography. Participants passively observed dynamic facial expressions of fear and happiness, or dynamic mosaics. Source-reconstruction analyses utilizing functional magnetic-resonance imaging data revealed higher activation in broad regions of the bilateral occipital and temporal cortices in response to dynamic facial expressions than in response to dynamic mosaics at 150-200 ms and some later time points. The right inferior frontal gyrus exhibited higher activity for dynamic faces versus mosaics at 300-350 ms. Dynamic causal-modeling analyses revealed that dynamic faces activated the dual visual routes and visual-motor route. Superior influences of feedforward and feedback connections were identified before and after 200 ms, respectively. These results indicate that hierarchical, bidirectional neural network dynamics within a few hundred milliseconds implement the processing of dynamic facial expressions.

Operant Conditioning of Primate Prefrontal Neurons

PubMed Central

Schultz, Wolfram; Sakagami, Masamichi

2010-01-01

An operant is a behavioral act that has an impact on the environment to produce an outcome, constituting an important component of voluntary behavior. Because the environment can be volatile, the same action may cause different consequences. Thus to obtain an optimal outcome, it is crucial to detect action–outcome relationships and adapt the behavior accordingly. Although prefrontal neurons are known to change activity depending on expected reward, it remains unknown whether prefrontal activity contributes to obtaining reward. We investigated this issue by setting variable relationships between levels of single-neuron activity and rewarding outcomes. Lateral prefrontal neurons changed their spiking activity according to the specific requirements for gaining reward, without the animals making a motor response. Thus spiking activity constituted an operant response. Data from a control task suggested that these changes were unlikely to reflect simple reward predictions. These data demonstrate a remarkable capacity of prefrontal neurons to adapt to specific operant requirements at the single-neuron level. PMID:20107129

Spatiotemporal neural network dynamics for the processing of dynamic facial expressions

PubMed Central

Sato, Wataru; Kochiyama, Takanori; Uono, Shota

2015-01-01

The dynamic facial expressions of emotion automatically elicit multifaceted psychological activities; however, the temporal profiles and dynamic interaction patterns of brain activities remain unknown. We investigated these issues using magnetoencephalography. Participants passively observed dynamic facial expressions of fear and happiness, or dynamic mosaics. Source-reconstruction analyses utilizing functional magnetic-resonance imaging data revealed higher activation in broad regions of the bilateral occipital and temporal cortices in response to dynamic facial expressions than in response to dynamic mosaics at 150–200 ms and some later time points. The right inferior frontal gyrus exhibited higher activity for dynamic faces versus mosaics at 300–350 ms. Dynamic causal-modeling analyses revealed that dynamic faces activated the dual visual routes and visual–motor route. Superior influences of feedforward and feedback connections were identified before and after 200 ms, respectively. These results indicate that hierarchical, bidirectional neural network dynamics within a few hundred milliseconds implement the processing of dynamic facial expressions. PMID:26206708

PKCδ activated by c-MET enhances infiltration of human glioblastoma cells through NOTCH2 signaling

PubMed Central

Kang, Seok-Gu; Kim, Rae-Kwon; Cui, Yan-Hong; Lee, Hae-June; Kim, Min-Jung; Lee, Jae-Seong; Kim, In-Gyu; Suh, Yongjoon; Lee, Su-Jae

2016-01-01

Poor prognosis of glioblastoma (GBM) is attributable to the propensity of tumor cells to infiltrate into the brain parenchyma. Protein kinase C (PKC) isozymes are highly expressed or aberrantly activated in GBM. However, how this signaling node translates to GBM cell invasiveness remains unknown. Here, we report that among PKC isoforms, PKCδ is strongly associated with infiltration of GBM cells. Notably, PKCδ enhanced Tyr418 phosphorylation of the non-receptor tyrosine kinase SRC, which in turn activated STAT3 and subsequent NOTCH2 signaling, ultimately leading to GBM cell invasiveness. Furthermore, we showed that PKCδ was aberrantly activated in GBM cells by c-MET, a receptor tyrosine kinase hyperactivated in GBM. In agreement, inhibition either component in the c-MET/PKCδ/SRC/STAT3 signaling axis effectively blocked the NOTCH2 signaling and invasiveness of GBM cells. Taken together, our findings shed a light on the signaling mechanisms behind the constitutive activation of PKCδ signaling in GBM. PMID:26700818

Resveratrol Improved the Progression of Chronic Prostatitis via the Downregulation of c-kit/SCF by Activating Sirt1.

PubMed

He, Yi; Zeng, Huizhi; Yu, Yang; Zhang, Jiashu; Zeng, Xiaona; Gong, Fengtao; Duan, Xingping; Liu, Qi; Yang, Bo

2017-07-19

The regulation mechanism of inflammation inducing prostate carcinogenesis remains largely unknown. Therefore, we investigated the role of the c-kit/SCF pathway, which has been associated with the control of prostate carcinogenesis, in chronic prostatitis (CP) rats and evaluated the anti-prostatitis effect of resveratrol. We performed hemolysin and eosin staining to evaluate the histopathological changes in prostates. Multiple approaches evaluated the expression levels of c-kit, stem cell factor (SCF), Sirt1, and carcinogenesis-associated proteins. The CP group exhibited severe diffuse chronic inflammation. Meanwhile, the prostate cells appeared atypia; the activity of c-kit/SCF was upregulated, and carcinogenesis-associated proteins are dysregulated significantly in CP rats. Resveratrol treatment significantly improved these factors by Sirt1 activation. In summary, CP could further cause prostate carcinogenesis, which may be associated with activated c-kit/SCF signaling. Resveratrol treatment could improve the progression of CP via the downregulation of c-kit/SCF by activating Sirt1.

Structural biology. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor.

PubMed

Burg, John S; Ingram, Jessica R; Venkatakrishnan, A J; Jude, Kevin M; Dukkipati, Abhiram; Feinberg, Evan N; Angelini, Alessandro; Waghray, Deepa; Dror, Ron O; Ploegh, Hidde L; Garcia, K Christopher

2015-03-06

Chemokines are small proteins that function as immune modulators through activation of chemokine G protein-coupled receptors (GPCRs). Several viruses also encode chemokines and chemokine receptors to subvert the host immune response. How protein ligands activate GPCRs remains unknown. We report the crystal structure at 2.9 angstrom resolution of the human cytomegalovirus GPCR US28 in complex with the chemokine domain of human CX3CL1 (fractalkine). The globular body of CX3CL1 is perched on top of the US28 extracellular vestibule, whereas its amino terminus projects into the central core of US28. The transmembrane helices of US28 adopt an active-state-like conformation. Atomic-level simulations suggest that the agonist-independent activity of US28 may be due to an amino acid network evolved in the viral GPCR to destabilize the receptor's inactive state. Copyright © 2015, American Association for the Advancement of Science.

Relationships between the Active Aging Index and Disability-Free Life Expectancy: A Case Study in the Rajshahi District of Bangladesh.

PubMed

Tareque, Md Ismail; Hoque, Nazrul; Islam, Towfiqua Mahfuza; Kawahara, Kazuo; Sugawa, Makiko

2013-12-01

Life expectancy has increased considerably throughout the world. In Bangladesh, life expectancy has increased from about 53 years in 1975 to 69 years in 2010. However, it is unknown whether the increase in life expectancy is simultaneously accompanied by an increase in disability-free life expectancy (DFLE). The purpose of the study described in this article was to explore the relationship between life expectancy and DFLE in the Rajshahi District of Bangladesh by examining the relationships between the Active Aging Index (AAI) and DFLE. The study fi ndings suggest that urban, more-educated, elderly males are more active in all aspects of life and have longer DFLE. Females are found to outlive males but are more likely to live a greater part of their remaining life with disability. Positive correlations between the AAI and DFLE suggest that older adults could enjoy more DFLE by involving themselves in active aging activities.

The Evolution of Lineage-Specific Regulatory Activities in the Human Embryonic Limb

PubMed Central

Cotney, Justin; Leng, Jing; Yin, Jun; Reilly, Steven K.; DeMare, Laura E.; Emera, Deena; Ayoub, Albert E.; Rakic, Pasko; Noonan, James P.

2013-01-01

SUMMARY The evolution of human anatomical features likely involved changes in gene regulation during development. However, the nature and extent of human-specific developmental regulatory functions remain unknown. We obtained a genome-wide view of cis-regulatory evolution in human embryonic tissues by comparing the histone modification H3K27ac, which provides a quantitative readout of promoter and enhancer activity, during human, rhesus, and mouse limb development. Based on increased H3K27ac, we find that 13% of promoters and 11% of enhancers have gained activity on the human lineage since the human-rhesus divergence. These gains largely arose by modification of ancestral regulatory activities in the limb or potential co-option from other tissues and are likely to have heterogeneous genetic causes. Most enhancers that exhibit gain of activity in humans originated in mammals. Gains at promoters and enhancers in the human limb are associated with increased gene expression, suggesting they include molecular drivers of human morphological evolution. PMID:23827682

New antibacterial germacrene from Verbesina negrensis.

PubMed

Mora, Flor D; Alpan, Lara; de Tommasi, Nunziatina; McCracken, Vance J; Nieto, Marcelo

2013-05-01

Several health benefits have been attributed to members of the Verbesina genus, including promotion of urinary and gastrointestinal health. Verbesina species are also reported to exhibit antibacterial, antiparasitic, and antioxidant activities. Although members of the Verbesina genus produce various pharmacologically relevant chemicals as secondary metabolites, including eudesmanes, flavonoids, guanidine alkaloids, acetylenic compounds, and germacrenes, the active compounds required for these benefits remain unknown. To investigate potential antimicrobial activities of Verbesina negrensis, crude extracts from plant aerial structures were evaluated. Following chemical fractionation, the chloroformic extract from Verbesina negrensis was subjected to bioassay-guided isolation using disk diffusion assays to determine antimicrobial activity. The active compound was characterized as 6β-cinnamoyloxy-1β-hydroxy-10α-metoxy-3-oxo-germacra-4,5Z-ene (1). Fractions containing 1 inhibited both Enterococcus faecalis (ATCC 29 212) and Staphylococcus aureus (ATCC 29213). The MIC for 1 was determined by microbroth dilution assay to be 64 µg/mL for both E. faecalis and S. aureus. Georg Thieme Verlag KG Stuttgart · New York.

Bilateral frontal activation associated with cutaneous stimulation of elixir field: an FMRI study.

PubMed

Chan, Agnes S; Cheung, Mei-Chun; Chan, Yu Leung; Yeung, David K W; Lam, Wan

2006-01-01

Elixir Field, or Dan Tian, is the area where energy is stored and nourished in the body according to traditional Chinese medicine (TCM). Although Dan Tian stimulation is a major concept in Qigong healing and has been practiced for thousands of years, and while there are some recent empirical evidence of its effect, its neurophysiological basis remains unknown. We used functional magnetic resonance imaging (fMRI) to study brain activations associated with external stimulation of the lower Elixir Field in ten normal subjects, and compared the results with the stimulation of their right hands. While right-hand stimulation resulted in left postcentral gyrus activation, stimulation of the lower Elixir Field resulted in bilateral activations including the medial and superior frontal gyrus, middle and superior temporal gyrus, thalamus, insula, and cingulate gyrus. These findings suggest that stimulation of the Elixir Field is not only associated with activation of the sensory motor cortex but also with cortical regions that mediate planning, attention, and memory.

Active music classes in infancy enhance musical, communicative and social development.

PubMed

Gerry, David; Unrau, Andrea; Trainor, Laurel J

2012-05-01

Previous studies suggest that musical training in children can positively affect various aspects of development. However, it remains unknown as to how early in development musical experience can have an effect, the nature of any such effects, and whether different types of music experience affect development differently. We found that random assignment to 6 months of active participatory musical experience beginning at 6 months of age accelerates acquisition of culture-specific knowledge of Western tonality in comparison to a similar amount of passive exposure to music. Furthermore, infants assigned to the active musical experience showed superior development of prelinguistic communicative gestures and social behaviour compared to infants assigned to the passive musical experience. These results indicate that (1) infants can engage in meaningful musical training when appropriate pedagogical approaches are used, (2) active musical participation in infancy enhances culture-specific musical acquisition, and (3) active musical participation in infancy impacts social and communication development. © 2012 Blackwell Publishing Ltd.

Rescue therapy with Tanshinone IIA hinders transition of acute kidney injury to chronic kidney disease via targeting GSK3β

PubMed Central

Jiang, Chunming; Zhu, Wei; Yan, Xiang; Shao, Qiuyuan; Xu, Biao; Zhang, Miao; Gong, Rujun

2016-01-01

Acute kidney injury (AKI) remains challenging for clinical practice and poses a risk of developing progressive chronic kidney disease (CKD) with no definitive treatment available yet. Tanshinone IIA, an active ingredient of Chinese herbal Salvia miltiorrhiza, has been widely used in Asia for the remarkable organoprotective activities. Its effect on established AKI, however, remains unknown. In mice with folic acid-induced AKI, delayed treatment with Tanshinone IIA, commenced early or late after injury, diminished renal expression of kidney injury markers, reduced apoptosis and improved kidney dysfunction, concomitant with mitigated histologic signs of AKI to CKD transition, including interstitial fibrosis and tubular atrophy, and with an ameliorated inflammatory infiltration in tubulointerstitium and a favored M2-skewed macrophage polarization. Mechanistically, Tanshinone IIA blunted glycogen synthase kinase (GSK)3β overactivity and hyperactivation of its downstream mitogen-activated protein kinases that are centrally implicated in renal fibrogenesis and inflammation. Inhibition of GSK3β is likely a key mechanism mediating the therapeutic activity of Tanshinone IIA, because sodium nitroprusside, a GSK3β activator, largely offset its renoprotective effect. In confirmatory studies, rescue treatment with Tanshinone IIA likewise ameliorated ischemia/reperfusion-induced kidney destruction in mice. Our data suggest that Tanshinone IIA represents a valuable treatment that improves post-AKI kidney salvage via targeting GSK3β. PMID:27857162

Metabolic Control of Vesicular Glutamate Transport and Release

PubMed Central

Juge, Narinobu; Gray, John A.; Omote, Hiroshi; Miyaji, Takaaki; Inoue, Tsuyoshi; Hara, Chiaki; Uneyama, Hisayuki; Edwards, Robert H.; Nicoll, Roger A.; Moriyama, Yoshinori

2010-01-01

Fasting has been used to control epilepsy since antiquity, but the mechanism of coupling between metabolic state and excitatory neurotransmission remains unknown. Previous work has shown that the vesicular glutamate transporters (VGLUTs) required for exocytotic release of glutamate undergo an unusual form of regulation by Cl−. Using functional reconstitution of the purified VGLUTs into proteoliposomes, we now show that Cl− acts as an allosteric activator, and the ketone bodies that increase with fasting inhibit glutamate release by competing with Cl− at the site of allosteric regulation. Consistent with these observations, acetoacetate reduced quantal size at hippocampal synapses, and suppresses glutamate release and seizures evoked with 4-aminopyridine in the brain. The results indicate an unsuspected link between metabolic state and excitatory neurotransmission through anion-dependent regulation of VGLUT activity. PMID:20920794

Population-based incidence, treatment and survival of patients with peritoneal metastases of unknown origin.

PubMed

Thomassen, Irene; Verhoeven, Rob H A; van Gestel, Yvette R B M; van de Wouw, Agnes J; Lemmens, Valery E P P; de Hingh, Ignace H J T

2014-01-01

Until recently, peritoneal metastases (PM) were regarded as an untreatable condition, regardless of the organ of origin. Currently, promising treatment options are available for selected patients with PM from colorectal, appendiceal, ovarian or gastric carcinoma. The aim of this study was to investigate the incidence, treatment and survival of patients presenting with PM in whom the origin of PM remains unknown. Data from patients diagnosed with PM of unknown origin during 1984-2010 were extracted from the Eindhoven Cancer Registry. European age-standardised incidence rates were calculated and data on treatment and survival were analysed. In total 1051 patients were diagnosed with PM of unknown origin. In 606 patients (58%) the peritoneum was the only site of metastasis, and 445 patients also had other metastases. Chemotherapy usage has increased from 8% in the earliest period to 16% in most recent years (p=.016). Median survival was extremely poor with only 42days (95% confidence interval (CI) 39-47days) and did not change over time. Median survival of patients not receiving chemotherapy was significantly worse than of those receiving chemotherapy (36 versus 218days, p<.0001). The prognosis of PM of unknown origin is extremely poor and did not improve over time. Given the recent progress that has been achieved in selected patients presenting with PM, maximum efforts should be undertaken in order to diagnose the origin of PM as accurately as possible. Potentially effective treatment strategies should be further explored for patients in whom the organ of origin remains unknown. Copyright © 2013 Elsevier Ltd. All rights reserved.

Whales Use Distinct Strategies to Counteract Solar Ultraviolet Radiation

PubMed Central

Martinez-Levasseur, Laura M.; Birch-Machin, Mark A.; Bowman, Amy; Gendron, Diane; Weatherhead, Elizabeth; Knell, Robert J.; Acevedo-Whitehouse, Karina

2013-01-01

A current threat to the marine ecosystem is the high level of solar ultraviolet radiation (UV). Large whales have recently been shown to suffer sun-induced skin damage from continuous UV exposure. Genotoxic consequences of such exposure remain unknown for these long-lived marine species, as does their capacity to counteract UV-induced insults. We show that UV exposure induces mitochondrial DNA damage in the skin of seasonally sympatric fin, sperm, and blue whales and that this damage accumulates with age. However, counteractive molecular mechanisms are markedly different between species. For example, sperm whales, a species that remains for long periods at the sea surface, activate genotoxic stress pathways in response to UV exposure whereas the paler blue whale relies on increased pigmentation as the season progresses. Our study also shows that whales can modulate their responses to fluctuating levels of UV, and that different evolutionary constraints may have shaped their response strategies. PMID:23989080

Using NMR spectroscopy to elucidate the role of molecular motions in enzyme function

PubMed Central

Lisi, George P.; Loria, J. Patrick

2015-01-01

Conformational motions play an essential role in enzyme function, often facilitating the formation of enzyme-substrate complexes and/or product release. Although considerable debate remains regarding the role of molecular motions in the conversion of enzymatic substrates to products, numerous examples have found motions to be crucial for optimization of enzyme scaffolds, effective substrate binding, and product dissociation. Conformational fluctuations are often rate-limiting to enzyme catalysis, primarily through product release, with the chemical reaction occurring much more quickly. As a result, the direct involvement of motions at various stages along the enzyme reaction coordinate remains largely unknown and untested. In the following review, we describe the use of solution NMR techniques designed to probe various timescales of molecular motions and detail examples in which motions play a role in propagating catalytic effects from the active site and directly participate in essential aspects of enzyme function. PMID:26952190

The colibactin warhead crosslinks DNA

NASA Astrophysics Data System (ADS)

Vizcaino, Maria I.; Crawford, Jason M.

2015-05-01

Members of the human microbiota are increasingly being correlated to human health and disease states, but the majority of the underlying microbial metabolites that regulate host-microbe interactions remain largely unexplored. Select strains of Escherichia coli present in the human colon have been linked to the initiation of inflammation-induced colorectal cancer through an unknown small-molecule-mediated process. The responsible non-ribosomal peptide-polyketide hybrid pathway encodes ‘colibactin’, which belongs to a largely uncharacterized family of small molecules. Genotoxic small molecules from this pathway that are capable of initiating cancer formation have remained elusive due to their high instability. Guided by metabolomic analyses, here we employ a combination of NMR spectroscopy and bioinformatics-guided isotopic labelling studies to characterize the colibactin warhead, an unprecedented substituted spirobicyclic structure. The warhead crosslinks duplex DNA in vitro, providing direct experimental evidence for colibactin's DNA-damaging activity. The data support unexpected models for both colibactin biosynthesis and its mode of action.

Post-supereruption recovery at Toba Caldera

NASA Astrophysics Data System (ADS)

Mucek, Adonara E.; Danišík, Martin; de Silva, Shanaka L.; Schmitt, Axel K.; Pratomo, Indyo; Coble, Matthew A.

2017-05-01

Large calderas, or supervolcanoes, are sites of the most catastrophic and hazardous events on Earth, yet the temporal details of post-supereruption activity, or resurgence, remain largely unknown, limiting our ability to understand how supervolcanoes work and address their hazards. Toba Caldera, Indonesia, caused the greatest volcanic catastrophe of the last 100 kyr, climactically erupting ~74 ka. Since the supereruption, Toba has been in a state of resurgence but its magmatic and uplift history has remained unclear. Here we reveal that new 14C, zircon U-Th crystallization and (U-Th)/He ages show resurgence commenced at 69.7+/-4.5 ka and continued until at least ~2.7 ka, progressing westward across the caldera, as reflected by post-caldera effusive lava eruptions and uplifted lake sediment. The major stratovolcano north of Toba, Sinabung, shows strong geochemical kinship with Toba, and zircons from recent eruption products suggest Toba's climactic magma reservoir extends beneath Sinabung and is being tapped during eruptions.

ATF3 activates Stat3 phosphorylation through inhibition of p53 expression in skin cancer cells.

PubMed

Hao, Zhen-Feng; Ao, Jun-Hong; Zhang, Jie; Su, You-Ming; Yang, Rong-Ya

2013-01-01

ATF3, a member of the ATF/CREB family of transcription factors, has been found to be selectively induced by calcineurin/NFAT inhibition and to enhance keratinocyte tumor formation, although the precise role of ATF3 in human skin cancer and possible mechanisms remain unknown. In this study, clinical analysis of 30 skin cancer patients and 30 normal donors revealed that ATF3 was accumulated in skin cancer tissues. Functional assays demonstrated that ATF3 significantly promoted skin cancer cell proliferation. Mechanically, ATF3 activated Stat3 phosphorylation in skin cancer cell through regulation of p53 expression. Moreover, the promotion effect of ATF3 on skin cancer cell proliferation was dependent on the p53-Stat3 signaling cascade. Together, the results indicate that ATF3 might promote skin cancer cell proliferation and enhance skin keratinocyte tumor development through inhibiting p53 expression and then activating Stat3 phosphorylation.

Ventral striatum and the evaluation of memory retrieval strategies.

PubMed

Badre, David; Lebrecht, Sophie; Pagliaccio, David; Long, Nicole M; Scimeca, Jason M

2014-09-01

Adaptive memory retrieval requires mechanisms of cognitive control that facilitate the recovery of goal-relevant information. Frontoparietal systems are known to support control of memory retrieval. However, the mechanisms by which the brain acquires, evaluates, and adapts retrieval strategies remain unknown. Here, we provide evidence that ventral striatal activation tracks the success of a retrieval strategy and correlates with subsequent reliance on that strategy. Human participants were scanned with fMRI while performing a lexical decision task. A rule was provided that indicated the likely semantic category of a target word given the category of a preceding prime. Reliance on the rule improved decision-making, as estimated within a drift diffusion framework. Ventral striatal activation tracked the benefit that relying on the rule had on decision-making. Moreover, activation in ventral striatum correlated with a participant's subsequent reliance on the rule. Taken together, these results support a role for ventral striatum in learning and evaluating declarative retrieval strategies.

A Xanthomonas uridine 5'-monophosphate transferase inhibits plant immune kinases.

PubMed

Feng, Feng; Yang, Fan; Rong, Wei; Wu, Xiaogang; Zhang, Jie; Chen, She; He, Chaozu; Zhou, Jian-Min

2012-04-15

Plant innate immunity is activated on the detection of pathogen-associated molecular patterns (PAMPs) at the cell surface, or of pathogen effector proteins inside the plant cell. Together, PAMP-triggered immunity and effector-triggered immunity constitute powerful defences against various phytopathogens. Pathogenic bacteria inject a variety of effector proteins into the host cell to assist infection or propagation. A number of effector proteins have been shown to inhibit plant immunity, but the biochemical basis remains unknown for the vast majority of these effectors. Here we show that the Xanthomonas campestris pathovar campestris type III effector AvrAC enhances virulence and inhibits plant immunity by specifically targeting Arabidopsis BIK1 and RIPK, two receptor-like cytoplasmic kinases known to mediate immune signalling. AvrAC is a uridylyl transferase that adds uridine 5'-monophosphate to and conceals conserved phosphorylation sites in the activation loop of BIK1 and RIPK, reducing their kinase activity and consequently inhibiting downstream signalling.

Structural basis of mitochondrial dysfunction in response to cytochrome c phosphorylation at tyrosine 48

PubMed Central

Moreno-Beltrán, Blas; Guerra-Castellano, Alejandra; Del Conte, Rebecca; García-Mauriño, Sofía M.; Díaz-Moreno, Sofía; González-Arzola, Katiuska; Santos-Ocaña, Carlos; Velázquez-Campoy, Adrián; De la Rosa, Miguel A.; Turano, Paola; Díaz-Moreno, Irene

2017-01-01

Regulation of mitochondrial activity allows cells to adapt to changing conditions and to control oxidative stress, and its dysfunction can lead to hypoxia-dependent pathologies such as ischemia and cancer. Although cytochrome c phosphorylation—in particular, at tyrosine 48—is a key modulator of mitochondrial signaling, its action and molecular basis remain unknown. Here we mimic phosphorylation of cytochrome c by replacing tyrosine 48 with p-carboxy-methyl-l-phenylalanine (pCMF). The NMR structure of the resulting mutant reveals significant conformational shifts and enhanced dynamics around pCMF that could explain changes observed in its functionality: The phosphomimetic mutation impairs cytochrome c diffusion between respiratory complexes, enhances hemeprotein peroxidase and reactive oxygen species scavenging activities, and hinders caspase-dependent apoptosis. Our findings provide a framework to further investigate the modulation of mitochondrial activity by phosphorylated cytochrome c and to develop novel therapeutic approaches based on its prosurvival effects. PMID:28348229

Multimodal Chemosensory Circuits Controlling Male Courtship in Drosophila.

PubMed

Clowney, E Josephine; Iguchi, Shinya; Bussell, Jennifer J; Scheer, Elias; Ruta, Vanessa

2015-09-02

Throughout the animal kingdom, internal states generate long-lasting and self-perpetuating chains of behavior. In Drosophila, males instinctively pursue females with a lengthy and elaborate courtship ritual triggered by activation of sexually dimorphic P1 interneurons. Gustatory pheromones are thought to activate P1 neurons but the circuit mechanisms that dictate their sensory responses to gate entry into courtship remain unknown. Here, we use circuit mapping and in vivo functional imaging techniques to trace gustatory and olfactory pheromone circuits to their point of convergence onto P1 neurons and reveal how their combined input underlies selective tuning to appropriate sexual partners. We identify inhibition, even in response to courtship-promoting pheromones, as a key circuit element that tunes and tempers P1 neuron activity. Our results suggest a circuit mechanism in which balanced excitation and inhibition underlie discrimination of prospective mates and stringently regulate the transition to courtship in Drosophila. Copyright © 2015 Elsevier Inc. All rights reserved.

Parallel processing by cortical inhibition enables context-dependent behavior.

PubMed

Kuchibhotla, Kishore V; Gill, Jonathan V; Lindsay, Grace W; Papadoyannis, Eleni S; Field, Rachel E; Sten, Tom A Hindmarsh; Miller, Kenneth D; Froemke, Robert C

2017-01-01

Physical features of sensory stimuli are fixed, but sensory perception is context dependent. The precise mechanisms that govern contextual modulation remain unknown. Here, we trained mice to switch between two contexts: passively listening to pure tones and performing a recognition task for the same stimuli. Two-photon imaging showed that many excitatory neurons in auditory cortex were suppressed during behavior, while some cells became more active. Whole-cell recordings showed that excitatory inputs were affected only modestly by context, but inhibition was more sensitive, with PV + , SOM + , and VIP + interneurons balancing inhibition and disinhibition within the network. Cholinergic modulation was involved in context switching, with cholinergic axons increasing activity during behavior and directly depolarizing inhibitory cells. Network modeling captured these findings, but only when modulation coincidently drove all three interneuron subtypes, ruling out either inhibition or disinhibition alone as sole mechanism for active engagement. Parallel processing of cholinergic modulation by cortical interneurons therefore enables context-dependent behavior.

Recurrent AA Amyloidosis Combined With Chronic Active Antibody-mediated Rejection After Kidney Transplantation.

PubMed

Yeo, Min-Kyung; Ham, Young Rok; Choi, Song-Yi; Lee, Yong-Moon; Park, Moon Hyang; Suh, Kwang-Sun

2017-07-01

Kidney transplantation for amyloidosis remains a contentious issue. Recurrence of amyloidosis is one of the risks of transplantation. Chronic active antibody-mediated rejection is an important cause of chronic allograft dysfunction. A 47-year-old woman underwent kidney transplantation due to renal AA amyloidosis with unknown etiology. Six years posttransplantation, a kidney biopsy showed AA amyloidosis with chronic active antibody-mediated rejection. Donor-specific antibody class II was positive. The patient underwent intravenous plasmapheresis and treatment with rituximab and colchicine. The relationship between recurrence of amyloidosis and rejection was not obvious. Clinical characteristics of kidney transplantation for AA amyloidosis were subjected to literature review and 315 cases were identified. The incidence of amyloidosis recurrence and acute and chronic rejection rates were 15%, 15%, and 8%, respectively. Five-year patient and graft survival rates were 77% and 82%, respectively. Clinical courses of kidney transplantation in AA amyloidosis were, thus, identified.

Multimodal chemosensory circuits controlling male courtship in Drosophila

PubMed Central

Clowney, E. Josephine; Iguchi, Shinya; Bussell, Jennifer J.; Scheer, Elias; Ruta, Vanessa

2015-01-01

Summary Throughout the animal kingdom, internal states generate long-lasting and self-perpetuating chains of behavior. In Drosophila, males instinctively pursue females with a lengthy and elaborate courtship ritual triggered by activation of sexually dimorphic P1 interneurons. Gustatory pheromones are thought to activate P1 neurons but the circuit mechanisms that dictate their sensory responses to gate entry into courtship remain unknown. Here, we use circuit mapping and in vivo functional imaging techniques to trace gustatory and olfactory pheromone circuits to their point of convergence onto P1 neurons and reveal how their combined input underlies selective tuning to appropriate sexual partners. We identify inhibition, even in response to courtship-promoting pheromones, as a key circuit element that tunes and tempers P1 neuron activity. Our results suggest a circuit mechanism in which balanced excitation and inhibition underlie discrimination of prospective mates and stringently regulate the transition to courtship in Drosophila. PMID:26279475

Altered [99mTc]Tc-MDP biodistribution from neutron activation sourced 99Mo.

PubMed

Demeter, Sandor; Szweda, Roman; Patterson, Judy; Grigoryan, Marine

2018-01-01

Given potential worldwide shortages of fission sourced 99 Mo/ 99m Tc medical isotopes there is increasing interest in alternate production strategies. A neutron activated 99 Mo source was utilized in a single center phase III open label study comparing 99m Tc, as 99m Tc Methylene Diphosphonate ([ 99m Tc]Tc-MDP), obtained from solvent generator separation of neutron activation produced 99 Mo, versus nuclear reactor produced 99 Mo (e.g., fission sourced) in oncology patients for which an [ 99m Tc]Tc-MDP bone scan would normally have been indicated. Despite the investigational [ 99m Tc]Tc-MDP passing all standard, and above standard of care, quality assurance tests, which would normally be sufficient to allow human administration, there was altered biodistribution which could lead to erroneous clinical interpretation. The cause of the altered biodistribution remains unknown and requires further research.

Direct Modulation of Heterotrimeric G Protein-coupled Signaling by a Receptor Kinase Complex.

PubMed

Tunc-Ozdemir, Meral; Urano, Daisuke; Jaiswal, Dinesh Kumar; Clouse, Steven D; Jones, Alan M

2016-07-01

Plants and some protists have heterotrimeric G protein complexes that activate spontaneously without canonical G protein-coupled receptors (GPCRs). In Arabidopsis, the sole 7-transmembrane regulator of G protein signaling 1 (AtRGS1) modulates the G protein complex by keeping it in the resting state (GDP-bound). However, it remains unknown how a myriad of biological responses is achieved with a single G protein modulator. We propose that in complete contrast to G protein activation in animals, plant leucine-rich repeat receptor-like kinases (LRR RLKs), not GPCRs, provide this discrimination through phosphorylation of AtRGS1 in a ligand-dependent manner. G protein signaling is directly activated by the pathogen-associated molecular pattern flagellin peptide 22 through its LRR RLK, FLS2, and co-receptor BAK1. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Dissolved organic carbon leaching from plastics stimulates microbial activity in the ocean.

PubMed

Romera-Castillo, Cristina; Pinto, Maria; Langer, Teresa M; Álvarez-Salgado, Xosé Antón; Herndl, Gerhard J

2018-04-12

Approximately 5.25 trillion plastic pieces are floating at the sea surface. The impact of plastic pollution on the lowest trophic levels of the food web, however, remains unknown. Here we show that plastics release dissolved organic carbon (DOC) into the ambient seawater stimulating the activity of heterotrophic microbes. Our estimates indicate that globally up to 23,600 metric tons of DOC are leaching from marine plastics annually. About 60% of it is available to microbial utilization in less than 5 days. If exposed to solar radiation, however, this DOC becomes less labile. Thus, plastic pollution of marine surface waters likely alters the composition and activity of the base of the marine food webs. It is predicted that plastic waste entering the ocean will increase by a factor of ten within the next decade, resulting in an increase in plastic-derived DOC that might have unaccounted consequences for marine microbes and for the ocean system.

Anti-oxidizing effect of the dichloromethane and hexane fractions from Orostachys japonicus in LPS-stimulated RAW 264.7 cells via upregulation of Nrf2 expression and activation of MAPK signaling pathway.

PubMed

Lee, Hyeong-Seon; Lee, Gyeong-Seon; Kim, Seon-Hee; Kim, Hyun-Kyung; Suk, Dong-Hee; Lee, Dong-Seok

2014-02-01

Orostachys japonicus shows various biological activities. However, the molecular mechanisms remain unknown in LPS-stimulated macrophages. Here, we investigated the anti-oxidizing effect of the dichloromethane (DCM) and hexane fractions from O. japonicus (OJD and OJH) against oxidative stress in RAW 264.7 cells stimulated by LPS. OJD and OJH significantly increased the expression of heme oxygenase-1 (HO-1) in a dose- and time-dependent manner. Additionally, it was found that the expression of HO-1 was stimulated by Nrf2 activated via degradation of Keap1. ERK and p38 inhibitors repressed HO-1 induced by OJD and OJH in LPS-stimulated cells, respectively. In conclusion, these results suggest that OJD and OJH may block oxidative damage stimulated by LPS, via increasing the expression of HO-1 and Nrf2, and MAPK signaling pathway.

Self-Regulation and Implicit Attitudes Toward Physical Activity Influence Exercise Behavior.

PubMed

Padin, Avelina C; Emery, Charles F; Vasey, Michael; Kiecolt-Glaser, Janice K

2017-08-01

Dual-process models of health behavior posit that implicit and explicit attitudes independently drive healthy behaviors. Prior evidence indicates that implicit attitudes may be related to weekly physical activity (PA) levels, but the extent to which self-regulation attenuates this link remains unknown. This study examined the associations between implicit attitudes and self-reported PA during leisure time among 150 highly active young adults and evaluated the extent to which effortful control (one aspect of self-regulation) moderated this relationship. Results indicated that implicit attitudes toward exercise were unrelated to average workout length among individuals with higher effortful control. However, those with lower effortful control and more negative implicit attitudes reported shorter average exercise sessions compared with those with more positive attitudes. Implicit and explicit attitudes were unrelated to total weekly PA. A combination of poorer self-regulation and negative implicit attitudes may leave individuals vulnerable to mental and physical health consequences of low PA.

Systematic Survey of Serine Hydrolase Activity in Mycobacterium tuberculosis Defines Changes Associated with Persistence

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

Ortega, Corrie; Anderson, Lindsey N.; Frando, Andrew

The transition between replication and non-replication underlies much of Mycobacterium tuberculosis (Mtb) pathogenicity, as non- or slowly replicating Mtb are responsible for persistence and poor treatment outcomes. Therapeutic targeting of non-replicating, persistent populations is a priority for tuberculosis treatment, but only few drug targets in non-replicating Mtb are currently known. Here, we directly measure the activity of the highly diverse and druggable serine hydrolases (SHs) during active replication and non-replication by activity-based proteomics. We predict serine hydrolase activity for 78 proteins, including 27 proteins with previously unknown function, and identify 37 SHs that remain active even in the absence ofmore » replication, providing a set of candidate persistence targets. Non-replication was associated with large shifts in the activity of the majority of SHs. These activity changes were largely independent of SH abundance, indicating extensive post-translational regulation. By probing a large cross-section of druggable Mtb enzyme space during replication and non-replication, we identify new SHs and suggest new persistence targets.« less

SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK

PubMed Central

Osinski, Adam; Tomchick, Diana R; Brautigam, Chad A

2017-01-01

The Hippo pathway controls tissue growth and homeostasis through a central MST-LATS kinase cascade. The scaffold protein SAV1 promotes the activation of this kinase cascade, but the molecular mechanisms remain unknown. Here, we discover SAV1-mediated inhibition of the PP2A complex STRIPAKSLMAP as a key mechanism of MST1/2 activation. SLMAP binding to autophosphorylated MST2 linker recruits STRIPAK and promotes PP2A-mediated dephosphorylation of MST2 at the activation loop. Our structural and biochemical studies reveal that SAV1 and MST2 heterodimerize through their SARAH domains. Two SAV1–MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer, in which MST2 undergoes trans-autophosphorylation. SAV1 directly binds to STRIPAK and inhibits its phosphatase activity, protecting MST2 activation-loop phosphorylation. Genetic ablation of SLMAP in human cells leads to spontaneous activation of the Hippo pathway and alleviates the need for SAV1 in Hippo signaling. Thus, SAV1 promotes Hippo activation through counteracting the STRIPAKSLMAP PP2A phosphatase complex. PMID:29063833

SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK

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

Bae, Sung Jun; Ni, Lisheng; Osinski, Adam

The Hippo pathway controls tissue growth and homeostasis through a central MST-LATS kinase cascade. The scaffold protein SAV1 promotes the activation of this kinase cascade, but the molecular mechanisms remain unknown. Here, we discover SAV1-mediated inhibition of the PP2A complex STRIPAKSLMAP as a key mechanism of MST1/2 activation. SLMAP binding to autophosphorylated MST2 linker recruits STRIPAK and promotes PP2A-mediated dephosphorylation of MST2 at the activation loop. Our structural and biochemical studies reveal that SAV1 and MST2 heterodimerize through their SARAH domains. Two SAV1–MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer, in which MST2 undergoes trans-autophosphorylation. SAV1more » directly binds to STRIPAK and inhibits its phosphatase activity, protecting MST2 activation-loop phosphorylation. Genetic ablation of SLMAP in human cells leads to spontaneous activation of the Hippo pathway and alleviates the need for SAV1 in Hippo signaling. Thus, SAV1 promotes Hippo activation through counteracting the STRIPAKSLMAP PP2A phosphatase complex.« less

Vitamin and Mineral Supplements Have a Nutritionally Significant Impact on Micronutrient Intakes of Older Adults Attending Senior Centers

USDA-ARS?s Scientific Manuscript database

Background: Older adults frequently report use of vitamin and mineral (VM) supplements, though the impact of supplements on dietary adequacy remains largely unknown. Despite possible improvements in dietary intake, concern remains over potential excessive nutrient consumption from VM supplement us...

The anti-spasticity drug baclofen alleviates collagen-induced arthritis and regulates dendritic cells.

PubMed

Huang, Shichao; Mao, Jianxin; Wei, Bin; Pei, Gang

2015-07-01

Baclofen is used clinically as a drug that treats spasticity, which is a syndrome characterized by excessive contraction of the muscles and hyperflexia in the central nervous system (CNS), by activating GABA(B) receptors (GABA(B)Rs). Baclofen was recently reported to desensitize chemokine receptors and to suppress inflammation through the activation of GABA(B)Rs. GABA(B)Rs are expressed in various immune cells, but the functions of these receptors in autoimmune diseases remain largely unknown. In this study, we investigated the effects of baclofen in murine collagen-induced arthritis (CIA). Oral administration of baclofen alleviated the clinical development of CIA, with a reduced number of IL-17-producing T helper 17 (T(H)17) cells. In addition, baclofen treatment suppressed dendritic cell (DC)-primed T(H)17 cell differentiation by reducing the production of IL-6 by DCs in vitro. Furthermore, the pharmacological and genetic blockade of GABA(B)Rs in DCs weakened the effects of baclofen, indicating that GABA(B)Rs are the molecular targets of baclofen on DCs. Thus, our findings revealed a potential role for baclofen in the treatment of CIA, as well as a previously unknown signaling pathway that regulates DC function. © 2014 Wiley Periodicals, Inc.

Livedoid vasculopathy in a patient with factor V mutation (Leiden).

PubMed

Biedermann, T; Flaig, M J; Sander, C A

2000-09-01

Frequently, no underlying disease can be detected in patients with livedoid vasculopathy. For these forms, an unknown vaso-occlusive or thrombogenic process has been accused to play a role. Thus, a patient with livedoid vasculopathy was examined for different parameters which can be involved in coagulopathies. Laboratory studies for different autoantigen reactive immunoglobulins, cryoglobulins, and circulating immune complexes were carried out. Besides dermatopathologic examination, a biopsy specimen was analyzed by direct immunofluorescence for immunoglobulin (Ig) and complement deposits. Furthermore, hemostaseological function tests including activated protein C (APC) resistance were undertaken. Positive only at very low titres were antinuclear antibodies and c-ANCA, all other parameters were within normal ranges or negative. Direct immunofluorescence revealed IgM, C3 and fibrogen deposits. Hemostaseological function tests demonstrated a pathologic activated protein c resistance and PCR analysis a heterozygous defect of the factor V (Leiden). The diagnosis of livedoid vasculopathy associated with factor V mutation (Leiden) was made. Since the underlying cause for livedoid vasculopathy often remains unknown, we suggest that hemostaseological function tests including APC resistance and factor V gene mutation analysis should be carried out. Further studies have to follow in order to elucidate the role of mutant factor V in livedoid vasculopathy and in cutaneous ulcerations.

The ketogenic diet: metabolic influences on brain excitability and epilepsy

PubMed Central

Lutas, Andrew; Yellen, Gary

2012-01-01

A dietary therapy for pediatric epilepsy known as the ketogenic diet has seen a revival in its clinical use in the past decade. Though the diet’s underlying mechanism remains unknown, modern scientific approaches like genetic disruption of glucose metabolism are allowing for more detailed questions to be addressed. Recent work indicates that several mechanisms may exist for the ketogenic diet including disruption of glutamatergic synaptic transmission, inhibition of glycolysis, and activation of ATP-sensitive potassium channels. Here we describe on-going work in these areas that is providing a better understanding of metabolic influences on brain excitability and epilepsy. PMID:23228828

A Systematic Protocol for the Characterization of Hsp90 Modulators

PubMed Central

Matts, Robert L.; Brandt, Gary E. L.; Lu, Yuanming; Dixit, Anshuman; Mollapour, Mehdi; Wang, Suiquan; Donnelly, Alison C.; Neckers, Leonard; Verkhivker, Gennady; Blagg, Brian S. J.

2015-01-01

Several Hsp90 modulators have been identified including the N-terminal ligand geldanamycin (GDA), the C-terminal ligand novobiocin (NB), and the co-chaperone disruptor celastrol. Other Hsp90 modulators elicit a mechanism of action that remains unknown. For example, the natural product gedunin and the synthetic anti-spermatogenic agent H2-gamendazole, recently identified Hsp90 modulators, manifest biological activity through undefined mechanisms. Herein, we report a series of biochemical techniques used to classify such modulators into identifiable categories. Such studies provided evidence that gedunin and H2-gamendazole both modulate Hsp90 via a mechanism similar to celastrol, and unlike NB or GDA. PMID:21129982

No novel, high penetrant gene might remain to be found in Japanese patients with unknown MODY.

PubMed

Horikawa, Yukio; Hosomichi, Kazuyoshi; Enya, Mayumi; Ishiura, Hiroyuki; Suzuki, Yutaka; Tsuji, Shoji; Sugano, Sumio; Inoue, Ituro; Takeda, Jun

2018-07-01

MODY 5 and 6 have been shown to be low-penetrant MODYs. As the genetic background of unknown MODY is assumed to be similar, a new analytical strategy is applied here to elucidate genetic predispositions to unknown MODY. We examined to find whether there are major MODY gene loci remaining to be identified using SNP linkage analysis in Japanese. Whole-exome sequencing was performed with seven families with typical MODY. Candidates for novel MODY genes were examined combined with in silico network analysis. Some peaks were found only in either parametric or non-parametric analysis; however, none of these peaks showed a LOD score greater than 3.7, which is approved to be the significance threshold of evidence for linkage. Exome sequencing revealed that three mutated genes were common among 3 families and 42 mutated genes were common in two families. Only one of these genes, MYO5A, having rare amino acid mutations p.R849Q and p.V1601G, was involved in the biological network of known MODY genes through the intermediary of the INS. Although only one promising candidate gene, MYO5A, was identified, no novel, high penetrant MODY genes might remain to be found in Japanese MODY.

In vitro Serotonergic Activity of Black Cohosh and Identification of Nω-Methylserotonin as a Potential Active Constituent

PubMed Central

POWELL, SHARLA L.; GÖDECKE, TANJA; NIKOLIC, DEJAN; CHEN, SHAO-NONG; AHN, SOYOUN; DIETZ, BIRGIT; FARNSWORTH, NORMAN R.; VAN BREEMEN, RICHARD B.; LANKIN, DAVID; PAULI, GUIDO F.; BOLTON, JUDY L.

2013-01-01

Cimicifuga racemosa(L.) Nutt. (syn. Actaea racemosa L., black cohosh) is used to relieve menopausal hot flashes, although clinical studies have provided conflicting data, and the active constituent(s) and mechanism(s) of action remain unknown. Since serotonergic receptors and transporters are involved with thermoregulation, black cohosh and its phytoconstituents were evaluated for serotonergic activity using 5-HT7 receptor binding, cAMP induction, and serotonin selective reuptake inhibitor (SSRI) assays. Crude extracts displayed 5-HT7 receptor binding activity and induced cAMP production. Fractionation of the methanol extract lead to isolation of phenolic acids and identification of Nω-methylserotonin by LC/MS-MS. Cimicifuga triterpenoids and phenolic acids bound weakly to the 5-HT7 receptor with no cAMP or SSRI activity. In contrast, Nω-methylserotonin showed 5-HT7 receptor binding (IC50 23 pM), induced cAMP (EC50 22 nM), and blocked serotonin reuptake (IC50 490 nM). These data suggest Nω-methylserotonin may be responsible for the serotonergic activity of black cohosh. PMID:19049296

Retinoic Acid Modulates Interferon-γ Production by Hepatic Natural Killer T Cells via Phosphatase 2A and the Extracellular Signal-Regulated Kinase Pathway

PubMed Central

Chang, Heng-Kwei

2015-01-01

Retinoic acid (RA), an active metabolite converted from vitamin A, plays an active role in immune function, such as defending against infections and immune regulation. Although RA affects various types of immune cells, including antigen-presenting cells, B lymphocytes, and T lymphocytes, whether it affects natural killer T (NKT) cells remain unknown. In this study, we found that RA decreased interferon (IFN)-γ production by activated NKT cells through T-cell receptor (TCR) and CD28. We also found that RA reduced extracellular signal-regulated kinase (ERK) phosphorylation, but increased phosphatase 2A (PP2A) activity in TCR/CD28-stimulated NKT cells. The increased PP2A activity, at least partly, contributed to the reduction of ERK phosphorylation. Since inhibition of ERK activation decreases IFN-γ production by TCR/CD28-stimulated NKT cells, RA may downregulate IFN-γ production by TCR/CD28-stimulated NKT cells through the PP2A-ERK pathway. Our results demonstrated a novel function of RA in modulating the IFN-γ expression by activated NKT cells. PMID:25343668

Weak vaccinia virus-induced NK cell regulation of CD4 T cells is associated with reduced NK cell differentiation and cytolytic activity.

PubMed

Hatfield, Steven D; Daniels, Keith A; O'Donnell, Carey L; Waggoner, Stephen N; Welsh, Raymond M

2018-06-01

Natural killer (NK) cells control antiviral adaptive immune responses in mice during some virus infections, but the universality of this phenomenon remains unknown. Lymphocytic choriomeningitis virus (LCMV) infection of mice triggered potent cytotoxic activity of NK cells (NK LCMV ) against activated CD4 T cells, tumor cells, and allogeneic lymphocytes. In contrast, NK cells activated by vaccinia virus (VACV) infection (NK VACV ) exhibited weaker cytolytic activity against each of these target cells. Relative to NK LCMV cells, NK VACV cells exhibited a more immature (CD11b - CD27 + ) phenotype, and lower expression levels of the activation marker CD69, cytotoxic effector molecules (perforin, granzyme B), and the transcription factor IRF4. NK VACV cells expressed higher levels of the inhibitory molecule NKG2A than NK LCMV cells. Consistent with this apparent lethargy, NK VACV cells only weakly constrained VACV-specific CD4 T-cell responses. This suggests that NK cell regulation of adaptive immunity, while universal, may be limited with viruses that poorly activate NK cells. Published by Elsevier Inc.

Probing Metabolic Activity of Deep Subseafloor Life with NanoSIMS

NASA Astrophysics Data System (ADS)

Morono, Y.; Terada, T.; Itoh, M.; Inagaki, F.

2014-12-01

There are very few natural environments where life is absent in the Earth's surface biosphere. However, uninhabitable region is expected to be exist in the deep subsurface biosphere, of which extent and constraining factor(s) have still remained largly unknown. Scientific ocean drilling have revealed that microbial communities in sediments are generally phylogenetically distinct from known spieces isolated from the Earth's surface biosphere, and hence metabolic functions of the deep subseafloor life remain unknown. In addition, activity of subseafloor microbial cells are thought to be extraordinally slow, as indicated by limited supply of neutrient and energy substrates. To understand the limits of the Earth's subseafloor biosphere and metabolic functions of microbial populations, detection and quantification of the deeply buried microbial cells in geological habitats are fundamentary important. Using newly developed cell separation techniques as well as an discriminative cell detection system, the current quantification limit of sedimentary microbial cells approaches to 102 cells/cm3. These techniques allow not only to assess very small microbial population close to the subsurface biotic fringe, but also to separate and sort the target cells using flow cytometric cell sorter. Once the deep subseafloor microbial cells are detached from mineral grains and sorted, it opens new windows to subsequent molecular ecological and element/isotopic analyses. With a combined use of nano-scale secondary ion masspectrometry (NanoSIMS) and stable isotope-probing techniques, it is possible to detect and measure activity of substrate incorporation into biomass, even for extremely slow metabolic processes such as uncharacteriszed deep subseafloor life. For example, it was evidenced by NanoSIMS that at least over 80% of microbial cells at ~200 meters-deep, 460,000-year-old sedimentary habitat are indeed live, which substrate incooporation was found to be low (10-15 gC/cell/day) even under the lab incubation condition. Also microbial activity in ultraoligotrophic biosphere samples such as the South Pacific Gyre (i.e., IODP Expeditions 329) will be shown. Our results demonstrates metabolic potential of microbes that have been survived for geological timescale in extremely starved condition.

'Unknown' proteins and 'orphan' enzymes: the missing half of the engineering parts list--and how to find it.

PubMed

Hanson, Andrew D; Pribat, Anne; Waller, Jeffrey C; de Crécy-Lagard, Valérie

2009-12-14

Like other forms of engineering, metabolic engineering requires knowledge of the components (the 'parts list') of the target system. Lack of such knowledge impairs both rational engineering design and diagnosis of the reasons for failures; it also poses problems for the related field of metabolic reconstruction, which uses a cell's parts list to recreate its metabolic activities in silico. Despite spectacular progress in genome sequencing, the parts lists for most organisms that we seek to manipulate remain highly incomplete, due to the dual problem of 'unknown' proteins and 'orphan' enzymes. The former are all the proteins deduced from genome sequence that have no known function, and the latter are all the enzymes described in the literature (and often catalogued in the EC database) for which no corresponding gene has been reported. Unknown proteins constitute up to about half of the proteins in prokaryotic genomes, and much more than this in higher plants and animals. Orphan enzymes make up more than a third of the EC database. Attacking the 'missing parts list' problem is accordingly one of the great challenges for post-genomic biology, and a tremendous opportunity to discover new facets of life's machinery. Success will require a co-ordinated community-wide attack, sustained over years. In this attack, comparative genomics is probably the single most effective strategy, for it can reliably predict functions for unknown proteins and genes for orphan enzymes. Furthermore, it is cost-efficient and increasingly straightforward to deploy owing to a proliferation of databases and associated tools.

Activity-dependent switch of GABAergic inhibition into glutamatergic excitation in astrocyte-neuron networks.

PubMed

Perea, Gertrudis; Gómez, Ricardo; Mederos, Sara; Covelo, Ana; Ballesteros, Jesús J; Schlosser, Laura; Hernández-Vivanco, Alicia; Martín-Fernández, Mario; Quintana, Ruth; Rayan, Abdelrahman; Díez, Adolfo; Fuenzalida, Marco; Agarwal, Amit; Bergles, Dwight E; Bettler, Bernhard; Manahan-Vaughan, Denise; Martín, Eduardo D; Kirchhoff, Frank; Araque, Alfonso

2016-12-24

Interneurons are critical for proper neural network function and can activate Ca 2+ signaling in astrocytes. However, the impact of the interneuron-astrocyte signaling into neuronal network operation remains unknown. Using the simplest hippocampal Astrocyte-Neuron network, i.e., GABAergic interneuron, pyramidal neuron, single CA3-CA1 glutamatergic synapse, and astrocytes, we found that interneuron-astrocyte signaling dynamically affected excitatory neurotransmission in an activity- and time-dependent manner, and determined the sign (inhibition vs potentiation) of the GABA-mediated effects. While synaptic inhibition was mediated by GABA A receptors, potentiation involved astrocyte GABA B receptors, astrocytic glutamate release, and presynaptic metabotropic glutamate receptors. Using conditional astrocyte-specific GABA B receptor ( Gabbr1 ) knockout mice, we confirmed the glial source of the interneuron-induced potentiation, and demonstrated the involvement of astrocytes in hippocampal theta and gamma oscillations in vivo. Therefore, astrocytes decode interneuron activity and transform inhibitory into excitatory signals, contributing to the emergence of novel network properties resulting from the interneuron-astrocyte interplay.

In vivo characterization of CYP2D6*12, *29 and *84 using dextromethorphan as a probe drug: a case report.

PubMed

Gaedigk, Andrea; Twist, Greyson P; Farrow, Emily G; Lowry, Jennifer A; Soden, Sarah E; Miller, Neil A

2017-04-01

CYP2D6*84 was first described in a Black South African subject, however, its function remains unknown. Astrolabe, a probabilistic scoring tool developed in our laboratory to call genotypes from whole genome sequence, identified CYP2D6*84 in a trio. The father presented with intermediate metabolism when challenged with the CYP2D6 probe drug dextromethorphan (DM/dextrorphan [DX] = 0.0839). Since his second allele, CYP2D6*12, is nonfunctional, the observed activity is derived by CYP2D6*84. This finding suggests that the allele's hallmark P267H causes decreased activity toward DM and that this allele should receive a value of 0.5 for Activity Score calculations. The mother's DM/DX of 0.0543 was consistent with the decreased activity classification of CYP2D6*29. The child, a critically ill neonate, was not phenotyped, but predicted to be a normal metabolizer.

Tiam1 interaction with the PAR complex promotes talin-mediated Rac1 activation during polarized cell migration

PubMed Central

Wang, Shujie; Watanabe, Takashi; Matsuzawa, Kenji; Katsumi, Akira; Kakeno, Mai; Matsui, Toshinori; Ye, Feng; Sato, Kazuhide; Murase, Kiyoko; Sugiyama, Ikuko; Kimura, Kazushi; Mizoguchi, Akira; Ginsberg, Mark H.; Collard, John G.

2012-01-01

Migrating cells acquire front-rear polarity with a leading edge and a trailing tail for directional movement. The Rac exchange factor Tiam1 participates in polarized cell migration with the PAR complex of PAR3, PAR6, and atypical protein kinase C. However, it remains largely unknown how Tiam1 is regulated and contributes to the establishment of polarity in migrating cells. We show here that Tiam1 interacts directly with talin, which binds and activates integrins to mediate their signaling. Tiam1 accumulated at adhesions in a manner dependent on talin and the PAR complex. The interactions of talin with Tiam1 and the PAR complex were required for adhesion-induced Rac1 activation, cell spreading, and migration toward integrin substrates. Furthermore, Tiam1 acted with talin to regulate adhesion turnover. Thus, we propose that Tiam1, with the PAR complex, binds to integrins through talin and, together with the PAR complex, thereby regulates Rac1 activity and adhesion turnover for polarized migration. PMID:23071154

Sensory Afferents Use Different Coding Strategies for Heat and Cold.

PubMed

Wang, Feng; Bélanger, Erik; Côté, Sylvain L; Desrosiers, Patrick; Prescott, Steven A; Côté, Daniel C; De Koninck, Yves

2018-05-15

Primary afferents transduce environmental stimuli into electrical activity that is transmitted centrally to be decoded into corresponding sensations. However, it remains unknown how afferent populations encode different somatosensory inputs. To address this, we performed two-photon Ca 2+ imaging from thousands of dorsal root ganglion (DRG) neurons in anesthetized mice while applying mechanical and thermal stimuli to hind paws. We found that approximately half of all neurons are polymodal and that heat and cold are encoded very differently. As temperature increases, more heating-sensitive neurons are activated, and most individual neurons respond more strongly, consistent with graded coding at population and single-neuron levels, respectively. In contrast, most cooling-sensitive neurons respond in an ungraded fashion, inconsistent with graded coding and suggesting combinatorial coding, based on which neurons are co-activated. Although individual neurons may respond to multiple stimuli, our results show that different stimuli activate distinct combinations of diversely tuned neurons, enabling rich population-level coding. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

How the Venus flytrap actively snaps: hydrodynamic measurements at the cellular level

NASA Astrophysics Data System (ADS)

Colombani, Mathieu; Forterre, Yoel; GEP Team

2012-11-01

Although they lack muscle, plants have evolved a remarkable range of mechanisms to create rapid motion, from the rapid folding of sensitive plants to seed dispersal. Of these spectacular examples that have long fascinated scientists, the carnivorous plant Venus flytrap, whose leaves snap together in a fraction of second to capture insects, has long been a paradigm for study. Recently, we have shown that this motion involves a snap-buckling instability due to the shell-like geometry of the leaves of the trap. However, the origin of the movement that allows the plant to cross the instability threshold and actively bend remains largely unknown. In this study, we investigate this active motion using a micro-fluidic pressure probe that gives direct hydraulic and mechanical measurements at the cellular level (osmotic pressure, cell membrane permeability, cell wall elasticity). Our results challenge the role of osmotically-driven water flows usually put forward to explain Venus flytrap's active closure.

The tyrosine kinase Stitcher activates Grainy head and epidermal wound healing in Drosophila.

PubMed

Wang, Shenqiu; Tsarouhas, Vasilios; Xylourgidis, Nikos; Sabri, Nafiseh; Tiklová, Katarína; Nautiyal, Naumi; Gallio, Marco; Samakovlis, Christos

2009-07-01

Epidermal injury initiates a cascade of inflammation, epithelial remodelling and integument repair at wound sites. The regeneration of the extracellular barrier and damaged tissue repair rely on the precise orchestration of epithelial responses triggered by the injury. Grainy head (Grh) transcription factors induce gene expression to crosslink the extracellular barrier in wounded flies and mice. However, the activation mechanisms and functions of Grh factors in re-epithelialization remain unknown. Here we identify stitcher (stit), a new Grh target in Drosophila melanogaster. stit encodes a Ret-family receptor tyrosine kinase required for efficient epidermal wound healing. Live imaging analysis reveals that Stit promotes actin cable assembly during wound re-epithelialization. Stit activation also induces extracellular signal-regulated kinase (ERK) phosphorylation along with the Grh-dependent expression of stit and barrier repair genes at the wound sites. The transcriptional stimulation of stit on injury triggers a positive feedback loop increasing the magnitude of epithelial responses. Thus, Stit activation upon wounding coordinates cytoskeletal rearrangements and the level of Grh-mediated transcriptional wound responses.

Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo.

PubMed

Galbo, Thomas; Perry, Rachel J; Jurczak, Michael J; Camporez, João-Paulo G; Alves, Tiago C; Kahn, Mario; Guigni, Blas A; Serr, Julie; Zhang, Dongyan; Bhanot, Sanjay; Samuel, Varman T; Shulman, Gerald I

2013-07-30

Hepatic insulin resistance is a principal component of type 2 diabetes, but the cellular and molecular mechanisms responsible for its pathogenesis remain unknown. Recent studies have suggested that saturated fatty acids induce hepatic insulin resistance through activation of the toll-like receptor 4 (TLR-4) receptor in the liver, which in turn transcriptionally activates hepatic ceramide synthesis leading to inhibition of insulin signaling. In this study, we demonstrate that TLR-4 receptor signaling is not directly required for saturated or unsaturated fat-induced hepatic insulin resistance in both TLR-4 antisense oligonucleotide treated and TLR-4 knockout mice, and that ceramide accumulation is not dependent on TLR-4 signaling or a primary event in hepatic steatosis and impairment of insulin signaling. Further, we show that both saturated and unsaturated fats lead to hepatic accumulation of diacylglycerols, activation of PKCε, and impairment of insulin-stimulated IRS-2 signaling. These data demonstrate that saturated fat-induced insulin resistance is independent of TLR-4 activation and ceramides.

Delayed coupling to feedback inhibition during a critical period for the integration of adult-born granule cells

PubMed Central

Temprana, Silvio G.; Mongiat, Lucas A.; Yang, Sung M.; Trinchero, Mariela F.; Alvarez, Diego D.; Kropff, Emilio; Giacomini, Damiana; Beltramone, Natalia; Lanuza, Guillermo M.; Schinder, Alejandro F.

2014-01-01

SUMMARY Developing granule cells (GCs) of the adult dentate gyrus undergo a critical period of enhanced activity and synaptic plasticity before becoming mature. The impact of developing GCs on the activity of preexisting dentate circuits remains unknown. Here we combine optogenetics, acute slice electrophysiology, and in vivo chemogenetics to activate GCs at different stages of maturation to study the recruitment of local target networks. We show that immature (four-week-old) GCs can efficiently drive distal CA3 targets, but poorly activate proximal interneurons responsible for feedback inhibition (FBI). As new GCs transition towards maturity, they reliably recruit GABAergic feedback loops that restrict spiking of neighbor GCs, a mechanism that would promote sparse coding. Such inhibitory loop impinges only weakly in new cohorts of young GCs. A computational model reveals that the delayed coupling of new GCs to FBI could be crucial to achieve a fine-grain representation of novel inputs in the dentate gyrus. PMID:25533485

Proximal Tubular Cannabinoid-1 Receptor Regulates Obesity-Induced CKD.

PubMed

Udi, Shiran; Hinden, Liad; Earley, Brian; Drori, Adi; Reuveni, Noa; Hadar, Rivka; Cinar, Resat; Nemirovski, Alina; Tam, Joseph

2017-12-01

Obesity-related structural and functional changes in the kidney develop early in the course of obesity and occur independently of hypertension, diabetes, and dyslipidemia. Activating the renal cannabinoid-1 receptor (CB 1 R) induces nephropathy, whereas CB 1 R blockade improves kidney function. Whether these effects are mediated via a specific cell type within the kidney remains unknown. Here, we show that specific deletion of CB 1 R in the renal proximal tubule cells did not protect the mice from obesity, but markedly attenuated the obesity-induced lipid accumulation in the kidney and renal dysfunction, injury, inflammation, and fibrosis. These effects associated with increased activation of liver kinase B1 and the energy sensor AMP-activated protein kinase, as well as enhanced fatty acid β -oxidation. Collectively, these findings indicate that renal proximal tubule cell CB 1 R contributes to the pathogenesis of obesity-induced renal lipotoxicity and nephropathy by regulating the liver kinase B1/AMP-activated protein kinase signaling pathway. Copyright © 2017 by the American Society of Nephrology.

Corticospinal neurons in macaque ventral premotor cortex with mirror properties: a potential mechanism for action suppression?

PubMed

Kraskov, Alexander; Dancause, Numa; Quallo, Marsha M; Shepherd, Samantha; Lemon, Roger N

2009-12-24

The discovery of "mirror neurons" in area F5 of the ventral premotor cortex has prompted many theories as to their possible function. However, the identity of mirror neurons remains unknown. Here, we investigated whether identified pyramidal tract neurons (PTNs) in area F5 of two adult macaques exhibited "mirror-like" activity. About half of the 64 PTNs tested showed significant modulation of their activity while monkeys observed precision grip of an object carried out by an experimenter, with somewhat fewer showing modulation during precision grip without an object or grasping concealed from the monkey. Therefore, mirror-like activity can be transmitted directly to the spinal cord via PTNs. A novel finding is that many PTNs (17/64) showed complete suppression of discharge during action observation, while firing actively when the monkey grasped food rewards. We speculate that this suppression of PTN discharge might be involved in the inhibition of self-movement during action observation. 2009 Elsevier Inc. All rights reserved.

Immunochemical detection of food-derived polyphenols in the aorta: macrophages as a major target underlying the anti-atherosclerotic activity of polyphenols.

PubMed

Kawai, Yoshichika

2011-01-01

It has been suggested that polyphenol-rich diets decrease the risk of cardiovascular diseases. Although studies of the bioavailability of polyphenols, particularly their absorption and metabolism, have been reported recently, the tissue and cellular distributions underlying their biological mechanisms remain unknown. It is difficult to evaluate the specific localization of tissue and/or cellular polyphenols, because the method is limited to chromatography. To overcome these difficulties, we have developed anti-polyphenol antibodies to characterize immunohistochemically the localization of polyphenols and their metabolites in vivo. Two novel monoclonal antibodies were raised against quercetin and tea catechins, which represent flavonoid-type polyphenols distributed in foods and beverages, and are expected to exhibit anti-oxidative and anti-inflammatory activities in vivo. Using these antibodies, we identified activated macrophages as a specific target of these flavonoids during the development of atherosclerotic lesions. This review describes recent findings on the molecular actions of flavonoids that underly their anti-atherosclerotic activity in vivo.

Relief of autoinhibition by conformational switch explains enzyme activation by a catalytically dead paralog

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

Volkov, Oleg A.; Kinch, Lisa; Ariagno, Carson

Catalytically inactive enzyme paralogs occur in many genomes. Some regulate their active counterparts but the structural principles of this regulation remain largely unknown. We report X-ray structures ofTrypanosoma brucei S-adenosylmethionine decarboxylase alone and in functional complex with its catalytically dead paralogous partner, prozyme. We show monomericTbAdoMetDC is inactive because of autoinhibition by its N-terminal sequence. Heterodimerization with prozyme displaces this sequence from the active site through a complex mechanism involving acis-to-transproline isomerization, reorganization of a β-sheet, and insertion of the N-terminal α-helix into the heterodimer interface, leading to enzyme activation. We propose that the evolution of this intricate regulatory mechanismmore » was facilitated by the acquisition of the dimerization domain, a single step that can in principle account for the divergence of regulatory schemes in the AdoMetDC enzyme family. These studies elucidate an allosteric mechanism in an enzyme and a plausible scheme by which such complex cooperativity evolved.« less

Delayed coupling to feedback inhibition during a critical period for the integration of adult-born granule cells.

PubMed

Temprana, Silvio G; Mongiat, Lucas A; Yang, Sung M; Trinchero, Mariela F; Alvarez, Diego D; Kropff, Emilio; Giacomini, Damiana; Beltramone, Natalia; Lanuza, Guillermo M; Schinder, Alejandro F

2015-01-07

Developing granule cells (GCs) of the adult dentate gyrus undergo a critical period of enhanced activity and synaptic plasticity before becoming mature. The impact of developing GCs on the activity of preexisting dentate circuits remains unknown. Here we combine optogenetics, acute slice electrophysiology, and in vivo chemogenetics to activate GCs at different stages of maturation to study the recruitment of local target networks. We show that immature (4-week-old) GCs can efficiently drive distal CA3 targets but poorly activate proximal interneurons responsible for feedback inhibition (FBI). As new GCs transition toward maturity, they reliably recruit GABAergic feedback loops that restrict spiking of neighbor GCs, a mechanism that would promote sparse coding. Such inhibitory loop impinges only weakly in new cohorts of young GCs. A computational model reveals that the delayed coupling of new GCs to FBI could be crucial to achieve a fine-grain representation of novel inputs in the dentate gyrus. Copyright © 2015 Elsevier Inc. All rights reserved.

A unified internal model theory to resolve the paradox of active versus passive self-motion sensation

PubMed Central

Angelaki, Dora E

2017-01-01

Brainstem and cerebellar neurons implement an internal model to accurately estimate self-motion during externally generated (‘passive’) movements. However, these neurons show reduced responses during self-generated (‘active’) movements, indicating that predicted sensory consequences of motor commands cancel sensory signals. Remarkably, the computational processes underlying sensory prediction during active motion and their relationship to internal model computations during passive movements remain unknown. We construct a Kalman filter that incorporates motor commands into a previously established model of optimal passive self-motion estimation. The simulated sensory error and feedback signals match experimentally measured neuronal responses during active and passive head and trunk rotations and translations. We conclude that a single sensory internal model can combine motor commands with vestibular and proprioceptive signals optimally. Thus, although neurons carrying sensory prediction error or feedback signals show attenuated modulation, the sensory cues and internal model are both engaged and critically important for accurate self-motion estimation during active head movements. PMID:29043978

Chronic inflammation triggered by the NLRP3 inflammasome in myeloid cells promotes growth plate dysplasia by mesenchymal cells.

PubMed

Wang, Chun; Xu, Can-Xin; Alippe, Yael; Qu, Chao; Xiao, Jianqiu; Schipani, Ernestina; Civitelli, Roberto; Abu-Amer, Yousef; Mbalaviele, Gabriel

2017-07-07

Skeletal complications are common features of neonatal-onset multisystem inflammatory disease (NOMID), a disorder caused by NLRP3-activating mutations. NOMID mice in which NLRP3 is activated globally exhibit several characteristics of the human disease, including systemic inflammation and cartilage dysplasia, but the mechanisms of skeletal manifestations remain unknown. In this study, we find that activation of NLRP3 in myeloid cells, but not mesenchymal cells triggers chronic inflammation, which ultimately, causes growth plate and epiphyseal dysplasia in mice. These responses are IL-1 signaling-dependent, but independent of PARP1, which also functions downstream of NLRP3 and regulates skeletal homeostasis. Mechanistically, inflammation causes severe anemia and hypoxia in the bone environment, yet down-regulates the HIF-1α pathway in chondrocytes, thereby promoting the demise of these cells. Thus, activation of NLRP3 in hematopoietic cells initiates IL-1β-driven paracrine cascades, which promote abnormal growth plate development in NOMID mice.

Platelet activation in essential hypertension during exercise: pre- and post-treatment changes with an angiotensin II receptor blocker.

PubMed

Gkaliagkousi, Eugenia; Gavriilaki, Eleni; Yiannaki, Efi; Markala, Dimitra; Papadopoulos, Nikolaos; Triantafyllou, Areti; Anyfanti, Panagiota; Petidis, Konstantinos; Garypidou, Vasileia; Doumas, Michael; Ferro, Albert; Douma, Stella

2014-04-01

Acute exercise may exert deleterious effects on the cardiovascular system through a variety of pathophysiological mechanisms, including increased platelet activation. However, the degree of exercise-induced platelet activation in untreated hypertensive (UH) individuals as compared with normotensive (NT) individuals has yet to be established. Furthermore, the effect of antihypertensive treatment on exercise-induced platelet activation in essential hypertension (EH) remains unknown. Study 1 consisted of 30 UH and 15 NT subjects. UH subjects who received treatment were included in study 2 and were followed-up after a 3-month treatment period with an angiotensin II receptor blocker (ARB; valsartan). Circulating monocyte-platelet aggregates (MPA) and platelet P-selectin were measured as platelet activation markers at baseline, immediately after a treadmill exercise test, and 10, 30, and 90 minutes later. Maximal platelet activation was observed at 10 minutes after peak exercise in both groups. In UH subjects, MPA levels remained increased at 30 minutes after peak exercise, despite BP fall to baseline levels. MPA levels were significantly higher in UH subjects than NT subjects at maximal exercise and at 10 and 30 minutes of recovery. Post-treatment MPA levels increased significantly only at 10 minutes into recovery and were similar to those of NT subjects. Acute high-intensity exercise exaggerates platelet activation in untreated patients with EH compared with NT individuals. Angiotensin II receptor blockade with adequate BP control greatly improves exercise-induced platelet activation in EH. Further studies are needed to clarify whether this phenomenon depends purely on BP lowering or benefits also from the pleiotropic effects of ARBs.

Stability of the insecticide cypermethrin during tomato processing and implications for endocrine activity.

PubMed

Lin, H M; Gerrard, J A; Shaw, I C

2005-01-01

The thermal and pH stabilities of cypermethrin during food processing were investigated using tomato as a model food system and high-performance liquid chromatography as the analytical method. Cypermethrin was thermally unstable in aqueous conditions, where the hydrolysis of the pesticide was accelerated by heat. The mean proportion remaining after heating cypermethrin in water for 10 min was 66%, falling to 27% after 1 h. Similarly, thermal processing of canned tomatoes caused cypermethrin to degrade, with remaining levels in the final product ranging from 30 to 60% of the original. Cypermethrin was unstable at extreme pHs, with acid hydrolysis occurring faster than alkaline hydrolysis in phosphate buffers. The acidity of tomato paste (pH 4.3) caused cypermethrin levels to decrease by 30% within 12 days at 5 degrees C. The studies indicate that cypermethrin residues are likely to degrade by hydrolysis during food processing, thus reducing the exposure of consumers to cypermethrin. 3-Phenoxybenzaldehyde, a hydrolysis breakdown product of cypermethrin, was detected in the tomato paste and from the heating of cypermethrin in water at 100 degrees C. There is concern that the risk of breakdown products in terms of endocrine activity is unknown since in vitro studies reported that cypermethrin breakdown products display endocrine activity.

How pristine is the interior of the comet 67P/Churyumov-Gerasimenko?

NASA Astrophysics Data System (ADS)

Capria, Maria Teresa; Capaccioni, Fabrizio; Filacchione, Gianrico; Tosi, Federico; De Sanctis, Maria Cristina; Mottola, Stefano; Ciarniello, Mauro; Formisano, Michelangelo; Longobardo, Andrea; Migliorini, Alessandra; Palomba, Ernesto; Raponi, Andrea; Kührt, Ekkehard; Bockelée-Morvan, Dominique; Erard, Stéphane; Leyrat, Cedric; Zinzi, Angelo

2017-07-01

Comets are usually considered to be the most primitive bodies in the Solar System. The level of truth of this paradigm, however, is a matter of debate, especially if by primitive we mean that they represent a sample of intact, unprocessed material. We now have the possibility of analysing the comet 67P/Churyumov-Gerasimenko with an unprecedented level of detail, but its interior remains largely unprobed and unknown. The questions we address in this paper concern the depth of the processed layers, and whether the comet nucleus, under these processed layers, is really representative of the original material. We applied the Rome model for the thermal evolution and differentiation of nuclei to give an estimation of the evolution and depth of the active layers and of the interplay between the erosion process and the penetration of the heat wave. In order to characterize the illumination regime and the activity on the nucleus, two locations with very different illumination histories were chosen for the simulation. For both locations, the bulk of the activity tends to be concentrated around the perihelion time, giving rise to a high erosion rate. As a consequence, the active layers tend to remain close to the surface, and the interior of the comet, below a layer of few tens of centimetres, can be considered as pristine.

Effect-directed identification of endocrine disruptors in plastic baby teethers.

PubMed

Berger, Elisabeth; Potouridis, Theodoros; Haeger, Astrid; Püttmann, Wilhelm; Wagner, Martin

2015-11-01

Concerns have been raised regarding the human health effects of endocrine disrupting chemicals (EDCs), many of which are associated with and leaching from plastics. As infants are particularly vulnerable to EDCs, we have investigated whether plastic teethers for babies represent a relevant source of exposure. Applying effect-directed analysis, we use bioassays to screen teethers, toys used to soothe a baby's teething ache, for endocrine activity and chemical analysis to identify the causative compounds. We detected significant endocrine activity in two of 10 plastic teethers. Those samples leached estrogenic and/or antiandrogenic activity as detected in the Yeast Estrogen Screen and Yeast Antiandrogen Screen. After sample fractionation, gas chromatography-mass spectrometry non-target screening revealed that methyl-, ethyl- and propylparaben were responsible for the observed estrogenic and antiandrogenic activity in one product. The second product is likely to contain at least six different antiandrogenic compounds that remain so far unidentified. This study demonstrates that plastic teethers can be a source of infant exposure to well-established and unknown EDCs. Because of their limited value to the product, but potential toxicity, manufacturers should critically revisit the use of parabens in plastic teethers and further toys. Moreover, plastic teethers might leach EDCs that escape routine analysis and, thus, toxicological evaluation. The resulting uncertainty in product safety poses a problem to consumers, producers and regulators that remain to be resolved. Copyright © 2015 John Wiley & Sons, Ltd.

75 FR 52021 - Notice of Inventory Completion: New York University College of Dentistry, New York, NY

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-24

... University College of Dentistry, New York, NY AGENCY: National Park Service, Interior. ACTION: Notice. Notice... University College of Dentistry, New York, NY. The human remains were removed from an unknown location. This... the human remains was made by New York University College of Dentistry professional staff in...

Evaluation of the ruminal bacterial diversity of cattle fed diets containing citrus pulp pellets

USDA-ARS?s Scientific Manuscript database

The rumen microbial ecosystem remains a mystery from a quantitative perspective. Dietary components and changes cause shifts in the ruminal microbial ecology that can play a role in animal health and productivity, but the magnitude of these changes remains unknown. The objective of this study was ...

75 FR 67999 - Notice of Inventory Completion: Anthropological Studies Center, Archaeological Collections...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-04

... occupation between A.D. 1500 and 1856. Although the exact age and identity of the individual is unknown, more... relationship of shared group identity that can be reasonably traced between the Native American human remains... January 1982, human remains representing a minimum of one individual were removed from the Diamond H...

77 FR 2082 - Notice of Inventory Completion: Minnesota Indian Affairs Council, Bemidji, MN

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-13

.... The remains were removed during construction of a building and subsequently transferred to Bemidji.... At an unknown date, human remains representing, at minimum, one individual were recovered from a road construction project on Hwy 197 in Beltrami County, MN, and transferred to the Minnesota Office of the State...

Sexual behavior and HIV transmission risk of Ugandan adults taking antiretroviral therapy: 3 year follow-up.

PubMed

Apondi, Rose; Bunnell, Rebecca; Ekwaru, John Paul; Moore, David; Bechange, Stevens; Khana, Kenneth; King, Rachel; Campbell, James; Tappero, Jordan; Mermin, Jonathan

2011-06-19

Long-term impact of antiretroviral therapy (ART) on sexual HIV-transmission risk in Africa is unknown. We assessed sexual behavior changes and estimated HIV transmission from HIV-infected adults on ART in Uganda. Between 2003 and 2007, we enrolled and followed ART-naive HIV-infected adults in a home-based AIDS program with annual counseling and testing for cohabitating partners, participant transmission risk-reduction plans, condom distribution and prevention support for cohabitating discordant couples. We assessed participants' HIV plasma viral load and partner-specific sexual behaviors. We defined risky sex as intercourse with inconsistent/no condom use with HIV-negative or unknown serostatus partners in previous 3 months. We compared rates using Poisson regression models, estimated transmission risk using established viral load-specific transmission estimates, and documented sero-conversion rates among HIV-discordant couples. Of 928 participants, 755 (81%) had 36 months data: 94 (10%) died and 79 (9%) missing data. Sexual activity increased from 28% (baseline) to 41% [36 months (P < 0.001)]. Of sexually active participants, 22% reported risky sex at baseline, 8% at 6 months (P < 0.001), and 14% at 36 months (P = 0.018). Median viral load among those reporting risky sex was 122,500 [interquartile range (IQR) 45 100-353 000] copies/ml pre-ART at baseline and undetectable at follow-up. One sero-conversion occurred among 62 cohabitating sero-discordant partners (0.5 sero-conversions/100 person-years). At 36 months, consistent condom use was 74% with discordant partners, 55% with unknown and 46% with concordant partners. Estimated HIV transmission risk reduced 91%, from 47.3 to 4.2/1000 person-years. Despite increased sexual activity among HIV-infected Ugandans over 3 years on ART, risky sex and estimated risk of HIV transmission remained lower than baseline levels. Integrated prevention programs could reduce HIV transmission in Africa.

DNA methylation mediates neural processing after odor learning in the honeybee

PubMed Central

Biergans, Stephanie D.; Claudianos, Charles; Reinhard, Judith; Galizia, C. Giovanni

2017-01-01

DNA methyltransferases (Dnmts) - epigenetic writers catalyzing the transfer of methyl-groups to cytosine (DNA methylation) – regulate different aspects of memory formation in many animal species. In honeybees, Dnmt activity is required to adjust the specificity of olfactory reward memories and bees’ relearning capability. The physiological relevance of Dnmt-mediated DNA methylation in neural networks, however, remains unknown. Here, we investigated how Dnmt activity impacts neuroplasticity in the bees’ primary olfactory center, the antennal lobe (AL) an equivalent of the vertebrate olfactory bulb. The AL is crucial for odor discrimination, an indispensable process in forming specific odor memories. Using pharmacological inhibition, we demonstrate that Dnmt activity influences neural network properties during memory formation in vivo. We show that Dnmt activity promotes fast odor pattern separation in trained bees. Furthermore, Dnmt activity during memory formation increases both the number of responding glomeruli and the response magnitude to a novel odor. These data suggest that Dnmt activity is necessary for a form of homoeostatic network control which might involve inhibitory interneurons in the AL network. PMID:28240742

Structural basis for Mob1-dependent activation of the core Mst–Lats kinase cascade in Hippo signaling

DOE PAGES

Ni, Lisheng; Zheng, Yonggang; Hara, Mayuko; ...

2015-06-24

The Mst–Lats kinase cascade is central to the Hippo tumor-suppressive pathway that controls organ size and tissue homeostasis. The adaptor protein Mob1 promotes Lats activation by Mst, but the mechanism remains unknown. Here, we show that human Mob1 binds to autophosphorylated docking motifs in active Mst2. This binding enables Mob1 phosphorylation by Mst2. Phosphorylated Mob1 undergoes conformational activation and binds to Lats1. We determine the crystal structures of phospho-Mst2–Mob1 and phospho-Mob1–Lats1 complexes, revealing the structural basis of both phosphorylation-dependent binding events. Further biochemical and functional analyses demonstrate that Mob1 mediates Lats1 activation through dynamic scaffolding and allosteric mechanisms. Thus, Mob1more » acts as a phosphorylation-regulated coupler of kinase activation by virtue of its ability to engage multiple ligands. We propose that stepwise, phosphorylation-triggered docking interactions of nonkinase elements enhance the specificity and robustness of kinase signaling cascades.« less

The pure anti-oestrogen ICI 182,780 (Faslodex™) activates large conductance Ca2+-activated K+ channels in smooth muscle

PubMed Central

Dick, Gregory M

2002-01-01

Oestrogen and tamoxifen activate large conductance Ca2+-activated K+ (BKCa) channels in smooth muscle through a non-genomic mechanism that depends on the regulatory β1 subunit and an extracellular binding site. It is unknown whether a ‘pure' anti-oestrogen such as ICI 182,780 (Faslodex™), that has no known oestrogenic properties, would have any effect on BKCa channels. Using single channel patch clamp techniques on canine colonic myocytes, the hypothesis that ICI 182,780 would activate BKCa channels was tested. ICI 182,780 increased the open probability of BKCa channels in inside-out patches with an EC50 of 1 μM. These data suggest that molecules with the ability to bind nuclear oestrogen receptors, regardless of oestrogenic or anti-oestrogenic nature, activate BKCa channels through this nongenomic, membrane-delimited mechanism. The identity and characteristics of this putative binding site remain unclear; however, it has pharmacological similarity to oestrogen receptors α and β, as ICI 182,780 interacts with it. PMID:12145095

Activation of acid-sensing ion channels by localized proton transient reveals their role in proton signaling

PubMed Central

Zeng, Wei-Zheng; Liu, Di-Shi; Liu, Lu; She, Liang; Wu, Long-Jun; Xu, Tian-Le

2015-01-01

Extracellular transients of pH alterations likely mediate signal transduction in the nervous system. Neuronal acid-sensing ion channels (ASICs) act as sensors for extracellular protons, but the mechanism underlying ASIC activation remains largely unknown. Here, we show that, following activation of a light-activated proton pump, Archaerhodopsin-3 (Arch), proton transients induced ASIC currents in both neurons and HEK293T cells co-expressing ASIC1a channels. Using chimera proteins that bridge Arch and ASIC1a by a glycine/serine linker, we found that successful coupling occurred within 15 nm distance. Furthermore, two-cell sniffer patch recording revealed that regulated release of protons through either Arch or voltage-gated proton channel Hv1 activated neighbouring cells expressing ASIC1a channels. Finally, computational modelling predicted the peak proton concentration at the intercellular interface to be at pH 6.7, which is acidic enough to activate ASICs in vivo. Our results highlight the pathophysiological role of proton signalling in the nervous system. PMID:26370138

Pungent products from garlic activate the sensory ion channel TRPA1

PubMed Central

Bautista, Diana M.; Movahed, Pouya; Hinman, Andrew; Axelsson, Helena E.; Sterner, Olov; Högestätt, Edward D.; Julius, David; Jordt, Sven-Eric; Zygmunt, Peter M.

2005-01-01

Garlic belongs to the Allium family of plants that produce organosulfur compounds, such as allicin and diallyl disulfide (DADS), which account for their pungency and spicy aroma. Many health benefits have been ascribed to Allium extracts, including hypotensive and vasorelaxant activities. However, the molecular mechanisms underlying these effects remain unknown. Intriguingly, allicin and DADS share structural similarities with allyl isothiocyanate, the pungent ingredient in wasabi and other mustard plants that induces pain and inflammation by activating TRPA1, an excitatory ion channel on primary sensory neurons of the pain pathway. Here we show that allicin and DADS excite an allyl isothiocyanate-sensitive subpopulation of sensory neurons and induce vasodilation by activating capsaicin-sensitive perivascular sensory nerve endings. Moreover, allicin and DADS activate the cloned TRPA1 channel when expressed in heterologous systems. These and other results suggest that garlic excites sensory neurons primarily through activation of TRPA1. Thus different plant genera, including Allium and Brassica, have developed evolutionary convergent strategies that target TRPA1 channels on sensory nerve endings to achieve chemical deterrence. PMID:16103371

Frontal lobe connectivity and cognitive impairment in pediatric frontal lobe epilepsy.

PubMed

Braakman, Hilde M H; Vaessen, Maarten J; Jansen, Jacobus F A; Debeij-van Hall, Mariette H J A; de Louw, Anton; Hofman, Paul A M; Vles, Johan S H; Aldenkamp, Albert P; Backes, Walter H

2013-03-01

Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its etiology is unknown. With functional magnetic resonance imaging (fMRI), we have explored the relationship between brain activation, functional connectivity, and cognitive functioning in a cohort of pediatric patients with FLE and healthy controls. Thirty-two children aged 8-13 years with FLE of unknown cause and 41 healthy age-matched controls underwent neuropsychological assessment and structural and functional brain MRI. We investigated to which extent brain regions activated in response to a working memory task and assessed functional connectivity between distant brain regions. Data of patients were compared to controls, and patients were grouped as cognitively impaired or unimpaired. Children with FLE showed a global decrease in functional brain connectivity compared to healthy controls, whereas brain activation patterns in children with FLE remained relatively intact. Children with FLE complicated by cognitive impairment typically showed a decrease in frontal lobe connectivity. This decreased frontal lobe connectivity comprised both connections within the frontal lobe as well as connections from the frontal lobe to the parietal lobe, temporal lobe, cerebellum, and basal ganglia. Decreased functional frontal lobe connectivity is associated with cognitive impairment in pediatric FLE. The importance of impairment of functional integrity within the frontal lobe network, as well as its connections to distant areas, provides new insights in the etiology of the broad-range cognitive impairments in children with FLE. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Neural substrates of updating the prediction through prediction error during decision making.

PubMed

Wang, Ying; Ma, Ning; He, Xiaosong; Li, Nan; Wei, Zhengde; Yang, Lizhuang; Zha, Rujing; Han, Long; Li, Xiaoming; Zhang, Daren; Liu, Ying; Zhang, Xiaochu

2017-08-15

Learning of prediction error (PE), including reward PE and risk PE, is crucial for updating the prediction in reinforcement learning (RL). Neurobiological and computational models of RL have reported extensive brain activations related to PE. However, the occurrence of PE does not necessarily predict updating the prediction, e.g., in a probability-known event. Therefore, the brain regions specifically engaged in updating the prediction remain unknown. Here, we conducted two functional magnetic resonance imaging (fMRI) experiments, the probability-unknown Iowa Gambling Task (IGT) and the probability-known risk decision task (RDT). Behavioral analyses confirmed that PEs occurred in both tasks but were only used for updating the prediction in the IGT. By comparing PE-related brain activations between the two tasks, we found that the rostral anterior cingulate cortex/ventral medial prefrontal cortex (rACC/vmPFC) and the posterior cingulate cortex (PCC) activated only during the IGT and were related to both reward and risk PE. Moreover, the responses in the rACC/vmPFC and the PCC were modulated by uncertainty and were associated with reward prediction-related brain regions. Electric brain stimulation over these regions lowered the performance in the IGT but not in the RDT. Our findings of a distributed neural circuit of PE processing suggest that the rACC/vmPFC and the PCC play a key role in updating the prediction through PE processing during decision making. Copyright © 2017 Elsevier Inc. All rights reserved.

Activity-Dependence of Synaptic Vesicle Dynamics

PubMed Central

Forte, Luca A.

2017-01-01

The proper function of synapses relies on efficient recycling of synaptic vesicles. The small size of synaptic boutons has hampered efforts to define the dynamical states of vesicles during recycling. Moreover, whether vesicle motion during recycling is regulated by neural activity remains largely unknown. We combined nanoscale-resolution tracking of individual synaptic vesicles in cultured hippocampal neurons from rats of both sexes with advanced motion analyses to demonstrate that the majority of recently endocytosed vesicles undergo sequences of transient dynamical states including epochs of directed, diffusional, and stalled motion. We observed that vesicle motion is modulated in an activity-dependent manner, with dynamical changes apparent in ∼20% of observed boutons. Within this subpopulation of boutons, 35% of observed vesicles exhibited acceleration and 65% exhibited deceleration, accompanied by corresponding changes in directed motion. Individual vesicles observed in the remaining ∼80% of boutons did not exhibit apparent dynamical changes in response to stimulation. More quantitative transient motion analyses revealed that the overall reduction of vesicle mobility, and specifically of the directed motion component, is the predominant activity-evoked change across the entire bouton population. Activity-dependent modulation of vesicle mobility may represent an important mechanism controlling vesicle availability and neurotransmitter release. SIGNIFICANCE STATEMENT Mechanisms governing synaptic vesicle dynamics during recycling remain poorly understood. Using nanoscale resolution tracking of individual synaptic vesicles in hippocampal synapses and advanced motion analysis tools we demonstrate that synaptic vesicles undergo complex sets of dynamical states that include epochs of directed, diffusive, and stalled motion. Most importantly, our analyses revealed that vesicle motion is modulated in an activity-dependent manner apparent as the reduction in overall vesicle mobility in response to stimulation. These results define the vesicle dynamical states during recycling and reveal their activity-dependent modulation. Our study thus provides fundamental new insights into the principles governing synaptic function. PMID:28954868

Human embryonic stem cell-derived neurons adopt and regulate the activity of an established neural network

PubMed Central

Weick, Jason P.; Liu, Yan; Zhang, Su-Chun

2011-01-01

Whether hESC-derived neurons can fully integrate with and functionally regulate an existing neural network remains unknown. Here, we demonstrate that hESC-derived neurons receive unitary postsynaptic currents both in vitro and in vivo and adopt the rhythmic firing behavior of mouse cortical networks via synaptic integration. Optical stimulation of hESC-derived neurons expressing Channelrhodopsin-2 elicited both inhibitory and excitatory postsynaptic currents and triggered network bursting in mouse neurons. Furthermore, light stimulation of hESC-derived neurons transplanted to the hippocampus of adult mice triggered postsynaptic currents in host pyramidal neurons in acute slice preparations. Thus, hESC-derived neurons can participate in and modulate neural network activity through functional synaptic integration, suggesting they are capable of contributing to neural network information processing both in vitro and in vivo. PMID:22106298

PRP5: a helicase-like protein required for mRNA splicing in yeast.

PubMed Central

Dalbadie-McFarland, G; Abelson, J

1990-01-01

A 96-kDa protein predicted by the DNA sequence of the Saccharomyces cerevisiae PRP5 gene contains a domain that bears a striking resemblance to a family of RNA helicases characterized by the conserved amino acid sequence Asp-Glu-Ala-Asp (D-E-A-D). Previous work indicated that the product of the PRP5 gene is required for splicing and that spliceosome assembly does not occur in its absence. However, its precise role in splicing and the nature of its biochemical activity remained unknown. To examine the role of PRP5 in splicing, we cloned the gene by complementation of a temperature-sensitive mutation and determined its DNA sequence. We discuss here the possible roles for an RNA helicase in splicing and for the activity of the PRP5 protein. Images PMID:2349233

Spatio-Temporal Patterning in Primary Motor Cortex at Movement Onset.

PubMed

Best, Matthew D; Suminski, Aaron J; Takahashi, Kazutaka; Brown, Kevin A; Hatsopoulos, Nicholas G

2017-02-01

Voluntary movement initiation involves the engagement of large populations of motor cortical neurons around movement onset. Despite knowledge of the temporal dynamics that lead to movement, the spatial structure of these dynamics across the cortical surface remains unknown. In data from 4 rhesus macaques, we show that the timing of attenuation of beta frequency local field potential oscillations, a correlate of locally activated cortex, forms a spatial gradient across primary motor cortex (MI). We show that these spatio-temporal dynamics are recapitulated in the engagement order of ensembles of MI neurons. We demonstrate that these patterns are unique to movement onset and suggest that movement initiation requires a precise spatio-temporal sequential activation of neurons in MI. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Specification of haematopoietic stem cell fate via modulation of mitochondrial activity

PubMed Central

Vannini, Nicola; Girotra, Mukul; Naveiras, Olaia; Nikitin, Gennady; Campos, Vasco; Giger, Sonja; Roch, Aline; Auwerx, Johan; Lutolf, Matthias P.

2016-01-01

Haematopoietic stem cells (HSCs) differ from their committed progeny by relying primarily on anaerobic glycolysis rather than mitochondrial oxidative phosphorylation for energy production. However, whether this change in the metabolic program is the cause or the consequence of the unique function of HSCs remains unknown. Here we show that enforced modulation of energy metabolism impacts HSC self-renewal. Lowering the mitochondrial activity of HSCs by chemically uncoupling the electron transport chain drives self-renewal under culture conditions that normally induce rapid differentiation. We demonstrate that this metabolic specification of HSC fate occurs through the reversible decrease of mitochondrial mass by autophagy. Our data thus reveal a causal relationship between mitochondrial metabolism and fate choice of HSCs and also provide a valuable tool to expand HSCs outside of their native bone marrow niches. PMID:27731316

Physiological basis of tingling paresthesia evoked by hydroxy-alpha-sanshool.

PubMed

Lennertz, Richard C; Tsunozaki, Makoto; Bautista, Diana M; Stucky, Cheryl L

2010-03-24

Hydroxy-alpha-sanshool, the active ingredient in plants of the prickly ash plant family, induces robust tingling paresthesia by activating a subset of somatosensory neurons. However, the subtypes and physiological function of sanshool-sensitive neurons remain unknown. Here we use the ex vivo skin-nerve preparation to examine the pattern and intensity with which the sensory terminals of cutaneous neurons respond to hydroxy-alpha-sanshool. We found that sanshool excites virtually all D-hair afferents, a distinct subset of ultrasensitive light-touch receptors in the skin and targets novel populations of Abeta and C fiber nerve afferents. Thus, sanshool provides a novel pharmacological tool for discriminating functional subtypes of cutaneous mechanoreceptors. The identification of sanshool-sensitive fibers represents an essential first step in identifying the cellular and molecular mechanisms underlying tingling paresthesia that accompanies peripheral neuropathy and injury.

Physiological basis of tingling paresthesia evoked by hydroxy-α-sanshool

PubMed Central

Lennertz, Richard C; Tsunozaki, Makoto; Bautista, Diana M; Stucky, Cheryl L

2010-01-01

Hydroxy-α-sanshool, the active ingredient in plants of the prickly ash plant family, induces robust tingling paresthesia by activating a subset of somatosensory neurons. However, the subtypes and physiological function of sanshool-sensitive neurons remain unknown. Here we use the ex vivo skin-nerve preparation to examine the pattern and intensity with which the sensory terminals of cutaneous neurons respond to hydroxy-α-sanshool. We found that sanshool excites virtually all D-hair afferents, a distinct subset of ultra-sensitive light touch receptors in the skin, and targets novel populations of Aβ and C-fiber nerve afferents. Thus, sanshool provides a novel pharmacological tool for discriminating functional subtypes of cutaneous mechanoreceptors. The identification of sanshool-sensitive fibers represents an essential first step in identifying the cellular and molecular mechanisms underlying tingling paresthesia that accompanies peripheral neuropathy and injury. PMID:20335471

Induction of Tca8113 tumor cell apoptosis by icotinib is associated with reactive oxygen species mediated p38-MAPK activation.

PubMed

Yang, Cailing; Yan, Jianguo; Yuan, Guoyan; Zhang, Yinghua; Lu, Derong; Ren, Mingxin; Cui, Weigang

2014-08-01

Icotinib, a selective EGFR tyrosine kinase inhibitor (EGFR-TKI), has been shown to exhibit anti-tumor activity against several tumor cell lines. However, the exact molecular mechanism of icotinib's anti-tumor effect remains unknown. This study aims to examine the zytotoxic effect of icotinib on Tca8113 cells and its potential molecular mechanism. Icotinib significantly resulted in dose-dependent cell death as determined by MTT assay, accompanied by increased levels of Bax and DNA fragmentation. Icotinib could also induce Reactive Oxygen Species (ROS) generation. Further studies confirmed that scavenging of reactive oxygen species by N-acetyl-L-cysteine (NAC), and pharmacological inhibition of MAPK reversed icotinib-induced apoptosis in Tca8113 cells. Our data provide evidence that icotinib induces apoptosis, possibly via ROS-mediated MAPK pathway in Tca8113 cells.

Orthosiphol A from the aerial parts of Orthosiphon aristatus is putatively responsible for hypoglycemic effect via alpha-glucosidase inhibition.

PubMed

Damsud, Thanakorn; Grace, Mary H; Adisakwattana, Sirichai; Phuwapraisirisan, Preecha

2014-05-01

An infusion of Orthosiphon aristatus has long been used for diabetes therapy; however, the active principles remained unknown. Herein, we report the identification of the putative agents responsible for this antidiabetic activity using an a-glucosidase-guided isolation. Four flavonoids named sinensetin (1), salvigenin (2), tetramethylscutellarein (3) and 3,7,4'-tri-O-methylkaempferol (4), together with a diterpenoid named orthosiphol A (5), were characterized, based on analysis of their spectroscopic data. Flavonoids 3 and 4 inhibited yeast a-glucosidase with IC,o values of 6.34 and 0.75 mM, respectively, whereas orthosiphol A (5) selectively inhibited intestinal maltase with an IC5o, value of 6.54 mM. A kinetic investigation of 5 indicated that it retarded maltase function in a noncompetitive manner.

Metabolic control of vesicular glutamate transport and release.

PubMed

Juge, Narinobu; Gray, John A; Omote, Hiroshi; Miyaji, Takaaki; Inoue, Tsuyoshi; Hara, Chiaki; Uneyama, Hisayuki; Edwards, Robert H; Nicoll, Roger A; Moriyama, Yoshinori

2010-10-06

Fasting has been used to control epilepsy since antiquity, but the mechanism of coupling between metabolic state and excitatory neurotransmission remains unknown. Previous work has shown that the vesicular glutamate transporters (VGLUTs) required for exocytotic release of glutamate undergo an unusual form of regulation by Cl(-). Using functional reconstitution of the purified VGLUTs into proteoliposomes, we now show that Cl(-) acts as an allosteric activator, and the ketone bodies that increase with fasting inhibit glutamate release by competing with Cl(-) at the site of allosteric regulation. Consistent with these observations, acetoacetate reduced quantal size at hippocampal synapses and suppresses glutamate release and seizures evoked with 4-aminopyridine in the brain. The results indicate an unsuspected link between metabolic state and excitatory neurotransmission through anion-dependent regulation of VGLUT activity. Copyright © 2010 Elsevier Inc. All rights reserved.

Basophil-activation tests in Hymenoptera allergy.

PubMed

Dubois, Anthony E J; van der Heide, Sicco

2007-08-01

Despite recent advances in our understanding of basophil biology and discovery of new markers for basophil activation, tests measuring basophil activation are not widely utilized in Hymenoptera allergy. Studies of the basophil-activation test in Hymenoptera allergy were examined and the clinical utility of this test was assessed. It has been demonstrated that the results of basophil-activation tests correlate quite well with those of serum IgE testing or skin-prick tests. Many studies compare test outcomes with history in patients and nonallergic controls, so that specificity in sensitized but clinically nonreactive individuals remains unknown. Although one study showed that the basophil-activation test might predict immunotherapy side effects, this could not be confirmed in a second study, and no role has been established for the basophil-activation test in the monitoring of venom immunotherapy. The basophil-activation test has no extra value in assessing sting challenges, although experience is limited. The measurement of basophil-activation markers may be useful in detecting IgE-mediated sensitization but the relevance for application of the basophil-activation test in prediction of clinical reactivity in Hymenoptera allergy is very limited. For this reason, this test currently has no established role in the diagnosis and management of patients with insect sting allergy.

Localization of Short-Chain Polyphosphate Enhances its Ability to Clot Flowing Blood Plasma

NASA Astrophysics Data System (ADS)

Yeon, Ju Hun; Mazinani, Nima; Schlappi, Travis S.; Chan, Karen Y. T.; Baylis, James R.; Smith, Stephanie A.; Donovan, Alexander J.; Kudela, Damien; Stucky, Galen D.; Liu, Ying; Morrissey, James H.; Kastrup, Christian J.

2017-02-01

Short-chain polyphosphate (polyP) is released from platelets upon platelet activation, but it is not clear if it contributes to thrombosis. PolyP has increased propensity to clot blood with increased polymer length and when localized onto particles, but it is unknown whether spatial localization of short-chain polyP can accelerate clotting of flowing blood. Here, numerical simulations predicted the effect of localization of polyP on clotting under flow, and this was tested in vitro using microfluidics. Synthetic polyP was more effective at triggering clotting of flowing blood plasma when localized on a surface than when solubilized in solution or when localized as nanoparticles, accelerating clotting at 10-200 fold lower concentrations, particularly at low to sub-physiological shear rates typical of where thrombosis occurs in large veins or valves. Thus, sub-micromolar concentrations of short-chain polyP can accelerate clotting of flowing blood plasma under flow at low to sub-physiological shear rates. However, a physiological mechanism for the localization of polyP to platelet or vascular surfaces remains unknown.

[18F-FDG PET/CT diagnosis of liver cyst infection in a patient with autosomal dominant polycystic kidney disease and fever of unknown origin].

PubMed

Banzo, J; Ubieto, M A; Gil, D; Prats, E; Razola, P; Tardín, L; Andrés, A; Rambalde, E F; Ayala, S M; Cáncer, L; Velilla, J

2013-01-01

The diagnosis, localization and treatment of infected cysts in the kidney or liver of patients with autosomal dominant polycystic kidney disease (ADPKD) remain a clinical challenge. We report the findings of (18)F-FDG PET-CT in an ADPKD diagnosed patient who required renal transplantation five years before and in his follow up presented repeated episodes of bacteriemia without known focus on radiological tests performed. The (18)F-FDG PET-CT scan showed numerous hypermetabolic images with focal or ring-shaped morphology related to the content and the wall of some hepatic cysts. The increased metabolic activity was localized on segments VI and VII. We proceeded to drainage of one cyst in segment VI, removing 110 cc of purulent fluid which grew E. Coli BLEE. The (18)F-FDG PET/CT scan should be included in the diagnostic algorithm for detecting infected liver cysts in patients with ADPKD and fever of unknown origin. Copyright © 2012 Elsevier España, S.L. and SEMNIM. All rights reserved.

Neighborhood Crime and Sexual Transmission Risk Behavior among Black Men Living with HIV

PubMed Central

Ojikutu, Bisola O.; Bogart, Laura M.; Klein, David J.; Galvan, Frank H.; Wagner, Glenn J.

2018-01-01

Here, we examined the association of exposure to neighborhood crime with sexual risk-taking behavior among Black men living with HIV. HIV-positive Black men on anti-retroviral therapy in California completed an audio computer-assisted self-interview. Crime risk per census block group was derived from the Federal Bureau of Investigation’s Uniform Crime Report. Among 193 men, the mean (SD) number of sexual partners among those who were sexually active was 2.7 (3.3). 49% reported condomless sex, and 23% reported sex with an HIV-negative or unknown-serostatus partner. In multivariate analysis, illicit drug use ([IRR=1.86; 95%CI: 1.20–2.89] p=.006), depressive symptoms ([IRR=1.59; 95%CI: 1.03–2.44] p=.03), an undetectable viral load ([IRR=1.91; 95%CI: 1.22–3.00] p=.005), and neighborhood total crime risk ([IRR=1.02; 95%CI: 1.01–1.04] p=.007) remained significant. Among Black men living with HIV, exposure to neighborhood crime is associated with having multiple sexual partners whose HIV status was negative or unknown. PMID:29503307

Purpurolic acid: A new natural alkaloid from Claviceps purpurea (Fr.) Tul.

PubMed

Roberts, Andrew; Beaumont, Claire; Manzarpour, Azita; Mantle, Peter

2016-01-01

A novel secondary metabolite from the sclerotia of Claviceps purpurea (Fr.) Tul. is described; the structure is based on (1)H and (13)C NMR spectroscopy and electrospray mass spectrometry. It has an elemental composition C10H16N2O7 and is comprised mainly of proline and alanine moieties, although without peptide linkage. Notably, these amino-acids are also components of the cyclic tripeptide side chain of several classic ergoline alkaloids. Designated as purpurolic acid, the new compound is the principal free amino-acid in ergot and its natural abundance exceeds that of the ergoline alkaloids with which it accumulates in parallel during parasitic development. In contrast, it does not accumulate in the fungus in axenic culture, even when ergotamine is synthesised. The extent to which the compound is a metabolite of other ergot fungi worldwide is unknown. Biological activity and metabolic significance also remain unknown, but purpurolic acid could become a biomarker for detection of ergot contamination in agricultural products of temperate latitudes. Copyright © 2015 The British Mycological Society. Published by Elsevier Ltd. All rights reserved.

Chronic ozone exposure alters the secondary metabolite profile, antioxidant potential, anti-inflammatory property, and quality of red pepper fruit from Capsicum baccatum.

PubMed

Bortolin, Rafael Calixto; Caregnato, Fernanda Freitas; Divan Junior, Armando Molina; Zanotto-Filho, Alfeu; Moresco, Karla Suzana; Rios, Alessandro de Oliveira; Salvi, Aguisson de Oliveira; Ortmann, Caroline Flach; de Carvalho, Pâmela; Reginatto, Flávio Henrique; Gelain, Daniel Pens; Moreira, José Cláudio Fonseca

2016-07-01

Tropospheric ozone (O3) background concentrations have increased since pre-industrial times, reaching phytotoxic concentrations in many regions globally. However, the effect of high O3 concentrations on quality of fruit and vegetables remains unknown. Here, we evaluated whether O3 pollution alters the quality of Capsicum baccatum peppers by changing the secondary compound profiles and biological activity of the fruit. C. baccatum pepper plants were exposed to ozone for 62 days in an open-top chamber at a mean O3 concentration of 171.6µg/m(3). Capsaicin levels decreased by 50% in the pericarp, but remained unchanged in the seeds. In contrast, the total carotenoid content increased by 52.8% in the pericarp. The content of total phenolic compounds increased by 17% in the pericarp. The total antioxidant potential decreased by 87% in seeds of O3-treated plants. The seeds contributed more than the pericarp to the total radical-trapping antioxidant potential and total antioxidant reactivity. O3 treatment impaired the ferric-reducing antioxidant power of the seeds and reduced NO(•)-scavenging activity in the pericarp. However, O3 treatment increased ferrous ion-chelating activity and hydroxyl radical-scavenging activity in the pericarp. Our results confirm that O3 alters the secondary metabolite profile of C. baccatum pepper fruits and, consequently, their biological activity profile. Copyright © 2016 Elsevier Inc. All rights reserved.

Strong induction of iodothyronine deiodinases by chemotherapeutic selenocompounds.

PubMed

Stoedter, M; Renko, K; Ibáñez, E; Plano, D; Becker, N-P; Martitz, J; Palop, J A; Calvo, A; Sanmartín, C; Schomburg, L

2015-02-01

The biological activity of thyroid hormones (TH) is regulated by selenoenzymes of the iodothyronine deiodinase (DIO) family catalysing TH activating and inactivating reactions. Besides TH metabolism, several studies indicate an important role of DIO isoenzymes in tumorigenesis and cancer growth. It is therefore of therapeutic importance to identify modulators of DIO expression. We have synthesized and studied a series of selenocompounds containing a methyl- or benzyl-imidoselenocarbamate backbone. One of these novel compounds had chemotherapeutic activities in a murine xenograft tumour model by an unknown mechanism. Therefore, we tested their effects on DIO expression in vitro. In HepG2 hepatocarcinoma cells, DIO1 activity was strongly (up to 10-fold) increased by the methyl- but not by the corresponding benzyl-imidoselenocarbamates. Steady-state mRNA levels remained unaltered under these conditions indicating a post-transcriptional mode of action. The effects were further characterized in HEK293 cells stably expressing DIO1, DIO2 or DIO3. Even within the artificial genetic context of the expression vectors, all three DIO isoenzymes were up-regulated by the methyl- and to a lesser extent by the benzyl-imidoselenocarbamates. Consistent stimulating effects were observed with methyl-N,N'-di(quinolin-3-ylcarbonyl)-imidoselenocarbamate (EI201), a selenocompound known for its anti-tumour activity. DIO inducing effects were unrelated to the intracellular accumulation of selenium, yet the precise mode of action remains elusive. Collectively, our data highlight that these selenocompounds may constitute interesting pharmacological compounds for modifying DIO expression potentially affecting the balance between cell differentiation and proliferation.

Twenty-five year socioeconomic trends in leisure-time and commuting physical activity among employed Finns.

PubMed

Mäkinen, T; Borodulin, K; Laatikainen, T; Fogelholm, M; Prättälä, R

2009-04-01

The trend of socioeconomic differences in physical activity is largely unknown in Finland. In this study, we examined socioeconomic trends in leisure-time and commuting physical activity among Finns in 1978-2002. Nationwide data were derived from an annually repeated cross-sectional Finnish Adult Health Behavior Survey. People under the age of 25, students, the unemployed, and retirees were excluded from the analysis. The final data set included 25 513 women and 25 302 men. Socioeconomic variables included education, occupation, and household income. Odds ratios for being physically active and 95% confidence intervals were calculated. People with the lowest income were less leisure-time and commuting physically active. Among women, low occupational status was associated with high commuting physical activity whereas among men such an association was not found. No educational differences among men in leisure-time and commuting physical activity over time were found. Some indications were found that educational differences in leisure-time physical activity among women might have been reversed. Our data suggest that socioeconomic differences in leisure-time and commuting physical activity are quite small and have remained similar between 1978 and 2002.

Subtotal Ablation of Parietal Epithelial Cells Induces Crescent Formation

PubMed Central

Sicking, Eva-Maria; Fuss, Astrid; Uhlig, Sandra; Jirak, Peggy; Dijkman, Henry; Wetzels, Jack; Engel, Daniel R.; Urzynicok, Torsten; Heidenreich, Stefan; Kriz, Wilhelm; Kurts, Christian; Ostendorf, Tammo; Floege, Jürgen; Smeets, Bart

2012-01-01

Parietal epithelial cells (PECs) of the renal glomerulus contribute to the formation of both cellular crescents in rapidly progressive GN and sclerotic lesions in FSGS. Subtotal transgenic ablation of podocytes induces FSGS but the effect of specific ablation of PECs is unknown. Here, we established an inducible transgenic mouse to allow subtotal ablation of PECs. Proteinuria developed during doxycycline-induced cellular ablation but fully reversed 26 days after termination of doxycycline administration. The ablation of PECs was focal, with only 30% of glomeruli exhibiting histologic changes; however, the number of PECs was reduced up to 90% within affected glomeruli. Ultrastructural analysis revealed disruption of PEC plasma membranes with cytoplasm shedding into Bowman’s space. Podocytes showed focal foot process effacement, which was the most likely cause for transient proteinuria. After >9 days of cellular ablation, the remaining PECs formed cellular extensions to cover the denuded Bowman’s capsule and expressed the activation marker CD44 de novo. The induced proliferation of PECs persisted throughout the observation period, resulting in the formation of typical cellular crescents with periglomerular infiltrate, albeit without accompanying proteinuria. In summary, subtotal ablation of PECs leads the remaining PECs to react with cellular activation and proliferation, which ultimately forms cellular crescents. PMID:22282596

Do owls use torpor? Winter thermoregulation in free-ranging pearl-spotted owlets and African scops-owls.

PubMed

Smit, Ben; McKechnie, Andrew E

2010-01-01

Numerous avian taxa use torpor, which involves pronounced reductions in body temperature (T(b)) to below normothermic levels. However, the occurrence of this phenomenon in owls (Strigidae) remains largely unknown. We investigated winter patterns of thermoregulation in the crepuscular 80-g pearl-spotted owlet Glaucidium perlatum and the strictly nocturnal 61-g African scops-owl Otus senegalensis by obtaining telemetric measurements of skin temperature (T(skin)) from free-ranging individuals in the Kalahari Desert of southern Africa. Pearl-spotted owlets remained homeothermic throughout the study period, whereas African scops-owls routinely used shallow torpor, with T(skin) reduced by 3.3 degrees -8.6 degrees C (pooled mean, 5.3+/- 1.1 degrees C) below normothermic levels for 3-4 h after sunrise. The mean lowest T(skin) recorded in three African scops-owl individuals was 29.0 degrees C +/- 0.1 degrees C. The thermoregulatory differences between these two species may be related to their diets and activity patterns. African scops-owls are almost exclusively insectivorous and experience a marked reduction in food availability on cold winter nights. In contrast, pearl-spotted owlets have more flexible activity patterns and include larger or diurnal vertebrate prey in their diet.

Elimination of GRK2 from cholinergic neurons reduces behavioral sensitivity to muscarinic receptor activation.

PubMed

Daigle, Tanya L; Caron, Marc G

2012-08-15

Although G-protein-coupled receptor kinase 2 (GRK2) is the most widely studied member of a family of kinases that has been shown to exert powerful influences on a variety of G-protein-coupled receptors, its role in the brain remains largely unknown. Here we report the localization of GRK2 in the mouse brain and generate novel conditional knock-out (KO) mice to assess the physiological importance of this kinase in cholinergic neurons. Mice with the selective deletion of GRK2 in this cell population (ChAT(IRES-cre)Grk2(f/f) KO mice) exhibit reduced behavioral responsiveness to challenge with oxotremorine-M (Oxo-M), a nonselective muscarinic acetylcholine receptor agonist. Specifically, Oxo-M-induced hypothermia, hypolocomotion, and salivation were markedly reduced in these animals, while analgesic responses were unaltered. In contrast, we found that GRK2 deficiency in cholinergic neurons does not alter cocaine-induced psychomotor activation, behavioral sensitization, or conditioned place preference. These results demonstrate that the elimination of GRK2 in cholinergic neurons reduces sensitivity to select muscarinic-mediated behaviors, while dopaminergic effects remain intact and further suggests that GRK2 may selectively impair muscarinic acetylcholine receptor-mediated function in vivo.

An unexpected role for the yeast nucleotide exchange factor Sil1 as a reductant acting on the molecular chaperone BiP

PubMed Central

Siegenthaler, Kevin D; Pareja, Kristeen A; Wang, Jie; Sevier, Carolyn S

2017-01-01

Unfavorable redox conditions in the endoplasmic reticulum (ER) can decrease the capacity for protein secretion, altering vital cell functions. While systems to manage reductive stress are well-established, how cells cope with an overly oxidizing ER remains largely undefined. In previous work (Wang et al., 2014), we demonstrated that the chaperone BiP is a sensor of overly oxidizing ER conditions. We showed that modification of a conserved BiP cysteine during stress beneficially alters BiP chaperone activity to cope with suboptimal folding conditions. How this cysteine is reduced to reestablish 'normal' BiP activity post-oxidative stress has remained unknown. Here we demonstrate that BiP's nucleotide exchange factor – Sil1 – can reverse BiP cysteine oxidation. This previously unexpected reductant capacity for yeast Sil1 has potential implications for the human ataxia Marinesco-Sjögren syndrome, where it is interesting to speculate that a disruption in ER redox-signaling (due to genetic defects in SIL1) may influence disease pathology. DOI: http://dx.doi.org/10.7554/eLife.24141.001 PMID:28257000

77 FR 2084 - Notice of Inventory Completion: Minnesota Indian Affairs Council, Bemidji, MN

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-13

... individual were removed from site 21-AN-1, Howard Lake, Anoka County, MN, by unknown person(s) and attached... Woodland Tradition. In 1950, L.A. Wilford of the University of Minnesota excavated human remains... the University of Minnesota. In 1999, the human remains were transferred to the MIAC (H355). No known...

Should nevirapine be used to prevent mother-to-child transmission of HIV among women of unknown serostatus?

PubMed Central

Sint, Tin Tin; Dabis, François; Kamenga, Claude; Shaffer, Nathan; de Zoysa, Isabelle F.

2005-01-01

At present, HIV testing and counselling during pregnancy represent the key entry point for women to learn their serostatus and for them to access, if they are HIV-positive, specific interventions to reduce mother-to-child transmission (MTCT) of HIV. However, the provision and uptake of testing and counselling services are inadequate, and many pregnant women in countries most affected by the HIV/AIDS epidemic remain unaware of their HIV status. The offer of single-dose nevirapine prophylaxis to women whose HIV status is unknown at the time of delivery has been proposed to circumvent these problems in high-prevalence settings. The potential advantages and disadvantages of three different programme approaches are considered: targeted programmes in which antiretroviral drugs are offered only to women who are known to be HIV-positive; combined programmes in which nevirapine prophylaxis is offered to women whose serostatus remains unknown at the time of delivery despite targeted programme inputs; and universal nevirapine prophylaxis programmes in which HIV testing and counselling are not available and all pregnant women, regardless of their serostatus, are offered nevirapine prophylaxis. PMID:15798847

The Information Available to a Moving Observer on Shape with Unknown, Isotropic BRDFs.

PubMed

Chandraker, Manmohan

2016-07-01

Psychophysical studies show motion cues inform about shape even with unknown reflectance. Recent works in computer vision have considered shape recovery for an object of unknown BRDF using light source or object motions. This paper proposes a theory that addresses the remaining problem of determining shape from the (small or differential) motion of the camera, for unknown isotropic BRDFs. Our theory derives a differential stereo relation that relates camera motion to surface depth, which generalizes traditional Lambertian assumptions. Under orthographic projection, we show differential stereo may not determine shape for general BRDFs, but suffices to yield an invariant for several restricted (still unknown) BRDFs exhibited by common materials. For the perspective case, we show that differential stereo yields the surface depth for unknown isotropic BRDF and unknown directional lighting, while additional constraints are obtained with restrictions on the BRDF or lighting. The limits imposed by our theory are intrinsic to the shape recovery problem and independent of choice of reconstruction method. We also illustrate trends shared by theories on shape from differential motion of light source, object or camera, to relate the hardness of surface reconstruction to the complexity of imaging setup.

Intrathecal immunoglobulin synthesis in patients with symptomatic epilepsy and epilepsy of unknown etiology ('cryptogenic').

PubMed

Fauser, S; Soellner, C; Bien, C G; Tumani, H

2017-09-01

To compare the frequency of intrathecal immunoglobulin (Ig) synthesis in patients with symptomatic epilepsy and epilepsy of unknown etiology ('cryptogenic'). Patients with epileptic (n = 301) and non-epileptic (n = 10) seizures were retrospectively screened for autochthonous intrathecal Ig synthesis and oligoclonal bands (OCBs) in the cerebrospinal fluid. Intrathecal IgG/OCBs were detected in 8% of patients with epilepsies of unknown etiology, 5% of patients with first seizures of unknown cause and 0-4% of patients with epilepsy due to brain tumors, cerebrovascular disease or other etiologies. Intrathecal IgG/OCBs were not seen in patients with psychogenic seizures. Identical OCBs in serum and cerebrospinal fluid were more common in all patient groups (10-40% depending on underlying etiology). Intrathecal IgG synthesis/OCBs were observed slightly more frequently in patients with 'cryptogenic' epilepsy and with first seizures of unknown etiology than in other patient groups. However, this remained an infrequent finding and thus we could not confirm humoral immunity as a leading disease mechanism in patients with epilepsy in general or with unknown etiology in particular. © 2017 EAN.

Superoxide dismutase activity of Cu-bound prion protein

NASA Astrophysics Data System (ADS)

Hodak, Miroslav; Lu, Wenchang; Bernholc, Jerry

2009-03-01

Misfolding of the prion protein, PrP, has been linked to a group of neurodegenerative diseases, including the mad cow disease in cattle and the Creutzfeldt-Jakob disease in humans. The normal function of PrP is still unknown, but it was found that the PrP can efficiently bind Cu(II) ions. Early experiments suggested that Cu-PrP complex possesses significant superoxide dismutase (SOD) activity, but later experiments failed to confirm it and at present this issue remains unresolved. Using a recently developed hybrid DFT/DFT method, which combines Kohn-Sham DFT for the solute and its first solvation shells with orbital-free DFT for the remainder of the solvent, we have investigated SOD activity of PrP. The PrP is capable of incorporating Cu(II) ions in several binding modes and our calculations find that each mode has a different SOD activity. The highest activity found is comparable to those of well-known SOD proteins, suggesting that the conflicting experimental results may be due to different bindings of Cu(II) in those experiments.

GARP regulates the bioavailability and activation of TGFβ.

PubMed

Wang, Rui; Zhu, Jianghai; Dong, Xianchi; Shi, Minlong; Lu, Chafen; Springer, Timothy A

2012-03-01

Glycoprotein-A repetitions predominant protein (GARP) associates with latent transforming growth factor-β (proTGFβ) on the surface of T regulatory cells and platelets; however, whether GARP functions in latent TGFβ activation and the structural basis of coassociation remain unknown. We find that Cys-192 and Cys-331 of GARP disulfide link to the TGFβ1 prodomain and that GARP with C192A and C331A mutations can also noncovalently associate with proTGFβ1. Noncovalent association is sufficiently strong for GARP to outcompete latent TGFβ-binding protein for binding to proTGFβ1. Association between GARP and proTGFβ1 prevents the secretion of TGFβ1. Integrin α(V)β(6) and to a lesser extent α(V)β(8) are able to activate TGFβ from the GARP-proTGFβ1 complex. Activation requires the RGD motif of latent TGFβ, disulfide linkage between GARP and latent TGFβ, and membrane association of GARP. Our results show that GARP is a latent TGFβ-binding protein that functions in regulating the bioavailability and activation of TGFβ.

6-Shogaol attenuates LPS-induced inflammation in BV2 microglia cells by activating PPAR-γ.

PubMed

Han, Qinghe; Yuan, Qinghai; Meng, Xiaolin; Huo, Junyuan; Bao, Yuxin; Xie, Guanghong

2017-06-27

6-Shogaol, a pungent agent isolated from Zingiber officinale Roscoe, has been known to have anti-tumor and anti-inflammatory effects. However, the anti-inflammatory effects and biological mechanism of 6-Shogaol in LPS-activated BV2 microglia remains largely unknown. In this study, we evaluated the anti-inflammatory effects of 6-Shogaol in LPS-activated BV2 microglia. 6-Shogaol was administrated 1 h before LPS treatment. The production of inflammatory mediators were detected by ELISA. The expression of NF-κB and PPAR-γ were detected by western blot analysis. Our results revealed that 6-Shogaol inhibited LPS-induced TNF-α, IL-1β, IL-6, and PGE2 production in a concentration dependent manner. Furthermore, 6-Shogaol inhibited LPS-induced NF-κB activation by inhibiting phosphorylation and nuclear translocation of NF-κB p65. In addition, 6-Shogaol could increase the expression of PPAR-γ. Moreover, inhibition of PPAR-γ by GW9662 could prevent the inhibition of 6-Shogaol on LPS-induced inflammatory mediator production. In conclusion, 6-Shogaol inhibits LPS-induced inflammation by activating PPAR-γ.

Membrane depolarization inhibits spiral ganglion neurite growth via activation of multiple types of voltage sensitive calcium channels and calpain

PubMed Central

Roehm, Pamela C.; Xu, Ningyong; Woodson, Erika A.; Green, Steven H.; Hansen, Marlan R.

2008-01-01

The effect of membrane electrical activity on spiral ganglion neuron (SGN) neurite growth remains unknown despite its relevance to cochlear implant technology. We demonstrate that membrane depolarization delays the initial formation and inhibits the subsequent extension of cultured SGN neurites. This inhibition depends directly on the level of depolarization with higher levels of depolarization causing retraction of existing neurites. Cultured SGNs express subunits for L-type, N-type, and P/Q type voltage-gated calcium channels (VGCCs) and removal of extracellular Ca2+ or treatment with a combination of L-type, N-type, P/Q-type VGCC antagonists rescues SGN neurite growth under depolarizing conditions. By measuring the fluorescence intensity of SGNs loaded with the fluorogenic calpain substrate t-butoxy carbonyl-Leu-Met-chloromethylaminocoumarin (20 μM), we demonstrate that depolarization activates calpains. Calpeptin (15 μM), a calpain inhibitor, prevents calpain activation by depolarization and rescues neurite growth in depolarized SGNs suggesting that calpain activation contributes to the inhibition of neurite growth by depolarization. PMID:18055215

Role of Complement on Broken Surfaces After Trauma.

PubMed

Huber-Lang, Markus; Ignatius, Anita; Brenner, Rolf E

2015-01-01

Activation of both the complement and coagulation cascade after trauma and subsequent local and systemic inflammatory response represent a major scientific and clinical problem. After severe tissue injury and bone fracture, exposure of innate immunity to damaged cells and molecular debris is considered a main trigger of the posttraumatic danger response. However, the effects of cellular fragments (e.g., histones) on complement activation remain enigmatic. Furthermore, direct effects of "broken" bone and cartilage surfaces on the fluid phase response of complement and its interaction with key cells of connective tissues are still unknown. Here, we summarize data suggesting direct and indirect complement activation by extracellular and cellular danger associated molecular patterns. In addition, key complement components and the corresponding receptors (such as C3aR, C5aR) have been detected on "exposed surfaces" of the damaged regions. On a cellular level, multiple effects of complement activation products on osteoblasts, osteoclasts, chondrocytes and mesenchymal stem cells have been found.In conclusion, the complement system may be activated by trauma-altered surfaces and is crucially involved in connective tissue healing and posttraumatic systemic inflammatory response.

Linear scaling relationships and volcano plots in homogeneous catalysis - revisiting the Suzuki reaction.

PubMed

Busch, Michael; Wodrich, Matthew D; Corminboeuf, Clémence

2015-12-01

Linear free energy scaling relationships and volcano plots are common tools used to identify potential heterogeneous catalysts for myriad applications. Despite the striking simplicity and predictive power of volcano plots, they remain unknown in homogeneous catalysis. Here, we construct volcano plots to analyze a prototypical reaction from homogeneous catalysis, the Suzuki cross-coupling of olefins. Volcano plots succeed both in discriminating amongst different catalysts and reproducing experimentally known trends, which serves as validation of the model for this proof-of-principle example. These findings indicate that the combination of linear scaling relationships and volcano plots could serve as a valuable methodology for identifying homogeneous catalysts possessing a desired activity through a priori computational screening.

Far transfer to language and math of a short software-based gaming intervention.

PubMed

Goldin, Andrea Paula; Hermida, María Julia; Shalom, Diego E; Elias Costa, Martín; Lopez-Rosenfeld, Matías; Segretin, María Soledad; Fernández-Slezak, Diego; Lipina, Sebastián J; Sigman, Mariano

2014-04-29

Executive functions (EF) in children can be trained, but it remains unknown whether training-related benefits elicit far transfer to real-life situations. Here, we investigate whether a set of computerized games might yield near and far transfer on an experimental and an active control group of low-SES otherwise typically developing 6-y-olds in a 3-mo pretest-training-posttest design that was ecologically deployed (at school). The intervention elicits transfer to some (but not all) facets of executive function. These changes cascade to real-world measures of school performance. The intervention equalizes academic outcomes across children who regularly attend school and those who do not because of social and familiar circumstances.

A potential peptide pathway from viruses to oral lichen planus.

PubMed

Lucchese, Alberta

2015-06-01

Oral lichen planus is an idiopathic inflammatory disease of oral mucous membranes, characterized by an autoimmune epidermis attack by T cells. It remains unknown, however, how such aggressive T cells are activated in vivo to cause epidermal damage. This study analyzes the relationship at the peptide level between viruses and oral lichen planus disease. Four potentially immunogenic peptides (SSSSSSS, QEQLEKA, LLLLLLA, and MLSGNAG) are found to be shared between HCV, EBV, HHV-7, HSV-1, and CMV and three human proteins (namely pinin, desmoglein-3, and plectin). The described peptide sharing might be of help in deciphering the still unexplained immunopathogenic pathway that leads to oral lichen planus. © 2015 Wiley Periodicals, Inc.

Cholinergic modulation of the CAN current may adjust neural dynamics for active memory maintenance, spatial navigation and time-compressed replay

PubMed Central

Yoshida, Motoharu; Knauer, Beate; Jochems, Arthur

2012-01-01

Suppression of cholinergic receptors and inactivation of the septum impair short-term memory, and disrupt place cell and grid cell activity in the medial temporal lobe (MTL). Location-dependent hippocampal place cell firing during active waking, when the acetylcholine level is high, switches to time-compressed replay activity during quiet waking and slow-wave-sleep (SWS), when the acetylcholine level is low. However, it remains largely unknown how acetylcholine supports short-term memory, spatial navigation, and the functional switch to replay mode in the MTL. In this paper, we focus on the role of the calcium-activated non-specific cationic (CAN) current which is activated by acetylcholine. The CAN current is known to underlie persistent firing, which could serve as a memory trace in many neurons in the MTL. Here, we review the CAN current and discuss possible roles of the CAN current in short-term memory and spatial navigation. We further propose a novel theoretical model where the CAN current switches the hippocampal place cell activity between real-time and time-compressed sequential activity during encoding and consolidation, respectively. PMID:22435051

Functioning of the dimeric GABAB receptor extracellular domain revealed by glycan wedge scanning

PubMed Central

Rondard, Philippe; Huang, Siluo; Monnier, Carine; Tu, Haijun; Blanchard, Bertrand; Oueslati, Nadia; Malhaire, Fanny; Li, Ying; Trinquet, Eric; Labesse, Gilles; Pin, Jean-Philippe; Liu, Jianfeng

2008-01-01

The G-protein-coupled receptor (GPCR) activated by the neurotransmitter GABA is made up of two subunits, GABAB1 and GABAB2. GABAB1 binds agonists, whereas GABAB2 is required for trafficking GABAB1 to the cell surface, increasing agonist affinity to GABAB1, and activating associated G proteins. These subunits each comprise two domains, a Venus flytrap domain (VFT) and a heptahelical transmembrane domain (7TM). How agonist binding to the GABAB1 VFT leads to GABAB2 7TM activation remains unknown. Here, we used a glycan wedge scanning approach to investigate how the GABAB VFT dimer controls receptor activity. We first identified the dimerization interface using a bioinformatics approach and then showed that introducing an N-glycan at this interface prevents the association of the two subunits and abolishes all activities of GABAB2, including agonist activation of the G protein. We also identified a second region in the VFT where insertion of an N-glycan does not prevent dimerization, but blocks agonist activation of the receptor. These data provide new insight into the function of this prototypical GPCR and demonstrate that a change in the dimerization interface is required for receptor activation. PMID:18388862

Adaptive Neural Output Feedback Control for Nonstrict-Feedback Stochastic Nonlinear Systems With Unknown Backlash-Like Hysteresis and Unknown Control Directions.

PubMed

Yu, Zhaoxu; Li, Shugang; Yu, Zhaosheng; Li, Fangfei

2018-04-01

This paper investigates the problem of output feedback adaptive stabilization for a class of nonstrict-feedback stochastic nonlinear systems with both unknown backlashlike hysteresis and unknown control directions. A new linear state transformation is applied to the original system, and then, control design for the new system becomes feasible. By combining the neural network's (NN's) parameterization, variable separation technique, and Nussbaum gain function method, an input-driven observer-based adaptive NN control scheme, which involves only one parameter to be updated, is developed for such systems. All closed-loop signals are bounded in probability and the error signals remain semiglobally bounded in the fourth moment (or mean square). Finally, the effectiveness and the applicability of the proposed control design are verified by two simulation examples.

Systematic discovery of novel eukaryotic transcriptional regulators using sequence homology independent prediction.

PubMed

Bossi, Flavia; Fan, Jue; Xiao, Jun; Chandra, Lilyana; Shen, Max; Dorone, Yanniv; Wagner, Doris; Rhee, Seung Y

2017-06-26

The molecular function of a gene is most commonly inferred by sequence similarity. Therefore, genes that lack sufficient sequence similarity to characterized genes (such as certain classes of transcriptional regulators) are difficult to classify using most function prediction algorithms and have remained uncharacterized. To identify novel transcriptional regulators systematically, we used a feature-based pipeline to screen protein families of unknown function. This method predicted 43 transcriptional regulator families in Arabidopsis thaliana, 7 families in Drosophila melanogaster, and 9 families in Homo sapiens. Literature curation validated 12 of the predicted families to be involved in transcriptional regulation. We tested 33 out of the 195 Arabidopsis putative transcriptional regulators for their ability to activate transcription of a reporter gene in planta and found twelve coactivators, five of which had no prior literature support. To investigate mechanisms of action in which the predicted regulators might work, we looked for interactors of an Arabidopsis candidate that did not show transactivation activity in planta and found that it might work with other members of its own family and a subunit of the Polycomb Repressive Complex 2 to regulate transcription. Our results demonstrate the feasibility of assigning molecular function to proteins of unknown function without depending on sequence similarity. In particular, we identified novel transcriptional regulators using biological features enriched in transcription factors. The predictions reported here should accelerate the characterization of novel regulators.

Vastus lateralis surface and single motor unit EMG following submaximal shortening and lengthening contractions.

PubMed

Altenburg, Teatske M; de Ruiter, Cornelis J; Verdijk, Peter W L; van Mechelen, Willem; de Haan, Arnold

2008-12-01

A single shortening contraction reduces the force capacity of muscle fibers, whereas force capacity is enhanced following lengthening. However, how motor unit recruitment and discharge rate (muscle activation) are adapted to such changes in force capacity during submaximal contractions remains unknown. Additionally, there is limited evidence for force enhancement in larger muscles. We therefore investigated lengthening- and shortening-induced changes in activation of the knee extensors. We hypothesized that when the same submaximal torque had to be generated following shortening, muscle activation had to be increased, whereas a lower activation would suffice to produce the same torque following lengthening. Muscle activation following shortening and lengthening (20 degrees at 10 degrees /s) was determined using rectified surface electromyography (rsEMG) in a 1st session (at 10% and 50% maximal voluntary contraction (MVC)) and additionally with EMG of 42 vastus lateralis motor units recorded in a 2nd session (at 4%-47%MVC). rsEMG and motor unit discharge rates following shortening and lengthening were normalized to isometric reference contractions. As expected, normalized rsEMG (1.15 +/- 0.19) and discharge rate (1.11 +/- 0.09) were higher following shortening (p < 0.05). Following lengthening, normalized rsEMG (0.91 +/- 0.10) was, as expected, lower than 1.0 (p < 0.05), but normalized discharge rate (0.99 +/- 0.08) was not (p > 0.05). Thus, muscle activation was increased to compensate for a reduced force capacity following shortening by increasing the discharge rate of the active motor units (rate coding). In contrast, following lengthening, rsEMG decreased while the discharge rates of active motor units remained similar, suggesting that derecruitment of units might have occurred.

Hepatic steatosis development with four weeks of physical inactivity in previously active, hyperphagic OLETF rats.

PubMed

Linden, Melissa A; Meers, Grace M; Ruebel, Meghan L; Jenkins, Nathan T; Booth, Frank W; Laughlin, M Harold; Ibdah, Jamal A; Thyfault, John P; Rector, R Scott

2013-05-01

Physical activity-induced prevention of hepatic steatosis is maintained during short-term (7-day) transitions to an inactive state; however, whether these protective effects are present under a longer duration of physical inactivity is largely unknown. Here, we sought to determine whether previous physical activity had protective effects on hepatic steatosis and metabolic health following 4 wk of physical inactivity. Four-week old, hyperphagic, male Otsuka Long-Evans Tokushima fatty (OLETF) rats were randomly assigned to either a sedentary group for 16 wk (OLETF-SED), given access to running wheels for 16 wk with wheels locked 5 h (OLETF-WL5hr) or given access to running wheels for 12 wk with wheels locked 4 wk (OLETF-WL4wk) prior to death. Four weeks of physical inactivity caused hepatic steatosis development, but liver triglycerides remained 60% lower than OLETF-SED (P < 0.01), and this was associated with only a partial loss in activity-induced improvements in body composition, serum lipids, and glycemic control. Total hepatic mitochondrial palmitate oxidation, citrate synthase, and β-HAD activity returned to SED levels following 4 wk of inactivity, whereas markers of fatty acid uptake and lipogenesis remained relatively suppressed following 4 wk of inactivity. In addition, 4 wk of inactivity caused a complete loss of activity-induced increases in serum IL-6 and reductions in regulated upon activation, normal T-cell expressed, and secreted (RANTES), and a partial loss in reductions in leptin, monocyte chemoattractant protein-1, and TNF-α. In conclusion, 4 wk of physical inactivity does not result in a complete loss in physical activity-induced benefits but does cause deterioration in the liver phenotype and overall metabolic health in hyperphagic OLETF rats.

Spondylitis Association of America

MedlinePlus

... Spondyloarthritis affects more people than Multiple Sclerosis (MS), Rheumatoid Arthritis, and Autism, yet it remains relatively unknown. MS (400,000) Rheumatoid Arthritis (1.3million) Autism (1.5million) Spondyloarthritis (2.7million) ...

A review of the musculoskeletal manifestations of sarcoidosis.

PubMed

Bechman, Katie; Christidis, Dimitrios; Walsh, Sarah; Birring, Surinder S; Galloway, James

2018-05-01

Sarcoidosis is a systemic disease of unknown aetiology that is characterized by granulomatous inflammation that can develop in almost any organ system. Musculoskeletal manifestations are seen in up to one-third of patients, ranging from arthralgia through to widespread destructive bone lesions. Inflammatory tendon lesions and periarticular swelling are more common than true joint synovitis. Despite advances in our understanding of the pathophysiology of the disease, diagnosis remains challenging. Definitive diagnosis, irrespective of organ site involvement, hinges on histological confirmation of non-caseating granuloma combined with an appropriate clinical syndrome. Musculoskeletal involvement usually develops early in the disease course. Imaging modalities, particularly fluorodeoxyglucose PET, are helpful in delineating the extent of involvement and measuring disease activity. Bone involvement may only become apparent following isotope imaging. Corticosteroids remain the cornerstone of treatment. MTX is the steroid-sparing agent of choice unless there is renal involvement. Biologic therapies are sometimes used in severe disease, although the evidence base for efficacy is inconsistent.

Parietal neurons encode expected gains in instrumental information

PubMed Central

Foley, Nicholas C.; Kelly, Simon P.; Mhatre, Himanshu; Gottlieb, Jacqueline

2017-01-01

In natural behavior, animals have access to multiple sources of information, but only a few of these sources are relevant for learning and actions. Beyond choosing an appropriate action, making good decisions entails the ability to choose the relevant information, but fundamental questions remain about the brain’s information sampling policies. Recent studies described the neural correlates of seeking information about a reward, but it remains unknown whether, and how, neurons encode choices of instrumental information, in contexts in which the information guides subsequent actions. Here we show that parietal cortical neurons involved in oculomotor decisions encode, before an information sampling saccade, the reduction in uncertainty that the saccade is expected to bring for a subsequent action. These responses were distinct from the neurons’ visual and saccadic modulations and from signals of expected reward or reward prediction errors. Therefore, even in an instrumental context when information and reward gains are closely correlated, individual cells encode decision variables that are based on informational factors and can guide the active sampling of action-relevant cues. PMID:28373569

Using NMR spectroscopy to elucidate the role of molecular motions in enzyme function.

PubMed

Lisi, George P; Loria, J Patrick

2016-02-01

Conformational motions play an essential role in enzyme function, often facilitating the formation of enzyme-substrate complexes and/or product release. Although considerable debate remains regarding the role of molecular motions in the conversion of enzymatic substrates to products, numerous examples have found motions to be crucial for optimization of enzyme scaffolds, effective substrate binding, and product dissociation. Conformational fluctuations are often rate-limiting to enzyme catalysis, primarily through product release, with the chemical reaction occurring much more quickly. As a result, the direct involvement of motions at various stages along the enzyme reaction coordinate remains largely unknown and untested. In the following review, we describe the use of solution NMR techniques designed to probe various timescales of molecular motions and detail examples in which motions play a role in propagating catalytic effects from the active site and directly participate in essential aspects of enzyme function. Copyright © 2015 Elsevier B.V. All rights reserved.

Post-supereruption recovery at Toba Caldera

PubMed Central

Mucek, Adonara E.; Danišík, Martin; de Silva, Shanaka L.; Schmitt, Axel K.; Pratomo, Indyo; Coble, Matthew A.

2017-01-01

Large calderas, or supervolcanoes, are sites of the most catastrophic and hazardous events on Earth, yet the temporal details of post-supereruption activity, or resurgence, remain largely unknown, limiting our ability to understand how supervolcanoes work and address their hazards. Toba Caldera, Indonesia, caused the greatest volcanic catastrophe of the last 100 kyr, climactically erupting ∼74 ka. Since the supereruption, Toba has been in a state of resurgence but its magmatic and uplift history has remained unclear. Here we reveal that new 14C, zircon U–Th crystallization and (U–Th)/He ages show resurgence commenced at 69.7±4.5 ka and continued until at least ∼2.7 ka, progressing westward across the caldera, as reflected by post-caldera effusive lava eruptions and uplifted lake sediment. The major stratovolcano north of Toba, Sinabung, shows strong geochemical kinship with Toba, and zircons from recent eruption products suggest Toba's climactic magma reservoir extends beneath Sinabung and is being tapped during eruptions. PMID:28508876

Post-supereruption recovery at Toba Caldera.

PubMed

Mucek, Adonara E; Danišík, Martin; de Silva, Shanaka L; Schmitt, Axel K; Pratomo, Indyo; Coble, Matthew A

2017-05-16

Large calderas, or supervolcanoes, are sites of the most catastrophic and hazardous events on Earth, yet the temporal details of post-supereruption activity, or resurgence, remain largely unknown, limiting our ability to understand how supervolcanoes work and address their hazards. Toba Caldera, Indonesia, caused the greatest volcanic catastrophe of the last 100 kyr, climactically erupting ∼74 ka. Since the supereruption, Toba has been in a state of resurgence but its magmatic and uplift history has remained unclear. Here we reveal that new 14 C, zircon U-Th crystallization and (U-Th)/He ages show resurgence commenced at 69.7±4.5 ka and continued until at least ∼2.7 ka, progressing westward across the caldera, as reflected by post-caldera effusive lava eruptions and uplifted lake sediment. The major stratovolcano north of Toba, Sinabung, shows strong geochemical kinship with Toba, and zircons from recent eruption products suggest Toba's climactic magma reservoir extends beneath Sinabung and is being tapped during eruptions.

Iron deposition and inflammation in multiple sclerosis. Which one comes first?

PubMed Central

2011-01-01

Whether iron deposition is an epiphenomenon of the multiple sclerosis (MS) disease process or may play a primary role in triggering inflammation and disease development remains unclear at this time, and should be studied at the early stages of disease pathogenesis. However, it is difficult to study the relationship between iron deposition and inflammation in early MS due to the delay between the onset of symptoms and diagnosis, and the poor availability of tissue specimens. In a recent article published in BMC Neuroscience, Williams et al. investigated the relationship between inflammation and iron deposition using an original animal model labeled as "cerebral experimental autoimmune encephalomyelitis", which develops CNS perivascular iron deposits. However, the relative contribution of iron deposition vs. inflammation in the pathogenesis and progression of MS remains unknown. Further studies should establish the association between inflammation, reduced blood flow, iron deposition, microglia activation and neurodegeneration. Creating a representative animal model that can study independently such relationship will be the key factor in this endeavor. PMID:21699686

A role for intestinal TLR4-driven inflammatory response during activity-based anorexia

PubMed Central

Belmonte, Liliana; Achamrah, Najate; Nobis, Séverine; Guérin, Charlène; Riou, Gaëtan; Bôle-Feysot, Christine; Boyer, Olivier; Richard, Vincent; Rego, Jean Claude Do; Déchelotte, Pierre; Goichon, Alexis; Coëffier, Moïse

2016-01-01

Anorexia nervosa (AN) is associated with low-grade systemic inflammation and altered gut microbiota. However, the molecular origin of the inflammation remains unknown. Toll-like receptors are key regulators of innate immune response and their activation seems also to be involved in the control of food intake. We used activity-based anorexia (ABA) model to investigate the role of TLR4 and its contribution in anorexia-associated low-grade inflammation. Here, we found that ABA affected early the intestinal inflammatory status and the hypothalamic response. Indeed, TLR4 was upregulated both on colonic epithelial cells and intestinal macrophages, leading to elevated downstream mucosal cytokine production. These mucosal changes occurred earlier than hypothalamic changes driving to increased levels of IL-1β and IL-1R1 as well as increased levels of plasma corticosterone. Paradoxically, TLR4-deficient mice exhibited greater vulnerability to ABA with increased mortality rate, suggesting a major contribution of TLR4-mediated responses during ABA-induced weight loss. PMID:27779218

Notch Promotes Dynamin-Dependent Endocytosis of Nephrin

PubMed Central

Waters, Aoife M.; Wu, Megan Yi Jun; Huang, Yi-Wei; Liu, Guang Ying; Holmyard, Doug; Onay, Tuncer; Jones, Nina; Egan, Sean E.; Robinson, Lisa A.

2012-01-01

Notch signaling in podocytes causes proteinuria and glomerulosclerosis in humans and rodents, but the underlying mechanism remains unknown. Here, we analyzed morphologic, molecular, and cellular events before the onset of proteinuria in newborn transgenic mice that express activated Notch in podocytes. Immunohistochemistry revealed a loss of the slit diaphragm protein nephrin exclusively in podocytes expressing activated Notch. Podocyte-specific deletion of Rbpj, which is essential for canonical Notch signaling, prevented this loss of nephrin. Overexpression of activated Notch decreased cell surface nephrin and increased cytoplasmic nephrin in transfected HEK293T cells; pharmacologic inhibition of dynamin, but not depletion of cholesterol, blocked these effects on nephrin, suggesting that Notch promotes dynamin-dependent, raft-independent endocytosis of nephrin. Supporting an association between Notch signaling and nephrin trafficking, electron microscopy revealed shortened podocyte foot processes and fewer slit diaphragms among the transgenic mice compared with controls. These data suggest that Notch signaling induces endocytosis of nephrin, thereby triggering the onset of proteinuria. PMID:22052054

The c-Jun N-terminal kinase prevents oxidative stress induced by UV and thermal stresses in corals and human cells.

PubMed

Courtial, Lucile; Picco, Vincent; Grover, Renaud; Cormerais, Yann; Rottier, Cécile; Labbe, Antoine; Pagès, Gilles; Ferrier-Pagès, Christine

2017-04-04

Coral reefs are of major ecological and socio-economic interest. They are threatened by global warming and natural pressures such as solar ultraviolet radiation. While great efforts have been made to understand the physiological response of corals to these stresses, the signalling pathways involved in the immediate cellular response exhibited by corals remain largely unknown. Here, we demonstrate that c-Jun N-terminal kinase (JNK) activation is involved in the early response of corals to thermal and UV stress. Furthermore, we found that JNK activity is required to repress stress-induced reactive oxygen species (ROS) accumulation in both the coral Stylophora pistillata and human skin cells. We also show that inhibiting JNK activation under stress conditions leads to ROS accumulation, subsequent coral bleaching and cell death. Taken together, our results suggest that an ancestral response, involving the JNK pathway, is remarkably conserved from corals to human, protecting cells from the adverse environmental effects.

[Involvement of researchers with patient associations: what is the role of their opinions, their clinical activity and their nature?].

PubMed

Demagny, Lise; Bungener, Martine; Faurisson, François

2015-11-01

Although the involvement of patient associations in biomedical research is well known, conversely, researchers' views and perceptions of these associations have remained unknown. For this reason, Inserm's Patients' Association Liaison Group (GRAM) launched the CAIRNET survey in 2012, based on questionnaires and interviews conducted with researchers working at Inserm. The variety of their opinions made it possible to distinguish four profiles, the committed, the pragmatic, the reticent and the distant. Thus 41 % of respondents reported ongoing relationships with at least one association, 72 % for the committed and 16 % for the distant. Although these relationships are formed more easily among researchers involved in clinical activity, they also encourage collaborations between clinicians and basic researchers. The apparently lower degree of involvement of female researchers proved to be associated with a lower level of clinical activity, limited permanent recruitment, and a lower hierarchical status. © 2015 médecine/sciences – Inserm.

Hunger and Satiety Signaling: Modeling Two Hypothalamomedullary Pathways for Energy Homeostasis.

PubMed

Nakamura, Kazuhiro; Nakamura, Yoshiko

2018-06-04

The recent discovery of the medullary circuit driving "hunger responses" - reduced thermogenesis and promoted feeding - has greatly expanded our knowledge on the central neural networks for energy homeostasis. However, how hypothalamic hunger and satiety signals generated under fasted and fed conditions, respectively, control the medullary autonomic and somatic motor mechanisms remains unknown. Here, in reviewing this field, we propose two hypothalamomedullary neural pathways for hunger and satiety signaling. To trigger hunger signaling, neuropeptide Y activates a group of neurons in the paraventricular hypothalamic nucleus (PVH), which then stimulate an excitatory pathway to the medullary circuit to drive the hunger responses. In contrast, melanocortin-mediated satiety signaling activates a distinct group of PVH neurons, which then stimulate a putatively inhibitory pathway to the medullary circuit to counteract the hunger signaling. The medullary circuit likely contains inhibitory and excitatory premotor neurons whose alternate phasic activation generates the coordinated masticatory motor rhythms to promote feeding. © 2018 The Authors. BioEssays Published by WILEY Periodicals, Inc.

Dissecting neural pathways for forgetting in Drosophila olfactory aversive memory

PubMed Central

Shuai, Yichun; Hirokawa, Areekul; Ai, Yulian; Zhang, Min; Li, Wanhe; Zhong, Yi

2015-01-01

Recent studies have identified molecular pathways driving forgetting and supported the notion that forgetting is a biologically active process. The circuit mechanisms of forgetting, however, remain largely unknown. Here we report two sets of Drosophila neurons that account for the rapid forgetting of early olfactory aversive memory. We show that inactivating these neurons inhibits memory decay without altering learning, whereas activating them promotes forgetting. These neurons, including a cluster of dopaminergic neurons (PAM-β′1) and a pair of glutamatergic neurons (MBON-γ4>γ1γ2), terminate in distinct subdomains in the mushroom body and represent parallel neural pathways for regulating forgetting. Interestingly, although activity of these neurons is required for memory decay over time, they are not required for acute forgetting during reversal learning. Our results thus not only establish the presence of multiple neural pathways for forgetting in Drosophila but also suggest the existence of diverse circuit mechanisms of forgetting in different contexts. PMID:26627257

GluCl a target of indole alkaloid okaramines: a 25 year enigma solved

NASA Astrophysics Data System (ADS)

Furutani, Shogo; Nakatani, Yuri; Miura, Yuka; Ihara, Makoto; Kai, Kenji; Hayashi, Hideo; Matsuda, Kazuhiko

2014-08-01

In 1989, indole alkaloid okaramines isolated from the fermentation products of Penicillium simplicissimum were shown to be insecticidal, yet the mechanism of their toxicity to insects remains unknown. We therefore examined the action of okaramine B on silkworm larval neurons using patch-clamp electrophysiology. Okaramine B induced inward currents which reversed close to the chloride equilibrium potential and were blocked by fipronil. Thus it was tested on the silkworm RDL (resistant-to-dieldrin) γ-aminobutyric-acid-gated chloride channel (GABACl) and a silkworm L-glutamate-gated chloride channel (GluCl) expressed in Xenopus laevis oocytes. Okaramine B activated GluCl, but not RDL. GluCl activation by okaramines correlated with their insecticidal activity, offering a solution to a long-standing enigma concerning their insecticidal actions. Also, unlike ivermectin, okaramine B was inactive at 10 μM on human α1β2γ2 GABACl and α1β glycine-gated chloride channels and provides a new lead for the development of safe insect control chemicals.

IL-15 Enhances Activation and IGF-1 Production of Dendritic Epidermal T Cells to Promote Wound Healing in Diabetic Mice.

PubMed

Wang, Yangping; Bai, Yang; Li, Yashu; Liang, Guangping; Jiang, Yufeng; Liu, Zhongyang; Liu, Meixi; Hao, Jianlei; Zhang, Xiaorong; Hu, Xiaohong; Chen, Jian; Wang, Rupeng; Yin, Zhinan; Wu, Jun; Luo, Gaoxing; He, Weifeng

2017-01-01

Altered homeostasis and dysfunction of dendritic epidermal T cells (DETCs) contribute to abnormal diabetic wound healing. IL-15 plays important roles in survival and activation of T lymphocytes. Recently, reduction of epidermal IL-15 has been reported as an important mechanism for abnormal DETC homeostasis in streptozotocin -induced diabetic animals. However, the role of IL-15 in impaired diabetic wound healing remains unknown. Here, we found that, through rescuing the insufficient activation of DETCs, IL-15 increased IGF-1 production by DETCs and thereby promoted diabetic skin wound repair. Regulation of IGF-1 in DETCs by IL-15 was partly dependent on the mTOR pathway. In addition, expression of IL-15 and IGF-1 were positively correlated in wounded epidermis. Together, our data indicated that IL-15 enhanced IGF-1 production by DETCs to promoting diabetic wound repair, suggesting IL-15 as a potential therapeutic agent for managing diabetic wound healing.

Excitatory motor neurons are local oscillators for backward locomotion

PubMed Central

Guan, Sihui Asuka; Fouad, Anthony D; Meng, Jun; Kawano, Taizo; Huang, Yung-Chi; Li, Yi; Alcaire, Salvador; Hung, Wesley; Lu, Yangning; Qi, Yingchuan Billy; Jin, Yishi; Alkema, Mark; Fang-Yen, Christopher

2018-01-01

Cell- or network-driven oscillators underlie motor rhythmicity. The identity of C. elegans oscillators remains unknown. Through cell ablation, electrophysiology, and calcium imaging, we show: (1) forward and backward locomotion is driven by different oscillators; (2) the cholinergic and excitatory A-class motor neurons exhibit intrinsic and oscillatory activity that is sufficient to drive backward locomotion in the absence of premotor interneurons; (3) the UNC-2 P/Q/N high-voltage-activated calcium current underlies A motor neuron’s oscillation; (4) descending premotor interneurons AVA, via an evolutionarily conserved, mixed gap junction and chemical synapse configuration, exert state-dependent inhibition and potentiation of A motor neuron’s intrinsic activity to regulate backward locomotion. Thus, motor neurons themselves derive rhythms, which are dually regulated by the descending interneurons to control the reversal motor state. These and previous findings exemplify compression: essential circuit properties are conserved but executed by fewer numbers and layers of neurons in a small locomotor network. PMID:29360035

Irisin Inhibits Hepatic Cholesterol Synthesis via AMPK-SREBP2 Signaling

PubMed Central

Tang, Hong; Yu, Ruili; Liu, Shiying; Huwatibieke, Bahetiyaer; Li, Ziru; Zhang, Weizhen

2016-01-01

Irisin, a myokine released during exercise, promotes browning of subcutaneous adipose tissue and regulates energy homeostasis. Although exercise constantly reduces blood cholesterol, whether irisin is involved in the regulation of cholesterol remains largely unknown. In the present study, subcutaneous infusion of irisin for 2 weeks induced a reduction in plasma and hepatic cholesterol in high fat diet-induced obese (DIO) mice. These alterations were associated with an activation of 5′ AMP-activated protein kinase (AMPK) and inhibition of sterol regulatory element-binding transcription factor 2 (SREBP2) transcription and nuclear translocation. In primary hepatocytes from either lean or DIO mice, irisin significantly decreased cholesterol content via sequential activation of AMPK and inhibition of SREBP2. Suppression of AMPK by compound C or AMPKα1 siRNA blocked irisin-induced alterations in cholesterol contents and SREBP2. In conclusion, irisin could suppress hepatic cholesterol production via a mechanism dependent of AMPK and SREBP2 signaling. These findings suggest that irisin is a promising therapeutic target for treatment of hypercholesterolemia. PMID:27211556

Excitatory motor neurons are local oscillators for backward locomotion.

PubMed

Gao, Shangbang; Guan, Sihui Asuka; Fouad, Anthony D; Meng, Jun; Kawano, Taizo; Huang, Yung-Chi; Li, Yi; Alcaire, Salvador; Hung, Wesley; Lu, Yangning; Qi, Yingchuan Billy; Jin, Yishi; Alkema, Mark; Fang-Yen, Christopher; Zhen, Mei

2018-01-23

Cell- or network-driven oscillators underlie motor rhythmicity. The identity of C. elegans oscillators remains unknown. Through cell ablation, electrophysiology, and calcium imaging, we show: (1) forward and backward locomotion is driven by different oscillators; (2) the cholinergic and excitatory A-class motor neurons exhibit intrinsic and oscillatory activity that is sufficient to drive backward locomotion in the absence of premotor interneurons; (3) the UNC-2 P/Q/N high-voltage-activated calcium current underlies A motor neuron's oscillation; (4) descending premotor interneurons AVA, via an evolutionarily conserved, mixed gap junction and chemical synapse configuration, exert state-dependent inhibition and potentiation of A motor neuron's intrinsic activity to regulate backward locomotion. Thus, motor neurons themselves derive rhythms, which are dually regulated by the descending interneurons to control the reversal motor state. These and previous findings exemplify compression: essential circuit properties are conserved but executed by fewer numbers and layers of neurons in a small locomotor network. © 2017, Gao et al.

Calcium activates the light-dependent conductance in melanopsin-expressing photoreceptors of amphioxus.

PubMed

Peinado, Gabriel; Osorno, Tomás; Gomez, María del Pilar; Nasi, Enrico

2015-06-23

Melanopsin, the photopigment of the "circadian" receptors that regulate the biological clock and the pupillary reflex in mammals, is homologous to invertebrate rhodopsins. Evidence supporting the involvement of phosphoinositides in light-signaling has been garnered, but the downstream effectors that control the light-dependent conductance remain unknown. Microvillar photoreceptors of the primitive chordate amphioxus also express melanopsin and transduce light via phospholipase-C, apparently not acting through diacylglycerol. We therefore examined the role of calcium in activating the photoconductance, using simultaneous, high time-resolution measurements of membrane current and Ca(2+) fluorescence. The light-induced calcium rise precedes the onset of the photocurrent, making it a candidate in the activation chain. Moreover, photolysis of caged Ca elicits an inward current of similar size, time course and pharmacology as the physiological photoresponse, but with a much shorter latency. Internally released calcium thus emerges as a key messenger to trigger the opening of light-dependent channels in melanopsin-expressing microvillar photoreceptors of early chordates.

DUSP11 – An RNA phosphatase that regulates host and viral non-coding RNAs in mammalian cells

PubMed Central

Burke, James M.; Sullivan, Christopher S.

2017-01-01

ABSTRACT Dual-specificity phosphatase 11 (DUSP11) is a conserved protein tyrosine phosphatase (PTP) in metazoans. The cellular substrates and physiologic activities of DUSP11 remain largely unknown. In nematodes, DUSP11 is required for normal development and RNA interference against endogenous RNAs (endo-RNAi) via molecular mechanisms that are not well understood. However, mammals lack analogous endo-RNAi pathways and consequently, a role for DUSP11 in mammalian RNA silencing was unanticipated. Recent work from our laboratory demonstrated that DUSP11 activity alters the silencing potential of noncanonical viral miRNAs in mammalian cells. Our studies further uncovered direct cellular substrates of DUSP11 and suggest that DUSP11 is part of regulatory pathway that controls the abundance of select triphosphorylated noncoding RNAs. Here, we highlight recent findings and present new data that advance understanding of mammalian DUSP11 during gene silencing and discuss the emerging biological activities of DUSP11 in mammalian cells. PMID:28296624

Altered effective connectivity of default model brain network underlying amnestic MCI

NASA Astrophysics Data System (ADS)

Yan, Hao; Wang, Yonghui; Tian, Jie

2012-02-01

Mild cognitive impairment (MCI) is the transitional, heterogeneous continuum from healthy elderly to Alzheimer's disease (AD). Previous studies have shown that brain functional activity in the default mode network (DMN) is impaired in MCI patients. However, the altered effective connectivity of the DMN in MCI patients remains largely unknown. The present study combined an independent component analysis (ICA) approach with Granger causality analysis (mGCA) to investigate the effective connectivity within the DMN in 12 amnestic MCI patients and 12 age-matched healthy elderly. Compared to the healthy control, the MCI exhibited decreased functional activity in the posterior DMN regions, as well as a trend towards activity increases in anterior DMN regions. Results from mGCA further supported this conclusion that the causal influence projecting to the precuneus/PCC became much weaker in MCI, while stronger interregional interactions emerged within the frontal-parietal cortices. These findings suggested that abnormal effective connectivity within the DMN may elucidate the dysfunctional and compensatory processes in MCI brain networks.

Noni (Morinda citrifolia L.) Fruit Extracts Improve Colon Microflora and Exert Anti-Inflammatory Activities in Caco-2 Cells.

PubMed

Huang, Hsin-Lun; Liu, Cheng-Tzu; Chou, Ming-Chih; Ko, Chien-Hui; Wang, Chin-Kun

2015-06-01

Intestinal microflora and inflammation are associated with the risk of inflammatory bowel diseases. Noni (Morinda citrifolia L.) has various bioactivities, but its effect on colon health remains unknown. This study focused on the effects of fermented noni fruit extracts on colon microflora and inflammation of colon epithelial cells. The anti-inflammatory activities of ethanol and ethyl acetate extracts on Caco-2 cells were evaluated including interleukin-8 (IL-8) and cyclooxygenase-2 (COX-2). The growth of Lactobacillus and Bifidobacterium species was promoted by ethanol extract. Ethyl acetate extract decreased intracellular reactive oxygen species and significantly suppressed COX-2, IL-8, and prostaglandin E2 production and neutrophil chemotaxis by suppressing the translocation of the p65 subunit. Quercetin was the main contributor to the anti-inflammatory activity. The fermented noni fruit promoted probiotic growths and downregulated the intracellular oxidation and inflammation in Caco-2 cells. These results suggest that fermented noni fruit might protect against inflammatory diseases of the colon.

Steroid receptor RNA activator (SRA1): unusual bifaceted gene products with suspected relevance to breast cancer

PubMed Central

Leygue, Etienne

2007-01-01

The steroid receptor RNA activator (SRA) is a unique modulator of steroid receptor transcriptional activity, as it is able to mediate its coregulatory effects as a RNA molecule. Recent findings, however, have painted a more complex picture of the SRA gene (SRA1) products. Indeed, even though SRA was initially thought to be noncoding, several RNA isoforms have now been found to encode an endogenous protein (SRAP), which is well conserved among Chordata. Although the function of SRAP remains largely unknown, it has been proposed that, much like its corresponding RNA, the protein itself might regulate estrogen and androgen receptor signaling pathways. As such, data suggest that both SRA and SRAP might participate in the mechanisms underlying breast, as well as prostate tumorigenesis. This review summarizes the published literature dealing with these two faces of the SRA gene products and underscores the relevance of this bifaceted system to breast cancer development. PMID:17710122

Prefrontal atrophy, disrupted NREM slow waves, and impaired hippocampal-dependent memory in aging

PubMed Central

Mander, Bryce A.; Rao, Vikram; Lu, Brandon; Saletin, Jared M.; Lindquist, John R.; Ancoli-Israel, Sonia; Jagust, William; Walker, Matthew P.

2014-01-01

Aging has independently been associated with regional brain atrophy, reduced non-rapid eye movement (NREM) slow-wave activity (SWA), and impaired long-term retention of episodic memories. However, that the interaction of these factors represents a neuropatholgical pathway associated with cognitive decline in later life remains unknown. Here, we show that age-related medial prefrontal cortex (mPFC) grey-matter atrophy is associated with reduced NREM SWA activity in older adults, the extent to which statistically mediates the impairment of overnight sleep-dependent memory retention. Moreover, this memory impairment was further associated with persistent hippocampal activation and reduced task-related hippocampal-prefrontal cortex connectivity, potentially representing impoverished hippocampal-neocortical memory transformation. Together, these data support a model in which age-related mPFC atrophy diminishes SWA, the functional consequence of which is impaired long-term memory. Such findings suggest that sleep disruption in the elderly, mediated by structural brain changes, represent a novel contributing factor to age-related cognitive decline in later life. PMID:23354332

Ezh2 phosphorylation state determines its capacity to maintain CD8+ T memory precursors for antitumor immunity.

PubMed

He, Shan; Liu, Yongnian; Meng, Lijun; Sun, Hongxing; Wang, Ying; Ji, Yun; Purushe, Janaki; Chen, Pan; Li, Changhong; Madzo, Jozef; Issa, Jean-Pierre; Soboloff, Jonathan; Reshef, Ran; Moore, Bethany; Gattinoni, Luca; Zhang, Yi

2017-12-14

Memory T cells sustain effector T-cell production while self-renewing in reaction to persistent antigen; yet, excessive expansion reduces memory potential and impairs antitumor immunity. Epigenetic mechanisms are thought to be important for balancing effector and memory differentiation; however, the epigenetic regulator(s) underpinning this process remains unknown. Herein, we show that the histone methyltransferase Ezh2 controls CD8 + T memory precursor formation and antitumor activity. Ezh2 activates Id3 while silencing Id2, Prdm1 and Eomes, promoting the expansion of memory precursor cells and their differentiation into functional memory cells. Akt activation phosphorylates Ezh2 and decreases its control of these transcriptional programs, causing enhanced effector differentiation at the expense of T memory precursors. Engineering T cells with an Akt-insensitive Ezh2 mutant markedly improves their memory potential and capability of controlling tumor growth compared to transiently inhibiting Akt. These findings establish Akt-mediated phosphorylation of Ezh2 as a critical target to potentiate antitumor immunotherapeutic strategies.

Formal Models of the Network Co-occurrence Underlying Mental Operations.

PubMed

Bzdok, Danilo; Varoquaux, Gaël; Grisel, Olivier; Eickenberg, Michael; Poupon, Cyril; Thirion, Bertrand

2016-06-01

Systems neuroscience has identified a set of canonical large-scale networks in humans. These have predominantly been characterized by resting-state analyses of the task-unconstrained, mind-wandering brain. Their explicit relationship to defined task performance is largely unknown and remains challenging. The present work contributes a multivariate statistical learning approach that can extract the major brain networks and quantify their configuration during various psychological tasks. The method is validated in two extensive datasets (n = 500 and n = 81) by model-based generation of synthetic activity maps from recombination of shared network topographies. To study a use case, we formally revisited the poorly understood difference between neural activity underlying idling versus goal-directed behavior. We demonstrate that task-specific neural activity patterns can be explained by plausible combinations of resting-state networks. The possibility of decomposing a mental task into the relative contributions of major brain networks, the "network co-occurrence architecture" of a given task, opens an alternative access to the neural substrates of human cognition.

Aggression is associated with greater subsequent alcohol consumption: A shared neural basis in the ventral striatum.

PubMed

Chester, David S; DeWall, C Nathan

2018-05-01

Alcohol use and abuse (e.g., binge drinking) are among the most reliable causes of aggressive behavior. Conversely, people with aggressive dispositions (e.g., intermittent explosive disorder) are at greater risk for subsequent substance abuse. Yet it remains unknown why aggression might promote subsequent alcohol use. Both aggressive acts and alcohol use are rewarding and linked to greater activity in neural reward circuitry. Through this shared instantiation of reward, aggression may then increase subsequent alcohol consumption. Supporting this mechanistic hypothesis, participants' aggressive behavior directed at someone who had recently rejected them, was associated with more subsequent beer consumption on an ad-lib drinking task. Using functional MRI, both aggressive behavior and beer consumption were associated with greater activity in the bilateral ventral striatum during acts of retaliatory aggression. These results imply that aggression is linked to subsequent alcohol abuse, and that a mechanism underlying this effect is likely to be the activation of the brain's reward circuitry during aggressive acts. © 2018 Wiley Periodicals, Inc.

Formal Models of the Network Co-occurrence Underlying Mental Operations

PubMed Central

Bzdok, Danilo; Varoquaux, Gaël; Grisel, Olivier; Eickenberg, Michael; Poupon, Cyril; Thirion, Bertrand

2016-01-01

Systems neuroscience has identified a set of canonical large-scale networks in humans. These have predominantly been characterized by resting-state analyses of the task-unconstrained, mind-wandering brain. Their explicit relationship to defined task performance is largely unknown and remains challenging. The present work contributes a multivariate statistical learning approach that can extract the major brain networks and quantify their configuration during various psychological tasks. The method is validated in two extensive datasets (n = 500 and n = 81) by model-based generation of synthetic activity maps from recombination of shared network topographies. To study a use case, we formally revisited the poorly understood difference between neural activity underlying idling versus goal-directed behavior. We demonstrate that task-specific neural activity patterns can be explained by plausible combinations of resting-state networks. The possibility of decomposing a mental task into the relative contributions of major brain networks, the "network co-occurrence architecture" of a given task, opens an alternative access to the neural substrates of human cognition. PMID:27310288

Ventral Striatum and the Evaluation of Memory Retrieval Strategies

PubMed Central

Badre, David; Lebrecht, Sophie; Pagliaccio, David; Long, Nicole M.; Scimeca, Jason M.

2015-01-01

Adaptive memory retrieval requires mechanisms of cognitive control that facilitate the recovery of goal-relevant information. Frontoparietal systems are known to support control of memory retrieval. However, the mechanisms by which the brain acquires, evaluates, and adapts retrieval strategies remain unknown. Here, we provide evidence that ventral striatal activation tracks the success of a retrieval strategy and correlates with subsequent reliance on that strategy. Human participants were scanned with fMRI while performing a lexical decision task. A rule was provided that indicated the likely semantic category of a target word given the category of a preceding prime. Reliance on the rule improved decision-making, as estimated within a drift diffusion framework. Ventral striatal activation tracked the benefit that relying on the rule had on decision-making. Moreover, activation in ventral striatum correlated with a participant’s subsequent reliance on the rule. Taken together, these results support a role for ventral striatum in learning and evaluating declarative retrieval strategies. PMID:24564466

A phenylalanine rotameric switch for signal-state control in bacterial chemoreceptors

NASA Astrophysics Data System (ADS)

Ortega, Davi R.; Yang, Chen; Ames, Peter; Baudry, Jerome; Parkinson, John S.; Zhulin, Igor B.

2013-12-01

Bacterial chemoreceptors are widely used as a model system for elucidating the molecular mechanisms of transmembrane signalling and have provided a detailed understanding of how ligand binding by the receptor modulates the activity of its associated kinase CheA. However, the mechanisms by which conformational signals move between signalling elements within a receptor dimer and how they control kinase activity remain unknown. Here, using long molecular dynamics simulations, we show that the kinase-activating cytoplasmic tip of the chemoreceptor fluctuates between two stable conformations in a signal-dependent manner. A highly conserved residue, Phe396, appears to serve as the conformational switch, because flipping of the stacked aromatic rings of an interacting F396-F396‧ pair in the receptor homodimer takes place concomitantly with the signal-related conformational changes. We suggest that interacting aromatic residues, which are common stabilizers of protein tertiary structure, might serve as rotameric molecular switches in other biological processes as well.

Functional characterisation of ganglioside-induced differentiation-associated protein 1 as a glutathione transferase.

PubMed

Shield, Alison J; Murray, Tracy P; Board, Philip G

2006-09-08

Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene have been linked with Charcot-Marie-Tooth (CMT) disease. This protein, and its paralogue GDAP1L1, appear to be structurally related to the cytosolic glutathione S-transferases (GST) including an N-terminal thioredoxin fold domain with conserved active site residues. The specific function, of GDAP1 remains unknown. To further characterise their structure and function we purified recombinant human GDAP1 and GDAP1L1 proteins using bacterial expression and immobilised metal affinity chromatography. Like other cytosolic GSTs, GDAP1 protein has a dimeric structure. Although the full-length proteins were largely insoluble, the deletion of a proposed C-terminal transmembrane domain allowed the preparation of soluble protein. The purified proteins were assayed for glutathione-dependent activity against a library of 'prototypic' GST substrates. No evidence of glutathione-dependent activity or an ability to bind glutathione immobilised on agarose was found.

Anti-bacterial and anti-inflammatory effects of ethanol extract from Houttuynia cordata poultice.

PubMed

Sekita, Yasuko; Murakami, Keiji; Yumoto, Hiromichi; Mizuguchi, Hiroyuki; Amoh, Takashi; Ogino, Satoshi; Matsuo, Takashi; Miyake, Yoichiro; Fukui, Hiroyuki; Kashiwada, Yoshiki

2016-06-01

Houttuynia cordata (HC) has been commonly used as many traditional remedies in local areas of Japan. Although many pharmacological activities of HC have been reported, the mechanism underlying the effect of HC remains unknown. We conducted the interview survey in Japan to verify how HC was actually used. The interview survey revealed that HC poultice (HCP) prepared from smothering fresh leaves of HC was most frequently used for the treatment of purulent skin diseases including furuncle and carbuncle with high effectiveness. Ethanol extract of HCP (eHCP) showed anti-bacterial effects against methicillin-resistant Staphylococcus aureus (MRSA), and showed an anti-biofilm activity against MRSA. eHCP showed dose-dependent inhibition of S. aureus lipoteichoic acid (LTA)-induced interleukin-8 and CCL20 production in human keratinocyte without any cytotoxicity. These results suggest that HCP is effective for skin abscess and its underlying mechanism might be the complicated multiple activities for both bacteria and host cells.

A role for intestinal TLR4-driven inflammatory response during activity-based anorexia.

PubMed

Belmonte, Liliana; Achamrah, Najate; Nobis, Séverine; Guérin, Charlène; Riou, Gaëtan; Bôle-Feysot, Christine; Boyer, Olivier; Richard, Vincent; Rego, Jean Claude Do; Déchelotte, Pierre; Goichon, Alexis; Coëffier, Moïse

2016-10-25

Anorexia nervosa (AN) is associated with low-grade systemic inflammation and altered gut microbiota. However, the molecular origin of the inflammation remains unknown. Toll-like receptors are key regulators of innate immune response and their activation seems also to be involved in the control of food intake. We used activity-based anorexia (ABA) model to investigate the role of TLR4 and its contribution in anorexia-associated low-grade inflammation. Here, we found that ABA affected early the intestinal inflammatory status and the hypothalamic response. Indeed, TLR4 was upregulated both on colonic epithelial cells and intestinal macrophages, leading to elevated downstream mucosal cytokine production. These mucosal changes occurred earlier than hypothalamic changes driving to increased levels of IL-1β and IL-1R1 as well as increased levels of plasma corticosterone. Paradoxically, TLR4-deficient mice exhibited greater vulnerability to ABA with increased mortality rate, suggesting a major contribution of TLR4-mediated responses during ABA-induced weight loss.

Autophagy is essential for the differentiation of porcine PSCs into insulin-producing cells.

PubMed

Ren, Lipeng; Yang, Hong; Cui, Yanhua; Xu, Shuanshuan; Sun, Fen; Tian, Na; Hua, Jinlian; Peng, Sha

2017-07-01

Porcine pancreatic stem cells (PSCs) are seed cells with potential use for diabetes treatment. Stem cell differentiation requires strict control of protein turnover and lysosomal digestion of organelles. Autophagy is a highly conserved process that controls the turnover of organelles and proteins within cells and contributes to the balance of cellular components. However, whether autophagy plays roles in PSC differentiation remains unknown. In this study, we successfully induced porcine PSCs into insulin-producing cells and found that autophagy was activated during the second induction stage. Inhibition of autophagy in the second stage resulted in reduced differentiational efficiency and impaired glucose-stimulated insulin secretion. Moreover, the expression of active β-catenin increased while autophagy was activated but was suppressed when autophagy was inhibited. Therefore, autophagy is essential to the formation of insulin-producing cells, and the effects of autophagy on differentiation may be regulated by canonical Wnt signalling pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

Resveratrol enhances HBV replication through activating Sirt1-PGC-1α-PPARα pathway.

PubMed

Shi, Yixian; Li, Yongjun; Huang, Chenjie; Ying, Lixiong; Xue, Jihua; Wu, Haicong; Chen, Zhi; Yang, Zhenggang

2016-04-21

The population of hepatitis B combined with a number of metabolic disorders is increasing significantly. Resveratrol (RSV) has been used as a preclinical drug for the treatment of the metabolic disorders. However, the impact of RSV on HBV replication remains unknown. In this study, the HBV-expressing hepatocelluar carcinoma cell line and mouse model created by hydrodynamic injection of viral DNA were used. We found that RSV activates Sirt1, which in turn deacetylates PGC-1α and subsequently increases the transcriptional activity of PPARα, leading to the enhanced HBV transcription and replication in vitro and in vivo. In addition, we found that this pathway is also required for fasting-induced HBV transcription. Taken together, this study identifies that RSV enhances HBV transcription and replication especially acting on the core promoter, which depends on Sirt1-PGC-1α-PPARα pathway. We conclude that RSV may exacerbate the progression of hepatitis B and that patients with hepatitis B infection should be cautious taking RSV as a dietary supplement.

Identification of a Phosphodiesterase-Inhibiting Fraction from Roasted Coffee (Coffea arabica) through Activity-Guided Fractionation.

PubMed

Röhrig, Teresa; Liesenfeld, David; Richling, Elke

2017-05-17

Recent reports that coffee can significantly inhibit cAMP phosphodiesterases (PDEs) in vitro, as well as in vivo, have described another beneficial effect of coffee consumption. However, the PDE-inhibiting substances remain mostly unknown. We chose activity-guided fractionation and an in vitro test system to identify the coffee components that are responsible for PDE inhibition. This approach indicated that a fraction of melanoidins reveals strong PDE-inhibiting potential (IC 50 = 130 ± 42 μg/mL). These melanoidins were characterized as water-soluble, low-molecular weight melanoidins (<3 kDa) with a nitrogen content of 4.2% and a carbohydrate content lower than those of other melanoidins. Fractions containing known PDE inhibitors such as chlorogenic acids, alkylpyrazines, or trigonelline as well as N-caffeoyl-tryptophan and N-p-coumaroyl-tryptophan did not exert PDE-inhibiting activity. We also observed that the known PDE inhibitor caffeine does not contribute to the PDE-inhibiting effects of coffee.

Resveratrol induces membrane and DNA disruption via pro-oxidant activity against Salmonella typhimurium.

PubMed

Lee, Wonjong; Lee, Dong Gun

2017-07-22

Resveratrol is a flavonoid found in various plants including grapes, which has been reported to be active against various pathogenic bacteria. However, antibacterial effects and mechanisms via pro-oxidant property of resveratrol remain unknown and speculative. This research investigated antibacterial mechanism of resveratrol against a food-borne human pathogen Salmonella typhimurium, and confirmed the cell death associated oxidative damage. Resveratrol increased outer membrane permeability and membrane depolarization. It also was observed DNA injury responses such as DNA fragmentation, increasing DNA contents and cell division inhibition. Intracellular ROS accumulation, GSH depletion and significant increased malondialdehyde levels were confirmed, which indicated pro-oxidant activity of resveratrol and oxidative stress. Furthermore, the observed lethal damages were reduced by antioxidant N-acetylcysteine treatment supported the view that resveratrol-induced oxidative stress stimulated S. typhimurium cell death. In conclusion, this study expands understanding on role of pro-oxidant property and insight into previously unrecognized oxygen-dependent anti-Salmonella mechanism on resveratrol. Copyright © 2017 Elsevier Inc. All rights reserved.

Inducible Knockout of the Cyclin-Dependent Kinase 5 Activator p35 Alters Hippocampal Spatial Coding and Neuronal Excitability

PubMed Central

Kamiki, Eriko; Boehringer, Roman; Polygalov, Denis; Ohshima, Toshio; McHugh, Thomas J.

2018-01-01

p35 is an activating co-factor of Cyclin-dependent kinase 5 (Cdk5), a protein whose dysfunction has been implicated in a wide-range of neurological disorders including cognitive impairment and disease. Inducible deletion of the p35 gene in adult mice results in profound deficits in hippocampal-dependent spatial learning and synaptic physiology, however the impact of the loss of p35 function on hippocampal in vivo physiology and spatial coding remains unknown. Here, we recorded CA1 pyramidal cell activity in freely behaving p35 cKO and control mice and found that place cells in the mutant mice have elevated firing rates and impaired spatial coding, accompanied by changes in the temporal organization of spiking both during exploration and rest. These data shed light on the role of p35 in maintaining cellular and network excitability and provide a physiological correlate of the spatial learning deficits in these mice. PMID:29867369

Coffee phenolic phytochemicals suppress colon cancer metastasis by targeting MEK and TOPK.

PubMed

Kang, Nam Joo; Lee, Ki Won; Kim, Bo Hyun; Bode, Ann M; Lee, Hyo-Jeong; Heo, Yong-Seok; Boardman, Lisa; Limburg, Paul; Lee, Hyong Joo; Dong, Zigang

2011-06-01

Epidemiological studies suggest that coffee consumption reduces the risk of cancers, including colon cancer, but the molecular mechanisms and target(s) underlying the chemopreventive effects of coffee and its active ingredient(s) remain unknown. Based on serving size or daily units, coffee contains larger amounts of phenolic phytochemicals than tea or red wine. Coffee or chlorogenic acid inhibited CT-26 colon cancer cell-induced lung metastasis by blocking phosphorylation of ERKs. Coffee or caffeic acid (CaA) strongly suppressed mitogen-activated MEK1 and TOPK activities and bound directly to either MEK1 or TOPK in an ATP-noncompetitive manner. Coffee or CaA, but not caffeine, inhibited ERKs phosphorylation, AP-1 and NF-κB transactivation and subsequently inhibited TPA-, EGF- and H-Ras-induced neoplastic transformation of JB6 P+ cells. Coffee consumption was also associated with a significant attenuation of ERKs phosphorylation in colon cancer patients. These results suggest that coffee and CaA target MEK1 and TOPK to suppress colon cancer metastasis and neoplastic cell transformation.

Autosomal gsdf acts as a male sex initiator in the fish medaka

PubMed Central

Zhang, Xi; Guan, Guijun; Li, Mingyou; Zhu, Feng; Liu, Qizhi; Naruse, Kiyoshi; Herpin, Amaury; Nagahama, Yoshitaka; Li, Jiale; Hong, Yunhan

2016-01-01

Sex is pivotal for reproduction, healthcare and evolution. In the fish medaka, the Y-chromosomal dmy (also dmrt1bY) serves the sex determiner, which activates dmrt1 for male sex maintenance. However, how dmy makes the male decision via initiating testicular differentiation has remained unknown. Here we report that autosomal gsdf serves a male sex initiator. Gene addition and deletion revealed that gsdf was necessary and sufficient for maleness via initiating testicular differentiation. We show that gsdf transcription is activated directly by dmy. These results establish the autosomal gsdf as the first male sex initiator. We propose that dmy determines maleness through activating gsdf and dmrt1 without its own participation in developmental processes of sex initiation and maintenance. gsdf may easily become a sex determiner or other autosomal genes can be recruited as new sex determiners to initiate gsdf expression. Our findings offer new insights into molecular mechanisms underlying sex development and evolution of sex-controlling genes in vertebrates. PMID:26813267

Structural Elements and Cough Suppressing Activity of Polysaccharides from Zingiber officinale Rhizome.

PubMed

Bera, K; Nosalova, G; Sivova, V; Ray, B

2016-01-01

Zingiber officinale is used for the management of fever, bronchial asthma and cough for thousands of years. While the link to a particular indication has been established in human, the active principle of the formulation remains unknown. Herein, we have investigated a water extracted polysaccharides (WEP) containing fraction from its rhizome. Utilizing a traditional aqueous extraction protocol and using chemical, chromatographic and spectroscopic methods a fraction containing a branched glucan and polygalaturonan in a ratio of 59:1 was characterized. This glucan, which has a molecular mass of 36 kDa, is made up of terminal-, (1,4)- and (1,4,6)-linked α-Glcp residues. Oral administration of WEP in doses of 25 and 50 mg/kg body weight significantly inhibited the number of citric acid-induced cough efforts in guinea pigs. It does not alter the specific airway smooth muscle reactivity significantly. Thus, traditional aqueous extraction method provides molecular entities, which induces antitussive activity without addiction. Copyright © 2015 John Wiley & Sons, Ltd.

Lateralization of brain activation in fluent and non-fluent preschool children: a magnetoencephalographic study of picture-naming.

PubMed

Sowman, Paul F; Crain, Stephen; Harrison, Elisabeth; Johnson, Blake W

2014-01-01

The neural causes of stuttering remain unknown. One explanation comes from neuroimaging studies that have reported abnormal lateralization of activation in the brains of people who stutter. However, these findings are generally based on data from adults with a long history of stuttering, raising the possibility that the observed lateralization anomalies are compensatory rather than causal. The current study investigated lateralization of brain activity in language-related regions of interest in young children soon after the onset of stuttering. We tested 24 preschool-aged children, half of whom had a positive diagnosis of stuttering. All children participated in a picture-naming experiment whilst their brain activity was recorded by magnetoencephalography. Source analysis performed during an epoch prior to speech onset was used to assess lateralized activation in three regions of interest. Activation was significantly lateralized to the left hemisphere in both groups and not different between groups. This study shows for the first time that significant speech preparatory brain activation can be identified in young children during picture-naming and supports the contention that, in stutterers, aberrant lateralization of brain function may be the result of neuroplastic adaptation that occurs as the condition becomes chronic.

Chemogenetic Activation of Midbrain Dopamine Neurons Affects Attention, but not Impulsivity, in the Five-Choice Serial Reaction Time Task in Rats.

PubMed

Boekhoudt, Linde; Voets, Elisa S; Flores-Dourojeanni, Jacques P; Luijendijk, Mieneke Cm; Vanderschuren, Louk Jmj; Adan, Roger Ah

2017-05-01

Attentional impairments and exaggerated impulsivity are key features of psychiatric disorders, such as attention-deficit/hyperactivity disorder, schizophrenia, and addiction. These deficits in attentional performance and impulsive behaviors have been associated with aberrant dopamine (DA) signaling, but it remains unknown whether these deficits result from enhanced DA neuronal activity in the midbrain. Here, we took a novel approach by testing the impact of chemogenetically activating DA neurons in the ventral tegmental area (VTA) or substantia nigra pars compacta (SNc) on attention and impulsivity in the five-choice serial reaction time task (5-CSRTT) in rats. We found that activation of DA neurons in both the VTA and SNc impaired attention by increasing trial omissions. In addition, SNc DA neuron activation decreased attentional accuracy. Surprisingly, enhanced DA neuron activity did not affect impulsive action in this task. These results show that enhanced midbrain DA neuronal activity induces deficits in attentional performance, but not impulsivity. Furthermore, DA neurons in the VTA and SNc have different roles in regulating attention. These findings contribute to our understanding of the neural substrates underlying attention deficits and impulsivity, and provide valuable insights to improve treatment of these symptoms.

TMPRSS4 induces cancer cell invasion through pro-uPA processing.

PubMed

Min, Hye-Jin; Lee, Myung Kyu; Lee, Jung Weon; Kim, Semi

2014-03-28

TMPRSS4 is a novel type II transmembrane serine protease that is highly expressed on the cell surface in pancreatic, thyroid, colon, and other cancer tissues. Previously, we demonstrated that TMPRSS4 mediates cancer cell invasion, epithelial-mesenchymal transition, and metastasis and that increased TMPRSS4 expression correlates with colorectal cancer progression. We also demonstrated that TMPRSS4 upregulates urokinase-type plasminogen activator (uPA) gene expression to induce cancer cell invasion. However, it remains unknown how proteolytic activity of TMPRSS4 contributes to invasion. In this study, we report that TMPRSS4 directly converted inactive pro-uPA into the active form through its proteolytic activity. Analysis of conditioned medium from cells overexpressing TMPRSS4 demonstrated that the active TMPRSS4 protease domain is released from the cells and is associated with the plasma membrane. Furthermore, TMPRSS4 could increase pro-uPA-mediated invasion in a serine proteolytic activity-dependent manner. These observations suggest that TMPRSS4 is an upstream regulator of pro-uPA activation. This study provides valuable insights into the proteolytic function of TMPRSS4 as well as mechanisms for the control of invasion. Copyright © 2014 Elsevier Inc. All rights reserved.

SUMOylation of the KRAB zinc-finger transcription factor PARIS/ZNF746 regulates its transcriptional activity.

PubMed

Nishida, Tamotsu; Yamada, Yoshiji

2016-05-13

Parkin-interacting substrate (PARIS), a member of the family of Krüppel-associated box (KRAB)-containing zinc-finger transcription factors, is a substrate of the ubiquitin E3 ligase parkin. PARIS represses the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), although the underlying mechanisms remain largely unknown. In the present study, we demonstrate that PARIS can be SUMOylated, and its SUMOylation plays a role in the repression of PGC-1a promoter activity. Protein inhibitor of activated STAT y (PIASy) was identified as an interacting protein of PARIS and shown to enhance its SUMOylation. PIASy repressed PGC-1a promoter activity, and this effect was attenuated by PARIS in a manner dependent on its SUMOylation status. Co-expression of SUMO-1 with PIASy completely repressed PGC-1a promoter activity independently of PARIS expression. PARIS-mediated PGC-1a promoter repression depended on the activity of histone deacetylases (HDAC), whereas PIASy repressed the PGC-1a promoter in an HDAC-independent manner. Taken together, these results suggest that PARIS and PIASy modulate PGC-1a gene transcription through distinct molecular mechanisms. Copyright © 2016 Elsevier Inc. All rights reserved.

The restoration of a maxillary central incisor fracture with the original crown fragment using a glass fiber-reinforced post: a clinical report.

PubMed

Durkan, Rukiye Kaplan; Ozel, M Birol; Celik, Davut; Bağiş, Bora

2008-12-01

This report describes an esthetic, conservative, and economical alternative restoration technique for a fractured central incisor using the patient's own tooth crown piece and a bondable reinforcement glass fiber. Although the long-term durability of this adhesive post core restoration remains unknown, it remains successful after 1 year.

Evaluation of the ruminal bacterial diversity of cattle fed diets containing citrus pulp pellets (CPP) using bacterial tag-encoded FLX amplicon pyrosequencing (bTEFAP)

USDA-ARS?s Scientific Manuscript database

The rumen microbial ecosystem has been extensively studied, but remains a mystery from a quantitative perspective. Dietary components and changes cause shifts in the ruminal microflora that can affect animal health and productivity, but the majority of these changes remain unknown. The objective of ...

Accessible cultural mind-set modulates default mode activity: evidence for the culturally situated brain.

PubMed

Wang, Chenbo; Oyserman, Daphna; Liu, Qiang; Li, Hong; Han, Shihui

2013-01-01

Self-construal priming modulates human behavior and associated neural activity. However, the neural activity associated with the self-construal priming procedure itself remains unknown. It is also unclear whether and how self-construal priming affects neural activity prior to engaging in a particular task. To address this gap, we scanned Chinese adults, using functional magnetic resonance imaging, during self-construal priming and a following resting state. We found that, relative to a calculation task, both interdependent and independent self-construal priming activated the ventral medial prefrontal cortex (MPFC) and the posterior cingulate cortex (PCC). The contrast of interdependent vs. independent self-construal priming also revealed increased activity in the dorsal MPFC and left middle frontal cortex. The regional homogeneity analysis of the resting-state activity revealed increased local synchronization of spontaneous activity in the dorsal MPFC but decreased local synchronization of spontaneous activity in the PCC when contrasting interdependent vs. independent self-construal priming. The functional connectivity analysis of the resting-state activity, however, did not show significant difference in synchronization of activities in remote brain regions between different priming conditions. Our findings suggest that accessible collectivistic/individualistic mind-set induced by self-construal priming is associated with modulations of both task-related and resting-state activity in the default mode network.

Respiratory status determines the effect of emodin on cell viability.

PubMed

Dumit, Verónica I; Zerbes, Ralf M; Kaeser-Pebernard, Stephanie; Rackiewicz, Michal; Wall, Mona T; Gretzmeier, Christine; Küttner, Victoria; van der Laan, Martin; Braun, Ralf J; Dengjel, Jörn

2017-06-06

The anthraquinone emodin has been shown to have antineoplastic properties and a wealth of unconnected effects have been linked to its use, most of which are likely secondary outcomes of the drug treatment. The primary activity of emodin on cells has remained unknown. In the present study we demonstrate dramatic and extensive effects of emodin on the redox state of cells and on mitochondrial homeostasis, irrespectively of the cell type and organism, ranging from the yeast Saccharomyces cerevisiae to human cell lines and primary cells. Emodin binds to redox-active enzymes and its effectiveness depends on the oxidative and respiratory status of cells. We show that cells with efficient respiratory metabolism are less susceptible to emodin, whereas cells under glycolytic metabolism are more vulnerable to the compound. Our findings indicate that emodin acts in a similar way as known uncouplers of the mitochondrial electron transport chain and causes oxidative stress that particularly disturbs cancer cells.

Respiratory status determines the effect of emodin on cell viability

PubMed Central

Dumit, Verónica I; Zerbes, Ralf M; Kaeser-Pebernard, Stephanie; Rackiewicz, Michal; Wall, Mona T; Gretzmeier, Christine; Küttner, Victoria; van der Laan, Martin; Braun, Ralf J; Dengjel, Jörn

2017-01-01

The anthraquinone emodin has been shown to have antineoplastic properties and a wealth of unconnected effects have been linked to its use, most of which are likely secondary outcomes of the drug treatment. The primary activity of emodin on cells has remained unknown. In the present study we demonstrate dramatic and extensive effects of emodin on the redox state of cells and on mitochondrial homeostasis, irrespectively of the cell type and organism, ranging from the yeast Saccharomyces cerevisiae to human cell lines and primary cells. Emodin binds to redox-active enzymes and its effectiveness depends on the oxidative and respiratory status of cells. We show that cells with efficient respiratory metabolism are less susceptible to emodin, whereas cells under glycolytic metabolism are more vulnerable to the compound. Our findings indicate that emodin acts in a similar way as known uncouplers of the mitochondrial electron transport chain and causes oxidative stress that particularly disturbs cancer cells. PMID:28415582

Afferent control mechanisms involved in the development of soleus fiber alterations in simulated hypogravity

NASA Astrophysics Data System (ADS)

Shenkman, B. S.; Nemirovskaya, T. L.; Shapovalova, K. B.; Podlubnaya, Z. A.; Vikhliantsev, I. M.; Moukhina, A. M.; Kozlovskaya, I. B.

2007-02-01

It was recently established that support withdrawal (withdrawal of support reaction force) in microgravity provokes a sequence of functional shifts in the activity of motor units (inactivation of slow ones) and peripheral muscle apparatus which lead to the decline of postural muscle contractility and alterations in fiber characteristics. However, mechanisms involved in inactivation of the slow motor units and appropriate slow-twitch muscle fiber disuse under the supportless conditions remained unknown. We show here that artificial inactivation of muscles-antagonists (which are known to be hyperactive during unloading) counteracts some of the unloading-induced events in the rat soleus (fiber size reduction, slow-to-fast fiber-type transition and decline of titin and nebulin content). It was also demonstrated that direct activation of the muscarinic receptors of the neostriatum neurons prevented slow-to-fast fiber-type transformation in soleus of hindlimb suspended rats.

Cryptochrome 1 interacts with PIF4 to regulate high temperature-mediated hypocotyl elongation in response to blue light.

PubMed

Ma, Dingbang; Li, Xu; Guo, Yongxia; Chu, Jingfang; Fang, Shuang; Yan, Cunyu; Noel, Joseph P; Liu, Hongtao

2016-01-05

Cryptochrome 1 (CRY1) is a blue light receptor that mediates primarily blue-light inhibition of hypocotyl elongation. Very little is known of the mechanisms by which CRY1 affects growth. Blue light and temperature are two key environmental signals that profoundly affect plant growth and development, but how these two abiotic factors integrate remains largely unknown. Here, we show that blue light represses high temperature-mediated hypocotyl elongation via CRY1. Furthermore, CRY1 interacts directly with PHYTOCHROME-INTERACTING FACTOR 4 (PIF4) in a blue light-dependent manner to repress the transcription activity of PIF4. CRY1 represses auxin biosynthesis in response to elevated temperature through PIF4. Our results indicate that CRY1 signal by modulating PIF4 activity, and that multiple plant photoreceptors [CRY1 and PHYTOCHROME B (PHYB)] and ambient temperature can mediate morphological responses through the same signaling component-PIF4.

Integrin αv in the mechanical response of osteoblast lineage cells.

PubMed

Kaneko, Keiko; Ito, Masako; Naoe, Yoshinori; Lacy-Hulbert, Adam; Ikeda, Kyoji

2014-05-02

Although osteoblast lineage cells, especially osteocytes, are thought to be a primary mechanosensory cell in bone, the identity of the mechano-receptor and downstream mechano-signaling pathways remain largely unknown. Here we show using osteoblastic cell model of mechanical stimulation with fluid shear stress that in the absence of integrin αv, phosphorylation of the Src substrate p130Cas and JNK was impaired, culminating in an inhibition of nuclear translocation of YAP/TAZ and subsequent transcriptional activation of target genes. Targeted deletion of the integrin αv in osteoblast lineage cells results in an attenuated response to mechanical loading in terms of Sost gene expression, indicative of a role for integrin αv in mechanoreception in vivo. Thus, integrin αv may be integral to a mechanosensing machinery in osteoblastic cells and involved in activation of a Src-JNK-YAP/TAZ pathway in response to mechanical stimulation. Copyright © 2014 Elsevier Inc. All rights reserved.

Parietal Epithelial Cells Participate in the Formation of Sclerotic Lesions in Focal Segmental Glomerulosclerosis

PubMed Central

Smeets, Bart; Kuppe, Christoph; Sicking, Eva-Maria; Fuss, Astrid; Jirak, Peggy; van Kuppevelt, Toin H.; Endlich, Karlhans; Wetzels, Jack F.M.; Gröne, Hermann-Josef; Floege, Jürgen

2011-01-01

The pathogenesis of the development of sclerotic lesions in focal segmental glomerulosclerosis (FSGS) remains unknown. Here, we selectively tagged podocytes or parietal epithelial cells (PECs) to determine whether PECs contribute to sclerosis. In three distinct models of FSGS (5/6-nephrectomy + DOCA-salt; the murine transgenic chronic Thy1.1 model; or the MWF rat) and in human biopsies, the primary injury to induce FSGS associated with focal activation of PECs and the formation of cellular adhesions to the capillary tuft. From this entry site, activated PECs invaded the affected segment of the glomerular tuft and deposited extracellular matrix. Within the affected segment, podocytes were lost and mesangial sclerosis developed within the endocapillary compartment. In conclusion, these results demonstrate that PECs contribute to the development and progression of the sclerotic lesions that define FSGS, but this pathogenesis may be relevant to all etiologies of glomerulosclerosis. PMID:21719782

In vitro prebiotic effects of seaweed polysaccharides

NASA Astrophysics Data System (ADS)

Chen, Xiaolin; Sun, Yuhao; Hu, Linfeng; Liu, Song; Yu, Huahua; Xing, Rong'e.; Li, Rongfeng; Wang, Xueqin; Li, Pengcheng

2017-09-01

Although prebiotic activities of alginate and agar oligosaccharides isolated from seaweeds have been reported, it remains unknown whether seaweed polysaccharides have prebiotic activity. In this study, we isolated polysaccharides from four species of seaweeds, such as Grateloupia filicina (GFP), Eucheuma spinosum (ESP), Ulva pertusa (UPP), and Ascophyllum nodosum (ANP), and characterized their structures and prebiotic effects in vitro. The results showed that these polysaccharides were different in total sugar and sulfate contents as well as monosaccharide composition. GFP and ESP significantly promoted bifidobacterium proliferation and 0.1% ESP and 0.4% GFP resulted in the highest proliferation rates of beneficial bacteria, whereas UPP and ANP inhibited the growth of beneficial bacteria at all tested concentrations (0.1%-0.5%). The different behaviors of the four seaweed-originated polysaccharides might be reflected by differences in monosaccharide composition and structure. Therefore, polysaccharides isolated from GFP and ESP could be utilized as prebiotics. However, more studies must be carried out in vivo.

Reduced Adult Hippocampal Neurogenesis and Cognitive Impairments following Prenatal Treatment of the Antiepileptic Drug Valproic Acid

PubMed Central

Juliandi, Berry; Tanemura, Kentaro; Igarashi, Katsuhide; Tominaga, Takashi; Furukawa, Yusuke; Otsuka, Maky; Moriyama, Noriko; Ikegami, Daigo; Abematsu, Masahiko; Sanosaka, Tsukasa; Tsujimura, Keita; Narita, Minoru; Kanno, Jun; Nakashima, Kinichi

2015-01-01

Summary Prenatal exposure to valproic acid (VPA), an established antiepileptic drug, has been reported to impair postnatal cognitive function in children born to VPA-treated epileptic mothers. However, how these defects arise and how they can be overcome remain unknown. Using mice, we found that comparable postnatal cognitive functional impairment is very likely correlated to the untimely enhancement of embryonic neurogenesis, which led to depletion of the neural precursor cell pool and consequently a decreased level of adult neurogenesis in the hippocampus. Moreover, hippocampal neurons in the offspring of VPA-treated mice showed abnormal morphology and activity. Surprisingly, these impairments could be ameliorated by voluntary running. Our study suggests that although prenatal exposure to antiepileptic drugs such as VPA may have detrimental effects that persist until adulthood, these effects may be offset by a simple physical activity such as running. PMID:26677766

Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake.

PubMed

Nakajima, Ken-ichiro; Cui, Zhenzhong; Li, Chia; Meister, Jaroslawna; Cui, Yinghong; Fu, Ou; Smith, Adam S; Jain, Shalini; Lowell, Bradford B; Krashes, Michael J; Wess, Jürgen

2016-01-08

Agouti-related peptide (AgRP) neurons of the hypothalamus play a key role in regulating food intake and body weight, by releasing three different orexigenic molecules: AgRP; GABA; and neuropeptide Y. AgRP neurons express various G protein-coupled receptors (GPCRs) with different coupling properties, including Gs-linked GPCRs. At present, the potential role of Gs-coupled GPCRs in regulating the activity of AgRP neurons remains unknown. Here we show that the activation of Gs-coupled receptors expressed by AgRP neurons leads to a robust and sustained increase in food intake. We also provide detailed mechanistic data linking the stimulation of this class of receptors to the observed feeding phenotype. Moreover, we show that this pathway is clearly distinct from other GPCR signalling cascades that are operative in AgRP neurons. Our data suggest that drugs able to inhibit this signalling pathway may become useful for the treatment of obesity.

The Role of Hydrogen for Sulfurimonas denitrificans’ Metabolism

PubMed Central

Han, Yuchen; Perner, Mirjam

2014-01-01

Sulfurimonas denitrificans was originally isolated from coastal marine sediments. It can grow with thiosulfate and nitrate or sulfide and oxygen. Recently sequencing of its genome revealed that it encodes periplasmic and cytoplasmic [NiFe]-hydrogenases but the role of hydrogen for its metabolism has remained unknown. We show the first experimental evidence that S. denitrificans can indeed express a functional hydrogen uptake active hydrogenase and can grow on hydrogen. In fact, under the provided conditions it grew faster and denser on hydrogen than on thiosulfate alone and even grew with hydrogen in the absence of reduced sulfur compounds. In our experiments, at the time points tested, the hydrogen uptake activity appeared to be related to the periplasmic hydrogenase and not to the cytoplasmic hydrogenase. Our data suggest that under the provided conditions S. denitrificans can grow more efficiently with hydrogen than with thiosulfate. PMID:25170905

Human brain networks function in connectome-specific harmonic waves.

PubMed

Atasoy, Selen; Donnelly, Isaac; Pearson, Joel

2016-01-21

A key characteristic of human brain activity is coherent, spatially distributed oscillations forming behaviour-dependent brain networks. However, a fundamental principle underlying these networks remains unknown. Here we report that functional networks of the human brain are predicted by harmonic patterns, ubiquitous throughout nature, steered by the anatomy of the human cerebral cortex, the human connectome. We introduce a new technique extending the Fourier basis to the human connectome. In this new frequency-specific representation of cortical activity, that we call 'connectome harmonics', oscillatory networks of the human brain at rest match harmonic wave patterns of certain frequencies. We demonstrate a neural mechanism behind the self-organization of connectome harmonics with a continuous neural field model of excitatory-inhibitory interactions on the connectome. Remarkably, the critical relation between the neural field patterns and the delicate excitation-inhibition balance fits the neurophysiological changes observed during the loss and recovery of consciousness.

Adrenaline Rush: The Role of Adrenergic Receptors in Stimulant-Induced Behaviors

PubMed Central

Schmidt, Karl T.

2014-01-01

Psychostimulants, such as cocaine and amphetamines, act primarily through the monoamine neurotransmitters dopamine (DA), norepinephrine, and serotonin. Although stimulant addiction research has largely focused on DA, medication development efforts targeting the dopaminergic system have thus far been unsuccessful, leading to alternative strategies aimed at abating stimulant abuse. Noradrenergic compounds have shown promise in altering the behavioral effects of stimulants in rodents, nonhuman primates, and humans. In this review, we discuss the contribution of each adrenergic receptor (AR) subtype (α1, α2, and β) to five stimulant-induced behaviors relevant to addiction: locomotor activity, conditioned place preference, anxiety, discrimination, and self-administration. AR manipulation has diverse effects on these behaviors; each subtype profoundly influences outcomes in some paradigms but is inconsequential in others. The functional neuroanatomy and intracellular signaling mechanisms underlying the impact of AR activation/blockade on these behaviors remain largely unknown, presenting a new frontier for research on psychostimulant–AR interactions. PMID:24499709

Non-cell autonomous cell death caused by transmission of Huntingtin aggregates in Drosophila.

PubMed

Babcock, Daniel T; Ganetzky, Barry

2015-01-01

Recent evidence indicates that protein aggregates can spread between neurons in several neurodegenerative diseases but much remains unknown regarding the underlying mechanisms responsible for this spreading and its role in disease progression. We recently demonstrated that mutant Huntingtin aggregates spread between cells within the Drosophila brain resulting in non-cell autonomous loss of a pair of large neurons in the posterior protocerebrum. However, the full extent of neuronal loss throughout the brain was not determined. Here we examine the effects of driving expression of mutant Huntingtin in Olfactory Receptor Neurons (ORNs) by using a marker for cleaved caspase activity to monitor neuronal apoptosis as a function of age. We find widespread caspase activity in various brain regions over time, demonstrating that non-cell autonomous damage is widespread. Improved understanding of which neurons are most vulnerable and why should be useful in developing treatment strategies for neurodegenerative diseases that involve transcellular spreading of aggregates.

Beyond static measures: A review of functional magnetic resonance spectroscopy and its potential to investigate dynamic glutamatergic abnormalities in schizophrenia.

PubMed

Jelen, Luke A; King, Sinead; Mullins, Paul G; Stone, James M

2018-05-01

Abnormalities of the glutamate system are increasingly implicated in schizophrenia but their exact nature remains unknown. Proton magnetic resonance spectroscopy ( 1 H-MRS), while fundamental in revealing glutamatergic alterations in schizophrenia, has, until recently, been significantly limited and thought to only provide static measures. Functional magnetic resonance spectroscopy (fMRS), which uses sequential scans for dynamic measurement of a range of brain metabolites in activated brain areas, has lately been applied to a variety of task or stimulus conditions, producing interesting insights into neurometabolite responses to neural activation. Here, we summarise the existing 1 H-MRS studies of brain glutamate in schizophrenia. We then present a comprehensive review of research studies that have utilised fMRS, and lastly consider how fMRS methods might further the understanding of glutamatergic abnormalities in schizophrenia.

Conjunctive Coding of Complex Object Features

PubMed Central

Erez, Jonathan; Cusack, Rhodri; Kendall, William; Barense, Morgan D.

2016-01-01

Critical to perceiving an object is the ability to bind its constituent features into a cohesive representation, yet the manner by which the visual system integrates object features to yield a unified percept remains unknown. Here, we present a novel application of multivoxel pattern analysis of neuroimaging data that allows a direct investigation of whether neural representations integrate object features into a whole that is different from the sum of its parts. We found that patterns of activity throughout the ventral visual stream (VVS), extending anteriorly into the perirhinal cortex (PRC), discriminated between the same features combined into different objects. Despite this sensitivity to the unique conjunctions of features comprising objects, activity in regions of the VVS, again extending into the PRC, was invariant to the viewpoints from which the conjunctions were presented. These results suggest that the manner in which our visual system processes complex objects depends on the explicit coding of the conjunctions of features comprising them. PMID:25921583

The tumor suppressor PTEN has a critical role in antiviral innate immunity.

PubMed

Li, Shun; Zhu, Mingzhu; Pan, Ruangang; Fang, Ting; Cao, Yuan-Yuan; Chen, Shuliang; Zhao, Xiaolu; Lei, Cao-Qi; Guo, Lin; Chen, Yu; Li, Chun-Mei; Jokitalo, Eija; Yin, Yuxin; Shu, Hong-Bing; Guo, Deyin

2016-03-01

The gene encoding PTEN is one of the most frequently mutated tumor suppressor-encoding genes in human cancer. While PTEN's function in tumor suppression is well established, its relationship to anti-microbial immunity remains unknown. Here we found a pivotal role for PTEN in the induction of type I interferon, the hallmark of antiviral innate immunity, that was independent of the pathway of the kinases PI(3)K and Akt. PTEN controlled the import of IRF3, a master transcription factor responsible for IFN-β production, into the nucleus. We further identified a PTEN-controlled negative phosphorylation site at Ser97 of IRF3 and found that release from this negative regulation via the phosphatase activity of PTEN was essential for the activation of IRF3 and its import into the nucleus. Our study identifies crosstalk between PTEN and IRF3 in tumor suppression and innate immunity.

CHIP promotes thyroid cancer proliferation via activation of the MAPK and AKT pathways.

PubMed

Zhang, Li; Liu, Lianyong; He, Xiaohua; Shen, Yunling; Liu, Xuerong; Wei, Jing; Yu, Fang; Tian, Jianqing

2016-08-26

The carboxyl terminus of Hsp70-interacting protein (CHIP) is a U box-type ubiquitin ligase that plays crucial roles in various biological processes, including tumor progression. To date, the functional mechanism of CHIP in thyroid cancer remains unknown. Here, we obtained evidence of upregulation of CHIP in thyroid cancer tissues and cell lines. CHIP overexpression markedly enhanced thyroid cancer cell viability and colony formation in vitro and accelerated tumor growth in vivo. Conversely, CHIP knockdown impaired cell proliferation and tumor growth. Notably, CHIP promoted cell growth through activation of MAPK and AKT pathways, subsequently decreasing p27 and increasing cyclin D1 and p-FOXO3a expression. Our findings collectively indicate that CHIP functions as an oncogene in thyroid cancer, and is therefore a potential therapeutic target for this disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Orexin modulates behavioral fear expression through the locus coeruleus.

PubMed

Soya, Shingo; Takahashi, Tohru M; McHugh, Thomas J; Maejima, Takashi; Herlitze, Stefan; Abe, Manabu; Sakimura, Kenji; Sakurai, Takeshi

2017-11-20

Emotionally salient information activates orexin neurons in the lateral hypothalamus, leading to increase in sympathetic outflow and vigilance level. How this circuit alters animals' behavior remains unknown. Here we report that noradrenergic neurons in the locus coeruleus (NA LC neurons) projecting to the lateral amygdala (LA) receive synaptic input from orexin neurons. Pharmacogenetic/optogenetic silencing of this circuit as well as acute blockade of the orexin receptor-1 (OX1R) decreases conditioned fear responses. In contrast, optogenetic stimulation of this circuit potentiates freezing behavior against a similar but distinct context or cue. Increase of orexinergic tone by fasting also potentiates freezing behavior and LA activity, which are blocked by pharmacological blockade of OX1R in the LC. These findings demonstrate the circuit involving orexin, NA LC and LA neurons mediates fear-related behavior and suggests inappropriate excitation of this pathway may cause fear generalization sometimes seen in psychiatric disorders, such as PTSD.

Suppression of PTEN transcription by UVA

PubMed Central

Zhao, Baozhong; Ming, Mei; He, Yu-Ying

2012-01-01

Although UVA has different physical and biological targets than UVB, the contribution of UVA to skin cancer susceptibility and its molecular basis remain largely unknown. Here we show that chronic UVA radiation suppresses PTEN expression at the mRNA level. Subchronic and acute UVA radiation also down-regulated PTEN in normal human epidermal keratinocytes, skin culture and mouse skin. At the molecular level, chronic UVA radiation decreased the transcriptional activity of the PTEN promoter in a methylation-independent manner, while it had no effect on the protein stability or mRNA stability of PTEN. In contrast, we found that UVA-induced activation of the Ras/ERK/AKT and NF-κB pathways plays an important role in UV-induced PTEN down-regulation. Inhibiting ERK or AKT increases PTEN expression. Our findings may provide unique insights into PTEN down-regulation as a critical component of UVA’s molecular impact during keratinocyte transformation. PMID:23129115

Adrenaline rush: the role of adrenergic receptors in stimulant-induced behaviors.

PubMed

Schmidt, Karl T; Weinshenker, David

2014-04-01

Psychostimulants, such as cocaine and amphetamines, act primarily through the monoamine neurotransmitters dopamine (DA), norepinephrine, and serotonin. Although stimulant addiction research has largely focused on DA, medication development efforts targeting the dopaminergic system have thus far been unsuccessful, leading to alternative strategies aimed at abating stimulant abuse. Noradrenergic compounds have shown promise in altering the behavioral effects of stimulants in rodents, nonhuman primates, and humans. In this review, we discuss the contribution of each adrenergic receptor (AR) subtype (α1, α2, and β) to five stimulant-induced behaviors relevant to addiction: locomotor activity, conditioned place preference, anxiety, discrimination, and self-administration. AR manipulation has diverse effects on these behaviors; each subtype profoundly influences outcomes in some paradigms but is inconsequential in others. The functional neuroanatomy and intracellular signaling mechanisms underlying the impact of AR activation/blockade on these behaviors remain largely unknown, presenting a new frontier for research on psychostimulant-AR interactions.

Golgi-localized STELLO proteins regulate the assembly and trafficking of cellulose synthase complexes in Arabidopsis.

PubMed

Zhang, Yi; Nikolovski, Nino; Sorieul, Mathias; Vellosillo, Tamara; McFarlane, Heather E; Dupree, Ray; Kesten, Christopher; Schneider, René; Driemeier, Carlos; Lathe, Rahul; Lampugnani, Edwin; Yu, Xiaolan; Ivakov, Alexander; Doblin, Monika S; Mortimer, Jenny C; Brown, Steven P; Persson, Staffan; Dupree, Paul

2016-06-09

As the most abundant biopolymer on Earth, cellulose is a key structural component of the plant cell wall. Cellulose is produced at the plasma membrane by cellulose synthase (CesA) complexes (CSCs), which are assembled in the endomembrane system and trafficked to the plasma membrane. While several proteins that affect CesA activity have been identified, components that regulate CSC assembly and trafficking remain unknown. Here we show that STELLO1 and 2 are Golgi-localized proteins that can interact with CesAs and control cellulose quantity. In the absence of STELLO function, the spatial distribution within the Golgi, secretion and activity of the CSCs are impaired indicating a central role of the STELLO proteins in CSC assembly. Point mutations in the predicted catalytic domains of the STELLO proteins indicate that they are glycosyltransferases facing the Golgi lumen. Hence, we have uncovered proteins that regulate CSC assembly in the plant Golgi apparatus.

Oriental orchid (Cymbidium floribundum) attracts the Japanese honeybee (Apis cerana japonica) with a mixture of 3-hydroxyoctanoic acid and 10-hydroxy- (E)-2-decenoic acid.

PubMed

Sugahara, Michio; Izutsu, Kazunari; Nishimura, Yasuichiro; Sakamoto, Fumio

2013-02-01

The flower of the oriental orchid Cymbidium floribundum is known to attract the Japanese honeybee Apis cerana japonica. This effect is observed not only in workers but also drones and queens; that is, it attracts even swarming and absconding bees. A mixture of 3-hydroxyoctanoic acid (3-HOAA) and 10-hydroxy-(E)-2-decenoic acid (10-HDA) was identified as the active principles from the orchid flower, whereas these compounds individually have no such activity. Both compounds are also mandibular gland components of worker honeybees with related compounds. This strongly supports the idea that orchid flowers mimic bee secretions, although the ecological consequences of this relationship remain unknown. Because the flower is used to capture swarms, the present identification may contribute to the development of new techniques in traditional beekeeping for Japanese bees as well as A. cerana in Southeast Asia.

Genetic variation in insulin-induced kinase signaling

PubMed Central

Wang, Isabel Xiaorong; Ramrattan, Girish; Cheung, Vivian G

2015-01-01

Individual differences in sensitivity to insulin contribute to disease susceptibility including diabetes and metabolic syndrome. Cellular responses to insulin are well studied. However, which steps in these response pathways differ across individuals remains largely unknown. Such knowledge is needed to guide more precise therapeutic interventions. Here, we studied insulin response and found extensive individual variation in the activation of key signaling factors, including ERK whose induction differs by more than 20-fold among our subjects. This variation in kinase activity is propagated to differences in downstream gene expression response to insulin. By genetic analysis, we identified cis-acting DNA variants that influence signaling response, which in turn affects downstream changes in gene expression and cellular phenotypes, such as protein translation and cell proliferation. These findings show that polymorphic differences in signal transduction contribute to individual variation in insulin response, and suggest kinase modulators as promising therapeutics for diseases characterized by insulin resistance. PMID:26202599

Immunohistochemical Evaluation of AKT Protein Activation in Canine Mast Cell Tumours

PubMed Central

Rodriguez, S.; Fadlalla, K.; Graham, T.; Tameru, B.; Fermin, C. D.; Samuel, T.

2011-01-01

Summary The pathogenesis of canine mast cell tumour (MCT) remains unknown. Moreover, therapeutic options are limited and resistance to targeted drugs and recurrences are common, necessitating the identification of additional cellular targets for therapy. In this study we investigated the expression of phosphorylated AKT protein in 25 archival canine MCT samples by immunohistochemistry and examined the correlation between the immunohistochemical scores and histopathological tumour grades. AKT protein was detected in all of the samples and 24 of the 25 samples expressed the phosphorylated form of the protein, albeit with variable intensity. However, when the immunohistochemical scores of weak, intermediate and strong labelling were compared with the histopathological grades of I to III, there was no strong correlation. This study suggests that canine MCT cells have activated AKT and indicates the need for further research on the role of the AKT protein and the possibility of targeting the AKT signalling pathway in MCTs. PMID:22289273

BDNF-TrkB signaling through Erk1/2MAPK phosphorylation mediates the enhancement of fear memory induced by glucocorticoids

PubMed Central

Revest, J-M; Le Roux, A; Roullot-Lacarrière, V; Kaouane, N; Vallée, M; Kasanetz, F; Rougé-Pont, F; Tronche, F; Desmedt, A; Piazza, P V

2014-01-01

Activation of glucocorticoid receptors (GR) by glucocorticoid hormones (GC) enhances contextual fear memories through the activation of the Erk1/2MAPK signaling pathway. However, the molecular mechanism mediating this effect of GC remains unknown. Here we used complementary molecular and behavioral approaches in mice and rats and in genetically modified mice in which the GR was conditionally deleted (GRNesCre). We identified the tPA-BDNF-TrkB signaling pathway as the upstream molecular effectors of GR-mediated phosphorylation of Erk1/2MAPK responsible for the enhancement of contextual fear memory. These findings complete our knowledge of the molecular cascade through which GC enhance contextual fear memory and highlight the role of tPA-BDNF-TrkB-Erk1/2MAPK signaling pathways as one of the core effectors of stress-related effects of GC. PMID:24126929

Neural representations of close others in collectivistic brains

PubMed Central

Wang, Gang; Mao, Lihua; Ma, Yina; Yang, Xuedong; Cao, Jingqian; Liu, Xi; Wang, Jinzhao; Wang, Xiaoying

2012-01-01

Our recent work showed that close relationships result in shared cognitive and neural representations of the self and one’s mother in collectivistic individuals (Zhu et al., 2007, Neuroimage, 34, 1310–7). However, it remains unknown whether close others, such as mother, father and best friend, are differentially represented in collectivistic brains. Here, using functional magnetic resonance imaging and a trait judgment task, we showed evidence that, while trait judgments of the self and mother generated comparable activity in the medial prefrontal cortex (MPFC) and anterior cingulate (ACC) of Chinese adults, trait judgments of mother induced greater MPFC/ACC activity than trait judgments of father and best friend. Our results suggest that, while neural representations of the self and mother overlapped in the MPFC/ACC, close others such as mother, father and best friend are unequally represented in the MPFC/ACC of collectivistic brains. PMID:21382966

In Vivo Characterization of an AHR-Dependent Long Noncoding RNA Required for Proper Sox9b Expression

PubMed Central

Garcia, Gloria R.; Goodale, Britton C.; Wiley, Michelle W.; La Du, Jane K.; Hendrix, David A.

2017-01-01

Xenobiotic activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prevents the proper formation of craniofacial cartilage and the heart in developing zebrafish. Downstream molecular targets responsible for AHR-dependent adverse effects remain largely unknown; however, in zebrafish sox9b has been identified as one of the most-reduced transcripts in several target organs and is hypothesized to have a causal role in TCDD-induced toxicity. The reduction of sox9b expression in TCDD-exposed zebrafish embryos has been shown to contribute to heart and jaw malformation phenotypes. The mechanisms by which AHR2 (functional ortholog of mammalian AHR) activation leads to reduced sox9b expression levels and subsequent target organ toxicity are unknown. We have identified a novel long noncoding RNA (slincR) that is upregulated by strong AHR ligands and is located adjacent to the sox9b gene. We hypothesize that slincR is regulated by AHR2 and transcriptionally represses sox9b. The slincR transcript functions as an RNA macromolecule, and slincR expression is AHR2 dependent. Antisense knockdown of slincR results in an increase in sox9b expression during both normal development and AHR2 activation, which suggests relief in repression. During development, slincR was expressed in tissues with sox9 essential functions, including the jaw/snout region, otic vesicle, eye, and brain. Reducing the levels of slincR resulted in altered neurologic and/or locomotor behavioral responses. Our results place slincR as an intermediate between AHR2 activation and the reduction of sox9b mRNA in the AHR2 signaling pathway. PMID:28385905

In Vivo Characterization of an AHR-Dependent Long Noncoding RNA Required for Proper Sox9b Expression.

PubMed

Garcia, Gloria R; Goodale, Britton C; Wiley, Michelle W; La Du, Jane K; Hendrix, David A; Tanguay, Robert L

2017-06-01

Xenobiotic activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) prevents the proper formation of craniofacial cartilage and the heart in developing zebrafish. Downstream molecular targets responsible for AHR-dependent adverse effects remain largely unknown; however, in zebrafish sox9b has been identified as one of the most-reduced transcripts in several target organs and is hypothesized to have a causal role in TCDD-induced toxicity. The reduction of sox9b expression in TCDD-exposed zebrafish embryos has been shown to contribute to heart and jaw malformation phenotypes. The mechanisms by which AHR2 (functional ortholog of mammalian AHR) activation leads to reduced sox9b expression levels and subsequent target organ toxicity are unknown. We have identified a novel long noncoding RNA ( slincR ) that is upregulated by strong AHR ligands and is located adjacent to the sox9b gene. We hypothesize that slincR is regulated by AHR2 and transcriptionally represses sox9b. The slincR transcript functions as an RNA macromolecule, and slincR expression is AHR2 dependent. Antisense knockdown of slincR results in an increase in sox9b expression during both normal development and AHR2 activation, which suggests relief in repression. During development, slincR was expressed in tissues with sox9 essential functions, including the jaw/snout region, otic vesicle, eye, and brain. Reducing the levels of slincR resulted in altered neurologic and/or locomotor behavioral responses. Our results place slincR as an intermediate between AHR2 activation and the reduction of sox9b mRNA in the AHR2 signaling pathway. Copyright © 2017 by The Author(s).

HIV status differences in venues where highly sexually active gay and bisexual men meet sex partners: results from a pilot study.

PubMed

Grov, Christian; Golub, Sarit A; Parsons, Jeffrey T

2010-12-01

Highly sexually active men who have sex with men (MSM) are a critical population in which to provide HIV prevention and education. To inform the tailoring and placement of such services, this study reports on HIV status differences in nine venues where 50 highly sexually active MSM (defined as those who had nine or more male partners in the past 90 days) met recent male sex partners. HIV-positive men (95%) were significantly more likely than HIV-negative/unknown status men (68%) to have used the Internet to meet partners but were less likely to meet partners in bars/clubs (37% vs. 71%). Although both HIV-positive and HIV-negative/unknown status men reported a sizable portion of their total partners from the Internet (55% and 29%, respectively), HIV-positive MSM also gravitated toward meeting partners through sexual networks (private sex parties and via other sex partners), whereas HIV-negative/unknown status also gravitated toward gay bars/clubs and public cruising. Overall, HIV-positive men were more likely to report unprotected anal sex than to HIV-negative/unknown status men. Among HIV-negative/unknown status men, the highest rates of unprotected sex were with men they met online (20% of online partners) and through other sex partners (25% of these partners). Efforts targeted toward highly sexually active HIV-negative/unknown status men might be best positioned online and in gay bars/clubs, whereas those tailored for highly sexually active HIV-positive men may consider targeting the Internet and peers/sexual networks.

Discovering the infectome of human endothelial cells challenged with Aspergillus fumigatus applying a mass spectrometry label-free approach.

PubMed

Curty, N; Kubitschek-Barreira, P H; Neves, G W; Gomes, D; Pizzatti, L; Abdelhay, E; Souza, G H M F; Lopes-Bezerra, L M

2014-01-31

Blood vessel invasion is a key feature of invasive aspergillosis. This angioinvasion process contributes to tissue thrombosis, which can impair the access of leukocytes and antifungal drugs to the site of infection. It has been demonstrated that human umbilical vein endothelial cells (HUVECs) are activated and assume a prothrombotic phenotype following contact with Aspergillus fumigatus hyphae or germlings, a process that is independent of fungus viability. However, the molecular mechanisms by which this pathogen can activate endothelial cells, together with the endothelial pathways that are involved in this process, remain unknown. Using a label-free approach by High Definition Mass Spectrometry (HDMS(E)), differentially expressed proteins were identified during HUVEC-A. fumigatus interaction. Among these, 89 proteins were determined to be up- or down-regulated, and another 409 proteins were exclusive to one experimental condition: the HUVEC control or HUVEC:AF interaction. The in silico predictions provided a general view of which biological processes and/or pathways were regulated during HUVEC:AF interaction, and they mainly included cell signaling, immune response and hemostasis pathways. This work describes the first global proteomic analysis of HUVECs following interaction with A. fumigatus germlings, the fungus morphotype that represents the first step of invasion and dissemination within the host. A. fumigatus causes the main opportunistic invasive fungal infection related to neutropenic hematologic patients. One of the key steps during the establishment of invasive aspergillosis is angioinvasion but the mechanism associated with the interaction of A. fumigatus with the vascular endothelium remains unknown. The identification of up- and down-regulated proteins expressed by human endothelial cells in response to the fungus infection can contribute to reveal the mechanism of endothelial response and, to understand the physiopathology of this high mortality disease. This article is part of a Special Issue entitled: Trends in Microbial Proteomics. © 2013 Elsevier B.V. All rights reserved.

Residual limb skin temperature and thermal comfort in people with amputation during activity in a cold environment.

PubMed

Segal, Ava D; Klute, Glenn K

2016-01-01

Thermal comfort remains a common problem for people with lower-limb amputation. Both donning a prosthesis and engaging in activity at room temperature can increase residual limb skin temperature; however, the effects of activity on skin temperature and comfort in more extreme environments remain unknown. We examined residual limb skin temperatures and perceived thermal comfort (PTC; 11-point Likert scale) of participants with unilateral transtibial amputation (n = 8) who were snowshoeing in a cold environment. Residual limb skin temperature increased by 3.9°C [3.0°C to 4.7°C] (mean difference [95% confidence interval (CI)], p < 0.001) after two 30 min exercise sessions separated by a 5 min rest session. Minimal cooling (-0.2°C [-1.1°C to 0.6°C]) occurred during the rest period. Similar changes in PTC were found for the residual limb, intact limb, and whole body, with a mean scale increase of 1.6 [1.1 to 2.1] and 1.3 [0.8 to 1.8] for the first and second exercise sessions, respectively (p < 0.001). Activity in a cold environment caused similar increases in residual limb skin temperature as those found in studies conducted at room temperature. Participants with amputation perceived warming as their skin temperature increased during exercise followed by the perception of cooling during rest, despite minimal associated decreases in skin temperature.

Nitroxyl Improves Cellular Heart Function by Directly Enhancing Cardiac Sarcoplasmic Reticulum Ca2+ Cycling

PubMed Central

Tocchetti, Carlo G.; Wang, Wang; Froehlich, Jeffrey P.; Huke, Sabine; Aon, Miguel A.; Wilson, Gerald M.; Benedetto, Giulietta Di; O’Rourke, Brian; Gao, Wei Dong; Wink, David A.; Toscano, John P.; Zaccolo, Manuela; Bers, Donald M.; Valdivia, Hector H.; Cheng, Heping; Kass, David A.; Paolocci, Nazareno

2009-01-01

Heart failure remains a leading cause of morbidity and mortality worldwide. Although depressed pump function is common, development of effective therapies to stimulate contraction has proven difficult. This is thought to be attributable to their frequent reliance on cAMP stimulation to increase activator Ca2+. A potential alternative is nitroxyl (HNO), the 1-electron reduction product of nitric oxide (NO) that improves contraction and relaxation in normal and failing hearts in vivo. The mechanism for myocyte effects remains unknown. Here, we show that this activity results from a direct interaction of HNO with the sarcoplasmic reticulum Ca2+ pump and the ryanodine receptor 2, leading to increased Ca2+ uptake and release from the sarcoplasmic reticulum. HNO increases the open probability of isolated ryanodine-sensitive Ca2+-release channels and accelerates Ca2+ reuptake into isolated sarcoplasmic reticulum by stimulating ATP-dependent Ca2+ transport. Contraction improves with no net rise in diastolic calcium. These changes are not induced by NO, are fully reversible by addition of reducing agents (redox sensitive), and independent of both cAMP/protein kinase A and cGMP/protein kinase G signaling. Rather, the data support HNO/thiolate interactions that enhance the activity of intracellular Ca2+ cycling proteins. These findings suggest HNO donors are attractive candidates for the pharmacological treatment of heart failure. PMID:17138943

What kind of noise is brain noise: anomalous scaling behavior of the resting brain activity fluctuations

PubMed Central

Fraiman, Daniel; Chialvo, Dante R.

2012-01-01

The study of spontaneous fluctuations of brain activity, often referred as brain noise, is getting increasing attention in functional magnetic resonance imaging (fMRI) studies. Despite important efforts, much of the statistical properties of such fluctuations remain largely unknown. This work scrutinizes these fluctuations looking at specific statistical properties which are relevant to clarify its dynamical origins. Here, three statistical features which clearly differentiate brain data from naive expectations for random processes are uncovered: First, the variance of the fMRI mean signal as a function of the number of averaged voxels remains constant across a wide range of observed clusters sizes. Second, the anomalous behavior of the variance is originated by bursts of synchronized activity across regions, regardless of their widely different sizes. Finally, the correlation length (i.e., the length at which the correlation strength between two regions vanishes) as well as mutual information diverges with the cluster's size considered, such that arbitrarily large clusters exhibit the same collective dynamics than smaller ones. These three properties are known to be exclusive of complex systems exhibiting critical dynamics, where the spatio-temporal dynamics show these peculiar type of fluctuations. Thus, these findings are fully consistent with previous reports of brain critical dynamics, and are relevant for the interpretation of the role of fluctuations and variability in brain function in health and disease. PMID:22934058

Fgf receptor 3 activation promotes selective growth and expansion of occipitotemporal cortex

PubMed Central

Thomson, Rachel E; Kind, Peter C; Graham, Nicholas A; Etherson, Michelle L; Kennedy, John; Fernandes, Ana C; Marques, Catia S; Hevner, Robert F; Iwata, Tomoko

2009-01-01

Background Fibroblast growth factors (Fgfs) are important regulators of cerebral cortex development. Fgf2, Fgf8 and Fgf17 promote growth and specification of rostromedial (frontoparietal) cortical areas. Recently, the function of Fgf15 in antagonizing Fgf8 in the rostral signaling center was also reported. However, regulation of caudal area formation by Fgf signaling remains unknown. Results In mutant mice with constitutive activation of Fgf receptor 3 (Fgfr3) in the forebrain, surface area of the caudolateral cortex was markedly expanded at early postnatal stage, while rostromedial surface area remained normal. Cortical thickness was also increased in caudal regions. The expression domain and levels of Fgf8, as well as overall patterning, were unchanged. In contrast, the changes in caudolateral surface area were associated with accelerated cell cycle in early stages of neurogenesis without an alteration of cell cycle exit. Moreover, a marked overproduction of intermediate neuronal progenitors was observed in later stages, indicating prolongation of neurogenesis. Conclusion Activation of Fgfr3 selectively promotes growth of caudolateral (occipitotemporal) cortex. These observations support the 'radial unit' and 'radial amplification' hypotheses and may explain premature sulcation of the occipitotemporal cortex in thanatophoric dysplasia, a human FGFR3 disorder. Together with previous work, this study suggests that formation of rostral and caudal areas are differentially regulated by Fgf signaling in the cerebral cortex. PMID:19192266

Metagenomic ventures into outer sequence space.

PubMed

Dutilh, Bas E

Sequencing DNA or RNA directly from the environment often results in many sequencing reads that have no homologs in the database. These are referred to as "unknowns," and reflect the vast unexplored microbial sequence space of our biosphere, also known as "biological dark matter." However, unknowns also exist because metagenomic datasets are not optimally mined. There is a pressure on researchers to publish and move on, and the unknown sequences are often left for what they are, and conclusions drawn based on reads with annotated homologs. This can cause abundant and widespread genomes to be overlooked, such as the recently discovered human gut bacteriophage crAssphage. The unknowns may be enriched for bacteriophage sequences, the most abundant and genetically diverse component of the biosphere and of sequence space. However, it remains an open question, what is the actual size of biological sequence space? The de novo assembly of shotgun metagenomes is the most powerful tool to address this question.

Known knowns, known unknowns and unknown unknowns in prokaryotic transposition.

PubMed

Siguier, Patricia; Gourbeyre, Edith; Chandler, Michael

2017-08-01

Although the phenomenon of transposition has been known for over 60 years, its overarching importance in modifying and streamlining genomes took some time to recognize. In spite of a robust understanding of transposition of some TE, there remain a number of important TE groups with potential high genome impact and unknown transposition mechanisms and yet others, only recently identified by bioinformatics, yet to be formally confirmed as mobile. Here, we point to some areas of limited understanding concerning well established important TE groups with DDE Tpases, to address central gaps in our knowledge of characterised Tn with other types of Tpases and finally, to highlight new potentially mobile DNA species. It is not exhaustive. Examples have been chosen to provide encouragement in the continued exploration of the considerable prokaryotic mobilome especially in light of the current threat to public health posed by the spread of multiple Ab R . Copyright © 2017 Elsevier Ltd. All rights reserved.

The effects of rod and cone loss on the photic regulation of locomotor activity and heart rate.

PubMed

Thompson, Stewart; Lupi, Daniela; Hankins, Mark W; Peirson, Stuart N; Foster, Russell G

2008-08-01

Behavioral responses to light indirectly affect cardiovascular output, but in anesthetized rodents a direct effect of light on heart rate has also been described. Both the basis for this response and the contribution of rods, cones and melanopsin-based photosensitive retinal ganglion cells (pRGCs) remains unknown. To understand how light acutely regulates heart rate we studied responses to light in mice lacking all rod and cone photoreceptors (rd/rd cl ) along with wild-type controls. Our initial experiments delivered light to anesthetized mice at Zeitgeber time (ZT)16 (4 h after lights off, mid-activity phase) and produced an increase in heart rate in wild-type mice, but not in rd/rd cl animals. By contrast, parallel experiments in freely-moving mice demonstrated that light exposure at this time suppressed heart rate and activity in both genotypes. Because of the effects of anesthesia, all subsequent studies were conducted in freely-moving animals. The effects of light were also assessed at ZT6 (mid-rest phase). At this timepoint, wild-type mice showed an irradiance-dependent increase in heart rate and activity. By contrast, rd/rd cl mice failed to show any modulation of heart rate or activity, even at very high irradiances. Increases in heart rate preceded increases in locomotor activity and remained elevated when locomotor activity ceased, suggesting that these two responses are at least partially uncoupled. Collectively, our results show an acute and phase-dependent effect of light on cardiovascular output in mice. Surprisingly, this irradiance detection response is dependent upon rod and cone photoreceptors, with no apparent contribution from melanopsin pRGCs.

Pharmacogenetic stimulation of cholinergic pedunculopontine neurons reverses motor deficits in a rat model of Parkinson's disease.

PubMed

Pienaar, Ilse S; Gartside, Sarah E; Sharma, Puneet; De Paola, Vincenzo; Gretenkord, Sabine; Withers, Dominic; Elson, Joanna L; Dexter, David T

2015-09-23

Patients with advanced Parkinson's disease (PD) often present with axial symptoms, including postural- and gait difficulties that respond poorly to dopaminergic agents. Although deep brain stimulation (DBS) of a highly heterogeneous brain structure, the pedunculopontine nucleus (PPN), improves such symptoms, the underlying neuronal substrate responsible for the clinical benefits remains largely unknown, thus hampering optimization of DBS interventions. Choline acetyltransferase (ChAT)::Cre(+) transgenic rats were sham-lesioned or rendered parkinsonian through intranigral, unihemispheric stereotaxic administration of the ubiquitin-proteasomal system inhibitor, lactacystin, combined with designer receptors exclusively activated by designer drugs (DREADD), to activate the cholinergic neurons of the nucleus tegmenti pedunculopontine (PPTg), the rat equivalent of the human PPN. We have previously shown that the lactacystin rat model accurately reflects aspects of PD, including a partial loss of PPTg cholinergic neurons, similar to what is seen in the post-mortem brains of advanced PD patients. In this manuscript, we show that transient activation of the remaining PPTg cholinergic neurons in the lactacystin rat model of PD, via peripheral administration of the cognate DREADD ligand, clozapine-N-oxide (CNO), dramatically improved motor symptoms, as was assessed by behavioral tests that measured postural instability, gait, sensorimotor integration, forelimb akinesia and general motor activity. In vivo electrophysiological recordings revealed increased spiking activity of PPTg putative cholinergic neurons during CNO-induced activation. c-Fos expression in DREADD overexpressed ChAT-immunopositive (ChAT+) neurons of the PPTg was also increased by CNO administration, consistent with upregulated neuronal activation in this defined neuronal population. Overall, these findings provide evidence that functional modulation of PPN cholinergic neurons alleviates parkinsonian motor symptoms.

Distinctive Recruitment of Endogenous Sleep-Promoting Neurons by Volatile Anesthetics and a Non-immobilizer

PubMed Central

Han, Bo; McCarren, Hilary S.; O'Neill, Dan; Kelz, Max B.

2014-01-01

BACKGROUND Numerous studies demonstrate that anesthetic-induced unconsciousness is accompanied by activation of hypothalamic sleep-promoting neurons, which occurs through both pre- and postsynaptic mechanisms. However, the correlation between drug exposure, neuronal activation, and onset of hypnosis remains incompletely understood. Moreover, the degree to which anesthetics activate both endogenous populations of GABAergic sleep-promoting neurons within the ventrolateral preoptic (VLPO) and median preoptic (MnPO) nuclei remains unknown. METHODS Mice were exposed to oxygen, hypnotic doses of isoflurane or halothane, or 1,2-dicholorhexafluorocyclobutane (F6), a nonimmobilizer. Hypothalamic brain slices prepared from anesthetic-naïve mice were also exposed to oxygen, volatile anesthetics, or F6 ex vivo, both in the presence and absence of tetrodotoxin. Double-label immunohistochemistry was performed to quantify the number of c-Fos-immunoreactive nuclei in the GABAergic subpopulation of neurons in the VLPO and the MnPO to test the hypothesis that volatile anesthetics, but not non-immobilizers, activate sleep-promoting neurons in both nuclei. RESULTS In vivo exposure to isoflurane and halothane doubled the fraction of active, c-Fos-expressing GABAergic neurons in the VLPO, while F6 failed to affect VLPO c-Fos expression. Both in the presence and absence of tetrodotoxin, isoflurane dose-dependently increased c-Fos expression in GABAergic neurons ex vivo, while F6 failed to alter expression. In GABAergic neurons of the MnPO, c-Fos expression increased with isoflurane and F6, but not with halothane exposure. CONCLUSIONS Anesthetic unconsciousness is not accompanied by global activation of all putative sleep-promoting neurons. However, within the VLPO hypnotic doses of volatile anesthetics, but not non-immobilizers, activate putative sleep-promoting neurons, correlating with the appearance of the hypnotic state. PMID:25057841

Active vibration control for piezoelectricity cantilever beam: an adaptive feedforward control method

NASA Astrophysics Data System (ADS)

Zhu, Qiao; Yue, Jun-Zhou; Liu, Wei-Qun; Wang, Xu-Dong; Chen, Jun; Hu, Guang-Di

2017-04-01

This work is focused on the active vibration control of piezoelectric cantilever beam, where an adaptive feedforward controller (AFC) is utilized to reject the vibration with unknown multiple frequencies. First, the experiment setup and its mathematical model are introduced. Due to that the channel between the disturbance and the vibration output is unknown in practice, a concept of equivalent input disturbance (EID) is employed to put an equivalent disturbance into the input channel. In this situation, the vibration control can be achieved by setting the control input be the identified EID. Then, for the EID with known multiple frequencies, the AFC is introduced to perfectly reject the vibration but is sensitive to the frequencies. In order to accurately identify the unknown frequencies of EID in presence of the random disturbances and un-modeled nonlinear dynamics, the time-frequency-analysis (TFA) method is employed to precisely identify the unknown frequencies. Consequently, a TFA-based AFC algorithm is proposed to the active vibration control with unknown frequencies. Finally, four cases are given to illustrate the efficiency of the proposed TFA-based AFC algorithm by experiment.

Trpv4 Mediates Hypotonic Inhibition of Central Osmosensory Neurons via Taurine Gliotransmission.

PubMed

Ciura, Sorana; Prager-Khoutorsky, Masha; Thirouin, Zahra S; Wyrosdic, Joshua C; Olson, James E; Liedtke, Wolfgang; Bourque, Charles W

2018-05-22

The maintenance of hydromineral homeostasis requires bidirectional detection of changes in extracellular fluid osmolality by primary osmosensory neurons (ONs) in the organum vasculosum laminae terminalis (OVLT). Hypertonicity excites ONs in part through the mechanical activation of a variant transient receptor potential vanilloid-1 channel (dn-Trpv1). However, the mechanism by which local hypotonicity inhibits ONs in the OVLT remains unknown. Here, we show that hypotonicity can reduce the basal activity of dn-Trpv1 channels and hyperpolarize acutely isolated ONs. Surprisingly, we found that mice lacking dn-Trpv1 maintain normal inhibitory responses to hypotonicity when tested in situ. In the intact setting, hypotonicity inhibits ONs through a non-cell-autonomous mechanism that involves glial release of the glycine receptor agonist taurine through hypotonicity activated anion channels (HAAC) that are activated subsequent to Ca 2+ influx through Trpv4 channels. Our study clarifies how Trpv4 channels contribute to the inhibition of OVLT ONs during hypotonicity in situ. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Attenuation of T cell receptor signaling by serine phosphorylation-mediated lysine 30 ubiquitination of SLP-76 protein.

PubMed

Wang, Xiaohong; Li, Ju-Pi; Chiu, Li-Li; Lan, Joung-Liang; Chen, Der-Yuan; Boomer, Jonathan; Tan, Tse-Hua

2012-10-05

SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa) is an adaptor protein that is essential for T cell development and T cell receptor (TCR) signaling activation. Previous studies have identified an important negative feedback regulation of SLP-76 by HPK1 (hematopoietic progenitor kinase 1; MAP4K1)-induced Ser-376 phosphorylation. Ser-376 phosphorylation of SLP-76 mediates 14-3-3 binding, resulting in the attenuation of SLP-76 activation and downstream signaling; however, the underlying mechanism of this action remains unknown. Here, we report that phosphorylated SLP-76 is ubiquitinated and targeted for proteasomal degradation during TCR signaling. SLP-76 ubiquitination is mediated by Ser-376 phosphorylation. Furthermore, Lys-30 is identified as a ubiquitination site of SLP-76. Loss of Lys-30 ubiquitination of SLP-76 results in enhanced anti-CD3 antibody-induced ERK and JNK activation. These results reveal a novel regulation mechanism of SLP-76 by ubiquitination and proteasomal degradation of activated SLP-76, which is mediated by Ser-376 phosphorylation, leading to down-regulation of TCR signaling.

Attenuation of T Cell Receptor Signaling by Serine Phosphorylation-mediated Lysine 30 Ubiquitination of SLP-76 Protein*

PubMed Central

Wang, Xiaohong; Li, Ju-Pi; Chiu, Li-Li; Lan, Joung-Liang; Chen, Der-Yuan; Boomer, Jonathan; Tan, Tse-Hua

2012-01-01

SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa) is an adaptor protein that is essential for T cell development and T cell receptor (TCR) signaling activation. Previous studies have identified an important negative feedback regulation of SLP-76 by HPK1 (hematopoietic progenitor kinase 1; MAP4K1)-induced Ser-376 phosphorylation. Ser-376 phosphorylation of SLP-76 mediates 14-3-3 binding, resulting in the attenuation of SLP-76 activation and downstream signaling; however, the underlying mechanism of this action remains unknown. Here, we report that phosphorylated SLP-76 is ubiquitinated and targeted for proteasomal degradation during TCR signaling. SLP-76 ubiquitination is mediated by Ser-376 phosphorylation. Furthermore, Lys-30 is identified as a ubiquitination site of SLP-76. Loss of Lys-30 ubiquitination of SLP-76 results in enhanced anti-CD3 antibody-induced ERK and JNK activation. These results reveal a novel regulation mechanism of SLP-76 by ubiquitination and proteasomal degradation of activated SLP-76, which is mediated by Ser-376 phosphorylation, leading to down-regulation of TCR signaling. PMID:22902619

Antitussive arabinogalactan of Andrographis paniculata demonstrates synergistic effect with andrographolide.

PubMed

Nosáľová, Gabriela; Majee, Sujay Kumar; Ghosh, Kanika; Raja, Washim; Chatterjee, Udipta Ranjan; Jureček, Ludovít; Ray, Bimalendu

2014-08-01

Traditional Indian medicines have been used in humans for thousands of years. While the link to a particular indication has been established in man, the active principle of the formulations often remains unknown. In this study, we aim to investigate the structural features and antitussive activity of fractions from Andrographis paniculata leaves. In vivo investigations of water extract (WE), and both ethanol-soluble (WES) and precipitated (WEP) fractions from WE on the citric-acid induced cough efforts and airways smooth muscle reactivity in guinea pigs were performed. Chemical, chromatographic and spectroscopic analysis revealed the existence of a highly branched pectic arabinogalactan (109kDa) in WEP and andrographolide in WES. WEP showed significant antitussive activity while the potencies of WE and WES are even higher. Neither WE nor WES significantly alter specific airway smooth muscle reactivity. Remarkably, the antitussive activity of arabinogalactan could be increased by synergistic action with andrographolide. Finally, traditional aqueous extraction method provides an arabinogalactan from A. paniculata, which stimulate biological response but without addiction. Copyright © 2014 Elsevier B.V. All rights reserved.

Common resting brain dynamics indicate a possible mechanism underlying zolpidem response in severe brain injury

PubMed Central

Williams, Shawniqua T; Conte, Mary M; Goldfine, Andrew M; Noirhomme, Quentin; Gosseries, Olivia; Thonnard, Marie; Beattie, Bradley; Hersh, Jennifer; Katz, Douglas I; Victor, Jonathan D; Laureys, Steven; Schiff, Nicholas D

2013-01-01

Zolpidem produces paradoxical recovery of speech, cognitive and motor functions in select subjects with severe brain injury but underlying mechanisms remain unknown. In three diverse patients with known zolpidem responses we identify a distinctive pattern of EEG dynamics that suggests a mechanistic model. In the absence of zolpidem, all subjects show a strong low frequency oscillatory peak ∼6–10 Hz in the EEG power spectrum most prominent over frontocentral regions and with high coherence (∼0.7–0.8) within and between hemispheres. Zolpidem administration sharply reduces EEG power and coherence at these low frequencies. The ∼6–10 Hz activity is proposed to arise from intrinsic membrane properties of pyramidal neurons that are passively entrained across the cortex by locally-generated spontaneous activity. Activation by zolpidem is proposed to arise from a combination of initial direct drug effects on cortical, striatal, and thalamic populations and further activation of underactive brain regions induced by restoration of cognitively-mediated behaviors. DOI: http://dx.doi.org/10.7554/eLife.01157.001 PMID:24252875

New insights into the molecular characteristics behind the function of Renilla luciferase.

PubMed

Fanaei-Kahrani, Zahra; Ganjalikhany, Mohamad Reza; Rasa, Seyed Mohammad Mahdi; Emamzadeh, Rahman

2018-02-01

Renilla Luciferase (RLuc) is a blue light emitter protein which can be applied as a valuable tool in medical diagnosis. But due to lack of the crystal structure of RLuc-ligand complex, the functional motions and catalytic mechanism of this enzyme remain largely unknown. In the present study, the active site properties and the ligand-receptor interactions of the native RLuc and its red-shifted light emitting variant (Super RLuc 8) were investigated using molecular docking approach, molecular dynamics (MD) analysis, and MM-PBSA method. The detailed analysis of the main clusters led to identifying a lid-like structure and its functional motions. Furthermore, an induced-fit mechanism is proposed where ligand-binding induces conformational changes of the active site. Our findings give an insight into the deeper understanding of RLuc conformational changes during binding steps and ligand-receptor pattern. Moreover, our work broaden our understanding of how active site geometry is adjusted to support the catalytic activity and red-shifted light emission in Super RLuc 8. © 2017 Wiley Periodicals, Inc.

Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo

PubMed Central

Galbo, Thomas; Perry, Rachel J.; Jurczak, Michael J.; Camporez‎, João-Paulo G.; Alves, Tiago C.; Kahn, Mario; Guigni, Blas A.; Serr, Julie; Zhang, Dongyan; Bhanot, Sanjay; Samuel, Varman T.; Shulman, Gerald I.

2013-01-01

Hepatic insulin resistance is a principal component of type 2 diabetes, but the cellular and molecular mechanisms responsible for its pathogenesis remain unknown. Recent studies have suggested that saturated fatty acids induce hepatic insulin resistance through activation of the toll-like receptor 4 (TLR-4) receptor in the liver, which in turn transcriptionally activates hepatic ceramide synthesis leading to inhibition of insulin signaling. In this study, we demonstrate that TLR-4 receptor signaling is not directly required for saturated or unsaturated fat-induced hepatic insulin resistance in both TLR-4 antisense oligonucleotide treated and TLR-4 knockout mice, and that ceramide accumulation is not dependent on TLR-4 signaling or a primary event in hepatic steatosis and impairment of insulin signaling. Further, we show that both saturated and unsaturated fats lead to hepatic accumulation of diacylglycerols, activation of PKCε, and impairment of insulin-stimulated IRS-2 signaling. These data demonstrate that saturated fat-induced insulin resistance is independent of TLR-4 activation and ceramides. PMID:23840067

Piezo1 in Smooth Muscle Cells Is Involved in Hypertension-Dependent Arterial Remodeling.

PubMed

Retailleau, Kevin; Duprat, Fabrice; Arhatte, Malika; Ranade, Sanjeev Sumant; Peyronnet, Rémi; Martins, Joana Raquel; Jodar, Martine; Moro, Céline; Offermanns, Stefan; Feng, Yuanyi; Demolombe, Sophie; Patel, Amanda; Honoré, Eric

2015-11-10

The mechanically activated non-selective cation channel Piezo1 is a determinant of vascular architecture during early development. Piezo1-deficient embryos die at midgestation with disorganized blood vessels. However, the role of stretch-activated ion channels (SACs) in arterial smooth muscle cells in the adult remains unknown. Here, we show that Piezo1 is highly expressed in myocytes of small-diameter arteries and that smooth-muscle-specific Piezo1 deletion fully impairs SAC activity. While Piezo1 is dispensable for the arterial myogenic tone, it is involved in the structural remodeling of small arteries. Increased Piezo1 opening has a trophic effect on resistance arteries, influencing both diameter and wall thickness in hypertension. Piezo1 mediates a rise in cytosolic calcium and stimulates activity of transglutaminases, cross-linking enzymes required for the remodeling of small arteries. In conclusion, we have established the connection between an early mechanosensitive process, involving Piezo1 in smooth muscle cells, and a clinically relevant arterial remodeling. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Mammalian Gcm genes induce Hes5 expression by active DNA demethylation and induce neural stem cells.

PubMed

Hitoshi, Seiji; Ishino, Yugo; Kumar, Akhilesh; Jasmine, Salma; Tanaka, Kenji F; Kondo, Takeshi; Kato, Shigeaki; Hosoya, Toshihiko; Hotta, Yoshiki; Ikenaka, Kazuhiro

2011-07-17

Signaling mediated by Notch receptors is crucial for the development of many organs and the maintenance of various stem cell populations. The activation of Notch signaling is first detectable by the expression of an effector gene, Hes5, in the neuroepithelium of mouse embryos at embryonic day (E) 8.0-8.5, and this activation is indispensable for the generation of neural stem cells. However, the molecular mechanism by which Hes5 expression is initiated in stem-producing cells remains unknown. We found that mammalian Gcm1 and Gcm2 (glial cells missing 1 and 2) are involved in the epigenetic regulation of Hes5 transcription by DNA demethylation independently of DNA replication. Loss of both Gcm genes and subsequent lack of Hes5 upregulation in the neuroepithelium of E7.5-8.5 Gcm1(-/-); Gcm2(-/-) mice resulted in the impaired induction of neural stem cells. Our data suggest that Hes5 expression is serially activated first by Gcms and later by the canonical Notch pathway.

Activity-dependent switch of GABAergic inhibition into glutamatergic excitation in astrocyte-neuron networks

PubMed Central

Perea, Gertrudis; Gómez, Ricardo; Mederos, Sara; Covelo, Ana; Ballesteros, Jesús J; Schlosser, Laura; Hernández-Vivanco, Alicia; Martín-Fernández, Mario; Quintana, Ruth; Rayan, Abdelrahman; Díez, Adolfo; Fuenzalida, Marco; Agarwal, Amit; Bergles, Dwight E; Bettler, Bernhard; Manahan-Vaughan, Denise; Martín, Eduardo D; Kirchhoff, Frank; Araque, Alfonso

2016-01-01

Interneurons are critical for proper neural network function and can activate Ca2+ signaling in astrocytes. However, the impact of the interneuron-astrocyte signaling into neuronal network operation remains unknown. Using the simplest hippocampal Astrocyte-Neuron network, i.e., GABAergic interneuron, pyramidal neuron, single CA3-CA1 glutamatergic synapse, and astrocytes, we found that interneuron-astrocyte signaling dynamically affected excitatory neurotransmission in an activity- and time-dependent manner, and determined the sign (inhibition vs potentiation) of the GABA-mediated effects. While synaptic inhibition was mediated by GABAA receptors, potentiation involved astrocyte GABAB receptors, astrocytic glutamate release, and presynaptic metabotropic glutamate receptors. Using conditional astrocyte-specific GABAB receptor (Gabbr1) knockout mice, we confirmed the glial source of the interneuron-induced potentiation, and demonstrated the involvement of astrocytes in hippocampal theta and gamma oscillations in vivo. Therefore, astrocytes decode interneuron activity and transform inhibitory into excitatory signals, contributing to the emergence of novel network properties resulting from the interneuron-astrocyte interplay. DOI: http://dx.doi.org/10.7554/eLife.20362.001 PMID:28012274

Protective Effects of Ferulic Acid on High Glucose-Induced Protein Glycation, Lipid Peroxidation, and Membrane Ion Pump Activity in Human Erythrocytes

PubMed Central

Sompong, Weerachat; Cheng, Henrique; Adisakwattana, Sirichai

2015-01-01

Ferulic acid (FA) is the ubiquitous phytochemical phenolic derivative of cinnamic acid. Experimental studies in diabetic models demonstrate that FA possesses multiple mechanisms of action associated with anti-hyperglycemic activity. The mechanism by which FA prevents diabetes-associated vascular damages remains unknown. The aim of study was to investigate the protective effects of FA on protein glycation, lipid peroxidation, membrane ion pump activity, and phosphatidylserine exposure in high glucose-exposed human erythrocytes. Our results demonstrated that FA (10-100 μM) significantly reduced the levels of glycated hemoglobin (HbA1c) whereas 0.1-100 μM concentrations inhibited lipid peroxidation in erythrocytes exposed to 45 mM glucose. This was associated with increased glucose consumption. High glucose treatment also caused a significant reduction in Na+/K+-ATPase activity in the erythrocyte plasma membrane which could be reversed by FA. Furthermore, we found that FA (0.1-100 μM) prevented high glucose-induced phosphatidylserine exposure. These findings provide insights into a novel mechanism of FA for the prevention of vascular dysfunction associated with diabetes. PMID:26053739

Uric Acid Induces Renal Inflammation via Activating Tubular NF-κB Signaling Pathway

PubMed Central

Zhou, Yang; Fang, Li; Jiang, Lei; Wen, Ping; Cao, Hongdi; He, Weichun; Dai, Chunsun; Yang, Junwei

2012-01-01

Inflammation is a pathologic feature of hyperuricemia in clinical settings. However, the underlying mechanism remains unknown. Here, infiltration of T cells and macrophages were significantly increased in hyperuricemia mice kidneys. This infiltration of inflammatory cells was accompanied by an up-regulation of TNF-α, MCP-1 and RANTES expression. Further, infiltration was largely located in tubular interstitial spaces, suggesting a role for tubular cells in hyperuricemia-induced inflammation. In cultured tubular epithelial cells (NRK-52E), uric acid, probably transported via urate transporter, induced TNF-α, MCP-1 and RANTES mRNA as well as RANTES protein expression. Culture media of NRK-52E cells incubated with uric acid showed a chemo-attractive ability to recruit macrophage. Moreover uric acid activated NF-κB signaling. The uric acid-induced up-regulation of RANTES was blocked by SN 50, a specific NF-κB inhibitor. Activation of NF-κB signaling was also observed in tubule of hyperuricemia mice. These results suggest that uric acid induces renal inflammation via activation of NF-κB signaling. PMID:22761883

CB1 Cannabinoid Receptors Couple to Focal Adhesion Kinase to Control Insulin Release*

PubMed Central

Malenczyk, Katarzyna; Jazurek, Magdalena; Keimpema, Erik; Silvestri, Cristoforo; Janikiewicz, Justyna; Mackie, Ken; Di Marzo, Vincenzo; Redowicz, Maria J.; Harkany, Tibor; Dobrzyn, Agnieszka

2013-01-01

Endocannabinoid signaling has been implicated in modulating insulin release from β cells of the endocrine pancreas. β Cells express CB1 cannabinoid receptors (CB1Rs), and the enzymatic machinery regulating anandamide and 2-arachidonoylglycerol bioavailability. However, the molecular cascade coupling agonist-induced cannabinoid receptor activation to insulin release remains unknown. By combining molecular pharmacology and genetic tools in INS-1E cells and in vivo, we show that CB1R activation by endocannabinoids (anandamide and 2-arachidonoylglycerol) or synthetic agonists acutely or after prolonged exposure induces insulin hypersecretion. In doing so, CB1Rs recruit Akt/PKB and extracellular signal-regulated kinases 1/2 to phosphorylate focal adhesion kinase (FAK). FAK activation induces the formation of focal adhesion plaques, multimolecular platforms for second-phase insulin release. Inhibition of endocannabinoid synthesis or FAK activity precluded insulin release. We conclude that FAK downstream from CB1Rs mediates endocannabinoid-induced insulin release by allowing cytoskeletal reorganization that is required for the exocytosis of secretory vesicles. These findings suggest a mechanistic link between increased circulating and tissue endocannabinoid levels and hyperinsulinemia in type 2 diabetes. PMID:24089517

Large heterogeneities in comet 67P as revealed by active pits from sinkhole collapse.

PubMed

Vincent, Jean-Baptiste; Bodewits, Dennis; Besse, Sébastien; Sierks, Holger; Barbieri, Cesare; Lamy, Philippe; Rodrigo, Rafael; Koschny, Detlef; Rickman, Hans; Keller, Horst Uwe; Agarwal, Jessica; A'Hearn, Michael F; Auger, Anne-Thérèse; Barucci, M Antonella; Bertaux, Jean-Loup; Bertini, Ivano; Capanna, Claire; Cremonese, Gabriele; Da Deppo, Vania; Davidsson, Björn; Debei, Stefano; De Cecco, Mariolino; El-Maarry, Mohamed Ramy; Ferri, Francesca; Fornasier, Sonia; Fulle, Marco; Gaskell, Robert; Giacomini, Lorenza; Groussin, Olivier; Guilbert-Lepoutre, Aurélie; Gutierrez-Marques, P; Gutiérrez, Pedro J; Güttler, Carsten; Hoekzema, Nick; Höfner, Sebastian; Hviid, Stubbe F; Ip, Wing-Huen; Jorda, Laurent; Knollenberg, Jörg; Kovacs, Gabor; Kramm, Rainer; Kührt, Ekkehard; Küppers, Michael; La Forgia, Fiorangela; Lara, Luisa M; Lazzarin, Monica; Lee, Vicky; Leyrat, Cédric; Lin, Zhong-Yi; Lopez Moreno, Josè J; Lowry, Stephen; Magrin, Sara; Maquet, Lucie; Marchi, Simone; Marzari, Francesco; Massironi, Matteo; Michalik, Harald; Moissl, Richard; Mottola, Stefano; Naletto, Giampiero; Oklay, Nilda; Pajola, Maurizio; Preusker, Frank; Scholten, Frank; Thomas, Nicolas; Toth, Imre; Tubiana, Cecilia

2015-07-02

Pits have been observed on many cometary nuclei mapped by spacecraft. It has been argued that cometary pits are a signature of endogenic activity, rather than impact craters such as those on planetary and asteroid surfaces. Impact experiments and models cannot reproduce the shapes of most of the observed cometary pits, and the predicted collision rates imply that few of the pits are related to impacts. Alternative mechanisms like explosive activity have been suggested, but the driving process remains unknown. Here we report that pits on comet 67P/Churyumov-Gerasimenko are active, and probably created by a sinkhole process, possibly accompanied by outbursts. We argue that after formation, pits expand slowly in diameter, owing to sublimation-driven retreat of the walls. Therefore, pits characterize how eroded the surface is: a fresh cometary surface will have a ragged structure with many pits, while an evolved surface will look smoother. The size and spatial distribution of pits imply that large heterogeneities exist in the physical, structural or compositional properties of the first few hundred metres below the current nucleus surface.

Structural analysis of the role of TPX2 in branching microtubule nucleation

PubMed Central

Thawani, Akanksha

2017-01-01

The mitotic spindle consists of microtubules (MTs), which are nucleated by the γ-tubulin ring complex (γ-TuRC). How the γ-TuRC gets activated at the right time and location remains elusive. Recently, it was uncovered that MTs nucleate from preexisting MTs within the mitotic spindle, which requires the protein TPX2, but the mechanism basis for TPX2 action is unknown. Here, we investigate the role of TPX2 in branching MT nucleation. We establish the domain organization of Xenopus laevis TPX2 and define the minimal TPX2 version that stimulates branching MT nucleation, which we find is unrelated to TPX2’s ability to nucleate MTs in vitro. Several domains of TPX2 contribute to its MT-binding and bundling activities. However, the property necessary for TPX2 to induce branching MT nucleation is contained within newly identified γ-TuRC nucleation activator motifs. Separation-of-function mutations leave the binding of TPX2 to γ-TuRC intact, whereas branching MT nucleation is abolished, suggesting that TPX2 may activate γ-TuRC to promote branching MT nucleation. PMID:28264915

Genetically increased cell-intrinsic excitability enhances neuronal integration into adult brain circuits

PubMed Central

Lin, Chia-Wei; Sim, Shuyin; Ainsworth, Alice; Okada, Masayoshi; Kelsch, Wolfgang; Lois, Carlos

2009-01-01

New neurons are added to the adult brain throughout life, but only half ultimately integrate into existing circuits. Sensory experience is an important regulator of the selection of new neurons but it remains unknown whether experience provides specific patterns of synaptic input, or simply a minimum level of overall membrane depolarization critical for integration. To investigate this issue, we genetically modified intrinsic electrical properties of adult-generated neurons in the mammalian olfactory bulb. First, we observed that suppressing levels of cell-intrinsic neuronal activity via expression of ESKir2.1 potassium channels decreases, whereas enhancing activity via expression of NaChBac sodium channels increases survival of new neurons. Neither of these modulations affects synaptic formation. Furthermore, even when neurons are induced to fire dramatically altered patterns of action potentials, increased levels of cell-intrinsic activity completely blocks cell death triggered by NMDA receptor deletion. These findings demonstrate that overall levels of cell-intrinsic activity govern survival of new neurons and precise firing patterns are not essential for neuronal integration into existing brain circuits. PMID:20152111

The C. elegans PRMT-3 possesses a type III protein arginine methyltransferase activity.

PubMed

Takahashi, Yuta; Daitoku, Hiroaki; Yokoyama, Atsuko; Nakayama, Kimihiro; Kim, Jun-Dal; Fukamizu, Akiyoshi

2011-04-01

Protein arginine methylation is a common post-translational modification in eukaryotes that is catalyzed by a family of the protein arginine methyltransferases (PRMTs). PRMTs are classified into three types: type I and type II add asymmetrically and symmetrically dimethyl groups to arginine, respectively, while type III adds solely monomethyl group to arginine. However, although the enzymatic activity of type I and type II PRMTs have been reported, the substrate specificity and the methylation activity of type III PRMTs still remains unknown. Here, we report the characterization of Caenorhabditis elegans PRMT-2 and PRMT-3, both of which are highly homologous to human PRMT7. We find that these two PRMTs can bind to S-adenosyl methionine (SAM), but only PRMT-3 has methyltransferase activity for histone H2A depending on its SAM-binding domain. Importantly, thin-layer chromatographic analysis demonstrates that PRMT-3 catalyzes the formation of monomethylated, but not dimethylated arginine. Our study thus identifies the first type III PRMT in C. elegans and provides a means to elucidate the physiological significance of arginine monomethylation in multicellular organisms.

RPA activates the XPF-ERCC1 endonuclease to initiate processing of DNA interstrand crosslinks.

PubMed

Abdullah, Ummi B; McGouran, Joanna F; Brolih, Sanja; Ptchelkine, Denis; El-Sagheer, Afaf H; Brown, Tom; McHugh, Peter J

2017-07-14

During replication-coupled DNA interstrand crosslink (ICL) repair, the XPF-ERCC1 endonuclease is required for the incisions that release, or "unhook", ICLs, but the mechanism of ICL unhooking remains largely unknown. Incisions are triggered when the nascent leading strand of a replication fork strikes the ICL Here, we report that while purified XPF-ERCC1 incises simple ICL-containing model replication fork structures, the presence of a nascent leading strand, modelling the effects of replication arrest, inhibits this activity. Strikingly, the addition of the single-stranded DNA (ssDNA)-binding replication protein A (RPA) selectively restores XPF-ERCC1 endonuclease activity on this structure. The 5'-3' exonuclease SNM1A can load from the XPF-ERCC1-RPA-induced incisions and digest past the crosslink to quantitatively complete the unhooking reaction. We postulate that these collaborative activities of XPF-ERCC1, RPA and SNM1A might explain how ICL unhooking is achieved in vivo . © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

Mesoamerican Nephropathy or Global Warming Nephropathy?

PubMed

Roncal-Jimenez, Carlos A; García-Trabanino, Ramon; Wesseling, Catharina; Johnson, Richard J

2016-01-01

An epidemic of chronic kidney disease (CKD) of unknown cause has emerged along the Pacific Coast of Central America. The disease primarily affects men working manually outdoors, and the major group affected is sugarcane workers. The disease presents with an asymptomatic rise in serum creatinine that progresses to end-stage renal disease over several years. Renal biopsies show chronic tubulointerstitial disease. While the cause remains unknown, recent studies suggest that it is driven by recurrent dehydration in the hot climate. Potential mechanisms include the development of hyperosmolarity with the activation of the aldose reductase-fructokinase pathway in the proximal tubule leading to local injury and inflammation, and the possibility that renal injury may be the consequence of repeated uricosuria and urate crystal formation as a consequence of both increased generation and urinary concentration, similar to a chronic tumor lysis syndrome. The epidemic is postulated to be increasing due to the effects of global warming. An epidemic of CKD has led to the death of more than 20,000 lives in Central America. The cause is unknown, but appears to be due to recurrent dehydration. Potential mechanisms for injury are renal damage as a consequence of recurrent hyperosmolarity and/or injury to the tubules from repeated episodes of uricosuria. The epidemic of CKD in Mesoamerica may be due to chronic recurrent dehydration as a consequence of global warming and working conditions. This entity may be one of the first major diseases attributed to climate change and the greenhouse effect. © 2016 S. Karger AG, Basel.

Dual-color STED microscopy reveals a sandwich structure of Bassoon and Piccolo in active zones of adult and aged mice.

PubMed

Nishimune, Hiroshi; Badawi, Yomna; Mori, Shuuichi; Shigemoto, Kazuhiro

2016-06-20

Presynaptic active zones play a pivotal role as synaptic vesicle release sites for synaptic transmission, but the molecular architecture of active zones in mammalian neuromuscular junctions (NMJs) at sub-diffraction limited resolution remains unknown. Bassoon and Piccolo are active zone specific cytosolic proteins essential for active zone assembly in NMJs, ribbon synapses, and brain synapses. These proteins are thought to colocalize and share some functions at active zones. Here, we report an unexpected finding of non-overlapping localization of these two proteins in mouse NMJs revealed using dual-color stimulated emission depletion (STED) super resolution microscopy. Piccolo puncta sandwiched Bassoon puncta and aligned in a Piccolo-Bassoon-Piccolo structure in adult NMJs. P/Q-type voltage-gated calcium channel (VGCC) puncta colocalized with Bassoon puncta. The P/Q-type VGCC and Bassoon protein levels decreased significantly in NMJs from aged mouse. In contrast, the Piccolo levels in NMJs from aged mice were comparable to levels in adult mice. This study revealed the molecular architecture of active zones in mouse NMJs at sub-diffraction limited resolution, and described the selective degeneration mechanism of active zone proteins in NMJs from aged mice. Interestingly, the localization pattern of active zone proteins described herein is similar to active zone structures described using electron microscope tomography.

Conformational Flexibility of a Short Loop near the Active Site of the SARS-3CLpro is Essential to Maintain Catalytic Activity

NASA Astrophysics Data System (ADS)

Li, Chunmei; Teng, Xin; Qi, Yifei; Tang, Bo; Shi, Hailing; Ma, Xiaomin; Lai, Luhua

2016-02-01

The SARS 3C-like proteinase (SARS-3CLpro), which is the main proteinase of the SARS coronavirus, is essential to the virus life cycle. This enzyme has been shown to be active as a dimer in which only one protomer is active. However, it remains unknown how the dimer structure maintains an active monomer conformation. It has been observed that the Ser139-Leu141 loop forms a short 310-helix that disrupts the catalytic machinery in the inactive monomer structure. We have tried to disrupt this helical conformation by mutating L141 to T in the stable inactive monomer G11A/R298A/Q299A. The resulting tetra-mutant G11A/L141T/R298A/Q299A is indeed enzymatically active as a monomer. Molecular dynamics simulations revealed that the L141T mutation disrupts the 310-helix and helps to stabilize the active conformation. The coil-310-helix conformational transition of the Ser139-Leu141 loop serves as an enzyme activity switch. Our study therefore indicates that the dimer structure can stabilize the active conformation but is not a required structure in the evolution of the active enzyme, which can also arise through simple mutations.

Experience-dependent emergence of beta and gamma band oscillations in the primary visual cortex during the critical period

PubMed Central

Chen, Guang; Rasch, Malte J.; Wang, Ran; Zhang, Xiao-hui

2015-01-01

Neural oscillatory activities have been shown to play important roles in neural information processing and the shaping of circuit connections during development. However, it remains unknown whether and how specific neural oscillations emerge during a postnatal critical period (CP), in which neuronal connections are most substantially modified by neural activity and experience. By recording local field potentials (LFPs) and single unit activity in developing primary visual cortex (V1) of head-fixed awake mice, we here demonstrate an emergence of characteristic oscillatory activities during the CP. From the pre-CP to CP, the peak frequency of spontaneous fast oscillatory activities shifts from the beta band (15–35 Hz) to the gamma band (40–70 Hz), accompanied by a decrease of cross-frequency coupling (CFC) and broadband spike-field coherence (SFC). Moreover, visual stimulation induced a large increase of beta-band activity but a reduction of gamma-band activity specifically from the CP onwards. Dark rearing of animals from the birth delayed this emergence of oscillatory activities during the CP, suggesting its dependence on early visual experience. These findings suggest that the characteristic neuronal oscillatory activities emerged specifically during the CP may represent as neural activity trait markers for the experience-dependent maturation of developing visual cortical circuits. PMID:26648548

A chemical perspective on the anthracycline antitumor antibiotics.

PubMed Central

Abdella, B R; Fisher, J

1985-01-01

The anthracycline antitumor antibiotics occupy a central position in the chemotherapeutic control of cancer. They remain, however, antibiotics of the last resort and thus exhibit toxicity both to the neoplasm and to the host organism. As part of the continuing effort to dissociate the molecular processes responsible for these two separate toxicities, attention has been drawn to the intrinsic redox capacity of their tetrahydronapthacenedione aglycone moiety, and to the possible expression of this redox activity against those biomolecules for which anthracyclines have a particular affinity (polynucleotides and membranes). This review is a synopsis of the present trends and thoughts concerning this relationship, written from the point of view of the intrinsic chemical competence of the anthracyclines and their metabolites. While our ignorance is profound--the precise molecular locus of the antitumor expression of the anthracyclines remains unknown--there is now evidence that the relationship of the anthracyclines to the DNA (possibly requiring enzymatic cooperation) and to the membranes, with neither event requiring redox chemistry, may comprise the core of the antitumor effects. The adventitious expression of the redox activity under either aerobic conditions (in which circumstances molecular oxygen is reduced) or anaerobic conditions (in which circumstances potentially reactive aglycone tautomers are obtained) is therefore thought to contribute more strongly to the host toxicity. Yet little remains proven, and the understanding of the intrinsic chemical competence can do little more than lightly define the boundaries within which are found these and numerous other working hypotheses. PMID:3913602

Asparagine deprivation mediated by Salmonella asparaginase causes suppression of activation-induced T cell metabolic reprogramming.

PubMed

Torres, AnnMarie; Luke, Joanna D; Kullas, Amy L; Kapilashrami, Kanishk; Botbol, Yair; Koller, Antonius; Tonge, Peter J; Chen, Emily I; Macian, Fernando; van der Velden, Adrianus W M

2016-02-01

Salmonellae are pathogenic bacteria that induce immunosuppression by mechanisms that remain largely unknown. Previously, we showed that a putative type II l-asparaginase produced by Salmonella Typhimurium inhibits T cell responses and mediates virulence in a murine model of infection. Here, we report that this putative L-asparaginase exhibits L-asparagine hydrolase activity required for Salmonella Typhimurium to inhibit T cells. We show that L-asparagine is a nutrient important for T cell activation and that L-asparagine deprivation, such as that mediated by the Salmonella Typhimurium L-asparaginase, causes suppression of activation-induced mammalian target of rapamycin signaling, autophagy, Myc expression, and L-lactate secretion. We also show that L-asparagine deprivation mediated by the Salmonella Typhimurium L-asparaginase causes suppression of cellular processes and pathways involved in protein synthesis, metabolism, and immune response. Our results advance knowledge of a mechanism used by Salmonella Typhimurium to inhibit T cell responses and mediate virulence, and provide new insights into the prerequisites of T cell activation. We propose a model in which l-asparagine deprivation inhibits T cell exit from quiescence by causing suppression of activation-induced metabolic reprogramming. © Society for Leukocyte Biology.

Site-specific Interaction Mapping of Phosphorylated Ubiquitin to Uncover Parkin Activation*♦

PubMed Central

Yamano, Koji; Queliconi, Bruno B.; Koyano, Fumika; Saeki, Yasushi; Hirokawa, Takatsugu; Tanaka, Keiji; Matsuda, Noriyuki

2015-01-01

Damaged mitochondria are eliminated through autophagy machinery. A cytosolic E3 ubiquitin ligase Parkin, a gene product mutated in familial Parkinsonism, is essential for this pathway. Recent progress has revealed that phosphorylation of both Parkin and ubiquitin at Ser65 by PINK1 are crucial for activation and recruitment of Parkin to the damaged mitochondria. However, the mechanism by which phosphorylated ubiquitin associates with and activates phosphorylated Parkin E3 ligase activity remains largely unknown. Here, we analyze interactions between phosphorylated forms of both Parkin and ubiquitin at a spatial resolution of the amino acid residue by site-specific photo-crosslinking. We reveal that the in-between-RING (IBR) domain along with RING1 domain of Parkin preferentially binds to ubiquitin in a phosphorylation-dependent manner. Furthermore, another approach, the Fluoppi (fluorescent-based technology detecting protein-protein interaction) assay, also showed that pathogenic mutations in these domains blocked interactions with phosphomimetic ubiquitin in mammalian cells. Molecular modeling based on the site-specific photo-crosslinking interaction map combined with mass spectrometry strongly suggests that a novel binding mechanism between Parkin and ubiquitin leads to a Parkin conformational change with subsequent activation of Parkin E3 ligase activity. PMID:26260794

Increased clinical anticipation with maternal transmission in benign adult familial myoclonus epilepsy in Japan.

PubMed

Hitomi, Takefumi; Kobayashi, Katsuya; Jingami, Naoto; Nakagawa, Tomokazu; Imamura, Hisaji; Matsumoto, Riki; Kondo, Takayuki; Chin, Kazuo; Takahashi, Ryosuke; Ikeda, Akio

2013-12-01

We recently reported clinical anticipation in Japanese families with benign adult familial myoclonus epilepsy (BAFME). However, it remains unknown whether clinical anticipation is predominantly associated with paternal or maternal transmission. We investigated the relationship between gender of the transmitting parent and clinical anticipation in nine BAFME families. Clinical anticipation regarding either cortical tremor or generalised seizures was observed in all 12 parent/child pairs (8 mother/child pairs and 4 father/child pairs). Moreover, a higher degree of clinical anticipation was associated with maternal transmission than with paternal transmission (p=0.03). Although a causative gene for BAFME still remains unknown, our finding suggests that BAFME and diseases with unstable expanding repeats, including those in non-coding regions, might share a similar molecular mechanism because such diseases often show clinical anticipation with maternal transmission.

Enhanced litter input rather than changes in litter chemistry drive soil carbon and nitrogen cycles under elevated CO2: a microcosm study

Treesearch

Lingli Lui; John S. King; Fitzgerald L. Booker; Christian P. Giardina; H. Lee Allen; Shuijin Hu

2009-01-01

Elevated CO2 has been shown to stimulate plant productivity and change litter chemistry. These changes in substrate availability may then alter soil microbial processes and possibly lead to feedback effects on N availability. However, the strength of this feedback, and even its direction, remains unknown. Further, uncertainty remains whether...

Nucleotide homeostasis and purinergic nociceptive signaling in rat meninges in migraine-like conditions.

PubMed

Yegutkin, Gennady G; Guerrero-Toro, Cindy; Kilinc, Erkan; Koroleva, Kseniya; Ishchenko, Yevheniia; Abushik, Polina; Giniatullina, Raisa; Fayuk, Dmitriy; Giniatullin, Rashid

2016-09-01

Extracellular ATP is suspected to contribute to migraine pain but regulatory mechanisms controlling pro-nociceptive purinergic mechanisms in the meninges remain unknown. We studied the peculiarities of metabolic and signaling pathways of ATP and its downstream metabolites in rat meninges and in cultured trigeminal cells exposed to the migraine mediator calcitonin gene-related peptide (CGRP). Under resting conditions, meningeal ATP and ADP remained at low nanomolar levels, whereas extracellular AMP and adenosine concentrations were one-two orders higher. CGRP increased ATP and ADP levels in meninges and trigeminal cultures and reduced adenosine concentration in trigeminal cells. Degradation rates for exogenous nucleotides remained similar in control and CGRP-treated meninges, indicating that CGRP triggers nucleotide release without affecting nucleotide-inactivating pathways. Lead nitrate-based enzyme histochemistry of whole mount meninges revealed the presence of high ATPase, ADPase, and AMPase activities, primarily localized in the medial meningeal artery. ATP and ADP induced large intracellular Ca(2+) transients both in neurons and in glial cells whereas AMP and adenosine were ineffective. In trigeminal glia, ATP partially operated via P2X7 receptors. ATP, but not other nucleotides, activated nociceptive spikes in meningeal trigeminal nerve fibers providing a rationale for high degradation rate of pro-nociceptive ATP. Pro-nociceptive effect of ATP in meningeal nerves was reproduced by α,β-meATP operating via P2X3 receptors. Collectively, extracellular ATP, which level is controlled by CGRP, can persistently activate trigeminal nerves in meninges which considered as the origin site of migraine headache. These data are consistent with the purinergic hypothesis of migraine pain and suggest new targets against trigeminal pain.

PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome.

PubMed

Kroeze, Wesley K; Sassano, Maria F; Huang, Xi-Ping; Lansu, Katherine; McCorvy, John D; Giguère, Patrick M; Sciaky, Noah; Roth, Bryan L

2015-05-01

G protein-coupled receptors (GPCRs) are essential mediators of cellular signaling and are important targets of drug action. Of the approximately 350 nonolfactory human GPCRs, more than 100 are still considered to be 'orphans' because their endogenous ligands remain unknown. Here, we describe a unique open-source resource that allows interrogation of the druggable human GPCRome via a G protein-independent β-arrestin-recruitment assay. We validate this unique platform at more than 120 nonorphan human GPCR targets, demonstrate its utility for discovering new ligands for orphan human GPCRs and describe a method (parallel receptorome expression and screening via transcriptional output, with transcriptional activation following arrestin translocation (PRESTO-Tango)) for the simultaneous and parallel interrogation of the entire human nonolfactory GPCRome.

Forced Normalization: Antagonism Between Epilepsy and Psychosis.

PubMed

Kawakami, Yasuhiko; Itoh, Yasuhiko

2017-05-01

The antagonism between epilepsy and psychosis has been discussed for a long time. Landolt coined the term "forced normalization" in the 1950s to describe psychotic episodes associated with the remission of seizures and disappearance of epileptiform activity on electroencephalograms in individuals with epilepsy. Since then, neurologists and psychiatrists have been intrigued by this phenomenon. However, although collaborative clinical studies and basic experimental researches have been performed, the mechanism of forced normalization remains unknown. In this review article, we present a historical overview of the concept of forced normalization, and discuss potential pathogenic mechanisms and clinical diagnosis. We also discuss the role of dopamine, which appears to be a key factor in the mechanism of forced normalization. Copyright © 2017 Elsevier Inc. All rights reserved.

Development of an enumeration method for arsenic methylating bacteria from mixed culture samples.

PubMed

Islam, S M Atiqul; Fukushi, Kensuke; Yamamoto, Kazuo

2005-12-01

Bacterial methylation of arsenic converts inorganic arsenic into volatile and non-volatile methylated species. It plays an important role in the arsenic cycle in the environment. Despite the potential environmental significance of AsMB, an assessment of their population size and activity remains unknown. This study has now established a protocol for enumeration of AsMB by means of the anaerobic-culture-tube, most probable number (MPN) method. Direct detection of volatile arsenic species is then done by GC-MS. This method is advantageous as it can simultaneously enumerate AsMB and acetate and formate-utilizing methanogens. The incubation time for this method was determined to be 6 weeks, sufficient time for AsMB growth.

A new regulatory pathway of mRNA export by an F-box protein, Mdm30.

PubMed

Durairaj, Geetha; Lahudkar, Shweta; Bhaumik, Sukesh R

2014-02-01

Mdm30, an F-box protein in yeast, has been recently shown to promote mRNA export. However, it remains unknown how Mdm30 facilitates mRNA export. Here, we show that Mdm30 targets the Sub2 component of the TREX (Transcription/Export) complex for ubiquitylation and subsequent proteasomal degradation. Such a targeted degradation of Sub2 enhances the recruitment of the mRNA export adaptor, Yra1, to the active genes to promote mRNA export. Together, these results elucidate that Mdm30 promotes mRNA export by lowering Sub2's stability and consequently enhancing Yra1 recruitment, thus illuminating new regulatory mechanisms of mRNA export by Mdm30.

Neural representations of social status hierarchy in human inferior parietal cortex.

PubMed

Chiao, Joan Y; Harada, Tokiko; Oby, Emily R; Li, Zhang; Parrish, Todd; Bridge, Donna J

2009-01-01

Mental representations of social status hierarchy share properties with that of numbers. Previous neuroimaging studies have shown that the neural representation of numerical magnitude lies within a network of regions within inferior parietal cortex. However the neural basis of social status hierarchy remains unknown. Using fMRI, we studied subjects while they compared social status magnitude of people, objects and symbols, as well as numerical magnitude. Both social status and number comparisons recruited bilateral intraparietal sulci. We also observed a semantic distance effect whereby neural activity within bilateral intraparietal sulci increased for semantically close relative to far numerical and social status comparisons. These results demonstrate that social status and number comparisons recruit distinct and overlapping neuronal representations within human inferior parietal cortex.

Sleep promotes branch-specific formation of dendritic spines after learning

PubMed Central

Yang, Guang; Lai, Cora Sau Wan; Cichon, Joseph; Ma, Lei; Li, Wei; Gan, Wen-Biao

2015-01-01

How sleep helps learning and memory remains unknown. We report in mouse motor cortex that sleep after motor learning promotes the formation of postsynaptic dendritic spines on a subset of branches of individual layer V pyramidal neurons. New spines are formed on different sets of dendritic branches in response to different learning tasks and are protected from being eliminated when multiple tasks are learned. Neurons activated during learning of a motor task are reactivated during subsequent non-rapid eye movement sleep, and disrupting this neuronal reactivation prevents branch-specific spine formation. These findings indicate that sleep has a key role in promoting learning-dependent synapse formation and maintenance on selected dendritic branches, which contribute to memory storage. PMID:24904169

Effectiveness of varicella vaccine in children infected with HIV.

PubMed

Son, Moeun; Shapiro, Eugene D; LaRussa, Philip; Neu, Natalie; Michalik, David E; Meglin, Michelle; Jurgrau, Andrea; Bitar, Wally; Vasquez, Marietta; Flynn, Patricia; Gershon, Anne A

2010-06-15

Although varicella vaccine is given to clinically stable human immunodeficiency virus (HIV)-infected children, its effectiveness is unknown. We assessed its effectiveness by reviewing the medical records of closely monitored HIV-infected children, including those receiving highly active antiretroviral therapy (HAART) between 1989 and 2007. Varicella immunization and development of varicella or herpes zoster were noted. Effectiveness was calculated by subtracting from 1 the rate ratios for the incidence rates of varicella or herpes zoster in vaccinated versus unvaccinated children. The effectiveness of the vaccine was 82% (95% confidence interval [CI], 24%-99%; P = .01) against varicella and was 100% (95% CI, 67%-100%; P < .001) against herpes zoster. When the analysis was controlled for receipt of HAART, vaccination remained highly protective against herpes zoster.

Far transfer to language and math of a short software-based gaming intervention

PubMed Central

Goldin, Andrea Paula; Hermida, María Julia; Shalom, Diego E.; Elias Costa, Martín; Lopez-Rosenfeld, Matías; Segretin, María Soledad; Fernández-Slezak, Diego; Lipina, Sebastián J.; Sigman, Mariano

2014-01-01

Executive functions (EF) in children can be trained, but it remains unknown whether training-related benefits elicit far transfer to real-life situations. Here, we investigate whether a set of computerized games might yield near and far transfer on an experimental and an active control group of low-SES otherwise typically developing 6-y-olds in a 3-mo pretest–training–posttest design that was ecologically deployed (at school). The intervention elicits transfer to some (but not all) facets of executive function. These changes cascade to real-world measures of school performance. The intervention equalizes academic outcomes across children who regularly attend school and those who do not because of social and familiar circumstances. PMID:24711403

The biology and function of exosomes in cancer.

PubMed

Kalluri, Raghu

2016-04-01

Humans circulate quadrillions of exosomes at all times. Exosomes are a class of extracellular vesicles released by all cells, with a size range of 40-150 nm and a lipid bilayer membrane. Exosomes contain DNA, RNA, and proteins. Exosomes likely remove excess and/or unnecessary constituents from the cells, functioning like garbage bags, although their precise physiological role remains unknown. Additionally, exosomes may mediate specific cell-to-cell communication and activate signaling pathways in cells they fuse or interact with. Exosomes are detected in the tumor microenvironment, and emerging evidence suggests that they play a role in facilitating tumorigenesis by regulating angiogenesis, immunity, and metastasis. Circulating exosomes can be used as liquid biopsies and noninvasive biomarkers for early detection, diagnosis, and treatment of cancer patients.

Changes in bacterial community of anthracene bioremediation in municipal solid waste composting soil*

PubMed Central

Zhang, Shu-ying; Wang, Qing-feng; Wan, Rui; Xie, Shu-guang

2011-01-01

Polycyclic aromatic hydrocarbons (PAHs) are common contaminants in a municipal solid waste (MSW) composting site. Knowledge of changes in microbial structure is useful to identify particular PAH degraders. However, the microbial community in the MSW composting soil and its change associated with prolonged exposure to PAHs and subsequent biodegradation remain largely unknown. In this study, anthracene was selected as a model compound. The bacterial community structure was investigated using terminal restriction fragment length polymorphism (TRFLP) and 16S rRNA gene clone library analysis. The two bimolecular tools revealed a large shift of bacterial community structure after anthracene amendment and subsequent biodegradation. Genera Methylophilus, Mesorhizobium, and Terrimonas had potential links to anthracene biodegradation, suggesting a consortium playing an active role. PMID:21887852

Searching molecular structure databases with tandem mass spectra using CSI:FingerID

PubMed Central

Dührkop, Kai; Shen, Huibin; Meusel, Marvin; Rousu, Juho; Böcker, Sebastian

2015-01-01

Metabolites provide a direct functional signature of cellular state. Untargeted metabolomics experiments usually rely on tandem MS to identify the thousands of compounds in a biological sample. Today, the vast majority of metabolites remain unknown. We present a method for searching molecular structure databases using tandem MS data of small molecules. Our method computes a fragmentation tree that best explains the fragmentation spectrum of an unknown molecule. We use the fragmentation tree to predict the molecular structure fingerprint of the unknown compound using machine learning. This fingerprint is then used to search a molecular structure database such as PubChem. Our method is shown to improve on the competing methods for computational metabolite identification by a considerable margin. PMID:26392543

SLP-2 negatively modulates mitochondrial sodium-calcium exchange.

PubMed

Da Cruz, Sandrine; De Marchi, Umberto; Frieden, Maud; Parone, Philippe A; Martinou, Jean-Claude; Demaurex, Nicolas

2010-01-01

Mitochondria play a major role in cellular calcium homeostasis. Despite decades of studies, the molecules that mediate and regulate the transport of calcium ions in and out of the mitochondrial matrix remain unknown. Here, we investigate whether SLP-2, an inner membrane mitochondrial protein of unknown function, modulates the activity of mitochondrial Ca(2+) transporters. In HeLa cells depleted of SLP-2, the amplitude and duration of mitochondrial Ca(2+) elevations evoked by agonists were decreased compared to control cells. SLP-2 depletion increased the rates of calcium extrusion from mitochondria. This effect disappeared upon Na(+) removal or addition of CGP-37157, an inhibitor of the mitochondrial Na(+)/Ca(2+) exchanger, and persisted in permeabilized cells exposed to a fixed cytosolic Na(+) and Ca(2+) concentration. The rates of mitochondrial Ca(2+) extrusion were prolonged in SLP-2 over-expressing cells, independently of the amplitude of mitochondrial Ca(2+) elevations. The amplitude of cytosolic Ca(2+) elevations was increased by SLP-2 depletion and decreased by SLP-2 over-expression. These data show that SLP-2 modulates mitochondrial calcium extrusion, thereby altering the ability of mitochondria to buffer Ca(2+) and to shape cytosolic Ca(2+) signals. 2009 Elsevier Ltd. All rights reserved.

Cinerama sickness and postural instability.

PubMed

Bos, Jelte E; Ledegang, Wietse D; Lubeck, Astrid J A; Stins, John F

2013-01-01

Motion sickness symptoms and increased postural instability induced by motion pictures have been reported in a laboratory, but not in a real cinema. We, therefore, carried out an observational study recording sickness severity and postural instability in 19 subjects before, immediately and 45 min after watching a 1 h 3D aviation documentary in a cinema. Sickness was significantly larger right after the movie than before, and in a lesser extent still so after 45 min. The average standard deviation of the lateral centre of pressure excursions was significantly larger only right afterwards. When low-pass filtered at 0.1 Hz, lateral and for-aft excursions were both significantly larger right after the movie, while for-aft excursions then remained larger even after 45 min. Speculating on previous findings, we predict more sickness and postural instability in 3D than in 2D movies, also suggesting a possible, but yet unknown risk for work-related activities and vehicle operation. Watching motion pictures may be sickening and posturally destabilising, but effects in a cinema are unknown. We, therefore, carried out an observational study showing that sickness then is mainly an issue during the exposure while postural instability is an issue afterwards.

Anamorelin hydrochloride for the treatment of cancer-anorexia-cachexia in NSCLC.

PubMed

Zhang, Hongjie; Garcia, Jose M

2015-06-01

Cancer anorexia-cachexia syndrome (CACS) is associated with increased morbidity and mortality. Anamorelin is a novel, orally active ghrelin receptor agonist in clinical development for the treatment of CACS in NSCLC. The aim of this review is to summarize preclinical and clinical studies evaluating anamorelin as a potential promising treatment for CACS in NSCLC. Pharmacodynamics, pharmacokinetics and metabolism, clinical efficacy, safety and tolerability of anamorelin for the treatment of CACS in NSCLC were reviewed. Anamorelin administration may lead to increases in food intake, body weight and lean body mass, and a stimulatory effect on growth hormone secretion in NSCLC patients. Anamorelin is well tolerated with no dose-limiting toxicities identified to date. Targeting ghrelin receptors presents the advantage of potentially addressing multiple mechanisms of CACS simultaneously including appetite, muscle protein balance, adipose tissue metabolism, energy expenditure and inflammation. Clinical data suggest that anamorelin is well tolerated and it effectively increases appetite, body weight and lean mass in patients with advanced NSCLC. Long-term safety remains unknown at this time. The potential synergistic effects of anamorelin with nutritional support or exercise as well as its efficacy/safety in other tumor types are also unknown.

Constraints on cosmic ray and PeV neutrino production in blazars

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

Zhang, B. Theodore; Li, Zhuo, E-mail: zhangbing91@pku.edu.cn, E-mail: zhuo.li@pku.edu.cn

2017-03-01

IceCube has detected a cumulative flux of PeV neutrinos, which origin is unknown. Blazars, active galactic nuclei with relativistic jets pointing to us, are long and widely expected to be one of the strong candidates of high energy neutrino sources. The neutrino production depends strongly on the cosmic ray power of blazar jets, which is largely unknown. The recent null results in stacking searches of neutrinos for several blazar samples by IceCube put upper limits on the neutrino fluxes from these blazars. Here we compute the cosmic ray power and PeV neutrino flux of Fermi-LAT blazars, and find that themore » upper limits for known blazar sources give stringent constraint on the cosmic ray loading factor of blazar jets (i.e., the ratio of the cosmic ray to bolometric radiation luminosity of blazar jets), ξ{sub cr} ∼< (2–10)ζ{sup −1} (with ζ ∼< 1 the remained fraction of cosmic ray energy when propagate into the blazar broad line region) for flat cosmic ray spectrum, and that the cumulative PeV neutrino flux contributed by all-sky blazars is a fraction ∼< (10–50)% of the IceCube detected flux.« less

Parkinson's Disease

MedlinePlus

... in sexual desire or performance. Prevention Because the cause of Parkinson's is unknown, proven ways to prevent the disease also remain a mystery. However, some research has shown that caffeine — which is found in coffee, tea and cola — ...

Correlates of Unknown HIV Status Among MSM Participating in the 2014 American Men's Internet Survey (AMIS).

PubMed

Traynor, S M; Brincks, A M; Feaster, D J

2017-08-29

Increasing serostatus awareness is a key HIV prevention strategy. Despite expanded testing efforts, some men who have sex with men (MSM) remain unaware of their HIV status. This study explored demographic characteristics, sexual identity, sexual role, and behavioral factors associated with unknown HIV status among MSM in the United States. Data from 9170 MSM in the 2014 American Men's Internet Survey were analyzed using logistic regression to identify correlates of unknown HIV status. Young age, race, low education, rural residence, and lack of recent healthcare visits were significantly associated with unknown HIV status. In addition, nondisclosure of one's sexual orientation (OR = 3.70, 95% CI 2.99-4.59) and a self-identified sexual role as "bottom" (OR = 1.45, 95% CI 1.24-1.70) were predictors of unknown HIV status. Post-hoc analysis showed HIV-negative MSM not tested in the last year had fewer self-reported risk behaviors than recent testers, suggesting that repeat testing among MSM may be aligned with individual risk.

Description of a Method to Obtain Complete One-Year Follow-Up in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry.

PubMed

Wooley, Jordan; Neatherlin, Holly; Mahoney, Cecile; Squiers, John J; Tabachnick, Deborah; Suresh, Mitta; Huff, Eleanor; Basra, Sukhdeep S; DiMaio, J Michael; Brown, David L; Mack, Michael J; Holper, Elizabeth M

2018-03-15

The Centers for Medicare and Medicaid Services National Coverage Determination requires centers performing transcatheter aortic valve implantation (TAVI) to report clinical outcomes up to 1 year. Many sites encounter challenges in obtaining complete 1-year follow-up. We report our process to address this challenge. A multidisciplinary process involving clinical personnel, data and quality managers, and research coordinators was initiated to collect TAVI data at baseline, 30 days, and 1 year. This process included (1) planned clinical follow-up of all patients at 30 days and 1 year; (2) query of health-care system-wide integrated data warehouse (IDW) to ascertain last date of clinical contact within the system for all patients; (3) online obituary search, cross-referencing for unique patient identifiers to determine if mortality occurred in remaining unknown patients; and (4) phone calls to remaining unknown patients or patients' families. Between January 2012 and December 2016, 744 patients underwent TAVI. All 744 patients were eligible for 30-day follow-up and 546 were eligible for 1-year follow-up. At routine clinical follow-up of 22 of 744 (3%) patients at 30 days and 180 of 546 (33%) patients at 1 year had unknown survival status. The integrated data warehouse query confirmed status-alive for an additional 1 of 22 patients at 30 days (55%) and 91 of 180 patients at 1 year (51%). Obituaries were identified for 23 of 180 additional patients at 1 year (13%). Phone contact identified the remaining unknown patients at 30 days and 1 year, resulting in 100% known survival status for patients at 30 days (744 of 744) and at 1 year (546 of 546). In conclusion, using a comprehensive approach, we were able to determine survival status in 100% of patients who underwent TAVI. Copyright © 2017 Elsevier Inc. All rights reserved.

Profiling and functional classification of esterases in olive (Olea europaea) pollen during germination.

PubMed

Rejón, Juan D; Zienkiewicz, Agnieszka; Rodríguez-García, María Isabel; Castro, Antonio J

2012-10-01

A pollen grain contains a number of esterases, many of which are released upon contact with the stigma surface. However, the identity and function of most of these esterases remain unknown. In this work, esterases from olive pollen during its germination were identifided and functionally characterized. The esterolytic capacity of olive (Olea europaea) pollen was examined using in vitro and in-gel enzymatic assays with different enzyme substrates. The functional analysis of pollen esterases was achieved by inhibition assays by using specific inhibitors. The cellular localization of esterase activities was performed using histochemical methods. Olive pollen showed high levels of non-specific esterase activity, which remained steady after hydration and germination. Up to 20 esterolytic bands were identified on polyacrylamide gels. All the inhibitors decreased pollen germinability, but only diisopropyl fluorophosphate (DIFP) hampered pollen tube growth. Non-specific esterase activity is localized on the surface of oil bodies (OBs) and small vesicles, in the pollen intine and in the callose layer of the pollen tube wall. Acetylcholinesterase (AChE) activity was mostly observed in the apertures, exine and pollen coat, and attached to the pollen tube wall surface and to small cytoplasmic vesicles. In this work, for the first time a systematic functional characterization of esterase enzymes in pollen from a plant species with wet stigma has been carried out. Olive pollen esterases belong to four different functional groups: carboxylesterases, acetylesterases, AChEs and lipases. The cellular localization of esterase activity indicates that the intine is a putative storage site for esterolytic enzymes in olive pollen. Based on inhibition assays and cellular localization of enzymatic activities, it can be concluded that these enzymes are likely to be involved in pollen germination, and pollen tube growth and penetration of the stigma.

Antimicrobial Stewardship: A Call to Action for Surgeons

PubMed Central

Duane, Therese M.; Catena, Fausto; Tessier, Jeffrey M.; Coccolini, Federico; Kao, Lillian S.; De Simone, Belinda; Labricciosa, Francesco M.; May, Addison K.; Ansaloni, Luca; Mazuski, John E.

2016-01-01

Abstract Despite current antimicrobial stewardship programs (ASPs) being advocated by infectious disease specialists and discussed by national and international policy makers, ASPs coverage remains limited to only certain hospitals as well as specific service lines within hospitals. The ASPs incorporate a variety of strategies to optimize antimicrobial agent use in the hospital, yet the exact set of interventions essential to ASP success remains unknown. Promotion of ASPs across clinical practice is crucial to their success to ensure standardization of antimicrobial agent use within an institution. To effectively accomplish this standardization, providers who actively engage in antimicrobial agent prescribing should participate in the establishment and support of these programs. Hence, surgeons need to play a major role in these collaborations. Surgeons must be aware that judicious antibiotic utilization is an integral part of any stewardship program and necessary to maximize clinical cure and minimize emergence of antimicrobial resistance. The battle against antibiotic resistance should be fought by all healthcare professionals. If surgeons around the world participate in this global fight and demonstrate awareness of the major problem of antimicrobial resistance, they will be pivotal leaders. If surgeons fail to actively engage and use antibiotics judiciously, they will find themselves deprived of the autonomy to treat their patients. PMID:27828764

The dynein cortical anchor Num1 activates dynein motility by relieving Pac1/LIS1-mediated inhibition

PubMed Central

Lammers, Lindsay G.

2015-01-01

Cortically anchored dynein orients the spindle through interactions with astral microtubules. In budding yeast, dynein is offloaded to Num1 receptors from microtubule plus ends. Rather than walking toward minus ends, dynein remains associated with plus ends due in part to its association with Pac1/LIS1, an inhibitor of dynein motility. The mechanism by which dynein is switched from “off” at the plus ends to “on” at the cell cortex remains unknown. Here, we show that overexpression of the coiled-coil domain of Num1 specifically depletes dynein–dynactin–Pac1/LIS1 complexes from microtubule plus ends and reduces dynein-Pac1/LIS1 colocalization. Depletion of dynein from plus ends requires its microtubule-binding domain, suggesting that motility is required. An enhanced Pac1/LIS1 affinity mutant of dynein or overexpression of Pac1/LIS1 rescues dynein plus end depletion. Live-cell imaging reveals minus end–directed dynein–dynactin motility along microtubules upon overexpression of the coiled-coil domain of Num1, an event that is not observed in wild-type cells. Our findings indicate that dynein activity is directly switched “on” by Num1, which induces Pac1/LIS1 removal. PMID:26483554

Oxytocin receptor gene and racial ingroup bias in empathy-related brain activity.

PubMed

Luo, Siyang; Li, Bingfeng; Ma, Yina; Zhang, Wenxia; Rao, Yi; Han, Shihui

2015-04-15

The human brain responds more strongly to racial ingroup than outgroup individuals' pain. This racial ingroup bias varies across individuals and has been attributed to social experiences. What remains unknown is whether the racial ingroup bias in brain activity is associated with a genetic polymorphism. We investigated genetic associations of racial ingroup bias in the brain activity to racial ingroup and outgroup faces that received painful or non-painful stimulations by scanning A/A and G/G homozygous of the oxytocin receptor gene polymorphism (OXTR rs53576) using functional MRI. We found that G/G compared to A/A individuals showed stronger activity in the anterior cingulate and supplementary motor area (ACC/SMA) in response to racial ingroup members' pain, whereas A/A relative to G/G individuals exhibited greater activity in the nucleus accumbens (NAcc) in response to racial outgroup members' pain. Moreover, the racial ingroup bias in ACC/SMA activity positively predicted participants' racial ingroup bias in implicit attitudes and NAcc activity to racial outgroup individuals' pain negatively predicted participants' motivations to reduce racial outgroup members' pain. Our results suggest that the two variants of OXTR rs53576 are associated with racial ingroup bias in brain activities that are linked to implicit attitude and altruistic motivation, respectively. Copyright © 2015 Elsevier Inc. All rights reserved.

Shoulder Muscle Activation of Novice and Resistance Trained Women during Variations of Dumbbell Press Exercises

PubMed Central

Luczak, Joshua; Bosak, Andy; Riemann, Bryan L.

2013-01-01

Previous research has compared the effects of trunk inclination angle on muscle activation using barbells and Smith machines in men. Whether similar effects occur with the use of dumbbells or in women remains unknown. The purpose was to compare upper extremity surface electromyographical (EMG) activity between dumbbell bench, incline, and shoulder presses. Dominate arm EMG data were recorded for collegiate-aged female resistance trained individuals (n = 12) and novice female resistance trained exercisers (n = 12) from which average EMG amplitude for each repetition phase (concentric, eccentric) was computed. No significant differences were found between experienced and novice resistance trained individuals. For the upper trapezius and anterior deltoid muscles, shoulder press activation was significantly greater than incline press which in turn was significantly greater than bench press across both phases. The bench and incline presses promoted significantly greater pectoralis major sternal activation compared to the shoulder press (both phases). While pectoralis major clavicular activation during the incline press eccentric phase was significantly greater than both the bench and shoulder presses, activation during the bench press concentric phase promoted significantly greater activation than the incline press which in turn was significantly greater than the shoulder press. These results provide evidence for selecting exercises in resistance and rehabilitation programs. PMID:26464884

A Case Study in Transnational Crime: Ukraine and Modern Slavery

DTIC Science & Technology

2007-06-01

remained unable to appropriate resources or plan efficiently. The full extent of the decline remains unknown, because statistics were manipulated to hide...information is estimated to average 1 hour per response, including the time for reviewing instruction, searching existing data sources, gathering and...maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of

APPL1 Mediates Adiponectin-Induced LKB1 Cytosolic Localization Through the PP2A-PKCζ Signaling Pathway

PubMed Central

Deepa, Sathyaseelan S.; Zhou, Lijun; Ryu, Jiyoon; Wang, Changhua; Mao, Xuming; Li, Cai; Zhang, Ning; Musi, Nicolas; DeFronzo, Ralph A.; Liu, Feng

2011-01-01

We recently found that the adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif (APPL)1 is essential for mediating adiponectin signal to induce liver kinase B (LKB)1 cytosloic translocation, an essential step for activation of AMP-activated protein kinase (AMPK) in cells. However, the underlying molecular mechanisms remain unknown. Here, we demonstrate that treating C2C12 myotubes with adiponectin promoted APPL1 interaction with protein phosphatase 2A (PP2A) and protein kinase Cζ (PKCζ), leading to the activation of PP2A and subsequent dephosphorylation and inactivation of PKCζ. The adiponectin-induced inactivation of PKCζ results in dephosphorylation of LKB1 at Ser307 and its subsequent translocation to the cytosol, where it stimulates AMPK activity. Interestingly, we found that metformin also induces LKB1 cytosolic translocation, but the stimulation is independent of APPL1 and the PP2A-PKCζ pathway. Together, our study uncovers a new mechanism underlying adiponectin-stimulated AMPK activation in muscle cells and shed light on potential targets for prevention and treatment of insulin resistance and its associated diseases. PMID:21835890

Seasonal, daily activity, and habitat use by three sympatric pit vipers (Serpentes, Viperidae) from southern Brazil.

PubMed

Rocha, Marcelo C; Hartmann, Paulo A; Winck, Gisele R; Cechin, Sonia Z

2014-04-25

Viperid snakes are widely distributed in the South America and the greater distribution range of the family is found at the Crotalinae subfamily. Despite the abundance of this snakes along their geographic distribution, some ecological aspects remain unknown, principally at subtropical areas. In the present study, we evaluated the activity (daily and seasonal) and the use of the habitat by Bothrops diporus, B. jararaca and B. jararacussu, in an Atlantic Forest area at southern Brazil. We observed higher incidence of viperid snakes during the months with higher temperatures, while no snakes were found during the months with lower temperatures. The data suggest the minimum temperature as environmental variable with the greatest influence on the seasonal activity of this species. Considering the daily activity, we observed a tendency of snakes to avoid the warmest hours. Bothrops jararacussu tend to avoid open areas, being registered only inside and at the edges of the forest. We compared our results with previous studies realized at tropical areas and we suggest the observed seasonal activity as an evolutive response, despite the influence of the different environmental variables, according to the occurence region.

Song Perception by Professional Singers and Actors: An MEG Study

PubMed Central

Rosslau, Ken; Herholz, Sibylle C.; Knief, Arne; Ortmann, Magdalene; Deuster, Dirk; Schmidt, Claus-Michael; Zehnhoff-Dinnesen, Antoinetteam; Pantev, Christo; Dobel, Christian

2016-01-01

The cortical correlates of speech and music perception are essentially overlapping, and the specific effects of different types of training on these networks remain unknown. We compared two groups of vocally trained professionals for music and speech, singers and actors, using recited and sung rhyme sequences from German art songs with semantic and/ or prosodic/melodic violations (i.e. violations of pitch) of the last word, in order to measure the evoked activation in a magnetoencephalographic (MEG) experiment. MEG data confirmed the existence of intertwined networks for the sung and spoken modality in an early time window after word violation. In essence for this early response, higher activity was measured after melodic/prosodic than semantic violations in predominantly right temporal areas. For singers as well as for actors, modality-specific effects were evident in predominantly left-temporal lateralized activity after semantic expectancy violations in the spoken modality, and right-dominant temporal activity in response to melodic violations in the sung modality. As an indication of a special group-dependent audiation process, higher neuronal activity for singers appeared in a late time window in right temporal and left parietal areas, both after the recited and the sung sequences. PMID:26863437

Aberrant Axonal Arborization of PDF Neurons Induced by Aβ42-Mediated JNK Activation Underlies Sleep Disturbance in an Alzheimer's Model.

PubMed

Song, Qian; Feng, Ge; Huang, Zehua; Chen, Xiaoman; Chen, Zhaohuan; Ping, Yong

2017-10-01

Impaired sleep patterns are common symptoms of Alzheimer's disease (AD). Cellular mechanisms underlying sleep disturbance in AD remain largely unknown. Here, using a Drosophila Aβ42 AD model, we show that Aβ42 markedly decreases sleep in a large population, which is accompanied with postdevelopmental axonal arborization of wake-promoting pigment-dispersing factor (PDF) neurons. The arborization is mediated in part via JNK activation and can be reversed by decreasing JNK signaling activity. Axonal arborization and impaired sleep are correlated in Aβ42 and JNK kinase hemipterous mutant flies. Image reconstruction revealed that these aberrant fibers preferentially project to pars intercerebralis (PI), a fly brain region analogous to the mammalian hypothalamus. Moreover, PDF signaling in PI neurons was found to modulate sleep/wake activities, suggesting that excessive release of PDF by these aberrant fibers may lead to the impaired sleep in Aβ42 flies. Finally, inhibition of JNK activation in Aβ42 flies restores nighttime sleep loss, decreases Aβ42 accumulation, and attenuates neurodegeneration. These data provide a new mechanism by which sleep disturbance could be induced by Aβ42 burden, a key initiator of a complex pathogenic cascade in AD.

Antioxidant Opuntia ficus-indica Extract Activates AHR-NRF2 Signaling and Upregulates Filaggrin and Loricrin Expression in Human Keratinocytes.

PubMed

Nakahara, Takeshi; Mitoma, Chikage; Hashimoto-Hachiya, Akiko; Takahara, Masakazu; Tsuji, Gaku; Uchi, Hiroshi; Yan, Xianghong; Hachisuka, Junichi; Chiba, Takahito; Esaki, Hitokazu; Kido-Nakahara, Makiko; Furue, Masutaka

2015-10-01

Opuntia ficus-indica (OFI) is a cactus species widely used as an anti-inflammatory, antilipidemic, and hypoglycemic agent. It has been shown that OFI extract (OFIE) inhibits oxidative stress in animal models of diabetes and hepatic disease; however, its antioxidant mechanism remains largely unknown. In this study, we demonstrated that OFIE exhibited potent antioxidant activity through the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and the downstream antioxidant enzyme quinone oxidoreductase 1 (NQO1), which inhibited the generation of reactive oxygen species in keratinocytes challenged with tumor necrosis factor α or benzo[α]pyrene. The antioxidant capacity of OFIE was canceled in NRF2 knockdown keratinocytes. OFIE exerted this NRF2-NQO1 upregulation through activation of the aryl hydrocarbon receptor (AHR). Moreover, the ligation of AHR by OFIE upregulated the expression of epidermal barrier proteins: filaggrin and loricrin. OFIE also prevented TH2 cytokine-mediated downregulation of filaggrin and loricrin expression in an AHR-dependent manner because it was canceled in AHR knockdown keratinocytes. Antioxidant OFIE is a potent activator of AHR-NRF2-NQO1 signaling and may be beneficial in treating barrier-disrupted skin disorders.

Marine Planktonic Archaea Take Up Amino Acids

PubMed Central

Ouverney, Cleber C.; Fuhrman, Jed A.

2000-01-01

Archaea are traditionally thought of as “extremophiles,” but recent studies have shown that marine planktonic Archaea make up a surprisingly large percentage of ocean midwater microbial communities, up to 60% of the total prokaryotes. However, the basic physiology and contribution of Archaea to community microbial activity remain unknown. We have studied Archaea from 200-m depths of the northwest Mediterranean Sea and the Pacific Ocean near California, measuring the archaeal activity under simulated natural conditions (8 to 17°C, dark and anaerobic) by means of a method called substrate tracking autoradiography fluorescence in situ hybridization (STARFISH) that simultaneously detects specific cell types by 16S rRNA probe binding and activity by microautoradiography. In the 200-m-deep Mediterranean and Pacific samples, cells binding the archaeal probes made up about 43 and 14% of the total countable cells, respectively. Our results showed that the Archaea are active in the uptake of dissolved amino acids from natural concentrations (nanomolar) with about 60% of the individuals in the archaeal communities showing measurable uptake. Bacteria showed a similar proportion of active cells. We concluded that a portion of these Archaea is heterotrophic and also appears to coexist successfully with Bacteria in the same water. PMID:11055931

Functional Proteomic Profiling of Secreted Serine Proteases in Health and Inflammatory Bowel Disease.

PubMed

Denadai-Souza, Alexandre; Bonnart, Chrystelle; Tapias, Núria Solà; Marcellin, Marlène; Gilmore, Brendan; Alric, Laurent; Bonnet, Delphine; Burlet-Schiltz, Odile; Hollenberg, Morley D; Vergnolle, Nathalie; Deraison, Céline

2018-05-18

While proteases are essential in gastrointestinal physiology, accumulating evidence indicates that dysregulated proteolysis plays a pivotal role in the pathophysiology of inflammatory bowel disease (IBD). Nonetheless, the identity of overactive proteases released by human colonic mucosa remains largely unknown. Studies of protease abundance have primarily investigated expression profiles, not taking into account their enzymatic activity. Herein we have used serine protease-targeted activity-based probes (ABPs) coupled with mass spectral analysis to identify active forms of proteases secreted by the colonic mucosa of healthy controls and IBD patients. Profiling of (Pro-Lys)-ABP bound proteases revealed that most of hyperactive proteases from IBD secretome are clustered at 28-kDa. We identified seven active proteases: the serine proteases cathepsin G, plasma kallikrein, plasmin, tryptase, chymotrypsin-like elastase 3 A, and thrombin and the aminopeptidase B. Only cathepsin G and thrombin were overactive in supernatants from IBD patient tissues compared to healthy controls. Gene expression analysis highlighted the transcription of genes encoding these proteases into intestinal mucosae. The functional ABP-targeted proteomic approach that we have used to identify active proteases in human colonic samples bears directly on the understanding of the role these enzymes may play in the pathophysiology of IBD.

6-Shogaol attenuates LPS-induced inflammation in BV2 microglia cells by activating PPAR-γ

PubMed Central

Han, Qinghe; Yuan, Qinghai; Meng, Xiaolin; Huo, Junyuan; Bao, Yuxin; Xie, Guanghong

2017-01-01

6-Shogaol, a pungent agent isolated from Zingiber officinale Roscoe, has been known to have anti-tumor and anti-inflammatory effects. However, the anti-inflammatory effects and biological mechanism of 6-Shogaol in LPS-activated BV2 microglia remains largely unknown. In this study, we evaluated the anti-inflammatory effects of 6-Shogaol in LPS-activated BV2 microglia. 6-Shogaol was administrated 1 h before LPS treatment. The production of inflammatory mediators were detected by ELISA. The expression of NF-κB and PPAR-γ were detected by western blot analysis. Our results revealed that 6-Shogaol inhibited LPS-induced TNF-α, IL-1β, IL-6, and PGE2 production in a concentration dependent manner. Furthermore, 6-Shogaol inhibited LPS-induced NF-κB activation by inhibiting phosphorylation and nuclear translocation of NF-κB p65. In addition, 6-Shogaol could increase the expression of PPAR-γ. Moreover, inhibition of PPAR-γ by GW9662 could prevent the inhibition of 6-Shogaol on LPS-induced inflammatory mediator production. In conclusion, 6-Shogaol inhibits LPS-induced inflammation by activating PPAR-γ. PMID:28410218

Examining Implicit Attitudes towards Exercisers with a Physical Disability

PubMed Central

Dionne, Cassandra D.; Gainforth, Heather L.; O'Malley, Deborah A.; Latimer-Cheung, Amy E.

2013-01-01

Background. Using measures of explicit attitudes, physical activity status has been established as a factor that reduces the stigma able-bodied people hold towards people with physical disabilities. This phenomenon is called the exerciser stereotype. However, whether the exerciser stereotype exists when using measures of implicit attitudes remains unknown. Objective. The aims of this study were to evaluate the prevalence of negative implicit attitudes towards people with physical disabilities and determine whether implicit attitudes towards people with physical disabilities were influenced by the exerciser stereotype. Methods. One hundred able-bodied participants (82 females, 18 males) completed two implicit association tests (IATs): the Disability-Attitudes IAT and the Disability-Activity IAT. The Disability-Attitudes IAT measured implicit attitudes towards people who were not disabled relative to disabled; the Disability-Activity IAT measured attitudes towards people with a physical disability who were active relative to inactive. Results. Results revealed that 83.8% of participants had negative implicit attitudes towards people with a disability. Participants held more positive attitudes towards active versus inactive people with a physical disability. Conclusions. The study findings indicate that the exerciser stereotype exists implicitly and may undermine negative attitudes towards people with physical disabilities. PMID:23710142

Postsynaptic activity reverses the sign of the acetylcholine-induced long-term plasticity of GABAA inhibition

PubMed Central

Domínguez, Soledad; Fernández de Sevilla, David; Buño, Washington

2014-01-01

Acetylcholine (ACh) regulates forms of plasticity that control cognitive functions but the underlying mechanisms remain largely unknown. ACh controls the intrinsic excitability, as well as the synaptic excitation and inhibition of CA1 hippocampal pyramidal cells (PCs), cells known to participate in circuits involved in cognition and spatial navigation. However, how ACh regulates inhibition in function of postsynaptic activity has not been well studied. Here we show that in rat PCs, a brief pulse of ACh or a brief stimulation of cholinergic septal fibers combined with repeated depolarization induces strong long-term enhancement of GABAA inhibition (GABAA-LTP). Indeed, this enhanced inhibition is due to the increased activation of α5βγ2 subunit-containing GABAA receptors by the GABA released. GABAA-LTP requires the activation of M1-muscarinic receptors and an increase in cytosolic Ca2+. In the absence of PC depolarization ACh triggered a presynaptic depolarization-induced suppression of inhibition (DSI), revealing that postsynaptic activity gates the effects of ACh from presynaptic DSI to postsynaptic LTP. These results provide key insights into mechanisms potentially linked with cognitive functions, spatial navigation, and the homeostatic control of abnormal hyperexcitable states. PMID:24938789

Berberine Suppresses Adipocyte Differentiation via Decreasing CREB Transcriptional Activity

PubMed Central

Deng, Ruyuan; Wang, Ning; Zhang, Yuqing; Wang, Yao; Liu, Yun; Li, Fengying; Wang, Xiao; Zhou, Libin

2015-01-01

Berberine, one of the major constituents of Chinese herb Rhizoma coptidis, has been demonstrated to lower blood glucose, blood lipid, and body weight in patients with type 2 diabetes mellitus. The anti-obesity effect of berberine has been attributed to its anti-adipogenic activity. However, the underlying molecular mechanism remains largely unknown. In the present study, we found that berberine significantly suppressed the expressions of CCAAT/enhancer-binding protein (C/EBP)α, peroxisome proliferators-activated receptor γ2 (PPARγ2), and other adipogenic genes in the process of adipogenesis. Berberine decreased cAMP-response element-binding protein (CREB) phosphorylation and C/EBPβ expression at the early stage of 3T3-L1 preadipocyte differentiation. In addition, CREB phosphorylation and C/EBPβ expression induced by 3-isobutyl-1-methylxanthine (IBMX) and forskolin were also attenuated by berberine. The binding activities of cAMP responsive element (CRE) stimulated by IBMX and forskolin were inhibited by berberine. The binding of phosphorylated CREB to the promoter of C/EBPβ was abrogated by berberine after the induction of preadipocyte differentiation. These results suggest that berberine blocks adipogenesis mainly via suppressing CREB activity, which leads to a decrease in C/EBPβ-triggered transcriptional cascades. PMID:25928058

How Force Might Activate Talin's Vinculin Binding Sites: SMD Reveals a Structural Mechanism

PubMed Central

Hytönen, Vesa P; Vogel, Viola

2008-01-01

Upon cell adhesion, talin physically couples the cytoskeleton via integrins to the extracellular matrix, and subsequent vinculin recruitment is enhanced by locally applied tensile force. Since the vinculin binding (VB) sites are buried in the talin rod under equilibrium conditions, the structural mechanism of how vinculin binding to talin is force-activated remains unknown. Taken together with experimental data, a biphasic vinculin binding model, as derived from steered molecular dynamics, provides high resolution structural insights how tensile mechanical force applied to the talin rod fragment (residues 486–889 constituting helices H1–H12) might activate the VB sites. Fragmentation of the rod into three helix subbundles is prerequisite to the sequential exposure of VB helices to water. Finally, unfolding of a VB helix into a completely stretched polypeptide might inhibit further binding of vinculin. The first events in fracturing the H1–H12 rods of talin1 and talin2 in subbundles are similar. The proposed force-activated α-helix swapping mechanism by which vinculin binding sites in talin rods are exposed works distinctly different from that of other force-activated bonds, including catch bonds. PMID:18282082

TAK1 regulates skeletal muscle mass and mitochondrial function

PubMed Central

Hindi, Sajedah M.; Sato, Shuichi; Xiong, Guangyan; Bohnert, Kyle R.; Gibb, Andrew A.; Gallot, Yann S.; McMillan, Joseph D.; Hill, Bradford G.

2018-01-01

Skeletal muscle mass is regulated by a complex array of signaling pathways. TGF-β–activated kinase 1 (TAK1) is an important signaling protein, which regulates context-dependent activation of multiple intracellular pathways. However, the role of TAK1 in the regulation of skeletal muscle mass remains unknown. Here, we report that inducible inactivation of TAK1 causes severe muscle wasting, leading to kyphosis, in both young and adult mice.. Inactivation of TAK1 inhibits protein synthesis and induces proteolysis, potentially through upregulating the activity of the ubiquitin-proteasome system and autophagy. Phosphorylation and enzymatic activity of AMPK are increased, whereas levels of phosphorylated mTOR and p38 MAPK are diminished upon inducible inactivation of TAK1 in skeletal muscle. In addition, targeted inactivation of TAK1 leads to the accumulation of dysfunctional mitochondria and oxidative stress in skeletal muscle of adult mice. Inhibition of TAK1 does not attenuate denervation-induced muscle wasting in adult mice. Finally, TAK1 activity is highly upregulated during overload-induced skeletal muscle growth, and inactivation of TAK1 prevents myofiber hypertrophy in response to functional overload. Overall, our study demonstrates that TAK1 is a key regulator of skeletal muscle mass and oxidative metabolism. PMID:29415881

Associations of endothelial function and air temperature in diabetic subjects

EPA Science Inventory

Background and Objective: Epidemiological studies consistently show that air temperature is associated with changes in cardiovascular morbidity and mortality. However, the biological mechanisms underlying the association remain largely unknown. As one index of endothelial functio...

A chemical genetic strategy identify the PHOSTIN, a synthetic molecule that triggers phosphate starvation responses in Arabidopsis thaliana.

PubMed

Bonnot, Clémence; Pinson, Benoît; Clément, Mathilde; Bernillon, Stéphane; Chiarenza, Serge; Kanno, Satomi; Kobayashi, Natsuko; Delannoy, Etienne; Nakanishi, Tomoko M; Nussaume, Laurent; Desnos, Thierry

2016-01-01

Plants display numerous strategies to cope with phosphate (Pi)-deficiency. Despite multiple genetic studies, the molecular mechanisms of low-Pi-signalling remain unknown. To validate the interest of chemical genetics to investigate this pathway we discovered and analysed the effects of PHOSTIN (PSN), a drug mimicking Pi-starvation in Arabidopsis. We assessed the effects of PSN and structural analogues on the induction of Pi-deficiency responses in mutants and wild-type and followed their accumulation in plants organs by high pressure liquid chromotography (HPLC) or mass-spectrophotometry. We show that PSN is cleaved in the growth medium, releasing its active motif (PSN11), which accumulates in plants roots. Despite the overaccumulation of Pi in the roots of treated plants, PSN11 elicits both local and systemic Pi-starvation effects. Nevertheless, albeit that the transcriptional activation of low-Pi genes by PSN11 is lost in the phr1;phl1 double mutant, neither PHO1 nor PHO2 are required for PSN11 effects. The range of local and systemic responses to Pi-starvation elicited, and their dependence on the PHR1/PHL1 function suggests that PSN11 affects an important and early step of Pi-starvation signalling. Its independence from PHO1 and PHO2 suggest the existence of unknown pathway(s), showing the usefulness of PSN and chemical genetics to bring new elements to this field. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

Systematic discovery of novel eukaryotic transcriptional regulators using sequence homology independent prediction

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

Bossi, Flavia; Fan, Jue; Xiao, Jun

Here, the molecular function of a gene is most commonly inferred by sequence similarity. Therefore, genes that lack sufficient sequence similarity to characterized genes (such as certain classes of transcriptional regulators) are difficult to classify using most function prediction algorithms and have remained uncharacterized. As a result, to identify novel transcriptional regulators systematically, we used a feature-based pipeline to screen protein families of unknown function. This method predicted 43 transcriptional regulator families in Arabidopsis thaliana, 7 families in Drosophila melanogaster, and 9 families in Homo sapiens. Literature curation validated 12 of the predicted families to be involved in transcriptional regulation.more » We tested 33 out of the 195 Arabidopsis putative transcriptional regulators for their ability to activate transcription of a reporter gene in planta and found twelve coactivators, five of which had no prior literature support. To investigate mechanisms of action in which the predicted regulators might work, we looked for interactors of an Arabidopsis candidate that did not show transactivation activity in planta and found that it might work with other members of its own family and a subunit of the Polycomb Repressive Complex 2 to regulate transcription. Our results demonstrate the feasibility of assigning molecular function to proteins of unknown function without depending on sequence similarity. In particular, we identified novel transcriptional regulators using biological features enriched in transcription factors. The predictions reported here should accelerate the characterization of novel regulators.« less

Systematic discovery of novel eukaryotic transcriptional regulators using sequence homology independent prediction

DOE PAGES

Bossi, Flavia; Fan, Jue; Xiao, Jun; ...

2017-06-26

Here, the molecular function of a gene is most commonly inferred by sequence similarity. Therefore, genes that lack sufficient sequence similarity to characterized genes (such as certain classes of transcriptional regulators) are difficult to classify using most function prediction algorithms and have remained uncharacterized. As a result, to identify novel transcriptional regulators systematically, we used a feature-based pipeline to screen protein families of unknown function. This method predicted 43 transcriptional regulator families in Arabidopsis thaliana, 7 families in Drosophila melanogaster, and 9 families in Homo sapiens. Literature curation validated 12 of the predicted families to be involved in transcriptional regulation.more » We tested 33 out of the 195 Arabidopsis putative transcriptional regulators for their ability to activate transcription of a reporter gene in planta and found twelve coactivators, five of which had no prior literature support. To investigate mechanisms of action in which the predicted regulators might work, we looked for interactors of an Arabidopsis candidate that did not show transactivation activity in planta and found that it might work with other members of its own family and a subunit of the Polycomb Repressive Complex 2 to regulate transcription. Our results demonstrate the feasibility of assigning molecular function to proteins of unknown function without depending on sequence similarity. In particular, we identified novel transcriptional regulators using biological features enriched in transcription factors. The predictions reported here should accelerate the characterization of novel regulators.« less

Watching sport on television, physical activity, and risk of obesity in older adults.

PubMed

Hamer, Mark; Weiler, Richard; Stamatakis, Emmanuel

2014-01-08

Television (TV) viewing has been associated with obesity although the effects of specific TV content on health and other behaviours remains unknown. We examined the association between watching sport on TV, physical activity levels, and risk of obesity. We studied 6,733 (aged 64.9 ± 9.2 yrs) men and women from the English Longitudinal Study of Ageing, a prospective study of community dwelling older adults. Data were collected on self reported TV time and content, and physical activity. Nurses measured height and weight for the calculation of body mass index. On average, participants reported viewing TV for 5.3 ± 4.1 hours per day and 30.3% of the sample watched sport on TV at least twice a week. There was no association between watching sport and physical activity levels. Participants that watched sports every day were at higher risk of obesity [odds ratio = 1.39, 95% CI, 1.15, 1.68) after adjustment for age, sex, smoking, alcohol, physical activity, total TV time, disability, and self-rated health. Watching elite athletes may have no role in the promotion of physical activity in older adults, which has implications for staging large sporting events with physical activity legacy promises.

Influence of human activity patterns on epidemiology of plague in Western Usambara Mountains, Tanzania.

PubMed

Hubeau, Marianne; Gulinck, Hubert; Kimaro, Didas N; Hieronimo, Proches; Meliyo, Joel

2014-07-01

Human plague has been a recurring public health threat in some villages in the Western Usambara Mountains, Tanzania, in the period between 1980 and 2004. Despite intensive past biological and medical research, the reasons for the plague outbreaks in the same set of villages remain unknown. Plague research needs to broaden its scope and formulate new hypotheses. This study was carried out to establish relationships between the nature and the spatial extent of selected human activities on one hand, and the reported plague cases on the other hand. Three outdoor activities namely, fetching water, collecting firewood and going to the market, were selected. Through enquiries the activity patterns related to these activities were mapped in 14 villages. Standard deviation ellipses represent the extent of action spaces. Over 130 activity types were identified and listed. Of these, fetching water, collecting firewood and going to the market were used for further analysis. The results indicate a significant correlation between the plague frequency and the size of these action spaces. Different characteristics of land use and related human activities were correlated with the plague frequency at village and hamlet levels. Significant relationships were found between plague frequency and specific sources of firewood and water, and specific market places.

Structure of the apoptosome: mechanistic insights into activation of an initiator caspase from Drosophila

PubMed Central

Pang, Yuxuan; Bai, Xiao-chen; Yan, Chuangye; Hao, Qi; Chen, Zheqin; Wang, Jia-Wei

2015-01-01

Apoptosis is executed by a cascade of caspase activation. The autocatalytic activation of an initiator caspase, exemplified by caspase-9 in mammals or its ortholog, Dronc, in fruit flies, is facilitated by a multimeric adaptor complex known as the apoptosome. The underlying mechanism by which caspase-9 or Dronc is activated by the apoptosome remains unknown. Here we report the electron cryomicroscopic (cryo-EM) structure of the intact apoptosome from Drosophila melanogaster at 4.0 Å resolution. Analysis of the Drosophila apoptosome, which comprises 16 molecules of the Dark protein (Apaf-1 ortholog), reveals molecular determinants that support the assembly of the 2.5-MDa complex. In the absence of dATP or ATP, Dronc zymogen potently induces formation of the Dark apoptosome, within which Dronc is efficiently activated. At 4.1 Å resolution, the cryo-EM structure of the Dark apoptosome bound to the caspase recruitment domain (CARD) of Dronc (Dronc-CARD) reveals two stacked rings of Dronc-CARD that are sandwiched between two octameric rings of the Dark protein. The specific interactions between Dronc-CARD and both the CARD and the WD40 repeats of a nearby Dark protomer are indispensable for Dronc activation. These findings reveal important mechanistic insights into the activation of initiator caspase by the apoptosome. PMID:25644603

Control of Spine Maturation and Pruning through ProBDNF Synthesized and Released in Dendrites

PubMed Central

Orefice, Lauren L.; Shih, Chien-Cheng; Xu, Haifei; Waterhouse, Emily G.; Xu, Baoji

2015-01-01

Excess synapses formed during early postnatal development are pruned over an extended period, while the remaining synapses mature. Synapse pruning is critical for activity-dependent refinement of neuronal connections and its dysregulation has been found in neurodevelopmental disorders such as autism spectrum disorders; however, the mechanism underlying synapse pruning remains largely unknown. As dendritic spines are the postsynaptic sites for the vast majority of excitatory synapses, spine maturation and pruning are indicators for maturation and elimination of these synapses. Our previous studies have found that dendritically localized mRNA for brain-derived neurotrophic factor (BDNF) regulates spine maturation and pruning. Here we investigated the mechanism by which dendritic Bdnf mRNA, but not somatically restricted Bdnf mRNA, promotes spine maturation and pruning. We found that neuronal activity stimulates both translation of dendritic Bdnf mRNA and secretion of its translation product mainly as proBDNF. The secreted proBDNF promotes spine maturation and pruning, and its effect on spine pruning is in part mediated by the p75NTR receptor via RhoA activation. Furthermore, some proBDNF is extracellularly converted to mature BDNF and then promotes maturation of stimulated spines by activating Rac1 through the TrkB receptor. In contrast, translation of somatic Bdnf mRNA and the release of its translation product mainly as mature BDNF are independent of action potentials. These results not only reveal a biochemical pathway regulating synapse pruning, but also suggest that BDNF synthesized in the soma and dendrites is released through distinct secretory pathways. PMID:26705735

Reduced CD5(+) CD24(hi) CD38(hi) and interleukin-10(+) regulatory B cells in active anti-neutrophil cytoplasmic autoantibody-associated vasculitis permit increased circulating autoantibodies.

PubMed

Aybar, L T; McGregor, J G; Hogan, S L; Hu, Y; Mendoza, C E; Brant, E J; Poulton, C J; Henderson, C D; Falk, R J; Bunch, D O

2015-05-01

Pathogenesis of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is B cell-dependent, although how particular B cell subsets modulate immunopathogenesis remains unknown. Although their phenotype remains controversial, regulatory B cells (Bregs ), play a role in immunological tolerance via interleukin (IL)-10. Putative CD19(+) CD24(hi) CD38(hi) and CD19(+) CD24(hi) CD27(+) Bregs were evaluated in addition to their CD5(+) subsets in 69 patients with ANCA-associated vasculitis (AAV). B cell IL-10 was verified by flow cytometry following culture with CD40 ligand and cytosine-phosphate-guanosine (CpG) DNA. Patients with active disease had decreased levels of CD5(+) CD24(hi) CD38(hi) B cells and IL-10(+) B cells compared to patients in remission and healthy controls (HCs). As IL-10(+) and CD5(+) CD24(hi) CD38(hi) B cells normalized in remission within an individual, ANCA titres decreased. The CD5(+) subset of CD24(hi) CD38(hi) B cells decreases in active disease and rebounds during remission similarly to IL-10-producing B cells. Moreover, CD5(+) B cells are enriched in the ability to produce IL-10 compared to CD5(neg) B cells. Together these results suggest that CD5 may identify functional IL-10-producing Bregs . The malfunction of Bregs during active disease due to reduced IL-10 expression may thus permit ANCA production. © 2014 British Society for Immunology.

Adaptive neural control for a class of nonlinear time-varying delay systems with unknown hysteresis.

PubMed

Liu, Zhi; Lai, Guanyu; Zhang, Yun; Chen, Xin; Chen, Chun Lung Philip

2014-12-01

This paper investigates the fusion of unknown direction hysteresis model with adaptive neural control techniques in face of time-delayed continuous time nonlinear systems without strict-feedback form. Compared with previous works on the hysteresis phenomenon, the direction of the modified Bouc-Wen hysteresis model investigated in the literature is unknown. To reduce the computation burden in adaptation mechanism, an optimized adaptation method is successfully applied to the control design. Based on the Lyapunov-Krasovskii method, two neural-network-based adaptive control algorithms are constructed to guarantee that all the system states and adaptive parameters remain bounded, and the tracking error converges to an adjustable neighborhood of the origin. In final, some numerical examples are provided to validate the effectiveness of the proposed control methods.

Structure-activity relationships of fluorinated dendrimers in DNA and siRNA delivery.

PubMed

Wang, Mingming; Cheng, Yiyun

2016-12-01

Fluorinated dendrimers have shown great promise in gene delivery due to their high transfection efficacy and low cytotoxicity, however, the structure-activity relationships of these polymers still remain unknown. Herein, we synthesized a library of fluorinated dendrimers with different dendrimer generations and fluorination degrees and investigated their behaviors in both DNA and siRNA delivery. The results show that fluorination significantly improves the transfection efficacy of G4-G7 polyamidoamine dendrimers in DNA and siRNA delivery. Fluorination on generation 5 dendrimer yields the most efficient polymers in gene delivery, and the transfection efficacy of fluorinated dendrimers depends on fluorination degree. All the fluorinated dendrimers cause minimal toxicity on the transfected cells at their optimal transfection conditions. This study provides a general and facile strategy to prepare high efficient and low cytotoxic gene carriers based on fluorinated polymers. The structure-activity relationships of fluorinated dendrimers in gene delivery is still unknown and the behavior of fluorinated dendrimers in siRNA delivery has not yet been investigated. Herein, we synthesized a library of fluorinated PAMAM dendrimers with different dendrimer generations and fluorination degrees and investigated their behaviors in both DNA and siRNA delivery. The results clearly indicate that fluorination significantly improves the transfection efficacy of dendrimers in both DNA and siRNA delivery without causing additional toxicity. G5 PAMAM dendrimer is best scaffold to synthesize fluorinated dendrimers and the transfection efficacy of fluorinated dendrimers depends on fluorination degree. This systematic study provides a general and facile strategy to prepare high efficient and low cytotoxic gene carriers based on fluorinated polymers. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

A mutation in an alternative untranslated exon of hexokinase 1 associated with hereditary motor and sensory neuropathy -- Russe (HMSNR).

PubMed

Hantke, Janina; Chandler, David; King, Rosalind; Wanders, Ronald J A; Angelicheva, Dora; Tournev, Ivailo; McNamara, Elyshia; Kwa, Marcel; Guergueltcheva, Velina; Kaneva, Radka; Baas, Frank; Kalaydjieva, Luba

2009-12-01

Hereditary Motor and Sensory Neuropathy -- Russe (HMSNR) is a severe autosomal recessive disorder, identified in the Gypsy population. Our previous studies mapped the gene to 10q22-q23 and refined the gene region to approximately 70 kb. Here we report the comprehensive sequencing analysis and fine mapping of this region, reducing it to approximately 26 kb of fully characterised sequence spanning the upstream exons of Hexokinase 1 (HK1). We identified two sequence variants in complete linkage disequilibrium, a G>C in a novel alternative untranslated exon (AltT2) and a G>A in the adjacent intron, segregating with the disease in affected families and present in the heterozygote state in only 5/790 population controls. Sequence conservation of the AltT2 exon in 16 species with invariable preservation of the G allele at the mutated site, strongly favour the exonic change as the pathogenic mutation. Analysis of the Hk1 upstream region in mouse mRNA from testis and neural tissues showed an abundance of AltT2-containing transcripts generated by extensive, developmentally regulated alternative splicing. Expression is very low compared with ubiquitous Hk1 and all transcripts skip exon1, which encodes the protein domain responsible for binding to the outer mitochondrial membrane, and regulation of energy production and apoptosis. Hexokinase activity measurement and immunohistochemistry of the peripheral nerve showed no difference between patients and controls. The mutational mechanism and functional effects remain unknown and could involve disrupted translational regulation leading to increased anti-apoptotic activity (suggested by the profuse regenerative activity in affected nerves), or impairment of an unknown HK1 function in the peripheral nervous system (PNS).

A mutation in an alternative untranslated exon of hexokinase 1 associated with Hereditary Motor and Sensory Neuropathy – Russe (HMSNR)

PubMed Central

Hantke, Janina; Chandler, David; King, Rosalind; Wanders, Ronald JA; Angelicheva, Dora; Tournev, Ivailo; McNamara, Elyshia; Kwa, Marcel; Guergueltcheva, Velina; Kaneva, Radka; Baas, Frank; Kalaydjieva, Luba

2009-01-01

Hereditary Motor and Sensory Neuropathy – Russe (HMSNR) is a severe autosomal recessive disorder, identified in the Gypsy population. Our previous studies mapped the gene to 10q22-q23 and refined the gene region to ∼70 kb. Here we report the comprehensive sequencing analysis and fine mapping of this region, reducing it to ∼26 kb of fully characterised sequence spanning the upstream exons of Hexokinase 1 (HK1). We identified two sequence variants in complete linkage disequilibrium, a G>C in a novel alternative untranslated exon (AltT2) and a G>A in the adjacent intron, segregating with the disease in affected families and present in the heterozygote state in only 5/790 population controls. Sequence conservation of the AltT2 exon in 16 species with invariable preservation of the G allele at the mutated site, strongly favour the exonic change as the pathogenic mutation. Analysis of the Hk1 upstream region in mouse mRNA from testis and neural tissues showed an abundance of AltT2-containing transcripts generated by extensive, developmentally regulated alternative splicing. Expression is very low compared with ubiquitous Hk1 and all transcripts skip exon1, which encodes the protein domain responsible for binding to the outer mitochondrial membrane, and regulation of energy production and apoptosis. Hexokinase activity measurement and immunohistochemistry of the peripheral nerve showed no difference between patients and controls. The mutational mechanism and functional effects remain unknown and could involve disrupted translational regulation leading to increased anti-apoptotic activity (suggested by the profuse regenerative activity in affected nerves), or impairment of an unknown HK1 function in the peripheral nervous system (PNS). PMID:19536174

Evaluation of liver and brain esterases in the spotted gar fish (Lepisosteus oculatus) as biomarkers of effect in the lower Mississippi River basin

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

Huang, T.L.; Obih, P.O.; Jaiswal, R.

1997-05-01

The responses of various xenobiotic metabolizing enzymes in fish models are rapidly evolving as important biomarkers for monitoring unacceptable levels of environmental contaminants. Ethoxyresorufin O-deethylase, a specific cytochrome P450-dependent monooxygenase, is often used as an indicator of polycyclic aromatic hydrocarbon pollution. Another class of enzymes which are potential biomarkers are the B-type esterases. These enzymes are sensitive to inhibition by organophosphates, and include the cholinesterases (ChE) and carboxylesterases. ChEs are further subdivided into acetylcholinesterase and butyryl cholinesterase. Among fish, AChE is predominantly localized in the brain and muscle, whereas, BuChE activity is found mainly in liver and plasma. The precisemore » physiological role of BuChE is unknown, although it has been regarded as a marker enzyme for glial or supportive cells or other non-neuronal elements. Inhibition of ChE activity has often been associated with exposure to organophosphate and carbamate insecticides and other neurotoxic xenobiotics. Chemicals other than carbarnates and organophosphates that are environmental contaminants can also affect the activity of ChEs. Carboxylesterases represent a heterogenous group of isozymes that can catalyze the hydrolysis of a wide range of xenobiotic esters, amides and thioesters. For most CaE, their natural substrates are unknown, therefore, their physiological functions remain to be elucidated. These enzymes (CaE) occur widely in most tissues and are generally found in high levels in the liver. The purpose of this research was to evaluate the liver and brain esterases in the spotted gar fish as biomarkers of effect to multiple contaminants in the lower Mississippi River basin. 15 refs., 3 figs., 2 tabs.« less

Mammary ductal growth is impaired in mice lacking leptin-dependent signal transducer and activator of transcription 3 signaling.

PubMed

Thorn, Stephanie R; Giesy, Sarah L; Myers, Martin G; Boisclair, Yves R

2010-08-01

Mice lacking leptin (ob/ob) or its full-length receptor (db/db) are obese and reproductively incompetent. Fertility, pregnancy, and lactation are restored, respectively, in ob/ob mice treated with leptin through mating, d 6.5 post coitum, and pregnancy. Therefore, leptin signaling is needed for lactation, but the timing of its action and the affected mammary process remain unknown. To address this issue, we used s/s mice lacking only leptin-dependent signal transducer and activator of transcription (STAT)3 signaling. These mice share many features with db/db mice, including obesity, but differ by retaining sufficient activity of the hypothalamic-pituitary-ovarian axis to support reproduction. The s/s mammary epithelium was normal at 3 wk of age but failed to expand through the mammary fat pad (MFP) during the subsequent pubertal period. Ductal growth failure was not corrected by estrogen therapy and did not relate to inadequate IGF-I production by the MFP or to the need for epithelial or stromal leptin-STAT3 signaling. Ductal growth failure coincided with adipocyte hypertrophy and increased MFP production of leptin, TNFalpha, and IL6. These cytokines, however, were unable to inhibit the proliferation of a collection of mouse mammary epithelial cell lines. In conclusion, the very first step of postnatal mammary development fails in s/s mice despite sufficient estrogen IGF-I and an hypothalamic-pituitary-ovarian axis capable of supporting reproduction. This failure is not caused by mammary loss of leptin-dependent STAT3 signaling or by the development of inflammation. These data imply the existence of an unknown mechanism whereby leptin-dependent STAT3 signaling and obesity alter mammary ductal development.

Experimental inoculation of house flies Musca domestica with Corynebacterium pseudotuberculosis serovar equi

USDA-ARS?s Scientific Manuscript database

Corynebacterium pseudotuberculosis (Actinomycetales: Corynebacteriaceae) infection in horses causes external abscesses, infection of internal organs and ulcerative lymphangitis. The exact mechanism of infection remains unknown, but fly transmission is suspected. Scientists at Auburn University and U...

An Indirect Adaptive Control Scheme in the Presence of Actuator and Sensor Failures

NASA Technical Reports Server (NTRS)

Sun, Joy Z.; Josh, Suresh M.

2009-01-01

The problem of controlling a system in the presence of unknown actuator and sensor faults is addressed. The system is assumed to have groups of actuators, and groups of sensors, with each group consisting of multiple redundant similar actuators or sensors. The types of actuator faults considered consist of unknown actuators stuck in unknown positions, as well as reduced actuator effectiveness. The sensor faults considered include unknown biases and outages. The approach employed for fault detection and estimation consists of a bank of Kalman filters based on multiple models, and subsequent control reconfiguration to mitigate the effect of biases caused by failed components as well as to obtain stability and satisfactory performance using the remaining actuators and sensors. Conditions for fault identifiability are presented, and the adaptive scheme is applied to an aircraft flight control example in the presence of actuator failures. Simulation results demonstrate that the method can rapidly and accurately detect faults and estimate the fault values, thus enabling safe operation and acceptable performance in spite of failures.

Lipidomic profiling reveals protective function of fatty acid oxidation in cocaine-induced hepatotoxicity[S

PubMed Central

Shi, Xiaolei; Yao, Dan; Gosnell, Blake A.; Chen, Chi

2012-01-01

During cocaine-induced hepatotoxicity, lipid accumulation occurs prior to necrotic cell death in the liver. However, the exact influences of cocaine on the homeostasis of lipid metabolism remain largely unknown. In this study, the progression of subacute hepatotoxicity, including centrilobular necrosis in the liver and elevation of transaminase activity in serum, was observed in a three-day cocaine treatment, accompanying the disruption of triacylglycerol (TAG) turnover. Serum TAG level increased on day 1 of cocaine treatment but remained unchanged afterwards. In contrast, hepatic TAG level was elevated continuously during three days of cocaine treatment and was better correlated with the development of hepatotoxicity. Lipidomic analyses of serum and liver samples revealed time-dependent separation of the control and cocaine-treated mice in multivariate models, which was due to the accumulation of long-chain acylcarnitines together with the disturbances of many bioactive phospholipid species in the cocaine-treated mice. An in vitro function assay confirmed the progressive inhibition of mitochondrial fatty acid oxidation after the cocaine treatment. Cotreatment of fenofibrate significantly increased the expression of peroxisome proliferator-activated receptor α (PPARα)-targeted genes and the mitochondrial fatty acid oxidation activity in the cocaine-treated mice, resulting in the inhibition of cocaine-induced acylcarnitine accumulation and other hepatotoxic effects. Overall, the results from this lipidomics-guided study revealed that the inhibition of fatty acid oxidation plays an important role in cocaine-induced liver injury. PMID:22904346

Launching of Active Galactic Nuclei Jets

NASA Astrophysics Data System (ADS)

Tchekhovskoy, Alexander

As black holes accrete gas, they often produce relativistic, collimated outflows, or jets. Jets are expected to form in the vicinity of a black hole, making them powerful probes of strong-field gravity. However, how jet properties (e.g., jet power) connect to those of the accretion flow (e.g., mass accretion rate) and the black hole (e.g., black hole spin) remains an area of active research. This is because what determines a crucial parameter that controls jet properties—the strength of large-scale magnetic flux threading the black hole—remains largely unknown. First-principles computer simulations show that due to this, even if black hole spin and mass accretion rate are held constant, the simulated jet powers span a wide range, with no clear winner. This limits our ability to use jets as a quantitative diagnostic tool of accreting black holes. Recent advances in computer simulations demonstrated that accretion disks can accumulate large-scale magnetic flux on the black hole, until the magnetic flux becomes so strong that it obstructs gas infall and leads to a magnetically-arrested disk (MAD). Recent evidence suggests that central black holes in jetted active galactic nuclei and tidal disruptions are surrounded by MADs. Since in MADs both the black hole magnetic flux and the jet power are at their maximum, well-defined values, this opens up a new vista in the measurements of black hole masses and spins and quantitative tests of accretion and jet theory.

RAB10 Interacts with the Male Germ Cell-Specific GTPase-Activating Protein during Mammalian Spermiogenesis.

PubMed

Lin, Ying-Hung; Ke, Chih-Chun; Wang, Ya-Yun; Chen, Mei-Feng; Chen, Tsung-Ming; Ku, Wei-Chi; Chiang, Han-Sun; Yeh, Chung-Hsin

2017-01-05

According to recent estimates, 2%-15% of couples are sterile, and approximately half of the infertility cases are attributed to male reproductive factors. However, the reasons remain undefined in approximately 25% of male infertility cases, and most infertility cases exhibit spermatogenic defects. Numerous genes involved in spermatogenesis still remain unknown. We previously identified Male Germ Cells Rab GTPase-Activating Proteins ( MGCRABGAPs ) through cDNA microarray analysis of human testicular tissues with spermatogenic defects. MGCRABGAP contains a conserved RABGAP catalytic domain, TBC (Tre2/Bub2/Cdc16). RABGAP family proteins regulate cellular function (e.g., cytoskeletal remodeling, vesicular trafficking, and cell migration) by inactivating RAB proteins. MGCRABGAP is a male germ cell-specific protein expressed in elongating and elongated spermatids during mammalian spermiogenesis. The purpose of this study was to identify proteins that interact with MGCRABGAP during mammalian spermiogenesis using a proteomic approach. We found that MGCRABGAP exhibited GTPase-activating bioability, and several MGCRABGAP interactors, possible substrates (e.g., RAB10, RAB5C, and RAP1), were identified using co-immunoprecipitation (co-IP) and nano liquid chromatography-mass spectrometry/mass spectrometry (nano LC-MS/MS). We confirmed the binding ability between RAB10 and MGCRABGAP via co-IP. Additionally, MGCRABGAP-RAB10 complexes were specifically colocalized in the manchette structure, a critical structure for the formation of spermatid heads, and were slightly expressed at the midpiece of mature spermatozoa. Based on these results, we propose that MGCRABGAP is involved in mammalian spermiogenesis by modulating RAB10.

The regulation of the Z- and G-box containing promoters by light signaling components, SPA1 and MYC2, in Arabidopsis.

PubMed

Gangappa, Sreeramaiah N; Maurya, Jay P; Yadav, Vandana; Chattopadhyay, Sudip

2013-01-01

Although many transcription factors and regulatory proteins have been identified and functionally characterized in light signaling pathways, photoperception to transcription remains largely fragmented. The Z-box is one of the LREs (Light responsive elements) that plays important role in the regulation of transcription during light-controlled Arabidopsis seedling development. The involvement of photoreceptors in the modulation of the activity of the Z-box containing promoters has been demonstrated. However, the role of downstream signaling components such as SPA1 and MYC2/ZBF1, which are functionally interrelated, remains unknown. In this study, we have investigated the regulation of the Z-box containing synthetic and native promoters by SPA1 and MYC2 by using stable transgenic lines. Our studies suggest that SPA1 negatively regulates the expression of CAB1 native promoter. MYC2 negatively regulates the activity of Z- and/or G-box containing synthetic as well as native promoters irrespective of light quality. Moreover, MYC2 negatively regulates the expression of Z/G-NOS101-GUS even in the darkness. Furthermore, analyses of tissue specific expression in adult plants suggest that MYC2 strongly regulates the activity of Z- and G-box containing promoters specifically in leaves and stems. In roots, whereas MYC2 positively regulates the activity of the Z-box containing synthetic promoter, it does not seem to control the activity of the G-box containing promoters. Taken together, these results provide insights into SPA1- and MYC2-mediated transcriptional regulation of the Z- and G-box containing promoters in light signaling pathways.

Re-estimating sample size in cluster randomised trials with active recruitment within clusters.

PubMed

van Schie, S; Moerbeek, M

2014-08-30

Often only a limited number of clusters can be obtained in cluster randomised trials, although many potential participants can be recruited within each cluster. Thus, active recruitment is feasible within the clusters. To obtain an efficient sample size in a cluster randomised trial, the cluster level and individual level variance should be known before the study starts, but this is often not the case. We suggest using an internal pilot study design to address this problem of unknown variances. A pilot can be useful to re-estimate the variances and re-calculate the sample size during the trial. Using simulated data, it is shown that an initially low or high power can be adjusted using an internal pilot with the type I error rate remaining within an acceptable range. The intracluster correlation coefficient can be re-estimated with more precision, which has a positive effect on the sample size. We conclude that an internal pilot study design may be used if active recruitment is feasible within a limited number of clusters. Copyright © 2014 John Wiley & Sons, Ltd.

Nesfatin-1-regulated oxytocinergic signaling in the paraventricular nucleus causes anorexia through a leptin-independent melanocortin pathway.

PubMed

Maejima, Yuko; Sedbazar, Udval; Suyama, Shigetomo; Kohno, Daisuke; Onaka, Tatsushi; Takano, Eisuke; Yoshida, Natsu; Koike, Masato; Uchiyama, Yasuo; Fujiwara, Ken; Yashiro, Takashi; Horvath, Tamas L; Dietrich, Marcelo O; Tanaka, Shigeyasu; Dezaki, Katsuya; Oh-I, Shinsuke; Hashimoto, Koushi; Shimizu, Hiroyuki; Nakata, Masanori; Mori, Masatomo; Yada, Toshihiko

2009-11-01

The hypothalamic paraventricular nucleus (PVN) functions as a center to integrate various neuronal activities for regulating feeding behavior. Nesfatin-1, a recently discovered anorectic molecule, is localized in the PVN. However, the anorectic neural pathway of nesfatin-1 remains unknown. Here we show that central injection of nesfatin-1 activates the PVN and brain stem nucleus tractus solitarius (NTS). In the PVN, nesfatin-1 targets both magnocellular and parvocellular oxytocin neurons and nesfatin-1 neurons themselves and stimulates oxytocin release. Immunoelectron micrographs reveal nesfatin-1 specifically in the secretory vesicles of PVN neurons, and immunoneutralization against endogenous nesfatin-1 suppresses oxytocin release in the PVN, suggesting paracrine/autocrine actions of nesfatin-1. Nesfatin-1-induced anorexia is abolished by an oxytocin receptor antagonist. Moreover, oxytocin terminals are closely associated with and oxytocin activates pro-opiomelanocortin neurons in the NTS. Oxytocin induces melanocortin-dependent anorexia in leptin-resistant Zucker-fatty rats. The present results reveal the nesfatin-1-operative oxytocinergic signaling in the PVN that triggers leptin-independent melanocortin-mediated anorexia.

Impaired Bioenergetics in Mutant Mitochondrial DNA Determines Cell Fate During Seizure-Like Activity.

PubMed

Kovac, Stjepana; Preza, Elisavet; Houlden, Henry; Walker, Matthew C; Abramov, Andrey Y

2018-04-27

Mutations in genes affecting mitochondrial proteins are increasingly recognised in patients with epilepsy, but the factors determining cell fate during seizure activity in these mutations remain unknown. Fluorescent dye imaging techniques were applied to fibroblast cell lines from patients suffering from common mitochondrial mutations and to age-matched controls. Using live cell imaging techniques in fibroblasts, we show that fibroblasts with mutations in the mitochondrial genome had reduced mitochondrial membrane potential and NADH pools and higher redox indices, indicative of respiratory chain dysfunction. Increasing concentrations of ferutinin, a Ca 2+ ionophore, led to oscillatory Ca 2+ signals in fibroblasts resembling dynamic Ca 2+ changes that occur during seizure-like activity. Co-monitoring of mitochondrial membrane potential (ΔΨ m ) changes induced by ferutinin showed accelerated membrane depolarisation and cell collapse in fibroblasts with mutations in the mitochondrial genome when compared to controls. Ca 2+ flash photolysis using caged Ca 2+ confirmed impaired Ca 2+ handling in fibroblasts with mitochondrial mutations. Findings indicate that intracellular Ca 2+ levels cannot be compensated during periods of hyperexcitability, leading to Ca 2+ overload and subsequent cell death in mitochondrial diseases.

Structural insight into the activation of a class B G-protein-coupled receptor by peptide hormones in live human cells

PubMed Central

Seidel, Lisa; Zarzycka, Barbara; Zaidi, Saheem A; Katritch, Vsevolod; Coin, Irene

2017-01-01

The activation mechanism of class B G-protein-coupled receptors (GPCRs) remains largely unknown. To characterize conformational changes induced by peptide hormones, we investigated interactions of the class B corticotropin-releasing factor receptor type 1 (CRF1R) with two peptide agonists and three peptide antagonists obtained by N-truncation of the agonists. Surface mapping with genetically encoded photo-crosslinkers and pair-wise crosslinking revealed distinct footprints of agonists and antagonists on the transmembrane domain (TMD) of CRF1R and identified numerous ligand-receptor contact sites, directly from the intact receptor in live human cells. The data enabled generating atomistic models of CRF- and CRF(12-41)-bound CRF1R, further explored by molecular dynamics simulations. We show that bound agonist and antagonist adopt different folds and stabilize distinct TMD conformations, which involves bending of helices VI and VII around flexible glycine hinges. Conservation of these glycine hinges among all class B GPCRs suggests their general role in activation of these receptors. DOI: http://dx.doi.org/10.7554/eLife.27711.001 PMID:28771403

Serotonin 1B Receptors Regulate Prefrontal Function by Gating Callosal and Hippocampal Inputs.

PubMed

Kjaerby, Celia; Athilingam, Jegath; Robinson, Sarah E; Iafrati, Jillian; Sohal, Vikaas S

2016-12-13

Both medial prefrontal cortex (mPFC) and serotonin play key roles in anxiety; however, specific mechanisms through which serotonin might act on the mPFC to modulate anxiety-related behavior remain unknown. Here, we use a combination of optogenetics and synaptic physiology to show that serotonin acts presynaptically via 5-HT1B receptors to selectively suppress inputs from the contralateral mPFC and ventral hippocampus (vHPC), while sparing those from mediodorsal thalamus. To elucidate how these actions could potentially regulate prefrontal circuit function, we infused a 5-HT1B agonist into the mPFC of freely behaving mice. Consistent with previous studies that have optogenetically inhibited vHPC-mPFC projections, activating prefrontal 5-HT1B receptors suppressed theta-frequency mPFC activity (4-12 Hz), and reduced avoidance of anxiogenic regions in the elevated plus maze. These findings suggest a potential mechanism, linking specific receptors, synapses, patterns of circuit activity, and behavior, through which serotonin may regulate prefrontal circuit function, including anxiety-related behaviors. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Maternal xNorrin, a Canonical Wnt Signaling Agonist and TGF-β Antagonist, Controls Early Neuroectoderm Specification in Xenopus

PubMed Central

Xu, Suhong; Cheng, Feng; Liang, Juan; Wu, Wei; Zhang, Jian

2012-01-01

Dorsal–ventral specification in the amphibian embryo is controlled by β-catenin, whose activation in all dorsal cells is dependent on maternal Wnt11. However, it remains unknown whether other maternally secreted factors contribute to β-catenin activation in the dorsal ectoderm. Here, we show that maternal Xenopus Norrin (xNorrin) promotes anterior neural tissue formation in ventralized embryos. Conversely, when xNorrin function is inhibited, early canonical Wnt signaling in the dorsal ectoderm and the early expression of the zygotic neural inducers Chordin, Noggin, and Xnr3 are severely suppressed, causing the loss of anterior structures. In addition, xNorrin potently inhibits BMP- and Nodal/Activin-related functions through direct binding to the ligands. Moreover, a subset of Norrin mutants identified in humans with Norrie disease retain Wnt activation but show defective inhibition of Nodal/Activin-related signaling in mesoderm induction, suggesting that this disinhibition causes Norrie disease. Thus, xNorrin is an unusual molecule that acts on two major signaling pathways, Wnt and TGF-β, in opposite ways and is essential for early neuroectoderm specification. PMID:22448144

Representation of time interval entrained by periodic stimuli in the visual thalamus of pigeons

PubMed Central

Wang, Shu-Rong

2017-01-01

Animals use the temporal information from previously experienced periodic events to instruct their future behaviors. The retina and cortex are involved in such behavior, but it remains largely unknown how the thalamus, transferring visual information from the retina to the cortex, processes the periodic temporal patterns. Here we report that the luminance cells in the nucleus dorsolateralis anterior thalami (DLA) of pigeons exhibited oscillatory activities in a temporal pattern identical to the rhythmic luminance changes of repetitive light/dark (LD) stimuli with durations in the seconds-to-minutes range. Particularly, after LD stimulation, the DLA cells retained the entrained oscillatory activities with an interval closely matching the duration of the LD cycle. Furthermore, the post-stimulus oscillatory activities of the DLA cells were sustained without feedback inputs from the pallium (equivalent to the mammalian cortex). Our study suggests that the experience-dependent representation of time interval in the brain might not be confined to the pallial/cortical level, but may occur as early as at the thalamic level. PMID:29284554

The Molecular Basis of Wound Healing Processes Induced by Lithospermi Radix: A Proteomics and Biochemical Analysis

PubMed Central

Hsiao, Chia-Yen; Tsai, Tung-Hu; Chak, Kin-Fu

2012-01-01

Lithospermi Radix (LR) is an effective traditional Chinese herb in various types of wound healing; however, its mechanism of action remains unknown. A biochemical and proteomic platform was generated to explore the biological phenomena associated with LR and its active component shikonin. We found that both LR ethanol extracts and shikonin are able to promote cell proliferation by up to 25%. The results of proteomic analysis revealed that twenty-two differentially expressed proteins could be identified when fibroblast cells were treated with LR or shikonin. The functions of those proteins are associated with antioxidant activity, antiapoptosis activity, the regulation of cell mobility, the secretion of collagen, the removal of abnormal proteins, and the promotion of cell proliferation, indicating that the efficacy of LR in wound healing may be derived from a synergistic effect on a number of factors induced by the herbal medicine. Furthermore, an animal model confirmed that LR is able to accelerate wound healing on the flank back of the SD rats. Together these findings help to pinpoint the molecular basis of wound healing process induced by LR. PMID:23024692

Role of the durum wheat dehydrin in the function of proteases conferring salinity tolerance in Arabidopsis thaliana transgenic lines.

PubMed

Saibi, Walid; Zouari, Nabil; Masmoudi, Khaled; Brini, Faiçal

2016-04-01

Dehydrins are claimed to stabilize macromolecules against freezing damage, dehydration, ionic or osmotic stresses, thermal stress and re-folding yield. However, their precise function remains unknown. In this context, we report the behavior of protease activities in dehydrin transgenic Arabidopsis lines against the wild type plant under salt stress (100mM NaCl). Indeed, proteases play key roles in plants, maintaining strict protein quality control and degrading specific sets of proteins in response to diverse environmental and developmental stimuli. We proved that durum wheat DHN-5 modulates the activity of some proteases, summarized on the promotion of the Cysteinyl protease and the decrease of the Aspartyl protease activity. This fact is also upgraded in salt stress conditions. We conclude that the dehydrin transgenic context encodes salinity tolerance in transgenic lines through the modulation of the interaction not only at transcriptional level but also at protein level and also with the impact of salt stress as an endogenous and exogenous effector on some biocatalysts like proteases. Copyright © 2016 Elsevier B.V. All rights reserved.

Noise-induced plasticity of KCNQ2/3 and HCN channels underlies vulnerability and resilience to tinnitus

PubMed Central

Li, Shuang; Kalappa, Bopanna I; Tzounopoulos, Thanos

2015-01-01

Vulnerability to noise-induced tinnitus is associated with increased spontaneous firing rate in dorsal cochlear nucleus principal neurons, fusiform cells. This hyperactivity is caused, at least in part, by decreased Kv7.2/3 (KCNQ2/3) potassium currents. However, the biophysical mechanisms underlying resilience to tinnitus, which is observed in noise-exposed mice that do not develop tinnitus (non-tinnitus mice), remain unknown. Our results show that noise exposure induces, on average, a reduction in KCNQ2/3 channel activity in fusiform cells in noise-exposed mice by 4 days after exposure. Tinnitus is developed in mice that do not compensate for this reduction within the next 3 days. Resilience to tinnitus is developed in mice that show a re-emergence of KCNQ2/3 channel activity and a reduction in HCN channel activity. Our results highlight KCNQ2/3 and HCN channels as potential targets for designing novel therapeutics that may promote resilience to tinnitus. DOI: http://dx.doi.org/10.7554/eLife.07242.001 PMID:26312501

Does bilirubin prevent hepatic steatosis through activation of the PPARα nuclear receptor?

PubMed

Hinds, Terry D; Adeosun, Samuel O; Alamodi, Abdulhadi A; Stec, David E

2016-10-01

Several large population studies have demonstrated a negative correlation between serum bilirubin levels and the development of obesity, hepatic steatosis, and cardiovascular disease. Despite the strong correlative data demonstrating the protective role of bilirubin, the mechanism by which bilirubin can protect against these pathologies remains unknown. Bilirubin has long been known as a powerful antioxidant and also has anti-inflammatory actions, each of which may contribute to the protection afforded by increased levels. We have recently described a novel function of bilirubin as a ligand for the peroxisome proliferator-activated receptor-alpha (PPARα), which we show specifically binds to the nuclear receptor. Bilirubin may function as a selective PPAR modulator (SPPARM) to control lipid accumulation and blood glucose. However, it is not known to what degree bilirubin activation of PPARα is responsible for the protection afforded to reduce hepatic steatosis. We hypothesize that bilirubin, acting as a novel SPPARM, increases hepatic fatty acid metabolism through a PPARα-dependent mechanism which reduces hepatic lipid accumulation and protects against hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). Copyright © 2016 Elsevier Ltd. All rights reserved.

Brain Bases of Morphological Processing in Young Children

PubMed Central

Arredondo, Maria M.; Ip, Ka I; Hsu, Lucy Shih-Ju; Tardif, Twila; Kovelman, Ioulia

2017-01-01

How does the developing brain support the transition from spoken language to print? Two spoken language abilities form the initial base of child literacy across languages: knowledge of language sounds (phonology) and knowledge of the smallest units that carry meaning (morphology). While phonology has received much attention from the field, the brain mechanisms that support morphological competence for learning to read remain largely unknown. In the present study, young English-speaking children completed an auditory morphological awareness task behaviorally (n = 69, ages 6–12) and in fMRI (n = 16). The data revealed two findings: First, children with better morphological abilities showed greater activation in left temporo-parietal regions previously thought to be important for supporting phonological reading skills, suggesting that this region supports multiple language abilities for successful reading acquisition. Second, children showed activation in left frontal regions previously found active in young Chinese readers, suggesting morphological processes for reading acquisition might be similar across languages. These findings offer new insights for developing a comprehensive model of how spoken language abilities support children’s reading acquisition across languages. PMID:25930011

SAM domain-dependent activity of PfTKL3, an essential tyrosine kinase-like kinase of the human malaria parasite Plasmodium falciparum.

PubMed

Abdi, Abdirahman; Eschenlauer, Sylvain; Reininger, Luc; Doerig, Christian

2010-10-01

Over the last decade, several protein kinases inhibitors have reached the market for cancer chemotherapy. The kinomes of pathogens represent potentially attractive targets in infectious diseases. The functions of the majority of protein kinases of Plasmodium falciparum, the parasitic protist responsible for the most virulent form of human malaria, remain unknown. Here we present a thorough characterisation of PfTKL3 (PF13_0258), an enzyme that belongs to the tyrosine kinase-like kinase (TKL) group. We demonstrate by reverse genetics that PfTKL3 is essential for asexual parasite proliferation in human erythrocytes. PfTKL3 is expressed in both asexual and gametocytes stages, and in the latter the protein co-localises with cytoskeleton microtubules. Recombinant PfTKL3 displays in vitro autophosphorylation activity and is able to phosphorylate exogenous substrates, and both activities are dramatically dependent on the presence of an N-terminal "sterile alpha-motif" domain. This study identifies PfTKL3 as a validated drug target amenable to high-throughput screening.

Thermally activated TRP channels: molecular sensors for temperature detection.

PubMed

Castillo, Karen; Diaz-Franulic, Ignacio; Canan, Jonathan; Gonzalez-Nilo, Fernando; Latorre, Ramon

2018-01-24

Temperature sensing is one of the oldest capabilities of living organisms, and is essential for sustaining life, because failure to avoid extreme noxious temperatures can result in tissue damage or death. A subset of members of the transient receptor potential (TRP) ion channel family is finely tuned to detect temperatures ranging from extreme cold to noxious heat, giving rise to thermoTRP channels. Structural and functional experiments have shown that thermoTRP channels are allosteric proteins, containing different domains that sense changes in temperature, among other stimuli, triggering pore opening. Although temperature-dependence is well characterized in thermoTRP channels, the molecular nature of temperature-sensing elements remains unknown. Importantly, thermoTRP channels are involved in pain sensation, related to pathological conditions. Here, we provide an overview of thermoTRP channel activation. We also discuss the structural and functional evidence supporting the existence of an intrinsic temperature sensor in this class of channels, and we explore the basic thermodynamic principles for channel activation. Finally, we give a view of their role in painful pathophysiological conditions.

Chronic corticosterone exposure reduces hippocampal glycogen level and induces depression-like behavior in mice.

PubMed

Zhang, Hui-yu; Zhao, Yu-nan; Wang, Zhong-li; Huang, Yu-fang

2015-01-01

Long-term exposure to stress or high glucocorticoid levels leads to depression-like behavior in rodents; however, the cause remains unknown. Increasing evidence shows that astrocytes, the most abundant cells in the central nervous system (CNS), are important to the nervous system. Astrocytes nourish and protect the neurons, and serve as glycogen repositories for the brain. The metabolic process of glycogen, which is closely linked to neuronal activity, can supply sufficient energy substrates for neurons. The research team probed into the effects of chronic corticosterone (CORT) exposure on the glycogen level of astrocytes in the hippocampal tissues of male C57BL/6N mice in this study. The results showed that chronic CORT injection reduced hippocampal neurofilament light protein (NF-L) and synaptophysin (SYP) levels, induced depression-like behavior in male mice, reduced hippocampal glycogen level and glycogen synthase activity, and increased glycogen phosphorylase activity. The results suggested that the reduction of the hippocampal glycogen level may be the mechanism by which chronic CORT treatment damages hippocampal neurons and induces depression-like behavior in male mice.

Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling

PubMed Central

Honda, Kenya; Yanai, Hideyuki; Mizutani, Tatsuaki; Negishi, Hideo; Shimada, Naoya; Suzuki, Nobutaka; Ohba, Yusuke; Takaoka, Akinori; Yeh, Wen-Chen; Taniguchi, Tadatsugu

2004-01-01

Toll-like receptor (TLR) activation is central to immunity, wherein the activation of the TLR9 subfamily members TLR9 and TLR7 results in the robust induction of type I IFNs (IFN-α/β) by means of the MyD88 adaptor protein. However, it remains unknown how the TLR signal “input” can be processed through MyD88 to “output” the induction of the IFN genes. Here, we demonstrate that the transcription factor IRF-7 interacts with MyD88 to form a complex in the cytoplasm. We provide evidence that this complex also involves IRAK4 and TRAF6 and provides the foundation for the TLR9-dependent activation of the IFN genes. The complex defined in this study represents an example of how the coupling of the signaling adaptor and effector kinase molecules together with the transcription factor regulate the processing of an extracellular signal to evoke its versatile downstream transcriptional events in a cell. Thus, we propose that this molecular complex may function as a cytoplasmic transductional-transcriptional processor. PMID:15492225

Hepcidin as a Major Component of Renal Antibacterial Defenses against Uropathogenic Escherichia coli

PubMed Central

Houamel, Dounia; Ducrot, Nicolas; Lefebvre, Thibaud; Daher, Raed; Moulouel, Boualem; Sari, Marie-Agnes; Letteron, Philippe; Lyoumi, Said; Millot, Sarah; Tourret, Jerome; Bouvet, Odile; Vaulont, Sophie; Vandewalle, Alain; Denamur, Erick; Puy, Hervé; Beaumont, Carole; Gouya, Laurent

2016-01-01

The iron-regulatory peptide hepcidin exhibits antimicrobial activity. Having previously shown hepcidin expression in the kidney, we addressed its role in urinary tract infection (UTI), which remains largely unknown. Experimental UTI was induced in wild-type (WT) and hepcidin-knockout (Hepc−/−) mice using the uropathogenic Escherichia coli CFT073 strain. Compared with infected WT mice, infected Hepc−/− mice showed a dramatic increase in renal bacterial load. Moreover, bacterial invasion was significantly dampened by the pretreatment of WT mice with hepcidin. Infected Hepc−/− mice exhibited decreased iron accumulation in the renal medulla and significant attenuation of the renal inflammatory response. Notably, we demonstrated in vitro bacteriostatic activity of hepcidin against CFT073. Furthermore, CFT073 repressed renal hepcidin, both in vivo and in cultured renal cells, and reduced phosphorylation of SMAD kinase in vivo, suggesting a bacterial strategy to escape the antimicrobial activities of hepcidin. In conclusion, we provide new mechanisms by which hepcidin contributes to renal host defense and suggest that targeting hepcidin offers a strategy to prevent bacterial invasion. PMID:26293821

Protein Tyrosine Phosphatase-PEST and β8 Integrin Regulate Spatiotemporal Patterns of RhoGDI1 Activation in Migrating Cells

PubMed Central

Lee, Hye Shin; Cheerathodi, Mujeeburahiman; Chaki, Sankar P.; Reyes, Steve B.; Zheng, Yanhua; Lu, Zhimin; Paidassi, Helena; DerMardirossian, Celine; Lacy-Hulbert, Adam; Rivera, Gonzalo M.

2015-01-01

Directional cell motility is essential for normal development and physiology, although how motile cells spatiotemporally activate signaling events remains largely unknown. Here, we have characterized an adhesion and signaling unit comprised of protein tyrosine phosphatase (PTP)-PEST and the extracellular matrix (ECM) adhesion receptor β8 integrin that plays essential roles in directional cell motility. β8 integrin and PTP-PEST form protein complexes at the leading edge of migrating cells and balance patterns of Rac1 and Cdc42 signaling by controlling the subcellular localization and phosphorylation status of Rho GDP dissociation inhibitor 1 (RhoGDI1). Translocation of Src-phosphorylated RhoGDI1 to the cell's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin-bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1/Cdc42 in the cytoplasm. Collectively, these data reveal a finely tuned regulatory mechanism for controlling signaling events at the leading edge of directionally migrating cells. PMID:25666508

TLR4 signaling shapes B cell dynamics via MyD88-dependent pathways and Rac GTPases.

PubMed

Barrio, Laura; Saez de Guinoa, Julia; Carrasco, Yolanda R

2013-10-01

B cells use a plethora of TLR to recognize pathogen-derived ligands. These innate signals have an important function in the B cell adaptive immune response and modify their trafficking and tissue location. The direct role of TLR signaling on B cell dynamics nonetheless remains almost entirely unknown. In this study, we used a state-of-the-art two-dimensional model combined with real-time microscopy to study the effect of TLR4 stimulation on mouse B cell motility in response to chemokines. We show that a minimum stimulation period is necessary for TLR4 modification of B cell behavior. TLR4 stimulation increased B cell polarization, migration, and directionality; these increases were dependent on the MyD88 signaling pathway and did not require ERK or p38 MAPK activity downstream of TLR4. In addition, TLR4 stimulation enhanced Rac GTPase activity and promoted sustained Rac activation in response to chemokines. These results increase our understanding of the regulation of B cell dynamics by innate signals and the underlying molecular mechanisms.

Psychedelics Recruit Multiple Cellular Types and Produce Complex Transcriptional Responses Within the Brain.

PubMed

Martin, David A; Nichols, Charles D

2016-09-01

There has recently been a resurgence of interest in psychedelics, substances that profoundly alter perception and cognition and have recently demonstrated therapeutic efficacy to treat anxiety, depression, and addiction in the clinic. The receptor mechanisms that drive their molecular and behavioral effects involve activation of cortical serotonin 5-HT 2A receptors, but the responses of specific cellular populations remain unknown. Here, we provide evidence that a small subset of 5-HT 2A -expressing excitatory neurons is directly activated by psychedelics and subsequently recruits other select cell types including subpopulations of inhibitory somatostatin and parvalbumin GABAergic interneurons, as well as astrocytes, to produce distinct and regional responses. To gather data regarding the response of specific neuronal populations, we developed methodology for fluorescence-activated cell sorting (FACS) to segregate and enrich specific cellular subtypes in the brain. These methods allow for robust neuronal sorting based on cytoplasmic epitopes followed by downstream nucleic acid analysis, expanding the utility of FACS in neuroscience research. Copyright © 2016 Forschungsgesellschaft für Arbeitsphysiologie und Arbeitschutz e.V. Published by Elsevier B.V. All rights reserved.

The effects of type I interferon on glioblastoma cancer stem cells.

PubMed

Du, Ziyun; Cai, Chun; Sims, Michelle; Boop, Frederick A; Davidoff, Andrew M; Pfeffer, Lawrence M

2017-09-16

Glioblastomas (GBMs) are highly invasive brain tumors that are extremely deadly. The highly aggressive nature of GBM as well as its heterogeneity at the molecular and cellular levels has been attributed to a rare subpopulation of GBM stem-like cells (GSCs). Interferons (IFNs) are a family of endogenous antiviral proteins that have anticancer activity in vitro, and have been used clinically to treat GBM. IFN inhibits the proliferation of various established GBM cell lines, but the effects of IFNs on GSCs remain relatively unknown. The present study explored the effects of IFN on the proliferation and the differentiation capacity of GSCs isolated from GBM patient-derived xenolines (PDXs) grown as xenografts in immunocompromised mice. We show that IFN inhibits the proliferation of GSCs, inhibits the sphere forming capacity of GSCs that is a hallmark of cancer stem cells, and inhibits the ability of GSCs to differentiate into astrocytic cells. In addition, we show that IFN induces transient STAT3 activation in GSCs, while induction of astrocytic differentiation in GSCs results in sustained STAT3 activation. Copyright © 2017 Elsevier Inc. All rights reserved.

Rapid mitogenic regulation of the mTORC1 inhibitor, DEPTOR, by phosphatidic acid.

PubMed

Yoon, Mee-Sup; Rosenberger, Christina L; Wu, Cong; Truong, Nga; Sweedler, Jonathan V; Chen, Jie

2015-05-07

The mammalian target of rapamycin complex 1 (mTORC1) is regulated, in part, by the endogenous inhibitor DEPTOR. However, the mechanism of DEPTOR regulation with regard to rapid mTORC1 activation remains unknown. We report that DEPTOR is rapidly and temporarily dissociated from mTORC1 upon mitogenic stimulation, suggesting a mechanism underlying acute mTORC1 activation. This mitogen-stimulated DEPTOR dissociation is blocked by inhibition or depletion of the mTORC1 regulator, phospholipase D (PLD), and recapitulated with the addition of the PLD product phosphatidic acid (PA). Our mass spectrometry analysis has independently identified DEPTOR as an mTOR binding partner dissociated by PA. Interestingly, only PA species with unsaturated fatty acid chains, such as those produced by PLD, are capable of displacing DEPTOR and activating mTORC1, with high affinity for the FRB domain of mTOR. Our findings reveal a mechanism of mTOR regulation and provide a molecular explanation for the exquisite specificity of PA function. Copyright © 2015 Elsevier Inc. All rights reserved.

Coffee phenolic phytochemicals suppress colon cancer metastasis by targeting MEK and TOPK

PubMed Central

Kang, Nam Joo; Lee, Ki Won; Kim, Bo Hyun; Bode, Ann M.; Lee, Hyo-Jeong; Heo, Yong-Seok; Boardman, Lisa; Limburg, Paul; Lee, Hyong Joo; Dong, Zigang

2011-01-01

Epidemiological studies suggest that coffee consumption reduces the risk of cancers, including colon cancer, but the molecular mechanisms and target(s) underlying the chemopreventive effects of coffee and its active ingredient(s) remain unknown. Based on serving size or daily units, coffee contains larger amounts of phenolic phytochemicals than tea or red wine. Coffee or chlorogenic acid inhibited CT-26 colon cancer cell-induced lung metastasis by blocking phosphorylation of ERKs. Coffee or caffeic acid (CaA) strongly suppressed mitogen-activated MEK1 and TOPK activities and bound directly to either MEK1 or TOPK in an ATP-noncompetitive manner. Coffee or CaA, but not caffeine, inhibited ERKs phosphorylation, AP-1 and NF-κB transactivation and subsequently inhibited TPA-, EGF- and H-Ras-induced neoplastic transformation of JB6 P+ cells. Coffee consumption was also associated with a significant attenuation of ERKs phosphorylation in colon cancer patients. These results suggest that coffee and CaA target MEK1 and TOPK to suppress colon cancer metastasis and neoplastic cell transformation. PMID:21317303

Mitochondrial ADCK3 employs an atypical protein kinase-like fold to enable coenzyme Q biosynthesis

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

Stefely, Jonathan A.; Reidenbach, Andrew G.; Ulbrich, Arne

The ancient UbiB protein kinase-like family is involved in isoprenoid lipid biosynthesis and is implicated in human diseases, but demonstration of UbiB kinase activity has remained elusive for unknown reasons. In this paper, we quantitatively define UbiB-specific sequence motifs and reveal their positions within the crystal structure of a UbiB protein, ADCK3. We find that multiple UbiB-specific features are poised to inhibit protein kinase activity, including an N-terminal domain that occupies the typical substrate binding pocket and a unique A-rich loop that limits ATP binding by establishing an unusual selectivity for ADP. A single alanine-to-glycine mutation of this loop flipsmore » this coenzyme selectivity and enables autophosphorylation but inhibits coenzyme Q biosynthesis in vivo, demonstrating functional relevance for this unique feature. Finally, our work provides mechanistic insight into UbiB enzyme activity and establishes a molecular foundation for further investigation of how UbiB family proteins affect diseases and diverse biological pathways.« less

Omega-3 Fatty Acids Modulate TRPV4 Function through Plasma Membrane Remodeling.

PubMed

Caires, Rebeca; Sierra-Valdez, Francisco J; Millet, Jonathan R M; Herwig, Joshua D; Roan, Esra; Vásquez, Valeria; Cordero-Morales, Julio F

2017-10-03

Dietary consumption of ω-3 polyunsaturated fatty acids (PUFAs), present in fish oils, is known to improve the vascular response, but their molecular targets remain largely unknown. Activation of the TRPV4 channel has been implicated in endothelium-dependent vasorelaxation. Here, we studied the contribution of ω-3 PUFAs to TRPV4 function by precisely manipulating the fatty acid content in Caenorhabditis elegans. By genetically depriving the worms of PUFAs, we determined that the metabolism of ω-3 fatty acids is required for TRPV4 activity. Functional, lipid metabolome, and biophysical analyses demonstrated that ω-3 PUFAs enhance TRPV4 function in human endothelial cells and support the hypothesis that lipid metabolism and membrane remodeling regulate cell reactivity. We propose a model whereby the eicosanoid's epoxide group location increases membrane fluidity and influences the endothelial cell response by increasing TRPV4 channel activity. ω-3 PUFA-like molecules might be viable antihypertensive agents for targeting TRPV4 to reduce systemic blood pressure. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Activity-Dependent IGF-1 Exocytosis is Controlled by the Ca2+-Sensor Synaptotagmin-10

PubMed Central

Cao, Peng; Maximov, Anton; Südhof, Thomas C.

2011-01-01

Synaptotagmins Syt1, Syt2, Syt7, and Syt9 act as Ca2+-sensors for synaptic and neuroendocrine exocytosis, but the function of other synaptotagmins remains unknown. Here, we show that olfactory bulb neurons secrete IGF-1 by an activity-dependent pathway of exocytosis, and that Syt10 functions as the Ca2+-sensor that triggers IGF-1 exocytosis in these neurons. Deletion of Syt10 impaired activity-dependent IGF-1 secretion in olfactory bulb neurons, resulting in smaller neurons and an overall decrease in synapse numbers. Exogenous IGF-1 completely reversed the Syt10 knockout phenotype. Syt10 co-localized with IGF-1 in somatodendritic vesicles of olfactory bulb neurons, and Ca2+-binding to Syt10 caused these vesicles to undergo exocytosis, thereby secreting IGF-1. Thus, Syt10 controls a previously unrecognized pathway of Ca2+-dependent exocytosis that is spatially and temporally distinct from Ca2+-dependent synaptic vesicle exocytosis controlled by Syt1 in the same neurons, and two different synaptotagmins regulate distinct Ca2+-dependent membrane fusion reactions during exocytosis in the same neuron. PMID:21496647

An Ime2-like mitogen-activated protein kinase is involved in cellulase expression in the filamentous fungus Trichoderma reesei.

PubMed

Chen, Fei; Chen, Xiu-Zhen; Su, Xiao-Yun; Qin, Li-Na; Huang, Zhen-Bang; Tao, Yong; Dong, Zhi-Yang

2015-10-01

Eukaryotic mitogen-activated protein kinases (MAPKs) play crucial roles in transducing environmental and developmental signals inside the cell and regulating gene expression, however, the roles of MAPKs remain largely unknown in Trichoderma reesei. T. reesei ime2 (TrIme2) encodes an Ime2-like MAPK in T. reesei. The deletion of the TrIme2 gene led to 90% increase in cellulase activity against filter paper during earlier period time of cellulase induction as well as the extracellular protein production. Compared to the parent strain, the transcriptional levels of the three major cellulase genes cbh1,cbh2, egl1 were increased by about 9 times, 4 times, 2 times, respectively, at 8 h after cellulase induction in the ΔTrIme2 mutant. In addition, the disruption of TrIme2 caused over 50% reduction of the transcript levels of cellulase transcriptional regulators cre1 and xyr1. TrIme2 functions in regulation of the expression of cellulase gene in T.reesei, and is a good candidate for genetically engineering of T. reesei for higher cellulase production.

Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus

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

Ji, Quanjiang; Chen, Peter J.; Qin, Guangrong

Most low GC Gram-positive bacteria possess an essential walKR two-component system (TCS) for signal transduction involved in regulating cell wall homoeostasis. Despite the well-established intracellular regulatory mechanism, the role of this TCS in extracellular signal recognition and factors that modulate the activity of this TCS remain largely unknown. Here we identify the extracellular receptor of the kinase ‘WalK’ (erWalK) as a key hub for bridging extracellular signal input and intracellular kinase activity modulation in Staphylococcus aureus. Characterization of the crystal structure of erWalK revealed a canonical Per-Arnt-Sim (PAS) domain for signal sensing. Single amino-acid mutation of potential signal-transduction residues resultedmore » in severely impaired function of WalKR. A small molecule derived from structure-based virtual screening against erWalK is capable of selectively activating the walKR TCS. Lastly, the molecular level characterization of erWalK will not only facilitate exploration of natural signal(s) but also provide a template for rational design of erWalK inhibitors.« less

Critical role of dendritic cell-derived IL-27 in antitumor immunity through regulating the recruitment and activation of NK and NKT cells.

PubMed

Wei, Jun; Xia, Siyuan; Sun, Huayan; Zhang, Song; Wang, Jingya; Zhao, Huiyuan; Wu, Xiaoli; Chen, Xi; Hao, Jianlei; Zhou, Xinglong; Zhu, Zhengmao; Gao, Xiang; Gao, Jian-xin; Wang, Puyue; Wu, Zhenzhou; Zhao, Liqing; Yin, Zhinan

2013-07-01

Critical roles of IL-27 in autoimmune diseases and infections have been reported; however, the contribution of endogenous IL-27 to tumor progression remains elusive. In this study, by using IL-27p28 conditional knockout mice, we demonstrate that IL-27 is critical in protective immune response against methyl-cholanthrene-induced fibrosarcoma and transplanted B16 melanoma, and dendritic cells (DCs) are the primary source. DC-derived IL-27 is required for shaping tumor microenvironment by inducing CXCL-10 expression in myeloid-derived suppressor cells and regulating IL-12 production from DCs, which lead to the recruitment and activation of NK and NKT cells resulting in immunological control of tumors. Indeed, reconstitution of IL-27 or CXCL-10 in tumor site significantly inhibits tumor growth and restores the number and activation of NK and NKT cells. In summary, our study identifies a previous unknown critical role of DC-derived IL-27 in NK and NKT cell-dependent antitumor immunity through shaping tumor microenvironment, and sheds light on developing novel therapeutic approaches based on IL-27.

Working memory training improves emotional states of healthy individuals

PubMed Central

Takeuchi, Hikaru; Taki, Yasuyuki; Nouchi, Rui; Hashizume, Hiroshi; Sekiguchi, Atsushi; Kotozaki, Yuka; Nakagawa, Seishu; Miyauchi, Carlos Makoto; Sassa, Yuko; Kawashima, Ryuta

2014-01-01

Working memory (WM) capacity is associated with various emotional aspects, including states of depression and stress, reactions to emotional stimuli, and regulatory behaviors. We have previously investigated the effects of WM training (WMT) on cognitive functions and brain structures. However, the effects of WMT on emotional states and related neural mechanisms among healthy young adults remain unknown. In the present study, we investigated these effects in young adults who underwent WMT or received no intervention for 4 weeks. Before and after the intervention, subjects completed self-report questionnaires related to their emotional states and underwent scanning sessions in which brain activities related to negative emotions were measured. Compared with controls, subjects who underwent WMT showed reduced anger, fatigue, and depression. Furthermore, WMT reduced activity in the left posterior insula during tasks evoking negative emotion, which was related to anger. It also reduced activity in the left frontoparietal area. These findings show that WMT can reduce negative mood and provide new insight into the clinical applications of WMT, at least among subjects with preclinical-level conditions. PMID:25360090

Valosin containing protein (VCP) interacts with macrolide antibiotics without mediating their anti-inflammatory activities.

PubMed

Nujić, Krunoslav; Smith, Marjorie; Lee, Michael; Belamarić, Daniela; Tomašković, Linda; Alihodžić, Sulejman; Malnar, Ivica; Polančec, Denis; Schneider, Klaus; Eraković Haber, Vesna

2012-02-29

In addition to antibacterial activity, some macrolide antibiotics, such as azithromycin and clarithromycin, also exhibit anti-inflammatory properties in vitro and in vivo, although the targets and mechanism(s) of action remain unknown. The aim of the present study was to identify protein targets of azithromycin and clarithromycin which could potentially explain their anti-inflammatory effects. Using chemical proteomics approach, based on compound-immobilized affinity chromatography, valosin containing protein (VCP) was identified as a potential target of the macrolides. Validation studies confirmed the interaction of macrolides and VCP and gave some structural characteristics of this interaction. Cell based assays however, including the use of gene silencing and the study of VCP specific cellular functions in J774.A1 (murine macrophage) and IB3-1 (human cystic fibrotic epithelial) cell lines, failed to confirm an association between the binding of the macrolides to VCP and anti-inflammatory effects. These findings suggest the absence of an abundant high affinity protein target and the potential involvement of other biological molecules in the anti-inflammatory activity of macrolides. Copyright © 2011 Elsevier B.V. All rights reserved.

Toll-like receptor-mediated inhibition of Gas6 and ProS expression facilitates inflammatory cytokine production in mouse macrophages

PubMed Central

Deng, Tingting; Zhang, Yue; Chen, Qiaoyuan; Yan, Keqin; Han, Daishu

2012-01-01

Activation of Toll-like receptors (TLRs) triggers rapid inflammatory cytokine production in various cell types. The exogenous product of growth-arrest-specific gene 6 (Gas6) and Protein S (ProS) inhibit the TLR-triggered inflammatory responses through the activation of Tyro3, Axl and Mer (TAM) receptors. However, regulation of the Gas6/ProS-TAM system remains largely unknown. In the current study, mouse macrophages are shown to constitutively express Gas6 and ProS, which synergistically suppress the basal and TLR-triggered production of inflammatory cytokines, including those of tumour necrosis factor-α, interleukin-6 and interleukin-1β, by the macrophages in an autocrine manner. Notably, TLR signalling markedly decreases Gas6 and ProS expression in macrophages through the activation of the nuclear factor-κB. Further, the down-regulation of Gas6 and ProS by TLR signalling facilitates the TLR-mediated inflammatory cytokine production in mouse macrophages. These results describe a self-regulatory mechanism of TLR signalling through the suppression of Gas6 and ProS expression. PMID:22043818

Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus

DOE PAGES

Ji, Quanjiang; Chen, Peter J.; Qin, Guangrong; ...

2016-03-18

Most low GC Gram-positive bacteria possess an essential walKR two-component system (TCS) for signal transduction involved in regulating cell wall homoeostasis. Despite the well-established intracellular regulatory mechanism, the role of this TCS in extracellular signal recognition and factors that modulate the activity of this TCS remain largely unknown. Here we identify the extracellular receptor of the kinase ‘WalK’ (erWalK) as a key hub for bridging extracellular signal input and intracellular kinase activity modulation in Staphylococcus aureus. Characterization of the crystal structure of erWalK revealed a canonical Per-Arnt-Sim (PAS) domain for signal sensing. Single amino-acid mutation of potential signal-transduction residues resultedmore » in severely impaired function of WalKR. A small molecule derived from structure-based virtual screening against erWalK is capable of selectively activating the walKR TCS. Lastly, the molecular level characterization of erWalK will not only facilitate exploration of natural signal(s) but also provide a template for rational design of erWalK inhibitors.« less

Graded Encoding of Food Odor Value in the Drosophila Brain

PubMed Central

Beshel, Jennifer

2013-01-01

Odors are highly evocative, yet how and where in the brain odors derive meaning remains unknown. Our analysis of the Drosophila brain extends the role of a small number of hunger-sensing neurons to include food-odor value representation. In vivo two-photon calcium imaging shows the amplitude of food odor-evoked activity in neurons expressing Drosophila neuropeptide F (dNPF), the neuropeptide Y homolog, strongly correlates with food-odor attractiveness. Hunger elevates neural and behavioral responses to food odors only, although food odors that elicit attraction in the fed state also evoke heightened dNPF activity in fed flies. Inactivation of a subset of dNPF-expressing neurons or silencing dNPF receptors abolishes food-odor attractiveness, whereas genetically enhanced dNPF activity not only increases food-odor attractiveness but promotes attraction to aversive odors. Varying the amount of presented odor produces matching graded neural and behavioral curves, which can function to predict preference between odors. We thus demonstrate a possible motivationally scaled neural “value signal” accessible from uniquely identifiable cells. PMID:24089477

Renal dopamine containing nerves. What is their functional significance?

PubMed

DiBona, G F

1990-06-01

Biochemical and morphological studies indicate that there are nerves within the kidney that contain dopamine and that various structures within the kidney contain dopamine receptors. However, the functional significance of these renal dopamine containing nerves in relation to renal dopamine receptors is unknown. The functional significance could be defined by demonstrating that an alteration in one or more renal functions occurring in response to reflex or electrical activation of efferent renal nerves is dependent on release of dopamine as the neurotransmitter from the renal nerve terminals acting on renal dopamine receptors. Thus, the hypothesis becomes: reflex or electrical activation of efferent renal nerves causes alterations in renal function (eg, renal blood flow, water and solute handling) that are inhibited by specific and selective dopamine receptor antagonists. As reviewed herein, the published experimental data do not support the hypothesis. Therefore, the view that alterations in one or more renal functions occurring in response to reflex or electrical activation of efferent renal nerves are dependent on release of dopamine as the neurotransmitter from the renal nerve terminals acting on renal dopamine receptors remains unproven.

Mitochondrial ADCK3 employs an atypical protein kinase-like fold to enable coenzyme Q biosynthesis

DOE PAGES

Stefely, Jonathan A.; Reidenbach, Andrew G.; Ulbrich, Arne; ...

2014-12-11

The ancient UbiB protein kinase-like family is involved in isoprenoid lipid biosynthesis and is implicated in human diseases, but demonstration of UbiB kinase activity has remained elusive for unknown reasons. In this paper, we quantitatively define UbiB-specific sequence motifs and reveal their positions within the crystal structure of a UbiB protein, ADCK3. We find that multiple UbiB-specific features are poised to inhibit protein kinase activity, including an N-terminal domain that occupies the typical substrate binding pocket and a unique A-rich loop that limits ATP binding by establishing an unusual selectivity for ADP. A single alanine-to-glycine mutation of this loop flipsmore » this coenzyme selectivity and enables autophosphorylation but inhibits coenzyme Q biosynthesis in vivo, demonstrating functional relevance for this unique feature. Finally, our work provides mechanistic insight into UbiB enzyme activity and establishes a molecular foundation for further investigation of how UbiB family proteins affect diseases and diverse biological pathways.« less

Organization of Functional Long-Range Circuits Controlling the Activity of Serotonergic Neurons in the Dorsal Raphe Nucleus.

PubMed

Zhou, Li; Liu, Ming-Zhe; Li, Qing; Deng, Juan; Mu, Di; Sun, Yan-Gang

2017-03-21

Serotonergic neurons play key roles in various biological processes. However, circuit mechanisms underlying tight control of serotonergic neurons remain largely unknown. Here, we systematically investigated the organization of long-range synaptic inputs to serotonergic neurons and GABAergic neurons in the dorsal raphe nucleus (DRN) of mice with a combination of viral tracing, slice electrophysiological, and optogenetic techniques. We found that DRN serotonergic neurons and GABAergic neurons receive largely comparable synaptic inputs from six major upstream brain areas. Upon further analysis of the fine functional circuit structures, we found both bilateral and ipsilateral patterns of topographic connectivity in the DRN for the axons from different inputs. Moreover, the upstream brain areas were found to bidirectionally control the activity of DRN serotonergic neurons by recruiting feedforward inhibition or via a push-pull mechanism. Our study provides a framework for further deciphering the functional roles of long-range circuits controlling the activity of serotonergic neurons in the DRN. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

MOFzyme: Intrinsic protease-like activity of Cu-MOF.

PubMed

Li, Bin; Chen, Daomei; Wang, Jiaqiang; Yan, Zhiying; Jiang, Liang; Deliang Duan; He, Jiao; Luo, Zhongrui; Zhang, Jinping; Yuan, Fagui

2014-10-24

The construction of efficient enzyme mimetics for the hydrolysis of peptide bonds in proteins is challenging due to the high stability of peptide bonds and the importance of proteases in biology and industry. Metal-organic frameworks (MOFs) consisting of infinite crystalline lattices with metal clusters and organic linkers may provide opportunities for protease mimic which has remained unknown. Herein, we report that Cu₂(C₉H₃O₆)₄/₃ MOF (which is well known as HKUST-1 and denoted as Cu-MOF here), possesses an intrinsic enzyme mimicking activity similar to that found in natural trypsin to bovine serum albumin (BSA) and casein. The Michaelis constant (Km) of Cu-MOF is about 26,000-fold smaller than that of free trypsin indicating a much higher affinity of BSA for Cu-MOF surface. Cu-MOF also exhibited significantly higher catalytic efficiency than homogeneous artificial metalloprotease Cu(II) complexes and could be reused for ten times without losing in its activity. Moreover, Cu-MOF was successfully used to simulate trypsinization in cell culture since it dissociated cells in culture even without EDTA.

MOFzyme: Intrinsic protease-like activity of Cu-MOF

NASA Astrophysics Data System (ADS)

Li, Bin; Chen, Daomei; Wang, Jiaqiang; Yan, Zhiying; Jiang, Liang; Deliang Duan; He, Jiao; Luo, Zhongrui; Zhang, Jinping; Yuan, Fagui

2014-10-01

The construction of efficient enzyme mimetics for the hydrolysis of peptide bonds in proteins is challenging due to the high stability of peptide bonds and the importance of proteases in biology and industry. Metal-organic frameworks (MOFs) consisting of infinite crystalline lattices with metal clusters and organic linkers may provide opportunities for protease mimic which has remained unknown. Herein, we report that Cu2(C9H3O6)4/3 MOF (which is well known as HKUST-1 and denoted as Cu-MOF here), possesses an intrinsic enzyme mimicking activity similar to that found in natural trypsin to bovine serum albumin (BSA) and casein. The Michaelis constant (Km) of Cu-MOF is about 26,000-fold smaller than that of free trypsin indicating a much higher affinity of BSA for Cu-MOF surface. Cu-MOF also exhibited significantly higher catalytic efficiency than homogeneous artificial metalloprotease Cu(II) complexes and could be reused for ten times without losing in its activity. Moreover, Cu-MOF was successfully used to simulate trypsinization in cell culture since it dissociated cells in culture even without EDTA.

MOFzyme: Intrinsic protease-like activity of Cu-MOF

PubMed Central

Li, Bin; Chen, Daomei; Wang, Jiaqiang; Yan, Zhiying; Jiang, Liang; Deliang Duan; He, Jiao; Luo, Zhongrui; Zhang, Jinping; Yuan, Fagui

2014-01-01

The construction of efficient enzyme mimetics for the hydrolysis of peptide bonds in proteins is challenging due to the high stability of peptide bonds and the importance of proteases in biology and industry. Metal-organic frameworks (MOFs) consisting of infinite crystalline lattices with metal clusters and organic linkers may provide opportunities for protease mimic which has remained unknown. Herein, we report that Cu2(C9H3O6)4/3 MOF (which is well known as HKUST-1 and denoted as Cu-MOF here), possesses an intrinsic enzyme mimicking activity similar to that found in natural trypsin to bovine serum albumin (BSA) and casein. The Michaelis constant (Km) of Cu-MOF is about 26,000-fold smaller than that of free trypsin indicating a much higher affinity of BSA for Cu-MOF surface. Cu-MOF also exhibited significantly higher catalytic efficiency than homogeneous artificial metalloprotease Cu(II) complexes and could be reused for ten times without losing in its activity. Moreover, Cu-MOF was successfully used to simulate trypsinization in cell culture since it dissociated cells in culture even without EDTA. PMID:25342169

Decreased A-to-I RNA editing as a source of keratinocytes' dsRNA in psoriasis.

PubMed

Shallev, Lea; Kopel, Eli; Feiglin, Ariel; Leichner, Gil S; Avni, Dror; Sidi, Yechezkel; Eisenberg, Eli; Barzilai, Aviv; Levanon, Erez Y; Greenberger, Shoshana

2018-06-01

Recognition of dsRNA molecules activates the MDA5-MAVS pathway and plays a critical role in stimulating type-I interferon responses in psoriasis. However, the source of the dsRNA accumulation in psoriatic keratinocytes remains largely unknown. A-to-I RNA editing is a common co- or post-transcriptional modification that diversifies adenosine in dsRNA, and leads to unwinding of dsRNA structures. Thus, impaired RNA editing activity can result in an increased load of endogenous dsRNAs. Here we provide a transcriptome-wide analysis of RNA editing across dozens of psoriasis patients, and we demonstrate a global editing reduction in psoriatic lesions. In addition to the global alteration, we also detect editing changes in functional recoding sites located in the IGFBP7 , COPA , and FLNA genes. Accretion of dsRNA activates autoimmune responses, and therefore the results presented here, linking for the first time an autoimmune disease to reduction in global editing level, are relevant to a wide range of autoimmune diseases. © 2018 Shallev et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Seizure Termination by Acidosis Depends on ASIC1a

PubMed Central

Ziemann, Adam E.; Schnizler, Mikael K.; Albert, Gregory W.; Severson, Meryl A.; Howard, Matthew A.; Welsh, Michael J.; Wemmie, John A.

2008-01-01

SUMMARY Most seizures stop spontaneously. However, the molecular mechanisms remain unknown. Earlier observations that seizures reduce brain pH and that acidosis inhibits seizures indicated that acidosis halts epileptic activity. Because acid–sensing ion channel–1a (ASIC1a) shows exquisite sensitivity to extracellular pH and regulates neuron excitability, we hypothesized that acidosis might activate ASIC1a to terminate seizures. Disrupting mouse ASIC1a increased the severity of chemoconvulsant–induced seizures, whereas overexpressing ASIC1a had the opposite effect. ASIC1a did not affect seizure threshold or onset, but shortened seizure duration and prevented progression. CO2 inhalation, long known to lower brain pH and inhibit seizures, also required ASIC1a to interrupt tonic–clonic seizures. Acidosis activated inhibitory interneurons through ASIC1a, suggesting that ASIC1a might limit seizures by increasing inhibitory tone. These findings identify ASIC1a as a key element in seizure termination when brain pH falls. The results suggest a molecular mechanism for how the brain stops seizures and suggest new therapeutic strategies. PMID:18536711

Structural Basis for Ligand Regulation of the Fatty Acid-binding Protein 5, Peroxisome Proliferator-activated Receptor β/δ (FABP5-PPARβ/δ) Signaling Pathway*

PubMed Central

Armstrong, Eric H.; Goswami, Devrishi; Griffin, Patrick R.; Noy, Noa; Ortlund, Eric A.

2014-01-01

Fatty acid-binding proteins (FABPs) are a widely expressed group of calycins that play a well established role in solubilizing cellular fatty acids. Recent studies, however, have recast FABPs as active participants in vital lipid-signaling pathways. FABP5, like its family members, displays a promiscuous ligand binding profile, capable of interacting with numerous long chain fatty acids of varying degrees of saturation. Certain “activating” fatty acids induce the protein's cytoplasmic to nuclear translocation, stimulating PPARβ/δ transactivation; however, the rules that govern this process remain unknown. Using a range of structural and biochemical techniques, we show that both linoleic and arachidonic acid elicit FABP5's translocation by permitting allosteric communication between the ligand-sensing β2 loop and a tertiary nuclear localization signal within the α-helical cap of the protein. Furthermore, we show that more saturated, nonactivating fatty acids inhibit nuclear localization signal formation by destabilizing this activation loop, thus implicating FABP5 specifically in cis-bonded, polyunsaturated fatty acid signaling. PMID:24692551

Volcanic emissions from soils at the base of La Fossa volcano, Vulcano island, Italy

NASA Astrophysics Data System (ADS)

Obenholzner, J. H.; Parks, J. L.

2006-12-01

A top-sealed plastic tube with a diameter of ca. 15 cm had been buried vertically at the base of La Fossa volcano, Volcano island, Italy, next to the front of the obsidian flow. The tube had been filled with quartz wool to condense vapors emanating from the soil. At ca. 75 cm below the surface the sample had been exposed to vapors from Sept. 2005 to April 2006. The leached sample had not been in touch with the ground. Another glass wool cushion (ca. 3 cm thick) had been underneath to minimize capillary effects. Leaching of the quartz wool and ICP-MS analysis documented positive values for: Mg, Al, Si, P, K, Ca, Cr, Mn, Ni, Cu, Zn, Cd, Sn, Pb. Leaching with nitric acid documented also V and Fe. Acid leaching produced higher values for all elements, except K and Sn, than leaching with deionized water. Negative values had been obtained for As, Se, Mo. Influence from soil breathing can be excluded as the active fumaroles contain As and Se. This experiment documents for the first time an unknown element transport by vapors/gases through a volcanic edifice interacting with hydrothermal and magmatic gases. It remains unknown if elements detected are entering the atmosphere or are getting adsorbed onto the volcanic ash soil particles derived from reworked surge beds. This question is very important as soils might be an unknown filter medium to filter volcanically polluted air in case of major volcanic crises. Data can be obtained from the authors.

Identification of Odorant-Receptor Interactions by Global Mapping of the Human Odorome

PubMed Central

Audouze, Karine; Tromelin, Anne; Le Bon, Anne Marie; Belloir, Christine; Petersen, Rasmus Koefoed; Kristiansen, Karsten; Brunak, Søren; Taboureau, Olivier

2014-01-01

The human olfactory system recognizes a broad spectrum of odorants using approximately 400 different olfactory receptors (hORs). Although significant improvements of heterologous expression systems used to study interactions between ORs and odorant molecules have been made, screening the olfactory repertoire of hORs remains a tremendous challenge. We therefore developed a chemical systems level approach based on protein-protein association network to investigate novel hOR-odorant relationships. Using this new approach, we proposed and validated new bioactivities for odorant molecules and OR2W1, OR51E1 and OR5P3. As it remains largely unknown how human perception of odorants influence or prevent diseases, we also developed an odorant-protein matrix to explore global relationships between chemicals, biological targets and disease susceptibilities. We successfully experimentally demonstrated interactions between odorants and the cannabinoid receptor 1 (CB1) and the peroxisome proliferator-activated receptor gamma (PPARγ). Overall, these results illustrate the potential of integrative systems chemical biology to explore the impact of odorant molecules on human health, i.e. human odorome. PMID:24695519

Phylogenetics beyond biology.

PubMed

Retzlaff, Nancy; Stadler, Peter F

2018-06-21

Evolutionary processes have been described not only in biology but also for a wide range of human cultural activities including languages and law. In contrast to the evolution of DNA or protein sequences, the detailed mechanisms giving rise to the observed evolution-like processes are not or only partially known. The absence of a mechanistic model of evolution implies that it remains unknown how the distances between different taxa have to be quantified. Considering distortions of metric distances, we first show that poor choices of the distance measure can lead to incorrect phylogenetic trees. Based on the well-known fact that phylogenetic inference requires additive metrics, we then show that the correct phylogeny can be computed from a distance matrix [Formula: see text] if there is a monotonic, subadditive function [Formula: see text] such that [Formula: see text] is additive. The required metric-preserving transformation [Formula: see text] can be computed as the solution of an optimization problem. This result shows that the problem of phylogeny reconstruction is well defined even if a detailed mechanistic model of the evolutionary process remains elusive.

Lineage-specific genomics: Frequent birth and death in the human genome: The human genome contains many lineage-specific elements created by both sequence and functional turnover.

PubMed

Young, Robert S

2016-07-01

Frequent evolutionary birth and death events have created a large quantity of biologically important, lineage-specific DNA within mammalian genomes. The birth and death of DNA sequences is so frequent that the total number of these insertions and deletions in the human population remains unknown, although there are differences between these groups, e.g. transposable elements contribute predominantly to sequence insertion. Functional turnover - where the activity of a locus is specific to one lineage, but the underlying DNA remains conserved - can also drive birth and death. However, this does not appear to be a major driver of divergent transcriptional regulation. Both sequence and functional turnover have contributed to the birth and death of thousands of functional promoters in the human and mouse genomes. These findings reveal the pervasive nature of evolutionary birth and death and suggest that lineage-specific regions may play an important but previously underappreciated role in human biology and disease. © 2016 The Authors BioEssays Published by WILEY Periodicals, Inc.

Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations—a review

PubMed Central

Stewart, Erin L.; Tan, Samuel Zhixing; Liu, Geoffrey

2015-01-01

Lung cancer is the leading cause of cancer related deaths in Canada with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Tumor characterization can identify cancer-driving mutations as treatment targets. One of the most successful examples of cancer targeted therapy is inhibition of mutated epidermal growth factor receptor (EGFR), which occurs in ~10-30% of NSCLC patients. While this treatment has benefited many patients with activating EGFR mutations, almost all who initially benefited will eventually acquire resistance. Approximately 50% of cases of acquired resistance (AR) are due to a secondary T790M mutation in exon 20 of the EGFR gene; however, many of the remaining mechanisms of resistance are still unknown. Much work has been done to elucidate the remaining mechanisms of resistance. This review aims to highlight both the mechanisms of resistance that have already been identified in patients and potential novel mechanisms identified in preclinical models which have yet to be validated in the patient settings. PMID:25806347

Arterial hypertension in the female world: pathophysiology and therapy.

PubMed

Cadeddu, Christian; Franconi, Flavia; Cassisa, Laura; Campesi, Ilaria; Pepe, Alessia; Cugusi, Lucia; Maffei, Silvia; Gallina, Sabina; Sciomer, Susanna; Mercuro, Giuseppe

2016-04-01

Hypertension is a major risk factor for cardiovascular disease and outcomes in women, and antihypertensive therapy is not always successful in achieving control over the blood pressure (BP). Nonoptimal control of BP remains a crucial risk factor for cardiovascular mortality, and in women, it could be related to sex-specific factors. Historically, women have been under-represented in clinical trials; therefore, the benefits of clinical outcomes and the safety profiles of antihypertensive therapies have been studied less extensively in women. The reasons for the sex differences in BP levels are multifactorial, implying different roles of the sex hormones, the renin-angiotensin system, sympathetic activity, and arterial stiffness. A complete understanding of the pathophysiological features of these differences requires further investigation.Nevertheless, the prevalence of the use of antihypertensive agents is higher among middle-aged women than among men. Notably, in the United States, hypertensive women use more diuretics and angiotensin receptor blockers than men, whereas hypertensive men more often receive beta-blockers, calcium channel antagonists, or inhibitors of angiotensin-converting enzyme. To date, the explanations for these sex differences in the consumption of antihypertensive drugs remain unknown.

Current thinking on genital herpes.

PubMed

Hofstetter, Annika M; Rosenthal, Susan L; Stanberry, Lawrence R

2014-02-01

Genital herpes has a high global prevalence and burden of disease. This manuscript highlights recent advances in our understanding of genital herpes simplex virus (HSV) infections. Studies demonstrate a changing epidemiological landscape with an increasing proportion of genital herpes cases associated with HSV type 1. There is also growing evidence that the majority of infected individuals exhibit frequent, brief shedding episodes that are most often asymptomatic, which likely contribute to high HSV transmission rates. Given this finding as well as readily available serological assays, some have proposed that routine HSV screening be performed; however, this remains controversial and is not currently recommended. Host immune responses, particularly local CD4 and CD8 T cell activity, are crucial for HSV control and clearance following initial infection, during latency and after reactivation. Prior HSV immunity may also afford partial protection against HSV reinfection and disease. Although HSV vaccine trials have been disappointing to date and existing antiviral medications are limited, novel prophylactic and therapeutic modalities are currently in development. Although much remains unknown about genital herpes, improved knowledge of HSV epidemiology, pathogenesis and host immunity may help guide new strategies for disease prevention and control.

Detectable close-in planets around white dwarfs through late unpacking

NASA Astrophysics Data System (ADS)

Veras, Dimitri; Gänsicke, Boris T.

2015-02-01

Although 25-50 per cent of white dwarfs (WDs) display evidence for remnant planetary systems, their orbital architectures and overall sizes remain unknown. Vibrant close-in (≃1 R⊙) circumstellar activity is detected at WDs spanning many Gyr in age, suggestive of planets further away. Here we demonstrate how systems with 4 and 10 closely packed planets that remain stable and ordered on the main sequence can become unpacked when the star evolves into a WD and experience pervasive inward planetary incursions throughout WD cooling. Our full-lifetime simulations run for the age of the Universe and adopt main-sequence stellar masses of 1.5, 2.0 and 2.5 M⊙, which correspond to the mass range occupied by the progenitors of typical present-day WDs. These results provide (i) a natural way to generate an ever-changing dynamical architecture in post-main-sequence planetary systems, (ii) an avenue for planets to achieve temporary close-in orbits that are potentially detectable by transit photometry and (iii) a dynamical explanation for how residual asteroids might pollute particularly old WDs.

Neural Reward and Punishment Sensitivity in Cigarette Smokers

PubMed Central

Potts, Geoffrey F.; Bloom, Erika; Evans, David E.; Drobes, David J.

2014-01-01

Background Nicotine addiction remains a major public health problem but the neural substrates of addictive behavior remain unknown. One characteristic of smoking behavior is impulsive choice, selecting the immediate reward of smoking despite the potential long-term negative consequences. This suggests that drug users, including cigarette smokers, may be more sensitive to rewards and less sensitive to punishment. Methods We used event-related potentials (ERPs) to test the hypothesis that smokers are more responsive to reward signals and less responsive to punishment, potentially predisposing them to risky behavior. We conducted two experiments, one using a reward prediction design to elicit a Medial Frontal Negativity (MFN) and one using a reward- and punishment-motivated flanker task to elicit an Error Related Negativity (ERN), ERP components thought to index activity in the cortical projection of the dopaminergic reward system. Results and Conclusions The smokers had a greater MFN response to unpredicted rewards, and non-smokers, but not smokers, had a larger ERN on punishment motivated trials indicating that smokers are more reward sensitive and less punishment sensitive than nonsmokers, overestimating the appetitive value and underestimating aversive outcomes of stimuli and actions. PMID:25292454