Modeling the dynamics of chromosomal alteration progression in cervical cancer: A computational model

PubMed Central

2017-01-01

Computational modeling has been applied to simulate the heterogeneity of cancer behavior. The development of Cervical Cancer (CC) is a process in which the cell acquires dynamic behavior from non-deleterious and deleterious mutations, exhibiting chromosomal alterations as a manifestation of this dynamic. To further determine the progression of chromosomal alterations in precursor lesions and CC, we introduce a computational model to study the dynamics of deleterious and non-deleterious mutations as an outcome of tumor progression. The analysis of chromosomal alterations mediated by our model reveals that multiple deleterious mutations are more frequent in precursor lesions than in CC. Cells with lethal deleterious mutations would be eliminated, which would mitigate cancer progression; on the other hand, cells with non-deleterious mutations would become dominant, which could predispose them to cancer progression. The study of somatic alterations through computer simulations of cancer progression provides a feasible pathway for insights into the transformation of cell mechanisms in humans. During cancer progression, tumors may acquire new phenotype traits, such as the ability to invade and metastasize or to become clinically important when they develop drug resistance. Non-deleterious chromosomal alterations contribute to this progression. PMID:28723940

Genetic evolution of nevus of Ota reveals clonal heterogeneity acquiring BAP1 and TP53 mutations.

PubMed

Vivancos, Ana; Caratú, Ginevra; Matito, Judit; Muñoz, Eva; Ferrer, Berta; Hernández-Losa, Javier; Bodet, Domingo; Pérez-Alea, Mileidys; Cortés, Javier; Garcia-Patos, Vicente; Recio, Juan A

2016-03-01

Melanoma presents molecular alterations based on its anatomical location and exposure to environmental factors. Due to its intrinsic genetic heterogeneity, a simple snapshot of a tumor's genetic alterations does not reflect the tumor clonal complexity or specific gene-gene cooperation. Here, we studied the genetic alterations and clonal evolution of a unique patient with a Nevus of Ota that developed into a recurring uveal-like dermal melanoma. The Nevus of Ota and ulterior lesions contained GNAQ mutations were c-KIT positive, and tumors showed an increased RAS pathway activity during progression. Whole-exome sequencing of these lesions revealed the acquisition of BAP1 and TP53 mutations during tumor evolution, thereby unmasking clonal heterogeneity and allowing the identification of cooperating genes within the same tumor. Our results highlight the importance of studying tumor genetic evolution to identify cooperating mechanisms and delineate effective therapies. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

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

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

2009-09-09

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

Mutations in the Drosophila neuroglian cell adhesion molecule affect motor neuron pathfinding and peripheral nervous system patterning.

PubMed

Hall, S G; Bieber, A J

1997-03-01

We have identified and characterized three embryonic lethal mutations that alter or abolish expression of Drosophila Neuroglian and have used these mutations to analyze Neuroglian function during development. Neuroglian is a member of the immunoglobulin superfamily. It is expressed by a variety of cell types during embryonic development, including expression on motoneurons and the muscle cells that they innervate. Examination of the nervous systems of neuroglian mutant embryos reveals that motoneurons have altered pathfinding trajectories. Additionally, the sensory cell bodies of the peripheral nervous system display altered morphology and patterning. Using a temperature-sensitive mutation, the phenocritical period for Neuroglian function was determined to occur during late embryogenesis, an interval which coincides with the period during which neuromuscular connections and the peripheral nervous system pattern are established.

Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes.

PubMed

Fan, Rongrong; Toubal, Amine; Goñi, Saioa; Drareni, Karima; Huang, Zhiqiang; Alzaid, Fawaz; Ballaire, Raphaelle; Ancel, Patricia; Liang, Ning; Damdimopoulos, Anastasios; Hainault, Isabelle; Soprani, Antoine; Aron-Wisnewsky, Judith; Foufelle, Fabienne; Lawrence, Toby; Gautier, Jean-Francois; Venteclef, Nicolas; Treuter, Eckardt

2016-07-01

Humans with obesity differ in their susceptibility to developing insulin resistance and type 2 diabetes (T2D). This variation may relate to the extent of adipose tissue (AT) inflammation that develops as their obesity progresses. The state of macrophage activation has a central role in determining the degree of AT inflammation and thus its dysfunction, and these states are driven by epigenomic alterations linked to gene expression. The underlying mechanisms that regulate these alterations, however, are poorly defined. Here we demonstrate that a co-repressor complex containing G protein pathway suppressor 2 (GPS2) crucially controls the macrophage epigenome during activation by metabolic stress. The study of AT from humans with and without obesity revealed correlations between reduced GPS2 expression in macrophages, elevated systemic and AT inflammation, and diabetic status. The causality of this relationship was confirmed by using macrophage-specific Gps2-knockout (KO) mice, in which inappropriate co-repressor complex function caused enhancer activation, pro-inflammatory gene expression and hypersensitivity toward metabolic-stress signals. By contrast, transplantation of GPS2-overexpressing bone marrow into two mouse models of obesity (ob/ob and diet-induced obesity) reduced inflammation and improved insulin sensitivity. Thus, our data reveal a potentially reversible disease mechanism that links co-repressor-dependent epigenomic alterations in macrophages to AT inflammation and the development of T2D.

Regulated expression of a calmodulin isoform alters growth and development in potato.

PubMed

Poovaiah, B W; Takezawa, D; An, G; Han, T J

1996-01-01

A transgene approach was taken to study the consequences of altered expression of a calmodulin isoform on plant growth and development. Eight genomic clones of potato calmodulin (PCM1 to 8) have been isolated and characterized (Takezawa et al., 1995). Among the potato calmodulin isoforms studied, PCM1 differs from the other isoforms because of its unique amino acid substitutions. Transgenic potato plants were produced carrying sense construct of PCM1 fused to the CaMV 35S promoter. Transgenic plants showing a moderate increase in PCM1 mRNA exhibited strong apical dominance, produced elongated tubers, and were taller than the controls. Interestingly, the plants expressing the highest level of PCM1 mRNA did not form underground tubers. Instead, these transgenic plants produced aerial tubers when allowed to grow for longer periods. The expression of different calmodulin isoforms (PCM1, 5, 6, and 8) was studied in transgenic plants. Among the four potato calmodulin isoforms, only the expression of PCM1 mRNA was altered in transgenic plants, while the expression of other isoforms was not significantly altered. Western analysis revealed increased PCM1 protein in transgenic plants, indicating that the expression of both mRNA and protein are altered in transgenic plants. These results suggest that increasing the expression of PCM1 alters growth and development in potato plants.

Psychedelic Research: Obstacles and Values

ERIC Educational Resources Information Center

Clark, Walter Houston

1975-01-01

Author considered the proper use of the LSD-type drugs, variously called hallucinogenic, mind-altering, mind-revealing, or psychedelic, and sampled the views of responsible researchers on the use of these drugs for mental health and for the study of the human mind and development. (Author/RK)

[EEG correlates of geno-phenotypical features of the brain development in children of the native and newcomers' population of the Russian North-East].

PubMed

Soroko, S I; Bekshaev, S S; Rozhkov, V P

2012-01-01

Traditional and original methods of EEG analysis were used to study the brain electrical activity maturation in 156 children and adolescents from 7 to 17 years old who represented the native (Koryaks and Evenks) and newcomers' populations living in severe climatic and geographic conditions of the Russian North-East. New data revealing age-, sex- and ethnic-related features in quantitative EEG parameters are presented. Markers are obtained that characterize alterations in the structure of interaction between different EEG rhythms. The results demonstrate age-dependent transformation of this structure separated in time for both different cortical areas and different EEG frequency bands. These alterations show time lag from 2 to 3 years in children of native population compared to the newcomers. The revealed differences are assumed to reflect geno-phenotypical features of morpho-functional CNS development in children of the native and newcomers' population that depend on strong adaptation tension for extreme environmental conditions.

Does Instruction Alter the Naturalistic Pattern of Pragmatic Development? A Case of Request Speech Act

ERIC Educational Resources Information Center

Taguchi, Naoko; Naganuma, Naeko; Budding, Carlos

2015-01-01

This study examined the effects of explicit instruction on the development of pragmatic competence in L2 English. The study is based on Taguchi's (2012) study conducted in an English-medium university in Japan, which revealed patterns of change in Japanese EFL students' production of requests in high- and low-imposition situations. Students showed…

odd skipped related1 reveals a novel role for endoderm in regulating kidney vs. vascular cell fate

PubMed Central

Mudumana, Sudha P.; Hentschel, Dirk; Liu, Yan; Vasilyev, Aleksandr; Drummond, Iain A.

2009-01-01

Summary The kidney and vasculature are intimately linked functionally and during development, where nephric and blood/vascular progenitor cells occupy adjacent bands of mesoderm in zebrafish and frog embryos. Developmental mechanisms underlying the differentiation of kidney vs. blood/vascular lineages remain unknown. The odd skipped related1 (osr1) gene encodes a zinc finger transcription factor that is expressed in the germ ring mesendoderm and subsequently in the endoderm and intermediate mesoderm, prior to the expression of definitive kidney or blood/vascular markers. Knockdown of osr1 in zebrafish embryos resulted in a complete, segment-specific loss of anterior kidney progenitors and a compensatory increase in the number of angioblast cells in the same trunk region. Histology revealed a subsequent absence of kidney tubules, enlarged cardinal vein, and expansion of the posterior venous plexus. Altered kidney vs. vascular development correlated with expanded endoderm development in osr1 knockdowns. Combined osr1 loss of function and blockade of endoderm development by knockdown of sox32/casanova rescued anterior kidney development. The results indicate that osr1 activity is required to limit endoderm differentiation from mesendoderm and, in the absence of osr1, excess endoderm alters mesoderm differentiation, shifting the balance from kidney toward vascular development. PMID:18787069

An Auxin Transport Independent Pathway Is Involved in Phosphate Stress-Induced Root Architectural Alterations in Arabidopsis. Identification of BIG as a Mediator of Auxin in Pericycle Cell Activation1

PubMed Central

López-Bucio, José; Hernández-Abreu, Esmeralda; Sánchez-Calderón, Lenin; Pérez-Torres, Anahí; Rampey, Rebekah A.; Bartel, Bonnie; Herrera-Estrella, Luis

2005-01-01

Arabidopsis (Arabidopsis thaliana) plants display a number of root developmental responses to low phosphate availability, including primary root growth inhibition, greater formation of lateral roots, and increased root hair elongation. To gain insight into the regulatory mechanisms by which phosphorus (P) availability alters postembryonic root development, we performed a mutant screen to identify genetic determinants involved in the response to P deprivation. Three low phosphate-resistant root lines (lpr1-1 to lpr1-3) were isolated because of their reduced lateral root formation in low P conditions. Genetic and molecular analyses revealed that all lpr1 mutants were allelic to BIG, which is required for normal auxin transport in Arabidopsis. Detailed characterization of lateral root primordia (LRP) development in wild-type and lpr1 mutants revealed that BIG is required for pericycle cell activation to form LRP in both high (1 mm) and low (1 μm) P conditions, but not for the low P-induced alterations in primary root growth, lateral root emergence, and root hair elongation. Exogenously supplied auxin restored normal lateral root formation in lpr1 mutants in the two P treatments. Treatment of wild-type Arabidopsis seedlings with brefeldin A, a fungal metabolite that blocks auxin transport, phenocopies the root developmental alterations observed in lpr1 mutants in both high and low P conditions, suggesting that BIG participates in vesicular targeting of auxin transporters. Taken together, our results show that auxin transport and BIG function have fundamental roles in pericycle cell activation to form LRP and promote root hair elongation. The mechanism that activates root system architectural alterations in response to P deprivation, however, seems to be independent of auxin transport and BIG. PMID:15681664

Characterization of the Tumor Microenvironment and Tumor–Stroma Interaction by Non-invasive Preclinical Imaging

PubMed Central

Ramamonjisoa, Nirilanto; Ackerstaff, Ellen

2017-01-01

Tumors are often characterized by hypoxia, vascular abnormalities, low extracellular pH, increased interstitial fluid pressure, altered choline-phospholipid metabolism, and aerobic glycolysis (Warburg effect). The impact of these tumor characteristics has been investigated extensively in the context of tumor development, progression, and treatment response, resulting in a number of non-invasive imaging biomarkers. More recent evidence suggests that cancer cells undergo metabolic reprograming, beyond aerobic glycolysis, in the course of tumor development and progression. The resulting altered metabolic content in tumors has the ability to affect cell signaling and block cellular differentiation. Additional emerging evidence reveals that the interaction between tumor and stroma cells can alter tumor metabolism (leading to metabolic reprograming) as well as tumor growth and vascular features. This review will summarize previous and current preclinical, non-invasive, multimodal imaging efforts to characterize the tumor microenvironment, including its stromal components and understand tumor–stroma interaction in cancer development, progression, and treatment response. PMID:28197395

Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

PubMed Central

Gentric, Géraldine; Maillet, Vanessa; Paradis, Valérie; Couton, Dominique; L’Hermitte, Antoine; Panasyuk, Ganna; Fromenty, Bernard; Celton-Morizur, Séverine; Desdouets, Chantal

2015-01-01

Polyploidization is one of the most dramatic changes that can occur in the genome. In the liver, physiological polyploidization events occur during both liver development and throughout adult life. Here, we determined that a pathological polyploidization takes place in nonalcoholic fatty liver disease (NAFLD), a widespread hepatic metabolic disorder that is believed to be a risk factor for hepatocellular carcinoma (HCC). In murine models of NAFLD, the parenchyma of fatty livers displayed alterations of the polyploidization process, including the presence of a large proportion of highly polyploid mononuclear cells, which are rarely observed in normal hepatic parenchyma. Biopsies from patients with nonalcoholic steatohepatitis (NASH) revealed the presence of alterations in hepatocyte ploidy compared with tissue from control individuals. Hepatocytes from NAFLD mice revealed that progression through the S/G2 phases of the cell cycle was inefficient. This alteration was associated with activation of a G2/M DNA damage checkpoint, which prevented activation of the cyclin B1/CDK1 complex. Furthermore, we determined that oxidative stress promotes the appearance of highly polyploid cells, and antioxidant-treated NAFLD hepatocytes resumed normal cell division and returned to a physiological state of polyploidy. Collectively, these findings indicate that oxidative stress promotes pathological polyploidization and suggest that this is an early event in NAFLD that may contribute to HCC development. PMID:25621497

Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease.

PubMed

Gentric, Géraldine; Maillet, Vanessa; Paradis, Valérie; Couton, Dominique; L'Hermitte, Antoine; Panasyuk, Ganna; Fromenty, Bernard; Celton-Morizur, Séverine; Desdouets, Chantal

2015-03-02

Polyploidization is one of the most dramatic changes that can occur in the genome. In the liver, physiological polyploidization events occur during both liver development and throughout adult life. Here, we determined that a pathological polyploidization takes place in nonalcoholic fatty liver disease (NAFLD), a widespread hepatic metabolic disorder that is believed to be a risk factor for hepatocellular carcinoma (HCC). In murine models of NAFLD, the parenchyma of fatty livers displayed alterations of the polyploidization process, including the presence of a large proportion of highly polyploid mononuclear cells, which are rarely observed in normal hepatic parenchyma. Biopsies from patients with nonalcoholic steatohepatitis (NASH) revealed the presence of alterations in hepatocyte ploidy compared with tissue from control individuals. Hepatocytes from NAFLD mice revealed that progression through the S/G2 phases of the cell cycle was inefficient. This alteration was associated with activation of a G2/M DNA damage checkpoint, which prevented activation of the cyclin B1/CDK1 complex. Furthermore, we determined that oxidative stress promotes the appearance of highly polyploid cells, and antioxidant-treated NAFLD hepatocytes resumed normal cell division and returned to a physiological state of polyploidy. Collectively, these findings indicate that oxidative stress promotes pathological polyploidization and suggest that this is an early event in NAFLD that may contribute to HCC development.

Three-dimensional Myoblast Aggregates--Effects of Modeled Microgravity

NASA Technical Reports Server (NTRS)

Byerly, Diane; Sognier, M. A.; Marquette, M. L.

2006-01-01

The overall objective of these studies is to elucidate the molecular and cellular alterations that contribute to muscle atrophy in astronauts caused by exposure to microgravity conditions in space. To accomplish this, a three-dimensional model test system was developed using mouse myoblast cells (C2C12). Myoblast cells were grown as three-dimensional aggregates (without scaffolding or other solid support structures) in both modeled microgravity (Rotary Cell Culture System, Synthecon, Inc.) and at unit gravity in coated Petri dishes. Evaluation of H&E stained thin sections of the aggregates revealed the absence of any necrosis. Confocal microscopy evaluations of cells stained with the Live/Dead assay (Molecular Probes) confirmed that viable cells were present throughout the aggregates with an average of only three dead cells observed per aggregate. Preliminary results from gene array analysis (Affymetrix chip U74Av2) showed that approximately 14% of the genes were down regulated (decreased more than 3 fold) and 4% were upregulated in cells exposed to modeled microgravity for 12 hours compared to unit gravity controls. Additional studies using fluorescent phallacidin revealed a decrease in F-actin in the cells exposed to modeled microgravity compared to unit gravity. Myoblast cells grown as aggregates in modeled microgravity exhibited spontaneous differentiation into syncitia while no differentiation was seen in the unit gravity controls. These studies show that 1)the model test system developed is suitable for assessing cellular and molecular alterations in myoblasts; 2) gene expression alterations occur rapidly (within 12 hours) following exposure to modeled microgravity; and 3) modeled microgravity conditions stimulated myoblast cell differentiation. Achieving a greater understanding of the molecular alterations leading to muscle atrophy will eventually enable the development of cell-based countermeasures, which may be valuable for treatment of muscle diseases on Earth and future space explorations.

Transient activation of dopaminergic neurons during development modulates visual responsiveness, locomotion and brain activity in a dopamine ontogeny model of schizophrenia.

PubMed

Calcagno, B; Eyles, D; van Alphen, B; van Swinderen, B

2013-01-08

It has been observed that certain developmental environmental risk factors for schizophrenia when modeled in rodents alter the trajectory of dopaminergic development, leading to persistent behavioural changes in adults. This has recently been articulated as the "dopamine ontogeny hypothesis of schizophrenia". To test one aspect of this hypothesis, namely that transient dopaminergic effects during development modulate attention-like behavior and arousal in adults, we turned to a small-brain model, Drosophila melanogaster. By applying genetic tools allowing transient activation or silencing of dopaminergic neurons in the fly brain, we investigated whether a critical window exists during development when altered dopamine (DA) activity levels could lead to impairments in arousal states in adult animals. We found that increased activity in dopaminergic neurons in later stages of development significantly increased visual responsiveness and locomotion, especially in adult males. This misallocation of visual salience and hyperactivity mimicked the effect of acute methamphetamine feeding to adult flies, suggesting up-regulated DA signaling could result from developmental manipulations. Finally, brain recordings revealed significantly reduced gamma-band activity in adult animals exposed to the transient developmental insult. Together, these data support the idea that transient alterations in DA signaling during development can permanently alter behavior in adults, and that a reductionist model such as Drosophila can be used to investigate potential mechanisms underlying complex cognitive disorders such as schizophrenia.

Noncanoncial signal recognition particle RNAs in a major eukaryotic phylum revealed by purification of SRP from the human pathogen Cryptococcus neoformans

PubMed Central

Dumesic, Phillip A.; Rosenblad, Magnus A.; Samuelsson, Tore; Nguyen, Tiffany; Moresco, James J.; Yates, John R.; Madhani, Hiten D.

2015-01-01

Despite conservation of the signal recognition particle (SRP) from bacteria to man, computational approaches have failed to identify SRP components from genomes of many lower eukaryotes, raising the possibility that they have been lost or altered in those lineages. We report purification and analysis of SRP in the human pathogen Cryptococcus neoformans, providing the first description of SRP in basidiomycetous yeast. The C. neoformans SRP RNA displays a predicted structure in which the universally conserved helix 8 contains an unprecedented stem-loop insertion. Guided by this sequence, we computationally identified 152 SRP RNAs throughout the phylum Basidiomycota. This analysis revealed additional helix 8 alterations including single and double stem-loop insertions as well as loop diminutions affecting RNA structural elements that are otherwise conserved from bacteria to man. Strikingly, these SRP RNA features in Basidiomycota are accompanied by phylum-specific alterations in the RNA-binding domain of Srp54, the SRP protein subunit that directly interacts with helix 8. Our findings reveal unexpected fungal SRP diversity and suggest coevolution of the two most conserved SRP features—SRP RNA helix 8 and Srp54—in basidiomycetes. Because members of this phylum include important human and plant pathogens, these noncanonical features provide new targets for antifungal compound development. PMID:26275773

Alterations in hepatic one-carbon metabolism and related pathways following a high-fat dietary intervention.

PubMed

Rubio-Aliaga, Isabel; Roos, Baukje de; Sailer, Manuela; McLoughlin, Gerard A; Boekschoten, Mark V; van Erk, Marjan; Bachmair, Eva-Maria; van Schothorst, Evert M; Keijer, Jaap; Coort, Susan L; Evelo, Chris; Gibney, Michael J; Daniel, Hannelore; Muller, Michael; Kleemann, Robert; Brennan, Lorraine

2011-04-27

Obesity frequently leads to insulin resistance and the development of hepatic steatosis. To characterize the molecular changes that promote hepatic steatosis, transcriptomics, proteomics, and metabolomics technologies were applied to liver samples from C57BL/6J mice obtained from two independent intervention trials. After 12 wk of high-fat feeding the animals became obese, hyperglycemic, and insulin resistant, had elevated levels of blood cholesterol and VLDL, and developed hepatic steatosis. Nutrigenomic analysis revealed alterations of key metabolites and enzyme transcript levels of hepatic one-carbon metabolism and related pathways. The hepatic oxidative capacity and the lipid milieu were significantly altered, which may play a key role in the development of insulin resistance. Additionally, high choline levels were observed after the high-fat diet. Previous studies have linked choline levels with insulin resistance and hepatic steatosis in conjunction with changes of certain metabolites and enzyme levels of one-carbon metabolism. The present results suggest that the coupling of high levels of choline and low levels of methionine plays an important role in the development of insulin resistance and liver steatosis. In conclusion, the complexities of the alterations induced by high-fat feeding are multifactorial, indicating that the interplay between several metabolic pathways is responsible for the pathological consequences.

A novel in vitro metabolomics approach for neurotoxicity testing, proof of principle for methyl mercury chloride and caffeine.

PubMed

van Vliet, Erwin; Morath, Siegfried; Eskes, Chantra; Linge, Jens; Rappsilber, Juri; Honegger, Paul; Hartung, Thomas; Coecke, Sandra

2008-01-01

There is a need for more efficient methods giving insight into the complex mechanisms of neurotoxicity. Testing strategies including in vitro methods have been proposed to comply with this requirement. With the present study we aimed to develop a novel in vitro approach which mimics in vivo complexity, detects neurotoxicity comprehensively, and provides mechanistic insight. For this purpose we combined rat primary re-aggregating brain cell cultures with a mass spectrometry (MS)-based metabolomics approach. For the proof of principle we treated developing re-aggregating brain cell cultures for 48 h with the neurotoxicant methyl mercury chloride (0.1-100 microM) and the brain stimulant caffeine (1-100 microM) and acquired cellular metabolic profiles. To detect toxicant-induced metabolic alterations the profiles were analysed using commercial software which revealed patterns in the multi-parametric dataset by principal component analyses (PCA), and recognised the most significantly altered metabolites. PCA revealed concentration-dependent cluster formations for methyl mercury chloride (0.1-1 microM), and treatment-dependent cluster formations for caffeine (1-100 microM) at sub-cytotoxic concentrations. Four relevant metabolites responsible for the concentration-dependent alterations following methyl mercury chloride treatment could be identified using MS-MS fragmentation analysis. These were gamma-aminobutyric acid, choline, glutamine, creatine and spermine. Their respective mass ion intensities demonstrated metabolic alterations in line with the literature and suggest that the metabolites could be biomarkers for mechanisms of neurotoxicity or neuroprotection. In addition, we evaluated whether the approach could identify neurotoxic potential by testing eight compounds which have target organ toxicity in the liver, kidney or brain at sub-cytotoxic concentrations. PCA revealed cluster formations largely dependent on target organ toxicity indicating possible potential for the development of a neurotoxicity prediction model. With such results it could be useful to perform a validation study to determine the reliability, relevance and applicability of this approach to neurotoxicity screening. Thus, for the first time we show the benefits and utility of in vitro metabolomics to comprehensively detect neurotoxicity and to discover new biomarkers.

Mapping the pathways of resistance to targeted therapies

PubMed Central

Wood, Kris C.

2015-01-01

Resistance substantially limits the depth and duration of clinical responses to targeted anticancer therapies. Through the use of complementary experimental approaches, investigators have revealed that cancer cells can achieve resistance through adaptation or selection driven by specific genetic, epigenetic, or microenvironmental alterations. Ultimately, these diverse alterations often lead to the activation of signaling pathways that, when co-opted, enable cancer cells to survive drug treatments. Recently developed methods enable the direct and scalable identification of the signaling pathways capable of driving resistance in specific contexts. Using these methods, novel pathways of resistance to clinically approved drugs have been identified and validated. By combining systematic resistance pathway mapping methods with studies revealing biomarkers of specific resistance pathways and pharmacological approaches to block these pathways, it may be possible to rationally construct drug combinations that yield more penetrant and lasting responses in patients. PMID:26392071

Current state of the use of neuroimaging techniques to understand and alter appetite control in humans.

PubMed

Spetter, Maartje S

2018-06-20

It is in the brain where the decision is made what and how much to eat. In the last decades neuroimaging research has contributed extensively to new knowledge about appetite control by revealing the underlying brain processes. Interestingly, there is the fast growing idea of using these methods to develop new treatments for obesity and eating disorders. In this review, we summarize the findings of the importance of the use of neuropharmacology and neuroimaging techniques in understanding and modifying appetite control. Appetite control is a complex interplay between homeostatic, hedonic, and cognitive processes. Administration of the neuropeptides insulin and oxytocin curb food intake and alter brain responses in reward and cognitive control areas. Additionally, these areas can be targeted for neuromodulation or neurofeedback to reduce food cravings and increase self-control to alter food intake. The recent findings reveal the potential of intranasal administration of hormones or modifying appetite control brain networks to reduce food consumption in volunteers with overweight and obesity or individuals with an eating disorder. Although long-term clinical studies are still needed.

Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers

PubMed Central

Okugawa, Yoshinaga; Grady, William M.; Goel, Ajay

2015-01-01

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. One of the fundamental processes driving the initiation and progression of CRC is the accumulation of a variety of genetic and epigenetic changes in colon epithelial cells. Over the past decade, major advances have been made in our understanding of cancer epigenetics, particularly regarding aberrant DNA methylation, microRNA (miRNA) and noncoding RNA deregulation, and alterations in histone modification states. Assessment of the colon cancer “epigenome” has revealed that virtually all CRCs have aberrantly methylated genes and altered miRNA expression. The average CRC methylome has hundreds to thousands of abnormally methylated genes and dozens of altered miRNAs. As with gene mutations in the cancer genome, a subset of these epigenetic alterations, called driver events, is presumed to have a functional role in CRC. In addition, the advances in our understanding of epigenetic alterations in CRC have led to these alterations being developed as clinical biomarkers for diagnostic, prognostic and therapeutic applications. Progress in this field suggests that these epigenetic alterations will be commonly used in the near future to direct the prevention and treatment of CRC. PMID:26216839

Altered brain arginine metabolism in schizophrenia.

PubMed

Liu, P; Jing, Y; Collie, N D; Dean, B; Bilkey, D K; Zhang, H

2016-08-16

Previous research implicates altered metabolism of l-arginine, a versatile amino acid with a number of bioactive metabolites, in the pathogenesis of schizophrenia. The present study, for we believe the first time, systematically compared the metabolic profile of l-arginine in the frontal cortex (Brodmann's area 8) obtained post-mortem from schizophrenic individuals and age- and gender-matched non-psychiatric controls (n=20 per group). The enzyme assays revealed no change in total nitric oxide synthase (NOS) activity, but significantly increased arginase activity in the schizophrenia group. Western blot showed reduced endothelial NOS protein expression and increased arginase II protein level in the disease group. High-performance liquid chromatography and liquid chromatography/mass spectrometric assays confirmed significantly reduced levels of γ-aminobutyric acid (GABA), but increased agmatine concentration and glutamate/GABA ratio in the schizophrenia cases. Regression analysis indicated positive correlations between arginase activity and the age of disease onset and between l-ornithine level and the duration of illness. Moreover, cluster analyses revealed that l-arginine and its main metabolites l-citrulline, l-ornithine and agmatine formed distinct groups, which were altered in the schizophrenia group. The present study provides further evidence of altered brain arginine metabolism in schizophrenia, which enhances our understanding of the pathogenesis of schizophrenia and may lead to the future development of novel preventions and/or therapeutics for the disease.

Cell wall, cell membrane, and volatile metabolism are altered by antioxidant treatment, temperature shifts, and peel necrosis during apple fruit storage.

PubMed

Leisso, Rachel; Buchanan, David; Lee, Jinwook; Mattheis, James; Rudell, David

2013-02-13

The transition from cold storage to ambient temperature alters apple quality through accelerated softening, flavor and color changes, and development of physiological peel disorders, such as superficial scald, in susceptible cultivars. To reveal global metabolism associated with this transition, the 'Granny Smith' peel metabolome was evaluated during storage of 6 months and shelf life periods. Treatment with the antioxidant diphenylamine (DPA) reduced scald, creating a metabolic contrast with untreated fruit, which developed superficial scald. Superficial scald symptoms developed on control fruit after 120 days of storage, and symptoms progressed following transition to ambient-temperature shelf life. The metabolic profile of control and DPA-treated fruit was divergent after 30 days of cold storage due to differing levels of α-farnesene oxidation products, methyl esters, phytosterols, and other compounds potentially associated with chloroplast integrity and oxidative stress response. Hierarchical cluster analysis revealed coregulation within the volatile synthesis pathway including control of the availability of methyl, propyl, ethyl, acetyl, and butyl alcohol and/or acid moieties for ester biosynthesis. Overall, the application of metabolomics techniques lends new insight into physiological processes leading to cell death and ripening processes that affect fruit flavor, appearance, and overall quality.

Time-sequential observation of spindle and phragmoplast orientation in BY-2 cells with altered cortical actin microfilament patterning.

PubMed

Kojo, Kei H; Yasuhara, Hiroki; Hasezawa, Seiichiro

2014-01-01

Precise division plane determination is essential for plant development. At metaphase, a dense actin microfilament meshwork appears on both sides of the cell center, forming a characteristic cortical actin microfilament twin peak pattern in BY-2 cells. We previously reported a strong correlation between altered cortical actin microfilament patterning and an oblique mitotic spindle orientation, implying that these actin microfilament twin peaks play a role in the regulation of mitotic spindle orientation. In the present study, time-sequential observation was used to reveal the progression from oblique phragmoplast to oblique cell plate orientation in cells with altered cortical actin microfilament patterning. In contrast to cells with normal actin microfilament twin peaks, oblique phragmoplast reorientation was rarely observed in cells with altered cortical actin microfilament patterning. These results support the important roles of cortical actin microfilament patterning in division plane orientation.

Time-sequential observation of spindle and phragmoplast orientation in BY-2 cells with altered cortical actin microfilament patterning.

PubMed

Kojo, Kei H; Yasuhara, Hiroki; Hasezawa, Seiichiro

2014-06-18

Precise division plane determination is essential for plant development. At metaphase, a dense actin microfilament meshwork appears on both sides of the cell center, forming a characteristic cortical actin microfilament twin peak pattern in BY-2 cells. We previously reported a strong correlation between altered cortical actin microfilament patterning and an oblique mitotic spindle orientation, implying that these actin microfilament twin peaks play a role in the regulation of mitotic spindle orientation. In the present study, time-sequential observation was used to reveal the progression from oblique phragmoplast to oblique cell plate orientation in cells with altered cortical actin microfilament patterning. In contrast to cells with normal actin microfilament twin peaks, oblique phragmoplast reorientation was rarely observed in cells with altered cortical actin microfilament patterning. These results support the important roles of cortical actin microfilament patterning in division plane orientation.

[The social catholic doctrine in the industrializing process of Francoist Spain: the case of the Alter pharmaceutical group].

PubMed

Rodríguez Nozal, Raúl; González Bueno, Antonio

2015-01-01

Alter Laboratories and the group of companies developed by Juan José Alonso Grijalba (1894-1962) under Franco's regime held the Catholic social doctrine as the foundation of his business. This pharmacist was a strong advocate and propagandist of these ideas. In this paper, we outline the biography of this entrepreneur, describe his ideological principles, and analyze how these theories were implemented in the Alter Laboratories in their economic, cultural-recreational, and moral-religious dimensions. The business approach revealed by the writings of Juan José Alonso is a "patriarchal patronage"; his goal appears to have been the conversion of Alter into a "factory convent" with the programmatic foundations of Catholic humanism, in which the employer assumes a clearly despotic role and the intervention of workers is reduced to accepting the standards and perks offered by the employer.

Development of a sensitive monitor for hydrazine

NASA Technical Reports Server (NTRS)

Eiceman, Gary A.; Limero, Thomas; James, John T.

1991-01-01

The development of hand-held, ambient-temperature instruments that utilize ion mobility spectrometry (IMS) in the detection of hydrazine and monomethylhydrazine is reviewed. A development effort to eliminate ammonia interference through altering the ionization chemistry, based on adding 5-nonanone as dopant in the ionization region of the IMS, is presented. Calibration of this instrument conducted before and after STS-37 revealed no more than a 5 percent difference between calibration curves, without any appreciable loss of equipment function.

Comparative proteomic analysis reveals alterations in development and photosynthesis-related proteins in diploid and triploid rice.

PubMed

Wang, Shuzhen; Chen, Wenyue; Yang, Changdeng; Yao, Jian; Xiao, Wenfei; Xin, Ya; Qiu, Jieren; Hu, Weimin; Yao, Haigen; Ying, Wu; Fu, Yaping; Tong, Jianxin; Chen, Zhongzhong; Ruan, Songlin; Ma, Huasheng

2016-09-13

Polyploidy has pivotal influences on rice (Oryza sativa L.) morphology and physiology, and is very important for understanding rice domestication and improving agricultural traits. Diploid (DP) and triploid (TP) rice shows differences in morphological parameters, such as plant height, leaf length, leaf width and the physiological index of chlorophyll content. However, the underlying mechanisms determining these morphological differences are remain to be defined. To better understand the proteomic changes between DP and TP, tandem mass tags (TMT) mass spectrometry (MS)/MS was used to detect the significant changes to protein expression between DP and TP. Results indicated that both photosynthesis and metabolic pathways were highly significantly associated with proteomic alteration between DP and TP based on biological process and pathway enrichment analysis, and 13 higher abundance chloroplast proteins involving in these two pathways were identified in TP. Quantitative real-time PCR analysis demonstrated that 5 of the 13 chloroplast proteins ATPF, PSAA, PSAB, PSBB and RBL in TP were higher abundance compared with those in DP. This study integrates morphology, physiology and proteomic profiling alteration of DP and TP to address their underlying different molecular mechanisms. Our finding revealed that ATPF, PSAA, PSAB, PSBB and RBL can induce considerable expression changes in TP and may affect the development and growth of rice through photosynthesis and metabolic pathways.

The Culture of Discourse on Educational Reform in Spain

ERIC Educational Resources Information Center

Teasley, Cathryn

2004-01-01

Where the education of subaltern multicultural student collectives is concerned, the case of contemporary developments in the discourse of reform in Spain is particularly poignant. A critical engagement with that discourse and its greater sociocultural context reveals some of the subtle ways in which cultural alterity comes to be represented. And…

Determinants of orofacial clefting I: Effects of 5-Aza-2'-deoxycytidine on cellular processes and gene expression during development of the first branchial arch.

PubMed

Mukhopadhyay, Partha; Seelan, Ratnam S; Rezzoug, Francine; Warner, Dennis R; Smolenkova, Irina A; Brock, Guy; Pisano, M Michele; Greene, Robert M

2017-01-01

In this study, we identify gene targets and cellular events mediating the teratogenic action(s) of 5-Aza-2'-deoxycytidine (AzaD), an inhibitor of DNA methylation, on secondary palate development. Exposure of pregnant mice (on gestation day (GD) 9.5) to AzaD for 12h resulted in the complete penetrance of cleft palate (CP) in fetuses. Analysis of cells of the embryonic first branchial arch (1-BA), in fetuses exposed to AzaD, revealed: 1) significant alteration in expression of genes encoding several morphogenetic factors, cell cycle inhibitors and regulators of apoptosis; 2) a decrease in cell proliferation; and, 3) an increase in apoptosis. Pyrosequencing of selected genes, displaying pronounced differential expression in AzaD-exposed 1-BAs, failed to reveal significant alterations in CpG methylation levels in their putative promoters or gene bodies. CpG methylation analysis suggested that the effects of AzaD on gene expression were likely indirect. Copyright © 2016 Elsevier Inc. All rights reserved.

The structural alteration and aggregation propensity of glycated lens crystallins in the presence of calcium: Importance of lens calcium homeostasis in development of diabetic cataracts

NASA Astrophysics Data System (ADS)

ZM, Sara Zafaranchi; Khoshaman, Kazem; Masoudi, Raheleh; Hemmateenejad, Bahram; Yousefi, Reza

2017-01-01

The imbalance of the calcium homeostasis in the lenticular tissues of diabetic patients is an important risk factor for development of cataract diseases. In the current study, the impact of elevated levels of calcium ions were investigated on structure and aggregation propensity of glycated lens crystallins using gel electrophoresis and spectroscopic assessments. The glycated proteins indicated significant resistance against calcium-induced structural insults and aggregation. While, glycated crystallins revealed an increased conformational stability; a slight instability was observed for these proteins upon interaction with calcium ions. Also, in the presence of calcium, the proteolytic pattern of native crystallins was altered and that of glycated protein counterparts remained almost unchanged. According to results of this study it is suggested that the structural alteration of lens crystallins upon glycation may significantly reduce their calcium buffering capacity in eye lenses. Therefore, under chronic hyperglycemia accumulation of this cataractogenic metal ion in the lenticular tissues may subsequently culminate in activation of different pathogenic pathways, leading to development of lens opacity and cataract diseases.

Selected sperm traits are simultaneously altered after scrotal heat stress and play specific roles in in vitro fertilization and embryonic development.

PubMed

Lucio, Aline C; Alves, Benner G; Alves, Kele A; Martins, Muller C; Braga, Lucas S; Miglio, Luisa; Alves, Bruna G; Silva, Thiago H; Jacomini, José O; Beletti, Marcelo E

2016-09-01

Improvements in the estimation of male fertility indicators require advances in laboratory tests for sperm assessment. The aims of the present work were (1) to apply a multivariate analysis to examine sperm set of alterations and interactions and (2) to evaluate the importance of sperm parameters on the outcome of standard IVF and embryonic development. Bulls (n = 3) were subjected to scrotal insulation, and ejaculates were collected before (preinsulation = Day 0) and through 56 days (Days 7, 14, 21, 28, 35, 42, 49, and 56) of the experimental period. Sperm head morphometry and chromatin variables were assessed by a computational image analysis, and IVF was performed. Scrotal heat stress induced alterations in all evaluated sperm head features, as well as cleavage and blastocyst rates. A principal component analysis revealed three main components (factors) that represented almost 89% of the cumulative variance. In addition, an association of factor scores with cleavage (factor 1) and blastocyst (factor 3) rates was observed. In conclusion, several sperm traits were simultaneously altered as a result of a thermal insult. These sperm traits likely play specific roles in IVF and embryonic development. Copyright © 2016 Elsevier Inc. All rights reserved.

Early Disruption of Extracellular Pleiotrophin Distribution Alters Cerebellar Neuronal Circuit Development and Function.

PubMed

Hamza, M M; Rey, S A; Hilber, P; Arabo, A; Collin, T; Vaudry, D; Burel, D

2016-10-01

The cerebellum is a structure of the central nervous system involved in balance, motor coordination, and voluntary movements. The elementary circuit implicated in the control of locomotion involves Purkinje cells, which receive excitatory inputs from parallel and climbing fibers, and are regulated by cerebellar interneurons. In mice as in human, the cerebellar cortex completes its development mainly after birth with the migration, differentiation, and synaptogenesis of granule cells. These cellular events are under the control of numerous extracellular matrix molecules including pleiotrophin (PTN). This cytokine has been shown to regulate the morphogenesis of Purkinje cells ex vivo and in vivo via its receptor PTPζ. Since Purkinje cells are the unique output of the cerebellar cortex, we explored the consequences of their PTN-induced atrophy on the function of the cerebellar neuronal circuit in mice. Behavioral experiments revealed that, despite a normal overall development, PTN-treated mice present a delay in the maturation of their flexion reflex. Moreover, patch clamp recording of Purkinje cells revealed a significant increase in the frequency of spontaneous excitatory postsynaptic currents in PTN-treated mice, associated with a decrease of climbing fiber innervations and an abnormal perisomatic localization of the parallel fiber contacts. At adulthood, PTN-treated mice exhibit coordination impairment on the rotarod test associated with an alteration of the synchronization gait. Altogether these histological, electrophysiological, and behavior data reveal that an early ECM disruption of PTN composition induces short- and long-term defaults in the establishment of proper functional cerebellar circuit.

Genetic transformation of rare Verbascum eriophorum Godr. plants and metabolic alterations revealed by NMR-based metabolomics.

PubMed

Marchev, Andrey; Yordanova, Zhenya; Alipieva, Kalina; Zahmanov, Georgi; Rusinova-Videva, Snezhana; Kapchina-Toteva, Veneta; Simova, Svetlana; Popova, Milena; Georgiev, Milen I

2016-09-01

To develop a protocol to transform Verbascum eriophorum and to study the metabolic differences between mother plants and hairy root culture by applying NMR and processing the datasets with chemometric tools. Verbascum eriophorum is a rare species with restricted distribution, which is poorly studied. Agrobacterium rhizogenes-mediated genetic transformation of V. eriophorum and hairy root culture induction are reported for the first time. To determine metabolic alterations, V. eriophorum mother plants and relevant hairy root culture were subjected to comprehensive metabolomic analyses, using NMR (1D and 2D). Metabolomics data, processed using chemometric tools (and principal component analysis in particular) allowed exploration of V. eriophorum metabolome and have enabled identification of verbascoside (by means of 2D-TOCSY NMR) as the most abundant compound in hairy root culture. Metabolomics data contribute to the elucidation of metabolic alterations after T-DNA transfer to the host V. eriophorum genome and the development of hairy root culture for sustainable bioproduction of high value verbascoside.

The Arabidopsis cax1 Mutant Exhibits Impaired Ion Homeostasis, Development, and Hormonal Responses and Reveals Interplay among Vacuolar Transporters

PubMed Central

Cheng, Ning-Hui; Pittman, Jon K.; Barkla, Bronwyn J.; Shigaki, Toshiro; Hirschi, Kendal D.

2003-01-01

The Arabidopsis Ca2+/H+ transporter CAX1 (Cation Exchanger1) may be an important regulator of intracellular Ca2+ levels. Here, we describe the preliminary localization of CAX1 to the tonoplast and the molecular and biochemical characterization of cax1 mutants. We show that these mutants exhibit a 50% reduction in tonoplast Ca2+/H+ antiport activity, a 40% reduction in tonoplast V-type H+-translocating ATPase activity, a 36% increase in tonoplast Ca2+-ATPase activity, and increased expression of the putative vacuolar Ca2+/H+ antiporters CAX3 and CAX4. Enhanced growth was displayed by the cax1 lines under Mn2+ and Mg2+ stress conditions. The mutants exhibited altered plant development, perturbed hormone sensitivities, and altered expression of an auxin-regulated promoter-reporter gene fusion. We propose that CAX1 regulates myriad plant processes and discuss the observed phenotypes with regard to the compensatory alterations in other transporters. PMID:12566577

The Arabidopsis cax1 mutant exhibits impaired ion homeostasis, development, and hormonal responses and reveals interplay among vacuolar transporters.

PubMed

Cheng, Ning-Hui; Pittman, Jon K; Barkla, Bronwyn J; Shigaki, Toshiro; Hirschi, Kendal D

2003-02-01

The Arabidopsis Ca(2+)/H(+) transporter CAX1 (Cation Exchanger1) may be an important regulator of intracellular Ca(2+) levels. Here, we describe the preliminary localization of CAX1 to the tonoplast and the molecular and biochemical characterization of cax1 mutants. We show that these mutants exhibit a 50% reduction in tonoplast Ca(2+)/H(+) antiport activity, a 40% reduction in tonoplast V-type H(+)-translocating ATPase activity, a 36% increase in tonoplast Ca(2+)-ATPase activity, and increased expression of the putative vacuolar Ca(2+)/H(+) antiporters CAX3 and CAX4. Enhanced growth was displayed by the cax1 lines under Mn(2+) and Mg(2+) stress conditions. The mutants exhibited altered plant development, perturbed hormone sensitivities, and altered expression of an auxin-regulated promoter-reporter gene fusion. We propose that CAX1 regulates myriad plant processes and discuss the observed phenotypes with regard to the compensatory alterations in other transporters.

Molecular determinants of caste differentiation in the highly eusocial honeybee Apis mellifera.

PubMed

Barchuk, Angel R; Cristino, Alexandre S; Kucharski, Robert; Costa, Luciano F; Simões, Zilá L P; Maleszka, Ryszard

2007-06-18

In honeybees, differential feeding of female larvae promotes the occurrence of two different phenotypes, a queen and a worker, from identical genotypes, through incremental alterations, which affect general growth, and character state alterations that result in the presence or absence of specific structures. Although previous studies revealed a link between incremental alterations and differential expression of physiometabolic genes, the molecular changes accompanying character state alterations remain unknown. By using cDNA microarray analyses of >6,000 Apis mellifera ESTs, we found 240 differentially expressed genes (DEGs) between developing queens and workers. Many genes recorded as up-regulated in prospective workers appear to be unique to A. mellifera, suggesting that the workers' developmental pathway involves the participation of novel genes. Workers up-regulate more developmental genes than queens, whereas queens up-regulate a greater proportion of physiometabolic genes, including genes coding for metabolic enzymes and genes whose products are known to regulate the rate of mass-transforming processes and the general growth of the organism (e.g., tor). Many DEGs are likely to be involved in processes favoring the development of caste-biased structures, like brain, legs and ovaries, as well as genes that code for cytoskeleton constituents. Treatment of developing worker larvae with juvenile hormone (JH) revealed 52 JH responsive genes, specifically during the critical period of caste development. Using Gibbs sampling and Expectation Maximization algorithms, we discovered eight overrepresented cis-elements from four gene groups. Graph theory and complex networks concepts were adopted to attain powerful graphical representations of the interrelation between cis-elements and genes and objectively quantify the degree of relationship between these entities. We suggest that clusters of functionally related DEGs are co-regulated during caste development in honeybees. This network of interactions is activated by nutrition-driven stimuli in early larval stages. Our data are consistent with the hypothesis that JH is a key component of the developmental determination of queen-like characters. Finally, we propose a conceptual model of caste differentiation in A. mellifera based on gene-regulatory networks.

Molecular determinants of caste differentiation in the highly eusocial honeybee Apis mellifera

PubMed Central

Barchuk, Angel R; Cristino, Alexandre S; Kucharski, Robert; Costa, Luciano F; Simões, Zilá LP; Maleszka, Ryszard

2007-01-01

Background In honeybees, differential feeding of female larvae promotes the occurrence of two different phenotypes, a queen and a worker, from identical genotypes, through incremental alterations, which affect general growth, and character state alterations that result in the presence or absence of specific structures. Although previous studies revealed a link between incremental alterations and differential expression of physiometabolic genes, the molecular changes accompanying character state alterations remain unknown. Results By using cDNA microarray analyses of >6,000 Apis mellifera ESTs, we found 240 differentially expressed genes (DEGs) between developing queens and workers. Many genes recorded as up-regulated in prospective workers appear to be unique to A. mellifera, suggesting that the workers' developmental pathway involves the participation of novel genes. Workers up-regulate more developmental genes than queens, whereas queens up-regulate a greater proportion of physiometabolic genes, including genes coding for metabolic enzymes and genes whose products are known to regulate the rate of mass-transforming processes and the general growth of the organism (e.g., tor). Many DEGs are likely to be involved in processes favoring the development of caste-biased structures, like brain, legs and ovaries, as well as genes that code for cytoskeleton constituents. Treatment of developing worker larvae with juvenile hormone (JH) revealed 52 JH responsive genes, specifically during the critical period of caste development. Using Gibbs sampling and Expectation Maximization algorithms, we discovered eight overrepresented cis-elements from four gene groups. Graph theory and complex networks concepts were adopted to attain powerful graphical representations of the interrelation between cis-elements and genes and objectively quantify the degree of relationship between these entities. Conclusion We suggest that clusters of functionally related DEGs are co-regulated during caste development in honeybees. This network of interactions is activated by nutrition-driven stimuli in early larval stages. Our data are consistent with the hypothesis that JH is a key component of the developmental determination of queen-like characters. Finally, we propose a conceptual model of caste differentiation in A. mellifera based on gene-regulatory networks. PMID:17577409

Caffeine exposure alters cardiac gene expression in embryonic cardiomyocytes

PubMed Central

Fang, Xiefan; Mei, Wenbin; Barbazuk, William B.; Rivkees, Scott A.

2014-01-01

Previous studies demonstrated that in utero caffeine treatment at embryonic day (E) 8.5 alters DNA methylation patterns, gene expression, and cardiac function in adult mice. To provide insight into the mechanisms, we examined cardiac gene and microRNA (miRNA) expression in cardiomyocytes shortly after exposure to physiologically relevant doses of caffeine. In HL-1 and primary embryonic cardiomyocytes, caffeine treatment for 48 h significantly altered the expression of cardiac structural genes (Myh6, Myh7, Myh7b, Tnni3), hormonal genes (Anp and BnP), cardiac transcription factors (Gata4, Mef2c, Mef2d, Nfatc1), and microRNAs (miRNAs; miR208a, miR208b, miR499). In addition, expressions of these genes were significantly altered in embryonic hearts exposed to in utero caffeine. For in utero experiments, pregnant CD-1 dams were treated with 20–60 mg/kg of caffeine, which resulted in maternal circulation levels of 37.3–65.3 μM 2 h after treatment. RNA sequencing was performed on embryonic ventricles treated with vehicle or 20 mg/kg of caffeine daily from E6.5-9.5. Differential expression (DE) analysis revealed that 124 genes and 849 transcripts were significantly altered, and differential exon usage (DEU) analysis identified 597 exons that were changed in response to prenatal caffeine exposure. Among the DE genes identified by RNA sequencing were several cardiac structural genes and genes that control DNA methylation and histone modification. Pathway analysis revealed that pathways related to cardiovascular development and diseases were significantly affected by caffeine. In addition, global cardiac DNA methylation was reduced in caffeine-treated cardiomyocytes. Collectively, these data demonstrate that caffeine exposure alters gene expression and DNA methylation in embryonic cardiomyocytes. PMID:25354728

Inhaled Diesel Emissions Alter Atherosclerotic Plaque Composition in ApoE−/− Mice

PubMed Central

Campen, Matthew J.; Lund, Amie K.; Knuckles, Travis L.; Conklin, Daniel J.; Bishop, Barbara; Young, David; Seilkop, Steven; Seagrave, JeanClare; Reed, Matthew D.; McDonald, Jacob D.

2009-01-01

Recent epidemiological studies suggest that traffic-related air pollution may have detrimental effects on cardiovascular health. Previous studies reveal that gasoline emissions can induce several enzyme pathways involved in the formation and development of atherosclerotic plaques. As a direct comparison, the present study examined the impact of diesel engine emissions on these pathways, and further examined the effects on vascular lesion pathology. Apolipoprotein E-null mice were simultaneously placed on a high fat chow diet and exposed to four concentrations, plus a high concentration exposure with particulates (PM) removed by filtration, of diesel emissions for 6 h/d for 50 days. Aortas were subsequently assayed for alteration in matrix metalloproteinase-9, endothelin-1, and several other biomarkers. Diesel induced dose-related alterations in gene markers of vascular remodeling and aortic lipid peroxidation; filtration of PM did not significantly alter these vascular responses, indicating that the gaseous portion of the exhaust was a principal driver. Immunohistochemical analysis of aortic leaflet sections revealed no net increase in lesion area, but a significant decrease in lipid-rich regions and increasing trends in macrophage accumulation and collagen content, suggesting that plaques were advanced to a more fragile, potentially more vulnerable state by diesel exhaust exposure. Combined with previous studies, these results indicate that whole emissions from mobile sources may have a significant role in promoting chronic vascular disease. PMID:19891982

Gut microbiota modulates alcohol withdrawal-induced anxiety in mice.

PubMed

Xiao, Hui-Wen; Ge, Chang; Feng, Guo-Xing; Li, Yuan; Luo, Dan; Dong, Jia-Li; Li, Hang; Wang, Haichao; Cui, Ming; Fan, Sai-Jun

2018-05-01

Excessive alcohol consumption remains a major public health problem that affects millions of people worldwide. Accumulative experimental evidence has suggested an important involvement of gut microbiota in the modulation of host's immunological and neurological functions. However, it is previously unknown whether enteric microbiota is implicated in the formation of alcohol withdrawal-induced anxiety. Using a murine model of chronic alcoholism and withdrawal, we examined the impact of alcohol consumption on the possible alterations of gut microbiota as well as alcohol withdrawal-induced anxiety and behavior changes. The 16S rRNA sequencing revealed that alcohol consumption did not alter the abundance of bacteria, but markedly changed the composition of gut microbiota. Moreover, the transplantation of enteric microbes from alcohol-fed mice to normal healthy controls remarkably shaped the composition of gut bacteria, and elicited behavioral signs of alcohol withdrawal-induced anxiety. Using quantitative real-time polymerase chain reaction, we further confirmed that the expression of genes implicated in alcohol addiction, BDNF, CRHR1 and OPRM1, was also altered by transplantation of gut microbes from alcohol-exposed donors. Collectively, our findings suggested a possibility that the alterations of gut microbiota composition might contribute to the development of alcohol withdrawal-induced anxiety, and reveal potentially new etiologies for treating alcohol addiction. Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

Altered brain arginine metabolism in schizophrenia

PubMed Central

Liu, P; Jing, Y; Collie, N D; Dean, B; Bilkey, D K; Zhang, H

2016-01-01

Previous research implicates altered metabolism of l-arginine, a versatile amino acid with a number of bioactive metabolites, in the pathogenesis of schizophrenia. The present study, for we believe the first time, systematically compared the metabolic profile of l-arginine in the frontal cortex (Brodmann's area 8) obtained post-mortem from schizophrenic individuals and age- and gender-matched non-psychiatric controls (n=20 per group). The enzyme assays revealed no change in total nitric oxide synthase (NOS) activity, but significantly increased arginase activity in the schizophrenia group. Western blot showed reduced endothelial NOS protein expression and increased arginase II protein level in the disease group. High-performance liquid chromatography and liquid chromatography/mass spectrometric assays confirmed significantly reduced levels of γ-aminobutyric acid (GABA), but increased agmatine concentration and glutamate/GABA ratio in the schizophrenia cases. Regression analysis indicated positive correlations between arginase activity and the age of disease onset and between l-ornithine level and the duration of illness. Moreover, cluster analyses revealed that l-arginine and its main metabolites l-citrulline, l-ornithine and agmatine formed distinct groups, which were altered in the schizophrenia group. The present study provides further evidence of altered brain arginine metabolism in schizophrenia, which enhances our understanding of the pathogenesis of schizophrenia and may lead to the future development of novel preventions and/or therapeutics for the disease. PMID:27529679

Quantitative Proteomic Profiling of Prostate Cancer Reveals a Role for miR-128 in Prostate Cancer*

PubMed Central

Khan, Amjad P.; Poisson, Laila M.; Bhat, Vadiraja B.; Fermin, Damian; Zhao, Rong; Kalyana-Sundaram, Shanker; Michailidis, George; Nesvizhskii, Alexey I.; Omenn, Gilbert S.; Chinnaiyan, Arul M.; Sreekumar, Arun

2010-01-01

Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of biomarkers of cancer invasion and disease aggressiveness. Although alterations in gene expression have been extensively quantified during neoplastic progression, complementary analyses of proteomic changes have been limited. Here we interrogate the proteomic alterations in a cohort of 15 prostate-derived tissues that included five each from adjacent benign prostate, clinically localized prostate cancer, and metastatic disease from distant sites. The experimental strategy couples isobaric tags for relative and absolute quantitation with multidimensional liquid phase peptide fractionation followed by tandem mass spectrometry. Over 1000 proteins were quantified across the specimens and delineated into clinically localized and metastatic prostate cancer-specific signatures. Included in these class-specific profiles were both proteins that were known to be dysregulated during prostate cancer progression and new ones defined by this study. Enrichment analysis of the prostate cancer-specific proteomic signature, to gain insight into the functional consequences of these alterations, revealed involvement of miR-128-a/b regulation during prostate cancer progression. This finding was validated using real time PCR analysis for microRNA transcript levels in an independent set of 15 clinical specimens. miR-128 levels were elevated in benign prostate epithelial cell lines compared with invasive prostate cancer cells. Knockdown of miR-128 induced invasion in benign prostate epithelial cells, whereas its overexpression attenuated invasion in prostate cancer cells. Taken together, our profiles of the proteomic alterations of prostate cancer progression revealed miR-128 as a potentially important negative regulator of prostate cancer cell invasion. PMID:19955085

FAT1 Gene Alteration in Facioscapulohumeral Muscular Dystrophy Type 1.

PubMed

Park, Hyung Jun; Lee, Wookjae; Kim, Se Hoon; Lee, Jung Hwan; Shin, Ha Young; Kim, Seung Min; Park, Kee Duk; Lee, Ji Hyun; Choi, Young Chul

2018-03-01

Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by contraction of the D4Z4 repeat array. Recent studies revealed that the FAT1 expression is associated with disease activity of FSHD, and the FAT1 alterations result in myopathy with a FSHD-like phenotype. We describe a 59-year-old woman with both contracted D4Z4 repeat units and a FAT1 mutation. Shoulder girdle muscle weakness developed at the age of 56 years, and was followed by proximal leg weakness. When we examined her at 59 years of age, she displayed asymmetric and predominant weakness of facial and proximal muscles. Muscle biopsy showed increased variation in fiber size and multifocal degenerating fibers with lymphocytic infiltration. Southern blot analysis revealed 8 D4Z4 repeat units, and targeted sequencing of modifier genes demonstrated the c.10331 A>G variant in the FAT1 gene. This FAT1 variant has previously been reported as pathogenic variant in a patient with FSHD-like phenotype. Our study is the first report of a FAT1 mutation in a FSHD1 patient, and suggests that FAT1 alterations might work as a genetic modifier. © Copyright: Yonsei University College of Medicine 2018.

Comprehensive Plasma Metabolomic Analyses of Atherosclerotic Progression Reveal Alterations in Glycerophospholipid and Sphingolipid Metabolism in Apolipoprotein E-deficient Mice

PubMed Central

Dang, Vi T.; Huang, Aric; Zhong, Lexy H.; Shi, Yuanyuan; Werstuck, Geoff H.

2016-01-01

Atherosclerosis is the major underlying cause of most cardiovascular diseases. Despite recent advances, the molecular mechanisms underlying the pathophysiology of atherogenesis are not clear. In this study, comprehensive plasma metabolomics were used to investigate early-stage atherosclerotic development and progression in chow-fed apolipoprotein E-deficient mice at 5, 10 and 15 weeks of age. Comprehensive plasma metabolomic profiles, based on 4365 detected metabolite features, differentiate atherosclerosis-prone from atherosclerosis-resistant models. Metabolites in the sphingomyelin pathway were significantly altered prior to detectable lesion formation and at all subsequent time-points. The cytidine diphosphate-diacylglycerol pathway was up-regulated during stage I of atherosclerosis, while metabolites in the phosphatidylethanolamine and glycosphingolipid pathways were augmented in mice with stage II lesions. These pathways, involving glycerophospholipid and sphingolipid metabolism, were also significantly affected during the course of atherosclerotic progression. Our findings suggest that distinct plasma metabolomic profiles can differentiate the different stages of atherosclerotic progression. This study reveals that alteration of specific, previously unreported pathways of glycerophospholipid and sphingolipid metabolism are associated with atherosclerosis. The clear difference in the level of several metabolites supports the use of plasma lipid profiling as a diagnostic tool of atherogenesis. PMID:27721472

A MICROARRAY ANALYSIS OF GENE EXPRESSION IN THE EMBRYONIC FORELIMB OF THE C57BL/6J MOUSE REVEALS SIGNIFICANT ALTERATIONS METABOLIC AND DEVELOPMENTAL REGULATION FOLLOWING ETHANOL EXPOSURE.

EPA Science Inventory

The observation of transcriptional changes following embryonic ethanol exposure may provide significant insights into the biological response to ethanol exposure. In this study, we used microarray analysis to examine the transcriptional response of the developing limb to a dose ...

Peripheral Nerve Injury in Developing Rats Reorganizes Representation Pattern in Motor Cortex

NASA Astrophysics Data System (ADS)

Donoghue, John P.; Sanes, Jerome N.

1987-02-01

We investigated the effect of neonatal nerve lesions on cerebral motor cortex organization by comparing the cortical motor representation of normal adult rats with adult rats that had one forelimb removed on the day of birth. Mapping of cerebral neocortex with electrical stimulation revealed an altered relationship between the motor cortex and the remaining muscles. Whereas distal forelimb movements are normally elicited at the lowest threshold in the motor cortex forelimb area, the same stimuli activated shoulder and trunk muscles in experimental animals. In addition, an expanded cortical representation of intact body parts was present and there was an absence of a distinct portion of motor cortex. These data demonstrate that representation patterns in motor cortex can be altered by peripheral nerve injury during development.

A Fiberless Seed Mutation in Cotton Is Associated with Lack of Fiber Cell Initiation in Ovule Epidermis and Alterations in Sucrose Synthase Expression and Carbon Partitioning in Developing Seeds1

PubMed Central

Ruan, Yong-Ling; Chourey, Prem S.

1998-01-01

Fiber cell initiation in the epidermal cells of cotton (Gossypium hirsutum L.) ovules represents a unique example of trichome development in higher plants. Little is known about the molecular and metabolic mechanisms controlling this process. Here we report a comparative analysis of a fiberless seed (fls) mutant (lacking fibers) and a normal (FLS) mutant to better understand the initial cytological events in fiber development and to analyze the metabolic changes that are associated with the loss of a major sink for sucrose during cellulose biosynthesis in the mutant seeds. On the day of anthesis (0 DAA), the mutant ovular epidermal cells lacked the typical bud-like projections that are seen in FLS ovules and are required for commitment to the fiber development pathway. Cell-specific gene expression analyses at 0 DAA showed that sucrose synthase (SuSy) RNA and protein were undetectable in fls ovules but were in abundant, steady-state levels in initiating fiber cells of the FLS ovules. Tissue-level analyses of developing seeds 15 to 35 DAA revealed an altered temporal pattern of SuSy expression in the mutant relative to the normal genotype. Whether the altered programming of SuSy expression is the cause or the result of the mutation is unknown. The developing seeds of the fls mutant have also shown several correlated changes that represent altered carbon partitioning in seed coats and cotyledons as compared with the FLS genotype. PMID:9765525

A fiberless seed mutation in cotton is associated with lack of fiber cell initiation in ovule epidermis and alterations in sucrose synthase expression and carbon partitioning in developing seeds

PubMed

Ruan; Chourey

1998-10-01

Fiber cell initiation in the epidermal cells of cotton (Gossypium hirsutum L.) ovules represents a unique example of trichome development in higher plants. Little is known about the molecular and metabolic mechanisms controlling this process. Here we report a comparative analysis of a fiberless seed (fls) mutant (lacking fibers) and a normal (FLS) mutant to better understand the initial cytological events in fiber development and to analyze the metabolic changes that are associated with the loss of a major sink for sucrose during cellulose biosynthesis in the mutant seeds. On the day of anthesis (0 DAA), the mutant ovular epidermal cells lacked the typical bud-like projections that are seen in FLS ovules and are required for commitment to the fiber development pathway. Cell-specific gene expression analyses at 0 DAA showed that sucrose synthase (SuSy) RNA and protein were undetectable in fls ovules but were in abundant, steady-state levels in initiating fiber cells of the FLS ovules. Tissue-level analyses of developing seeds 15 to 35 DAA revealed an altered temporal pattern of SuSy expression in the mutant relative to the normal genotype. Whether the altered programming of SuSy expression is the cause or the result of the mutation is unknown. The developing seeds of the fls mutant have also shown several correlated changes that represent altered carbon partitioning in seed coats and cotyledons as compared with the FLS genotype.

Genome-wide network analysis of Wnt signaling in three pediatric cancers

NASA Astrophysics Data System (ADS)

Bao, Ju; Lee, Ho-Jin; Zheng, Jie J.

2013-10-01

Genomic structural alteration is common in pediatric cancers, and analysis of data generated by the Pediatric Cancer Genome Project reveals such tumor-related alterations in many Wnt signaling-associated genes. Most pediatric cancers are thought to arise within developing tissues that undergo substantial expansion during early organ formation, growth and maturation, and Wnt signaling plays an important role in this development. We examined three pediatric tumors--medullobastoma, early T-cell precursor acute lymphoblastic leukemia, and retinoblastoma--that show multiple genomic structural variations within Wnt signaling pathways. We mathematically modeled this pathway to investigate the effects of cancer-related structural variations on Wnt signaling. Surprisingly, we found that an outcome measure of canonical Wnt signaling was consistently similar in matched cancer cells and normal cells, even in the context of different cancers, different mutations, and different Wnt-related genes. Our results suggest that the cancer cells maintain a normal level of Wnt signaling by developing multiple mutations.

Alteration heterogeneities in peridotites tectonically exhumed along slow-spreading ridges

NASA Astrophysics Data System (ADS)

Rouméjon, S.; Frueh-Green, G. L.; Williams, M. J.

2017-12-01

Serpentinized peridotites associated with mafic lithologies commonly outcrop along slow-spreading ridges. They are exhumed along large offset normal faults, called detachment faults, that uplift fresh peridotites and gabbros from the base of the brittle lithosphere to shallower levels where they are hydrothermally altered. Numerous petrological studies in these environments reveal that peridotites are variably altered depending on factors such as the temperature, redox state, intensity of hydrothermal fluid input and the chemistry of these fluids. It follows that the detachment footwalls are heterogeneous at scales less than a kilometer, reflecting initial distribution of primary lithologies and later variable alteration. Here we investigate the nature, distribution and typical length scales of alteration heterogeneities. We primarily focus on samples drilled at five sites across the Atlantis Massif (Mid-Atlantic Ridge, 30°N) during IODP Exp. 357 (Nov. 2015, RRS James Cook) and on samples dredged along the easternmost Southwest Indian Ridge (Smoothseafloor cruise, Oct. 2010, N/O Marion Dufresne). Multiple petrological observations are combined: hand sample description, sequences of textures and the associated mineralogical assemblages identifiable in thin section, in situ major and trace elements data as well as bulk rock and in situ oxygen isotopes ratios in serpentine textures. We show that all serpentinized peridotites develop serpentine mesh textures. However, some domains of the footwall are overprinted by further serpentine recrystallization and veins (mostly chrysotile- or antigorite-bearing) as a result of localized fluid-rock interaction and evolving fluids. Other domains are impacted by the alteration of the surrounding mafic bodies that influences both the mineralogy and chemistry of the altered peridotites. Using these results, we propose a conceptual model for the development of alteration heterogeneities during exhumation at slow-spreading ridges.

Using the concentration-volume (C-V) fractal model in the delineation of gold mineralized zones within the Tepeoba porphyry Cu-Mo-Au, Balikesir, NW Turkey

NASA Astrophysics Data System (ADS)

Kumral, Mustafa; Abdelnasser, Amr; Karaman, Muhittin; Budakoglu, Murat

2016-04-01

The Tepeoba porphyry Cu-Mo-Au mineralization that located at the Biga peninsula (W Turkey) developed around the Eybek pluton concentrated at its southern contact. This mineralization that hosted in the hornfels rocks of Karakaya Complex is associated with three main alteration zones; potassic, phyllic and propylitic alterations along the fault controlled margins of the Eybek pluton and quartz stockwork veining as well as brecciation zones. As well as two mineralized zones were occurred in the mine area; hypogene and oxidation/supergene zone. The hypogene zone has differentiated alteration types; high potassic and low phyllic alteration, while the oxidation/supergene zone has high phyllic and propylitic alterations. This work deals with the delineation of gold mineralized zone within this porphyry deposit using the concentration-volume (C-V) fractal model. Five zones of gold were calculated using its power-law C-V relationship that revealed that the main phase of gold mineralization stated at 5.3083 ppm Au concentration. In addition, the C-V log-log plot shows that the highly and moderately Au mineralization zone developed in western part of deposit correlated with oxidation zone related to propylitic alteration. On the other hand, its weakly mineralization zone has a widespread in the hypogene zone related to potassic alteration. This refers to the enrichment of gold and depletion of copper at the oxidation/supergene zone is due to the oxidation/supergene alteration processes that enrich the deposits by the meteoric water. Keywords: Concentration-volume (C-V) fractal model; gold mineralized zone; Tepeoba porphyry Cu-Mo-Au; Balikesir; NW Turkey.

Long-Term Effects of Environmental Endocrine Disruptors on Reproductive Physiology and Behavior

PubMed Central

Patisaul, Heather B.; Adewale, Heather B.

2009-01-01

It is well established that, over the course of development, hormones shape the vertebrate brain such that sex specific physiology and behaviors emerge. Much of this occurs in discrete developmental windows that span gestation through the prenatal period, although it is now becoming clear that at least some of this process continues through puberty. Perturbation of this developmental progression can permanently alter the capacity for reproductive success. Wildlife studies have revealed that exposure to endocrine disrupting compounds (EDCs), either naturally occurring or man made, can profoundly alter reproductive physiology and ultimately impact entire populations. Laboratory studies in rodents and other species have elucidated some of the mechanisms by which this occurs and strongly indicate that humans are also vulnerable to disruption. Use of hormonally active compounds in human medicine has also unfortunately revealed that the developing fetus can be exposed to and affected by endocrine disruptors, and that it might take decades for adverse effects to manifest. Research within the field of environmental endocrine disruption has also contributed to the general understanding of how early life experiences can alter reproductive physiology and behavior through non-genomic, epigenetic mechanisms such as DNA methylation and histone acetylation. These types of effects have the potential to impact future generations if the germ line is affected. This review provides an overview of how exposure to EDCs, particularly those that interfere with estrogen action, impacts reproductive physiology and behaviors in vertebrates. PMID:19587848

Genetic alterations of m6A regulators predict poorer survival in acute myeloid leukemia.

PubMed

Kwok, Chau-To; Marshall, Amy D; Rasko, John E J; Wong, Justin J L

2017-02-02

Methylation of N 6 adenosine (m 6 A) is known to be important for diverse biological processes including gene expression control, translation of protein, and messenger RNA (mRNA) splicing. However, its role in the development of human cancers is poorly understood. By analyzing datasets from the Cancer Genome Atlas Research Network (TCGA) acute myeloid leukemia (AML) study, we discover that mutations and/or copy number variations of m 6 A regulatory genes are strongly associated with the presence of TP53 mutations in AML patients. Further, our analyses reveal that alterations in m 6 A regulatory genes confer a worse survival in AML. Our work indicates that genetic alterations of m 6 A regulatory genes may cooperate with TP53 and/or its regulator/downstream targets in the pathogenesis and/or maintenance of AML.

Increased leaf mesophyll porosity following transient retinoblastoma-related protein silencing is revealed by microcomputed tomography imaging and leads to a system-level physiological response to the altered cell division pattern

PubMed Central

Dorca-Fornell, Carmen; Pajor, Radoslaw; Lehmeier, Christoph; Pérez-Bueno, Marísa; Bauch, Marion; Sloan, Jen; Osborne, Colin; Rolfe, Stephen; Sturrock, Craig; Mooney, Sacha; Fleming, Andrew

2013-01-01

The causal relationship between cell division and growth in plants is complex. Although altered expression of cell-cycle genes frequently leads to altered organ growth, there are many examples where manipulation of the division machinery leads to a limited outcome at the level of organ form, despite changes in constituent cell size. One possibility, which has been under-explored, is that altered division patterns resulting from manipulation of cell-cycle gene expression alter the physiology of the organ, and that this has an effect on growth. We performed a series of experiments on retinoblastoma-related protein (RBR), a well characterized regulator of the cell cycle, to investigate the outcome of altered cell division on leaf physiology. Our approach involved combination of high-resolution microCT imaging and physiological analysis with a transient gene induction system, providing a powerful approach for the study of developmental physiology. Our investigation identifies a new role for RBR in mesophyll differentiation that affects tissue porosity and the distribution of air space within the leaf. The data demonstrate the importance of RBR in early leaf development and the extent to which physiology adapts to modified cellular architecture resulting from altered cell-cycle gene expression. PMID:24118480

Hydrothermal alteration of deep fractured granite: Effects of dissolution and precipitation

NASA Astrophysics Data System (ADS)

Nishimoto, Shoji; Yoshida, Hidekazu

2010-03-01

This paper investigates the mineralogical effects of hydrothermal alteration at depth in fractures in granite. A fracture accompanied by an alteration halo and filled with clay was found at a depth of 200 m in a drill core through Toki granite, Gifu, central Japan. Microscopic observation, XRD, XRF, EPMA and SXAM investigations revealed that the microcrystalline clays consist of illite, quartz and pyrite and that the halo round the fracture can be subdivided into a phyllic zone adjacent to the fracture, surrounded by a propylitic zone in which Fe-phyllosilicates are present, and a distinctive outer alteration front characterized by plagioclase breakdown. The processes that result in these changes took place in three successive stages: 1) partial dissolution of plagioclase with partial chloritization of biotite; 2) biotite dissolution and precipitation of Fe-phyllosilicate in the dissolution pores; 3) dissolution of K-feldspar and Fe-phyllosilicate, and illite precipitation associated with development of microcracks. These hydrothermal alterations of the granite proceed mainly by a dissolution-precipitation process resulting from the infiltration of hydrothermal fluid along microcracks. Such infiltration causes locally high mobility of Al and increases the ratio of fluid to rock in the alteration halo. These results contribute to an understanding of how granitic rock becomes altered in orogenic fields such as the Japanese island arc.

Merkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma.

PubMed

Starrett, Gabriel J; Marcelus, Christina; Cantalupo, Paul G; Katz, Joshua P; Cheng, Jingwei; Akagi, Keiko; Thakuria, Manisha; Rabinowits, Guilherme; Wang, Linda C; Symer, David E; Pipas, James M; Harris, Reuben S; DeCaprio, James A

2017-01-03

Merkel cell polyomavirus is the primary etiological agent of the aggressive skin cancer Merkel cell carcinoma (MCC). Recent studies have revealed that UV radiation is the primary mechanism for somatic mutagenesis in nonviral forms of MCC. Here, we analyze the whole transcriptomes and genomes of primary MCC tumors. Our study reveals that virus-associated tumors have minimally altered genomes compared to non-virus-associated tumors, which are dominated by UV-mediated mutations. Although virus-associated tumors contain relatively small mutation burdens, they exhibit a distinct mutation signature with observable transcriptionally biased kataegic events. In addition, viral integration sites overlap focal genome amplifications in virus-associated tumors, suggesting a potential mechanism for these events. Collectively, our studies indicate that Merkel cell polyomavirus is capable of hijacking cellular processes and driving tumorigenesis to the same severity as tens of thousands of somatic genome alterations. A variety of mutagenic processes that shape the evolution of tumors are critical determinants of disease outcome. Here, we sequenced the entire genome of virus-positive and virus-negative primary Merkel cell carcinomas (MCCs), revealing distinct mutation spectra and corresponding expression profiles. Our studies highlight the strong effect that Merkel cell polyomavirus has on the divergent development of viral MCC compared to the somatic alterations that typically drive nonviral tumorigenesis. A more comprehensive understanding of the distinct mutagenic processes operative in viral and nonviral MCCs has implications for the effective treatment of these tumors. Copyright © 2017 Starrett et al.

Metabolomic changes in follicular fluid induced by soy isoflavones administered to rats from weaning until sexual maturity

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

Wang, Wenxiang; Zhang, Wenchang, E-mail: wenchang2002@sina.com; Liu, Jin

Female Wistar rats at 21 days of age were treated with one of three concentrations of soy isoflavones (SIF) (50, 100 or 200 mg/kg body weight, orally, once per day) from weaning until sexual maturity (3 months) in order to evaluate the influence of SIF on ovarian follicle development. After treatment, the serum sex hormone levels and enumeration of ovarian follicles of the ovary were measured. The metabolic profile of follicular fluid was determined using HPLC-MS. Principal component analysis (PCA) and partial least-squares-discriminant analysis (PLS-DA) was used to identify differences in metabolites and reveal useful toxic biomarkers. The results indicatedmore » that modest doses of SIF affect ovarian follicle development, as demonstrated by decreased serum estradiol levels and increases in both ovarian follicle atresia and corpora lutea number in the ovary. SIF treatment-related metabolic alterations in follicular fluid were also found in the PCA and PLS-DA models. The 24 most significantly altered metabolites were identified, including primary sex hormones, amino acids, fatty acids and metabolites involved in energy metabolism. These findings may indicate that soy isoflavones affect ovarian follicle development by inducing metabolomic variations in the follicular fluid. - Highlights: ► Modest doses of soy isoflavones (SIF) do affect ovarian follicle development. ► SIF treatment-related metabolic alterations in follicular fluid were found. ► The 24 most significantly altered metabolites were identified.« less

Alterations of protein glycosylation in embryonic stem cells during adipogenesis

PubMed Central

Liu, Wei; Wang, Yangyang; Rao, Yang; Yu, Hanjie; Cui, Jihong; Xie, Xin; Sun, Mei; Yin, Lu; Li, Hongmin; Chen, Fulin

2018-01-01

The understanding of adipose tissue development is crucial for the treatment of obesity-related diseases. Adipogenesis has been extensively investigated at the gene and protein levels in recent years. However, the alterations in protein glycosylation during this process remains unknown, particularly that of parthenogenetic embryonic stem cells (pESCs), a type of ESCs with low immunogenicity and no ethical concerns regarding their use. Protein glycosylation markedly affects cell growth and development, cell-to-cell communication, tumour growth and metastasis. In the present study, the adipogenic potentials of J1 ESCs and pESCs were first compared and the results demonstrated that pESCs had lower adipogenic potential compared with J1 ESCs. Lectin microarray was then used to screen the alteration of protein glycosylation during adipogenesis. The results revealed that protein modification of GlcNAc and α-1-2-fucosylation increased, whereas α-1-6-fucosylation, α-2-6-sialylation and α-1-6-mannosylation decreased in J1 ESCs and pESCs during this process. In addition, α-1-3-mannosylation decreased only in pESCs. Lectin histochemistry and quantitative polymerase chain reaction of glycosyltransferase confirmed the results obtained by lectin microarray. Therefore, protein glycosylation of ESCs was significantly altered during adipogenesis, indicating that protein glycosylation analysis is not only helpful for studying the mechanism of adipogenesis, but may also be used as a marker to monitor adipogenic development. PMID:29115405

Craniofacial structure alterations of foetuses from folic acid deficient pregnant mice.

PubMed

Maldonado, Estela; López, Yamila; Herrera, Manuel; Martínez-Sanz, Elena; Martínez-Álvarez, Concepción; Pérez-Miguelsanz, Juliana

2018-03-28

Craniofacial development in mammals is a complex process that involves a coordinated series of molecular and morphogenetic events. Folic acid (FA) deficiency has historically been associated with congenital spinal cord malformations, but the effect that a maternal diet deficient in FA has on the development of other structures has been poorly explored. In the present study, the objective was to describe and quantify the alterations of craniofacial structures presented in mouse foetuses from dams fed a FA deficient (FAD) diet compared with controls that were given a regular maternal diet. E17 mouse foetuses were removed from dams that were fed with a control diet or with a FAD diet for several weeks. Foetuses with maternal FAD diets were selected for the study when they showed an altered tongue or mandible. Histological sections were used to quantify the dimensions of the head, tongue, mandibular bone and masseter muscle areas using ImageJ software. The muscles of the tongue, suprahyoid muscles, lingual septum, submandibular ducts, and lingual arteries were also analysed. The heads of malformed foetuses were smaller than the heads of the controls, and they showed different types of malformations: microglossia with micrognathia (some of which were combined with cleft palate) and aglossia with either micrognathia or agnathia. Lingual and suprahyoid muscles were affected in different forms and degrees. We also found alterations in the lingual arteries and in the ducts of the submandibular glands. Summarised we can state that pharyngeal arches-derived structures were affected, and the main malformations observed corroborate the vulnerability of cranial neural crest cells to FA deficiency. The present study reveals alterations in the development of craniofacial structures in FAD foetuses. This study provides a new focus for the role of FA during embryological development. Copyright © 2018 Elsevier GmbH. All rights reserved.

Deep mRNA sequencing reveals stage-specific transcriptome alterations during microsclerotia development in the smoke tree vascular wilt pathogen, Verticillium dahliae

USDA-ARS?s Scientific Manuscript database

Verticillium dahliae is a soil-borne fungus that causes vascular wilt diseases in a wide range of plant hosts. V. dahliae produces multicelled, melanized resting bodies, also known as microsclerotia (MS) that can survive for years in the soil. Thus, MS formation marks an important event in the disea...

Altered Pathway Analyzer: A gene expression dataset analysis tool for identification and prioritization of differentially regulated and network rewired pathways

PubMed Central

Kaushik, Abhinav; Ali, Shakir; Gupta, Dinesh

2017-01-01

Gene connection rewiring is an essential feature of gene network dynamics. Apart from its normal functional role, it may also lead to dysregulated functional states by disturbing pathway homeostasis. Very few computational tools measure rewiring within gene co-expression and its corresponding regulatory networks in order to identify and prioritize altered pathways which may or may not be differentially regulated. We have developed Altered Pathway Analyzer (APA), a microarray dataset analysis tool for identification and prioritization of altered pathways, including those which are differentially regulated by TFs, by quantifying rewired sub-network topology. Moreover, APA also helps in re-prioritization of APA shortlisted altered pathways enriched with context-specific genes. We performed APA analysis of simulated datasets and p53 status NCI-60 cell line microarray data to demonstrate potential of APA for identification of several case-specific altered pathways. APA analysis reveals several altered pathways not detected by other tools evaluated by us. APA analysis of unrelated prostate cancer datasets identifies sample-specific as well as conserved altered biological processes, mainly associated with lipid metabolism, cellular differentiation and proliferation. APA is designed as a cross platform tool which may be transparently customized to perform pathway analysis in different gene expression datasets. APA is freely available at http://bioinfo.icgeb.res.in/APA. PMID:28084397

Suppressing Farnesyl Diphosphate Synthase Alters Chloroplast Development and Triggers Sterol-Dependent Induction of Jasmonate- and Fe-Related Responses1[OPEN

PubMed Central

Andrade, Paola; Caudepón, Daniel; Arró, Montserrat

2016-01-01

Farnesyl diphosphate synthase (FPS) catalyzes the synthesis of farnesyl diphosphate from isopentenyl diphosphate and dimethylallyl diphosphate. Arabidopsis (Arabidopsis thaliana) contains two genes (FPS1 and FPS2) encoding FPS. Single fps1 and fps2 knockout mutants are phenotypically indistinguishable from wild-type plants, while fps1/fps2 double mutants are embryo lethal. To assess the effect of FPS down-regulation at postembryonic developmental stages, we generated Arabidopsis conditional knockdown mutants expressing artificial microRNAs devised to simultaneously silence both FPS genes. Induction of silencing from germination rapidly caused chlorosis and a strong developmental phenotype that led to seedling lethality. However, silencing of FPS after seed germination resulted in a slight developmental delay only, although leaves and cotyledons continued to show chlorosis and altered chloroplasts. Metabolomic analyses also revealed drastic changes in the profile of sterols, ubiquinones, and plastidial isoprenoids. RNA sequencing and reverse transcription-quantitative polymerase chain reaction transcriptomic analysis showed that a reduction in FPS activity levels triggers the misregulation of genes involved in biotic and abiotic stress responses, the most prominent one being the rapid induction of a set of genes related to the jasmonic acid pathway. Down-regulation of FPS also triggered an iron-deficiency transcriptional response that is consistent with the iron-deficient phenotype observed in FPS-silenced plants. The specific inhibition of the sterol biosynthesis pathway by chemical and genetic blockage mimicked these transcriptional responses, indicating that sterol depletion is the primary cause of the observed alterations. Our results highlight the importance of sterol homeostasis for normal chloroplast development and function and reveal important clues about how isoprenoid and sterol metabolism is integrated within plant physiology and development. PMID:27382138

Suppressing Farnesyl Diphosphate Synthase Alters Chloroplast Development and Triggers Sterol-Dependent Induction of Jasmonate- and Fe-Related Responses.

PubMed

Manzano, David; Andrade, Paola; Caudepón, Daniel; Altabella, Teresa; Arró, Montserrat; Ferrer, Albert

2016-09-01

Farnesyl diphosphate synthase (FPS) catalyzes the synthesis of farnesyl diphosphate from isopentenyl diphosphate and dimethylallyl diphosphate. Arabidopsis (Arabidopsis thaliana) contains two genes (FPS1 and FPS2) encoding FPS. Single fps1 and fps2 knockout mutants are phenotypically indistinguishable from wild-type plants, while fps1/fps2 double mutants are embryo lethal. To assess the effect of FPS down-regulation at postembryonic developmental stages, we generated Arabidopsis conditional knockdown mutants expressing artificial microRNAs devised to simultaneously silence both FPS genes. Induction of silencing from germination rapidly caused chlorosis and a strong developmental phenotype that led to seedling lethality. However, silencing of FPS after seed germination resulted in a slight developmental delay only, although leaves and cotyledons continued to show chlorosis and altered chloroplasts. Metabolomic analyses also revealed drastic changes in the profile of sterols, ubiquinones, and plastidial isoprenoids. RNA sequencing and reverse transcription-quantitative polymerase chain reaction transcriptomic analysis showed that a reduction in FPS activity levels triggers the misregulation of genes involved in biotic and abiotic stress responses, the most prominent one being the rapid induction of a set of genes related to the jasmonic acid pathway. Down-regulation of FPS also triggered an iron-deficiency transcriptional response that is consistent with the iron-deficient phenotype observed in FPS-silenced plants. The specific inhibition of the sterol biosynthesis pathway by chemical and genetic blockage mimicked these transcriptional responses, indicating that sterol depletion is the primary cause of the observed alterations. Our results highlight the importance of sterol homeostasis for normal chloroplast development and function and reveal important clues about how isoprenoid and sterol metabolism is integrated within plant physiology and development. © 2016 American Society of Plant Biologists. All rights reserved.

Low levels of the herbicide atrazine alter sex ratios and reduce metamorphic success in Rana pipiens tadpoles raised in outdoor mesocosms.

PubMed

Langlois, Valérie S; Carew, Amanda C; Pauli, Bruce D; Wade, Michael G; Cooke, Gerard M; Trudeau, Vance L

2010-04-01

There are conflicting reports regarding the effects of atrazine (ATZ) on amphibian development. Therefore, further studies are needed to examine the potential mechanisms of action of ATZ in amphibians. Our aim in this study was to determine whether low concentrations of ATZ affect gonadal development and metamorphosis in the Northern leopard frog, Rana pipiens. Tadpoles were exposed in outdoor mesocosms to nominal concentrations of 0.1 and 1.8 microg/L of formulated ATZ from Gosner stage 27 (G27) to metamorphic climax (G42). Exposure to 17alpha-ethinylestradiol (EE2; 1.5 microg/L) provided a positive control for induction of testicular oocytes in males. Endocrine-related gene expression and gonadal histopathology were examined at G42 and in a subset of premetamorphic G34 tadpoles that failed to metamorphose. Gonadal gross morphology revealed that the 1.8-microg/L ATZ treatment produced 20% more females compared with the control. Histologic analysis revealed that 22% of EE2-treated males had testicular oocytes, whereas none were observed in any animals from the control or either ATZ groups. ATZ increased brain estrogen receptor alpha mRNA to 2.5 times that of the control at premetamorphosis and altered liver levels of 5beta-reductase activity at metamorphosis. In contrast, brain aromatase mRNA level and activity did not change. ATZ treatments significantly reduced metamorphic success (number of animals reaching metamorphosis) without affecting body weight, snout-vent length, or age at metamorphosis. Gene expression analysis indicated that ATZ decreased the expression of deiodinase type 3 in the tail at premetamorphosis. Our study indicates that exposure to low concentrations of ATZ in experimental mesocosms alters gonadal differentiation and metamorphosis in developing R. pipiens.

Increased proliferation of late-born retinal progenitor cells by gestational lead exposure delays rod and bipolar cell differentiation.

PubMed

Chaney, Shawnta Y; Mukherjee, Shradha; Giddabasappa, Anand; Rueda, Elda M; Hamilton, W Ryan; Johnson, Jerry E; Fox, Donald A

2016-01-01

Studies of neuronal development in the retina often examine the stages of proliferation, differentiation, and synaptic development, albeit independently. Our goal was to determine if a known neurotoxicant insult to a population of retinal progenitor cells (RPCs) would affect their eventual differentiation and synaptic development. To that end, we used our previously published human equivalent murine model of low-level gestational lead exposure (GLE). Children and animals with GLE exhibit increased scotopic electroretinogram a- and b-waves. Adult mice with GLE exhibit an increased number of late-born RPCs, a prolonged period of RPC proliferation, and an increased number of late-born rod photoreceptors and rod and cone bipolar cells (BCs), with no change in the number of late-born Müller glial cells or early-born neurons. The specific aims of this study were to determine whether increased and prolonged RPC proliferation alters the spatiotemporal differentiation and synaptic development of rods and BCs in early postnatal GLE retinas compared to control retinas. C57BL/6N mouse pups were exposed to lead acetate via drinking water throughout gestation and until postnatal day 10, which is equivalent to the human gestation period for retinal neurogenesis. RT-qPCR, immunohistochemical analysis, and western blots of well-characterized, cell-specific genes and proteins were performed at embryonic and early postnatal ages to assess rod and cone photoreceptor differentiation, rod and BC differentiation and synaptic development, and Müller glial cell differentiation. Real-time quantitative PCR (RT-qPCR) with the rod-specific transcription factors Nrl , Nr2e3 , and Crx and the rod-specific functional gene Rho , along with central retinal confocal studies with anti-recoverin and anti-rhodopsin antibodies, revealed a two-day delay in the differentiation of rod photoreceptors in GLE retinas. Rhodopsin immunoblots supported this conclusion. No changes in glutamine synthetase gene or protein expression, a marker for late-born Müller glial cells, were observed in the developing retinas. In the retinas from the GLE mice, anti-PKCα, - Chx10 (Vsx2) and -secretagogin antibodies revealed a two- to three-day delay in the differentiation of rod and cone BCs, whereas the expression of the proneural and BC genes Otx2 and Chx10 , respectively, increased. In addition, confocal studies of proteins associated with functional synapses (e.g., vesicular glutamate transporter 1 [VGluT1], plasma membrane calcium ATPase [PMCA], transient receptor potential channel M1 [TRPM1], and synaptic vesicle glycoprotein 2B [SV2B]) revealed a two-day delay in the formation of the outer and inner plexiform layers of the GLE retinas. Moreover, several markers revealed that the initiation of the differentiation and intensity of the labeling of early-born cells in the retinal ganglion cell and inner plexiform layers were not different in the control retinas. Our combined gene, confocal, and immunoblot findings revealed that the onset of rod and BC differentiation and their subsequent synaptic development is delayed by two to three days in GLE retinas. These results suggest that perturbations during the early proliferative stages of late-born RPCs fated to be rods and BCs ultimately alter the coordinated time-dependent progression of rod and BC differentiation and synaptic development. These GLE effects were selective for late-born neurons. Although the molecular mechanisms are unknown, alterations in soluble neurotrophic factors and/or their receptors are likely to play a role. Since neurodevelopmental delays and altered synaptic connectivity are associated with neuropsychiatric and behavioral disorders as well as cognitive deficits, future work is needed to determine if similar effects occur in the brains of GLE mice and whether children with GLE experience similar delays in retinal and brain neuronal differentiation and synaptic development.

The C. elegans neural editome reveals an ADAR target mRNA required for proper chemotaxis

PubMed Central

Deffit, Sarah N; Yee, Brian A; Manning, Aidan C; Rajendren, Suba; Vadlamani, Pranathi; Wheeler, Emily C; Domissy, Alain; Washburn, Michael C

2017-01-01

ADAR proteins alter gene expression both by catalyzing adenosine (A) to inosine (I) RNA editing and binding to regulatory elements in target RNAs. Loss of ADARs affects neuronal function in all animals studied to date. Caenorhabditis elegans lacking ADARs exhibit reduced chemotaxis, but the targets responsible for this phenotype remain unknown. To identify critical neural ADAR targets in C. elegans, we performed an unbiased assessment of the effects of ADR-2, the only A-to-I editing enzyme in C. elegans, on the neural transcriptome. Development and implementation of publicly available software, SAILOR, identified 7361 A-to-I editing events across the neural transcriptome. Intersecting the neural editome with adr-2 associated gene expression changes, revealed an edited mRNA, clec-41, whose neural expression is dependent on deamination. Restoring clec-41 expression in adr-2 deficient neural cells rescued the chemotaxis defect, providing the first evidence that neuronal phenotypes of ADAR mutants can be caused by altered gene expression. PMID:28925356

N-cadherin adhesive interactions modulate matrix mechanosensing and fate commitment of mesenchymal stem cells

NASA Astrophysics Data System (ADS)

Cosgrove, Brian D.; Mui, Keeley L.; Driscoll, Tristan P.; Caliari, Steven R.; Mehta, Kush D.; Assoian, Richard K.; Burdick, Jason A.; Mauck, Robert L.

2016-12-01

During mesenchymal development, the microenvironment gradually transitions from one that is rich in cell-cell interactions to one that is dominated by cell-ECM (extracellular matrix) interactions. Because these cues cannot readily be decoupled in vitro or in vivo, how they converge to regulate mesenchymal stem cell (MSC) mechanosensing is not fully understood. Here, we show that a hyaluronic acid hydrogel system enables, across a physiological range of ECM stiffness, the independent co-presentation of the HAVDI adhesive motif from the EC1 domain of N-cadherin and the RGD adhesive motif from fibronectin. Decoupled presentation of these cues revealed that HAVDI ligation (at constant RGD ligation) reduced the contractile state and thereby nuclear YAP/TAZ localization in MSCs, resulting in altered interpretation of ECM stiffness and subsequent changes in downstream cell proliferation and differentiation. Our findings reveal that, in an evolving developmental context, HAVDI/N-cadherin interactions can alter stem cell perception of the stiffening extracellular microenvironment.

A rare cause of hyperthyroidism: functioning thyroid metastases.

PubMed

Gardner, Daphne; Ho, Su Chin

2014-10-09

Hyperthyroidism is a common medical problem that is readily treated with antithyroid medications. However, attributing the correct aetiology of hyperthyroidism alters management and outcome. We present a case of a 66-year-old woman with a seemingly common problem of hyperthyroidism associated with a goitre, which was initially attributed to a toxic nodule. However, Tc-99m pertechnetate uptake scan and thyroid-stimulating hormone receptor antibody were negative, inconsistent with a toxic nodule or Grave's disease. Her thyroid function tests proved difficult to control over the next few months. She eventually proceeded to a total thyroidectomy and histology revealed follicular variant papillary thyroid carcinoma. She was started on levothyroxine postoperatively but developed severe hyperthyroidism, revealing the cause of hyperthyroidism to be autonomously functioning thyroid metastases. Although functioning thyroid metastases are very rare, they need to be considered among the differential diagnoses of hyperthyroidism, as there are nuances in management that could alter the eventual outcome. 2014 BMJ Publishing Group Ltd.

Influence of chronic back pain on kinematic reactions to unpredictable arm pulls.

PubMed

Götze, Martin; Ernst, Michael; Koch, Markus; Blickhan, Reinhard

2015-03-01

There is evidence that muscle reflexes are delayed in patients with chronic low back pain in response to perturbations. It is still unrevealed whether these delays accompanied by an altered kinematic or compensated by adaption of other muscle parameters. The aim of this study was to investigate whether chronic low back pain patients show an altered kinematic reaction and if such data are reliable for the classification of chronic low back pain. In an experiment involving 30 females, sudden lateral perturbations were applied to the arm of a subject in an upright, standing position. Kinematics was used to distinguish between chronic low back pain patients and healthy controls. A calculated model of a stepwise discriminant function analysis correctly predicted 100% of patients and 80% of healthy controls. The estimation of the classification error revealed a constant rate for the classification of the healthy controls and a slightly decreased rate for the patients. Observed reflex delays and identified kinematic differences inside and outside the region of pain during impaired movement indicated that chronic low back pain patients have an altered motor control that is not restricted to the lumbo-pelvic region. This applied paradigm of external perturbations can be used to detect chronic low back pain patients and also persons without chronic low back pain but with an altered motor control. Further investigations are essential to reveal whether healthy persons with changes in motor function have an increased potential to develop chronic back pain. Copyright © 2015 Elsevier Ltd. All rights reserved.

Examining temporal alterations in Social Anxiety Disorder and Posttraumatic Stress Disorder: The relation between autobiographical memory, future goals, and current self-views.

PubMed

Krans, Julie; Peeters, Manon; Näring, Gérard; Brown, Adam D; de Bree, June; van Minnen, Agnes

2017-12-01

The self is a multi-faceted and temporally dynamic construct reflecting representations and beliefs about identity in the past, present, and future. Clinical studies have shown that individuals with Posttraumatic Stress Disorder (PTSD) and Social Anxiety Disorder (SAD) exhibit alterations in self-related processing but these studies have focused primarily on memory. Few studies in PTSD and SAD have examined self-related processing for the present and future, and no studies have directly compared these processes across these two disorders. Individuals diagnosed with PTSD (n=21), SAD (n=21), and healthy controls (n=21) completed cognitive tasks related to the past, present, and future. Disorder congruent temporal alterations were found across both disorders. Further, regression analyses revealed that trauma-related memories were significantly predicted by future goals related to the trauma, whereas social anxiety-related recall was predicted by current socially anxious self-views. Thus, although self-related processing may be common in PTSD and SAD, those aspects of the self most strongly associated with disorder-congruent recall differ by disorder. Self-alterations may be modifiable and developing a better understanding of past, present, and future self-processing might aid in the development of interventions that target these process. Copyright © 2017 Elsevier Ltd. All rights reserved.

Genetic alterations in hepatocellular carcinoma: An update

PubMed Central

Niu, Zhao-Shan; Niu, Xiao-Jun; Wang, Wen-Hong

2016-01-01

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC. PMID:27895396

Label-free Raman spectroscopy provides early determination and precise localization of breast cancer-colonized bone alterations.

PubMed

Zhang, Chi; Winnard, Paul T; Dasari, Sidarth; Kominsky, Scott L; Doucet, Michele; Jayaraman, Swaathi; Raman, Venu; Barman, Ishan

2018-01-21

Breast neoplasms frequently colonize bone and induce development of osteolytic bone lesions by disrupting the homeostasis of the bone microenvironment. This degenerative process can lead to bone pain and pathological bone fracture, a major cause of cancer morbidity and diminished quality of life, which is exacerbated by our limited ability to monitor early metastatic disease in bone and assess fracture risk. Spurred by its label-free, real-time nature and its exquisite molecular specificity, we employed spontaneous Raman spectroscopy to assess and quantify early metastasis driven biochemical alterations to bone composition. As early as two weeks after intracardiac inoculations of MDA-MB-435 breast cancer cells in NOD-SCID mice, Raman spectroscopic measurements in the femur and spine revealed consistent changes in carbonate substitution, overall mineralization as well as crystallinity increase in tumor-bearing bones when compared with their normal counterparts. Our observations reveal the possibility of early stage detection of biochemical changes in the tumor-bearing bones - significantly before morphological variations are captured through radiographic diagnosis. This study paves the way for a better molecular understanding of altered bone remodeling in such metastatic niches, and for further clinical studies with the goal of establishing a non-invasive tool for early metastasis detection and prediction of pathological fracture risk in breast cancer.

Single-nanotube tracking reveals the nanoscale organization of the extracellular space in the live brain

NASA Astrophysics Data System (ADS)

Godin, Antoine G.; Varela, Juan A.; Gao, Zhenghong; Danné, Noémie; Dupuis, Julien P.; Lounis, Brahim; Groc, Laurent; Cognet, Laurent

2017-03-01

The brain is a dynamic structure with the extracellular space (ECS) taking up almost a quarter of its volume. Signalling molecules, neurotransmitters and nutrients transit via the ECS, which constitutes a key microenvironment for cellular communication and the clearance of toxic metabolites. The spatial organization of the ECS varies during sleep, development and aging and is probably altered in neuropsychiatric and degenerative diseases, as inferred from electron microscopy and macroscopic biophysical investigations. Here we show an approach to directly observe the local ECS structures and rheology in brain tissue using super-resolution imaging. We inject single-walled carbon nanotubes into rat cerebroventricles and follow the near-infrared emission of individual nanotubes as they diffuse inside the ECS for tens of minutes in acute slices. Because of the interplay between the nanotube geometry and the ECS local environment, we can extract information about the dimensions and local viscosity of the ECS. We find a striking diversity of ECS dimensions down to 40 nm, and as well as of local viscosity values. Moreover, by chemically altering the extracellular matrix of the brains of live animals before nanotube injection, we reveal that the rheological properties of the ECS are affected, but these alterations are local and inhomogeneous at the nanoscale.

Plant Signaling and Metabolic Pathways Enabling Arbuscular Mycorrhizal Symbiosis.

PubMed

MacLean, Allyson M; Bravo, Armando; Harrison, Maria J

2017-10-01

Plants have lived in close association with arbuscular mycorrhizal (AM) fungi for over 400 million years. Today, this endosymbiosis occurs broadly in the plant kingdom where it has a pronounced impact on plant mineral nutrition. The symbiosis develops deep within the root cortex with minimal alterations in the external appearance of the colonized root; however, the absence of macroscopic alterations belies the extensive signaling, cellular remodeling, and metabolic alterations that occur to enable accommodation of the fungal endosymbiont. Recent research has revealed the involvement of a novel N -acetyl glucosamine transporter and an alpha/beta-fold hydrolase receptor at the earliest stages of AM symbiosis. Calcium channels required for symbiosis signaling have been identified, and connections between the symbiosis signaling pathway and key transcriptional regulators that direct AM-specific gene expression have been established. Phylogenomics has revealed the existence of genes conserved for AM symbiosis, providing clues as to how plant cells fine-tune their biology to enable symbiosis, and an exciting coalescence of genome mining, lipid profiling, and tracer studies collectively has led to the conclusion that AM fungi are fatty acid auxotrophs and that plants provide their fungal endosymbionts with fatty acids. Here, we provide an overview of the molecular program for AM symbiosis and discuss these recent advances. © 2017 American Society of Plant Biologists. All rights reserved.

Epigenetics and Colorectal Cancer

PubMed Central

Lao, Victoria Valinluck; Grady, William M.

2012-01-01

Colorectal cancer is a leading cause of cancer deaths in the world. It results from an accumulation of genetic and epigenetic changes in colon epithelial cells that transforms them into adenocarcinomas. There have been major advances in our understanding of cancer epigenetics over the last decade, particularly regarding aberrant DNA methylation. Assessment of the colon cancer epigenome has revealed that virtually all colorectal cancers have aberrantly methylated genes and the average colorectal cancer methylome has hundreds to thousands of abnormally methylated genes. As with gene mutations in the cancer genome, a subset of these methylated genes, called driver genes, is presumed to play a functional role in colorectal cancer. The assessment of methylated genes in colorectal cancers has also revealed a unique molecular subgroup of colorectal cancers called CpG Island Methylator Phenotype (CIMP) cancers; these tumors have a particularly high frequency of methylated genes. The advances in our understanding of aberrant methylation in colorectal cancer has led to epigenetic alterations being developed as clinical biomarkers for diagnostic, prognostic, and therapeutic applications. Progress in the assessment of epigenetic alterations in colorectal cancer and their clinical applications has shown that these alterations will be commonly used in the near future as molecular markers to direct the prevention and treatment of colorectal cancer. PMID:22009203

DTI and VBM reveal white matter changes without associated gray matter changes in patients with idiopathic restless legs syndrome

PubMed Central

Belke, Marcus; Heverhagen, Johannes T; Keil, Boris; Rosenow, Felix; Oertel, Wolfgang H; Stiasny-Kolster, Karin; Knake, Susanne; Menzler, Katja

2015-01-01

Background and Purpose We evaluated cerebral white and gray matter changes in patients with iRLS in order to shed light on the pathophysiology of this disease. Methods Twelve patients with iRLS were compared to 12 age- and sex-matched controls using whole-head diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) techniques. Evaluation of the DTI scans included the voxelwise analysis of the fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). Results Diffusion tensor imaging revealed areas of altered FA in subcortical white matter bilaterally, mainly in temporal regions as well as in the right internal capsule, the pons, and the right cerebellum. These changes overlapped with changes in RD. Voxel-based morphometry did not reveal any gray matter alterations. Conclusions We showed altered diffusion properties in several white matter regions in patients with iRLS. White matter changes could mainly be attributed to changes in RD, a parameter thought to reflect altered myelination. Areas with altered white matter microstructure included areas in the internal capsule which include the corticospinal tract to the lower limbs, thereby supporting studies that suggest changes in sensorimotor pathways associated with RLS. PMID:26442748

Studying a Complex Tumor—Potential and Pitfalls

PubMed Central

Zheng, Siyuan; Chheda, Milan G.; Verhaak, Roel G.W.

2012-01-01

Glioblastoma multiforme (GBM) is a histopathologically heterogeneous disease with few treatment options. Therapy based on genomic alterations is rapidly gaining popularity because of the high response rate and high specificity. DNA copy number and exon sequencing studies of GBM samples have revealed recurrent genomic alterations in genes such as TP53, EGFR and IDH1 but to date this has not resulted in novel GBM therapies. Identification of expression subtypes have resulted in new insights such as the association between genomic abnormalities and expression signatures. This review describes the types of genomic studies that have been performed and that are underway, the most prominent results and the implications of genomic research for development of clinical treatment modalities. PMID:22290264

Development of Novel Therapeutics for Neglected Tropical Disease Leishmaniasis

DTIC Science & Technology

2015-10-01

Approved for public release; distribution unlimited We undertook planning of kick off coordination meeting. A low dose infection model of CL was validated...A large scale synthesis of PEN optimized and in vitro studies were performed revealed that PEN alters parasite lipidome. Further studies were...Pentalinonsterol, Leishmania, cutaneous leishmaniasis, treatment Accomplishments • Undertook planning of kick off coordination meeting • Large scale synthesis of

Resting state fMRI reveals a default mode dissociation between retrosplenial and medial prefrontal subnetworks in ASD despite motion scrubbing.

PubMed

Starck, Tuomo; Nikkinen, Juha; Rahko, Jukka; Remes, Jukka; Hurtig, Tuula; Haapsamo, Helena; Jussila, Katja; Kuusikko-Gauffin, Sanna; Mattila, Marja-Leena; Jansson-Verkasalo, Eira; Pauls, David L; Ebeling, Hanna; Moilanen, Irma; Tervonen, Osmo; Kiviniemi, Vesa J

2013-01-01

In resting state functional magnetic resonance imaging (fMRI) studies of autism spectrum disorders (ASDs) decreased frontal-posterior functional connectivity is a persistent finding. However, the picture of the default mode network (DMN) hypoconnectivity remains incomplete. In addition, the functional connectivity analyses have been shown to be susceptible even to subtle motion. DMN hypoconnectivity in ASD has been specifically called for re-evaluation with stringent motion correction, which we aimed to conduct by so-called scrubbing. A rich set of default mode subnetworks can be obtained with high dimensional group independent component analysis (ICA) which can potentially provide more detailed view of the connectivity alterations. We compared the DMN connectivity in high-functioning adolescents with ASDs to typically developing controls using ICA dual-regression with decompositions from typical to high dimensionality. Dual-regression analysis within DMN subnetworks did not reveal alterations but connectivity between anterior and posterior DMN subnetworks was decreased in ASD. The results were very similar with and without motion scrubbing thus indicating the efficacy of the conventional motion correction methods combined with ICA dual-regression. Specific dissociation between DMN subnetworks was revealed on high ICA dimensionality, where networks centered at the medial prefrontal cortex and retrosplenial cortex showed weakened coupling in adolescents with ASDs compared to typically developing control participants. Generally the results speak for disruption in the anterior-posterior DMN interplay on the network level whereas local functional connectivity in DMN seems relatively unaltered.

Cooperative genomic alteration network reveals molecular classification across 12 major cancer types

PubMed Central

Zhang, Hongyi; Deng, Yulan; Zhang, Yong; Ping, Yanyan; Zhao, Hongying; Pang, Lin; Zhang, Xinxin; Wang, Li; Xu, Chaohan; Xiao, Yun; Li, Xia

2017-01-01

The accumulation of somatic genomic alterations that enables cells to gradually acquire growth advantage contributes to tumor development. This has the important implication of the widespread existence of cooperative genomic alterations in the accumulation process. Here, we proposed a computational method HCOC that simultaneously consider genetic context and downstream functional effects on cancer hallmarks to uncover somatic cooperative events in human cancers. Applying our method to 12 TCGA cancer types, we totally identified 1199 cooperative events with high heterogeneity across human cancers, and then constructed a pan-cancer cooperative alteration network. These cooperative events are associated with genomic alterations of some high-confident cancer drivers, and can trigger the dysfunction of hallmark associated pathways in a co-defect way rather than single alterations. We found that these cooperative events can be used to produce a prognostic classification that can provide complementary information with tissue-of-origin. In a further case study of glioblastoma, using 23 cooperative events identified, we stratified patients into molecularly relevant subtypes with a prognostic significance independent of the Glioma-CpG Island Methylator Phenotype (GCIMP). In summary, our method can be effectively used to discover cancer-driving cooperative events that can be valuable clinical markers for patient stratification. PMID:27899621

Methamphetamine treatment during development attenuates the dopaminergic deficits caused by subsequent high-dose methamphetamine administration.

PubMed

McFadden, Lisa M; Hoonakker, Amanda J; Vieira-Brock, Paula L; Stout, Kristen A; Sawada, Nicole M; Ellis, Jonathan D; Allen, Scott C; Walters, Elliot T; Nielsen, Shannon M; Gibb, James W; Alburges, Mario E; Wilkins, Diana G; Hanson, Glen R; Fleckenstein, Annette E

2011-08-01

Administration of high doses of methamphetamine (METH) causes persistent dopaminergic deficits in both nonhuman preclinical models and METH-dependent persons. Noteworthy, adolescent [i.e., postnatal day (PND) 40] rats are less susceptible to this damage than young adult (PND90) rats. In addition, biweekly treatment with METH, beginning at PND40 and continuing throughout development, prevents the persistent dopaminergic deficits caused by a "challenge" high-dose METH regimen when administered at PND90. Mechanisms underlying this "resistance" were thus investigated. Results revealed that biweekly METH treatment throughout development attenuated both the acute and persistent deficits in VMAT2 function, as well as the acute hyperthermia, caused by a challenge METH treatment. Pharmacokinetic alterations did not appear to contribute to the protection afforded by the biweekly treatment. Maintenance of METH-induced hyperthermia abolished the protection against both the acute and persistent VMAT2-associated deficits suggesting that alterations in thermoregulation were caused by exposure of rats to METH during development. These findings suggest METH during development prevents METH-induced hyperthermia and the consequent METH-related neurotoxicity. Copyright © 2011 Wiley-Liss, Inc.

Characterization of a cinnamoyl-CoA reductase 1 (CCR1) mutant in maize: effects on lignification, fibre development, and global gene expression

PubMed Central

Tamasloukht, Barek; Wong Quai Lam, Mary Sarah-Jane; Martinez, Yves; Tozo, Koffi; Barbier, Odile; Jourda, Cyril; Jauneau, Alain; Borderies, Gisèle; Balzergue, Sandrine; Renou, Jean-Pierre; Huguet, Stéphanie; Martinant, Jean Pierre; Tatout, Christophe; Lapierre, Catherine; Barrière, Yves; Goffner, Deborah; Pichon, Magalie

2011-01-01

Cinnamoyl-CoA reductase (CCR), which catalyses the first committed step of the lignin-specific branch of monolignol biosynthesis, has been extensively characterized in dicot species, but few data are available in monocots. By screening a Mu insertional mutant collection in maize, a mutant in the CCR1 gene was isolated named Zmccr1–. In this mutant, CCR1 gene expression is reduced to 31% of the residual wild-type level. Zmccr1– exhibited enhanced digestibility without compromising plant growth and development. Lignin analysis revealed a slight decrease in lignin content and significant changes in lignin structure. p-Hydroxyphenyl units were strongly decreased and the syringyl/guaiacyl ratio was slightly increased. At the cellular level, alterations in lignin deposition were mainly observed in the walls of the sclerenchymatic fibre cells surrounding the vascular bundles. These cell walls showed little to no staining with phloroglucinol. These histochemical changes were accompanied by an increase in sclerenchyma surface area and an alteration in cell shape. In keeping with this cell type-specific phenotype, transcriptomics performed at an early stage of plant development revealed the down-regulation of genes specifically associated with fibre wall formation. To the present authors’ knowledge, this is the first functional characterization of CCR1 in a grass species. PMID:21493812

Prenatal Exposure to BPA Alters the Epigenome of the Rat Mammary Gland and Increases the Propensity to Neoplastic Development

PubMed Central

Dhimolea, Eugen; Wadia, Perinaaz R.; Murray, Tessa J.; Settles, Matthew L.; Treitman, Jo D.; Sonnenschein, Carlos; Shioda, Toshi; Soto, Ana M.

2014-01-01

Exposure to environmental estrogens (xenoestrogens) may play a causal role in the increased breast cancer incidence which has been observed in Europe and the US over the last 50 years. The xenoestrogen bisphenol A (BPA) leaches from plastic food/beverage containers and dental materials. Fetal exposure to BPA induces preneoplastic and neoplastic lesions in the adult rat mammary gland. Previous results suggest that BPA acts through the estrogen receptors which are detected exclusively in the mesenchyme during the exposure period by directly altering gene expression, leading to alterations of the reciprocal interactions between mesenchyme and epithelium. This initiates a long sequence of altered morphogenetic events leading to neoplastic transformation. Additionally, BPA induces epigenetic changes in some tissues. To explore this mechanism in the mammary gland, Wistar-Furth rats were exposed subcutaneously via osmotic pumps to vehicle or 250 µg BPA/kg BW/day, a dose that induced ductal carcinomas in situ. Females exposed from gestational day 9 to postnatal day (PND) 1 were sacrificed at PND4, PND21 and at first estrus after PND50. Genomic DNA (gDNA) was isolated from the mammary tissue and immuno-precipitated using anti-5-methylcytosine antibodies. Detection and quantification of gDNA methylation status using the Nimblegen ChIP array revealed 7412 differentially methylated gDNA segments (out of 58207 segments), with the majority of changes occurring at PND21. Transcriptomal analysis revealed that the majority of gene expression differences between BPA- and vehicle-treated animals were observed later (PND50). BPA exposure resulted in higher levels of pro-activation histone H3K4 trimethylation at the transcriptional initiation site of the alpha-lactalbumin gene at PND4, concomitantly enhancing mRNA expression of this gene. These results show that fetal BPA exposure triggers changes in the postnatal and adult mammary gland epigenome and alters gene expression patterns. These events may contribute to the development of pre-neoplastic and neoplastic lesions that manifest during adulthood. PMID:24988533

Altered Hematopoiesis in Mice Lacking DNA Polymerase μ Is Due to Inefficient Double-Strand Break Repair

PubMed Central

Lucas, Daniel; Escudero, Beatriz; Ligos, José Manuel; Segovia, Jose Carlos; Estrada, Juan Camilo; Terrados, Gloria; Blanco, Luis; Samper, Enrique; Bernad, Antonio

2009-01-01

Polymerase mu (Polμ) is an error-prone, DNA-directed DNA polymerase that participates in non-homologous end-joining (NHEJ) repair. In vivo, Polμ deficiency results in impaired Vκ-Jκ recombination and altered somatic hypermutation and centroblast development. In Polμ−/− mice, hematopoietic development was defective in several peripheral and bone marrow (BM) cell populations, with about a 40% decrease in BM cell number that affected several hematopoietic lineages. Hematopoietic progenitors were reduced both in number and in expansion potential. The observed phenotype correlates with a reduced efficiency in DNA double-strand break (DSB) repair in hematopoietic tissue. Whole-body γ-irradiation revealed that Polμ also plays a role in DSB repair in non-hematopoietic tissues. Our results show that Polμ function is required for physiological hematopoietic development with an important role in maintaining early progenitor cell homeostasis and genetic stability in hematopoietic and non-hematopoietic tissues. PMID:19229323

HIV-1, Reactive Oxygen Species and Vascular Complications

PubMed Central

Porter, Kristi M.; Sutliff, Roy L.

2012-01-01

Over 1 million people in the United States and 33 million individuals worldwide suffer from HIV/AIDS. Since its discovery, HIV/AIDS has been associated with an increased susceptibility to opportunistic infection due to immune dysfunction. Highly active antiretroviral therapies (HAART) restore immune function and, as a result, people infected with HIV-1 are living longer. This improved survival of HIV-1 patients has revealed a previously unrecognized risk of developing vascular complications, such as atherosclerosis and pulmonary hypertension. The mechanisms underlying these HIV-associated vascular disorders are poorly understood. However, HIV-induced elevations in reactive oxygen species, including superoxide and hydrogen peroxide, may contribute to vascular disease development and progression by altering cell function and redox-sensitive signaling pathways. In this review, we summarize the clinical and experimental evidence demonstrating HIV- and HIV antiretroviral therapy-induced alterations in reactive oxygen species (ROS) and how these effects likely contribute to vascular dysfunction and disease. PMID:22564529

Cecal Perforation Associated with Clostridium difficile Infection: A Case Report.

PubMed

Luthe, Sarah Kyuragi; Sato, Ryota

2017-04-01

Various complications are reported with Clostridium difficile infection (CDI), including fulminant CDI. Fulminant CDI is an underappreciated life-threatening condition associated with complications such as toxic megacolon and bowel perforation. A 79-year-old woman presented to the Emergency Department with altered mental status. She was admitted and conservatively treated for a left thalamic hemorrhage. While hospitalized, she developed watery diarrhea due to Clostridium difficile. Although metronidazole was initiated, she developed altered mental status and septic shock. Abdominal x-ray study and computed tomography revealed a significantly dilatated colon and a massive pneumoperitoneum. She underwent subtotal colectomy with a 14-day course of intravenous meropenem. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case suggests that we must be aware of the complications that CDI may present and adequately consider surgical management because early diagnosis and surgical treatment is critical to reduce the mortality of fulminant CDI. Copyright © 2016 Elsevier Inc. All rights reserved.

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

PubMed Central

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

2015-01-01

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

Defects in Mitochondrial Dynamics and Metabolomic Signatures of Evolving Energetic Stress in Mouse Models of Familial Alzheimer's Disease

PubMed Central

Trushina, Eugenia; Nemutlu, Emirhan; Zhang, Song; Christensen, Trace; Camp, Jon; Mesa, Janny; Siddiqui, Ammar; Tamura, Yasushi; Sesaki, Hiromi; Wengenack, Thomas M.; Dzeja, Petras P.; Poduslo, Joseph F.

2012-01-01

Background The identification of early mechanisms underlying Alzheimer's Disease (AD) and associated biomarkers could advance development of new therapies and improve monitoring and predicting of AD progression. Mitochondrial dysfunction has been suggested to underlie AD pathophysiology, however, no comprehensive study exists that evaluates the effect of different familial AD (FAD) mutations on mitochondrial function, dynamics, and brain energetics. Methods and Findings We characterized early mitochondrial dysfunction and metabolomic signatures of energetic stress in three commonly used transgenic mouse models of FAD. Assessment of mitochondrial motility, distribution, dynamics, morphology, and metabolomic profiling revealed the specific effect of each FAD mutation on the development of mitochondrial stress and dysfunction. Inhibition of mitochondrial trafficking was characteristic for embryonic neurons from mice expressing mutant human presenilin 1, PS1(M146L) and the double mutation of human amyloid precursor protein APP(Tg2576) and PS1(M146L) contributing to the increased susceptibility of neurons to excitotoxic cell death. Significant changes in mitochondrial morphology were detected in APP and APP/PS1 mice. All three FAD models demonstrated a loss of the integrity of synaptic mitochondria and energy production. Metabolomic profiling revealed mutation-specific changes in the levels of metabolites reflecting altered energy metabolism and mitochondrial dysfunction in brains of FAD mice. Metabolic biomarkers adequately reflected gender differences similar to that reported for AD patients and correlated well with the biomarkers currently used for diagnosis in humans. Conclusions Mutation-specific alterations in mitochondrial dynamics, morphology and function in FAD mice occurred prior to the onset of memory and neurological phenotype and before the formation of amyloid deposits. Metabolomic signatures of mitochondrial stress and altered energy metabolism indicated alterations in nucleotide, Krebs cycle, energy transfer, carbohydrate, neurotransmitter, and amino acid metabolic pathways. Mitochondrial dysfunction, therefore, is an underlying event in AD progression, and FAD mouse models provide valuable tools to study early molecular mechanisms implicated in AD. PMID:22393443

Oral intake of zirconia nanoparticle alters neuronal development and behaviour of Drosophila melanogaster

NASA Astrophysics Data System (ADS)

Mishra, Monalisa; Sabat, Debabrat; Ekka, Basanti; Sahu, Swetapadma; P, Unnikannan; Dash, Priyabrat

2017-08-01

Zirconia nanoparticles (ZrO2 NPs) have been extensively used in teeth and bone implants and thus get a chance to interact with the physiological system. The current study investigated the oral administration of various concentrations of ZrO2 NPs synthesized by the hydrothermal method (0.25 to 5.0 mg L-1) on Drosophila physiology and behaviour. The size of the currently studied nanoparticle varies from 10 to 12 nm. ZrO2 NPs accumulated within the gut in a concentration-dependent manner and generate reactive oxygen species (ROS) only at 2.5 and 5.0 mg L-1 concentrations. ROS was detected by nitroblue tetrazolium (NBT) assay and 2',7'-dichlorofluorescein http://www.ncbi.nlm.nih.gov/pubmed/20370560 (H2DCF) staining. The ROS toxicity alters the larval gut structure as revealed by DAPI staining. The NP stress of larvae affects the Drosophila development by distressing pupa count and varying the phenotypic changes in sensory organs (eye, thorax bristle, wings). Besides phenotypic changes, flawed climbing behaviour against gravity was seen in ZrO2 NP-treated flies. All together, for the first time, we have reported that a ROS-mediated ZrO2 NP toxicity alters neuronal development and functioning using Drosophila as a model organism. [Figure not available: see fulltext.

Nonlinear optical microscopy reveals invading endothelial cells anisotropically alter three-dimensional collagen matrices

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

Lee, P.-F.; Yeh, Alvin T.; Bayless, Kayla J.

The interactions between endothelial cells (ECs) and the extracellular matrix (ECM) are fundamental in mediating various steps of angiogenesis, including cell adhesion, migration and sprout formation. Here, we used a noninvasive and non-destructive nonlinear optical microscopy (NLOM) technique to optically image endothelial sprouting morphogenesis in three-dimensional (3D) collagen matrices. We simultaneously captured signals from collagen fibers and endothelial cells using second harmonic generation (SHG) and two-photon excited fluorescence (TPF), respectively. Dynamic 3D imaging revealed EC interactions with collagen fibers along with quantifiable alterations in collagen matrix density elicited by EC movement through and morphogenesis within the matrix. Specifically, we observedmore » increased collagen density in the area between bifurcation points of sprouting structures and anisotropic increases in collagen density around the perimeter of lumenal structures, but not advancing sprout tips. Proteinase inhibition studies revealed membrane-associated matrix metalloproteinase were utilized for sprout advancement and lumen expansion. Rho-associated kinase (p160ROCK) inhibition demonstrated that the generation of cell tension increased collagen matrix alterations. This study followed sprouting ECs within a 3D matrix and revealed that the advancing structures recognize and significantly alter their extracellular environment at the periphery of lumens as they progress.« less

The Transcription Factor Atonal homolog 8 Regulates Gata4 and Friend of Gata-2 during Vertebrate Development

PubMed Central

Rawnsley, David R.; Xiao, Jiping; Lee, John S.; Liu, Xi; Mericko-Ishizuka, Patricia; Kumar, Vinayak; He, Jie; Basu, Arindam; Lu, MinMin; Lynn, Francis C.; Pack, Michael; Gasa, Rosa; Kahn, Mark L.

2013-01-01

GATA and Friend of GATA (FOG) form a transcriptional complex that plays a key role in cardiovascular development in both fish and mammals. In the present study we demonstrate that the basic helix-loop-helix transcription factor Atonal homolog 8 (Atoh8) is required for development of the heart in fish but not in mice. Genetic studies reveal that Atoh8 interacts specifically with Gata4 and Fog1 during development of the heart and swim bladder in the fish. Biochemical studies reveal that ATOH8, GATA4, and FOG2 associate in a single complex in vitro. In contrast to fish, ATOH8-deficient mice exhibit normal cardiac development and loss of ATOH8 does not alter cardiac development in Gata4+/− mice. This species difference in the role of ATOH8 is explained in part by LacZ and GFP reporter alleles that reveal restriction of Atoh8 expression to atrial but not ventricular myocardium in the mouse. Our findings identify ATOH8 as a novel regulator of GATA-FOG function that is required for cardiac development in the fish but not the mouse. Whether ATOH8 modulates GATA-FOG function at other sites or in more subtle ways in mammals is not yet known. PMID:23836893

Development of a Facility for Combustion Stability Experiments at Supercritical Pressure

DTIC Science & Technology

2013-12-01

by the exhaust orifice. This technique adds freedom for designing a large array experimental conditions, because chamber pressure is controlled...analytical examination reveals a broad array of frequencies. The analytical relationship between chamber length L, acoustic frequency fF, and the speed...the pressure amplitude is directly controlled by altering the voltage input to the sirens, similar to a traditional loudspeaker . Last, both a PN and

In utero exposure to chloroquine alters sexual development in the male fetal rat

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

Clewell, Rebecca A.; Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709; Pluta, Linda

Chloroquine (CQ), a drug that has been used extensively for the prevention and treatment of malaria, is currently considered safe for use during pregnancy. However, CQ has been shown to disrupt steroid homeostasis in adult rats and similar compounds, such as quinacrine, inhibit steroid production in the Leydig cell in vitro. To explore the effect of in utero CQ exposure on fetal male sexual development, pregnant Sprague-Dawley rats were given a daily dose of either water or chloroquine diphosphate from GD 16-18 by oral gavage. Chloroquine was administered as 200 mg/kg CQ base on GD 16, followed by two maintenancemore » doses of 100 mg/kg CQ base on GD 16 and 18. Three days of CQ treatment resulted in reduced maternal and fetal weight on GD 19 and increased necrosis and steatosis in the maternal liver. Fetal livers also displayed mild lipid accumulation. Maternal serum progesterone was increased after CQ administration. Fetal testes testosterone, however, was significantly decreased. Examination of the fetal testes revealed significant alterations in vascularization and seminiferous tubule development after short-term CQ treatment. Anogenital distance was not altered. Microarray and RT-PCR showed down-regulation of several genes associated with cholesterol transport and steroid synthesis in the fetal testes. This study indicates that CQ inhibits testosterone synthesis and normal testis development in the rat fetus at human relevant doses.« less

Simultaneous Downregulation of MTHFR and COMT in Switchgrass Affects Plant Performance and Induces Lesion-Mimic Cell Death.

PubMed

Liu, Sijia; Fu, Chunxiang; Gou, Jiqing; Sun, Liang; Huhman, David; Zhang, Yunwei; Wang, Zeng-Yu

2017-01-01

Switchgrass ( Panicum virgatum ) has been developed into a model lignocellulosic bioenergy crop. Downregulation of caffeic acid O -methyltransferase (COMT), a key enzyme in lignin biosynthesis, has been shown to alter lignification and increase biofuel yield in switchgrass. Methylenetetrahydrofolate reductase (MTHFR) mediates C1 metabolism and provides methyl units consumed by COMT. It was predicted that co-silencing of MTHFR and COMT would impact lignification even more than either of the single genes. However, our results showed that strong downregulation of MTHFR in a COMT -deficient background led to altered plant growth and development, but no significant change in lignin content or composition was found when compared with COMT plants. Another unexpected finding was that the double MTHFR/COMT downregulated plants showed a novel lesion-mimic leaf phenotype. Molecular analyses revealed that the lesion-mimic phenotype was caused by the synergistic effect of MTHFR and COMT genes, with MTHFR playing a predominant role. Microarray analysis showed significant induction of genes related to oxidative and defense responses. The results demonstrated the lack of additive effects of MTHFR and COMT on lignification. Furthermore, this research revealed an unexpected role of the two genes in the modulation of lesion-mimic cell death as well as their synergistic effects on agronomic performance.

Simultaneous Downregulation of MTHFR and COMT in Switchgrass Affects Plant Performance and Induces Lesion-Mimic Cell Death

PubMed Central

Liu, Sijia; Fu, Chunxiang; Gou, Jiqing; Sun, Liang; Huhman, David; Zhang, Yunwei; Wang, Zeng-Yu

2017-01-01

Switchgrass (Panicum virgatum) has been developed into a model lignocellulosic bioenergy crop. Downregulation of caffeic acid O-methyltransferase (COMT), a key enzyme in lignin biosynthesis, has been shown to alter lignification and increase biofuel yield in switchgrass. Methylenetetrahydrofolate reductase (MTHFR) mediates C1 metabolism and provides methyl units consumed by COMT. It was predicted that co-silencing of MTHFR and COMT would impact lignification even more than either of the single genes. However, our results showed that strong downregulation of MTHFR in a COMT-deficient background led to altered plant growth and development, but no significant change in lignin content or composition was found when compared with COMT plants. Another unexpected finding was that the double MTHFR/COMT downregulated plants showed a novel lesion-mimic leaf phenotype. Molecular analyses revealed that the lesion-mimic phenotype was caused by the synergistic effect of MTHFR and COMT genes, with MTHFR playing a predominant role. Microarray analysis showed significant induction of genes related to oxidative and defense responses. The results demonstrated the lack of additive effects of MTHFR and COMT on lignification. Furthermore, this research revealed an unexpected role of the two genes in the modulation of lesion-mimic cell death as well as their synergistic effects on agronomic performance. PMID:28676804

Role of dopaminergic and serotonergic neurotransmitters in behavioral alterations observed in rodent model of hepatic encephalopathy.

PubMed

Dhanda, Saurabh; Sandhir, Rajat

2015-06-01

The present study was designed to evaluate the role of biogenic amines in behavioral alterations observed in rat model of hepatic encephalopathy (HE) following bile duct ligation (BDL). Male Wistar rats subjected to BDL developed biliary fibrosis after four weeks which was supported by altered liver function tests, increased ammonia levels and histological staining (Sirius red). Animals were assessed for their behavioral performance in terms of cognitive, anxiety and motor functions. The levels of dopamine (DA), serotonin (5-HT), epinephrine and norepinephrine (NE) were estimated in different regions of brain viz. cortex, hippocampus, striatum and cerebellum using HPLC along with activity of monoamine oxidase (MAO). Cognitive assessment of BDL rats revealed a progressive decline in learning, memory formation, retrieval, exploration of novel environment and spontaneous locomotor activity along with decrease in 5-HT and NE levels. This was accompanied by an increase in MAO activity. Motor functions of BDL rats were also altered which were evident from decrease in the time spent on the rotating rod and higher foot faults assessed using narrow beam walk task. A global decrease was observed in the DA content along with an increase in MAO activity. Histopathological studies using hematoxylin-eosin (H&E) and cresyl violet exhibited marked neuronal degeneration, wherein neurons appeared more pyknotic, condensed and damaged. The results reveal that dopaminergic and serotonergic pathways are disturbed in chronic liver failure post-BDL which may be responsible for behavioral impairments observed in HE. Copyright © 2015 Elsevier B.V. All rights reserved.

Alteration mapping at Goldfield, Nevada, by cluster and discriminant analysis of LANDSAT digital data

NASA Technical Reports Server (NTRS)

Ballew, G.

1977-01-01

The ability of Landsat multispectral digital data to differentiate among 62 combinations of rock and alteration types at the Goldfield mining district of Western Nevada was investigated by using statistical techniques of cluster and discriminant analysis. Multivariate discriminant analysis was not effective in classifying each of the 62 groups, with classification results essentially the same whether data of four channels alone or combined with six ratios of channels were used. Bivariate plots of group means revealed a cluster of three groups including mill tailings, basalt and all other rock and alteration types. Automatic hierarchical clustering based on the fourth dimensional Mahalanobis distance between group means of 30 groups having five or more samples was performed. The results of the cluster analysis revealed hierarchies of mill tailings vs. natural materials, basalt vs. non-basalt, highly reflectant rocks vs. other rocks and exclusively unaltered rocks vs. predominantly altered rocks. The hierarchies were used to determine the order in which sets of multiple discriminant analyses were to be performed and the resulting discriminant functions were used to produce a map of geology and alteration which has an overall accuracy of 70 percent for discriminating exclusively altered rocks from predominantly altered rocks.

Comparative proteomic analysis reveals heart toxicity induced by chronic arsenic exposure in rats.

PubMed

Huang, Qingyu; Xi, Guochen; Alamdar, Ambreen; Zhang, Jie; Shen, Heqing

2017-10-01

Arsenic is a widespread metalloid in the environment, which poses a broad spectrum of adverse effects on human health. However, a global view of arsenic-induced heart toxicity is still lacking, and the underlying molecular mechanisms remain unclear. By performing a comparative quantitative proteomic analysis, the present study aims to investigate the alterations of proteome profile in rat heart after long-term exposure to arsenic. As a result, we found that the abundance of 81 proteins were significantly altered by arsenic treatment (35 up-regulated and 46 down-regulated). Among these, 33 proteins were specifically associated with cardiovascular system development and function, including heart development, heart morphology, cardiac contraction and dilation, and other cardiovascular functions. It is further proposed that the aberrant regulation of 14 proteins induced by arsenic would disturb cardiac contraction and relaxation, impair heart morphogenesis and development, and induce thrombosis in rats, which is mediated by the Akt/p38 MAPK signaling pathway. Overall, these findings will augment our knowledge of the involved mechanisms and develop useful biomarkers for cardiotoxicity induced by environmental arsenic exposure. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tomato Flower Abnormalities Induced by Low Temperatures Are Associated with Changes of Expression of MADS-Box Genes1

PubMed Central

Lozano, Rafael; Angosto, Trinidad; Gómez, Pedro; Payán, Carmen; Capel, Juan; Huijser, Peter; Salinas, Julio; Martínez-Zapater, José M.

1998-01-01

Flower and fruit development in tomato (Lycopersicon esculentum Mill.) were severely affected when plants were grown at low temperatures, displaying homeotic and meristic transformations and alterations in the fusion pattern of the organs. Most of these homeotic transformations modified the identity of stamens and carpels, giving rise to intermediate organs. Complete homeotic transformations were rarely found and always affected organs of the reproductive whorls. Meristic transformations were also commonly observed in the reproductive whorls, which developed with an excessive number of organs. Scanning electron microscopy revealed that meristic transformations take place very early in the development of the flower and are related to a significant increase in the floral meristem size. However, homeotic transformations should occur later during the development of the organ primordia. Steady-state levels of transcripts corresponding to tomato MADS-box genes TM4, TM5, TM6, and TAG1 were greatly increased by low temperatures and could be related to these flower abnormalities. Moreover, in situ hybridization analyses showed that low temperatures also altered the stage-specific expression of TM4. PMID:9576778

A prospective study of gait related risk factors for exercise-related lower leg pain.

PubMed

Willems, T M; De Clercq, D; Delbaere, K; Vanderstraeten, G; De Cock, A; Witvrouw, E

2006-01-01

The purpose of this study was to determine prospectively gait related risk factors for exercise-related lower leg pain (ERLLP) in 400 physical education students. Static lower leg alignment was determined, and 3D gait kinematics combined with plantar pressure profiles were collected. After this evaluation, all sports injuries were registered by the same sports physician during the duration of the study. Forty six subjects developed ERLLP and 29 of them developed bilateral symptoms thus giving 75 symptomatic lower legs. Bilateral lower legs of 167 subjects who developed no injuries in the lower extremities served as controls. Cox regression analysis revealed that subjects who developed ERLLP had an altered running pattern before the injury compared to the controls and included (1) a significantly more central heel-strike, (2) a significantly increased pronation, accompanied with more pressure underneath the medial side of the foot, and (3) a significantly more lateral roll-off. These findings suggest that altered biomechanics play a role in the genesis of ERLLP and thus should be considered in prevention and rehabilitation.

Metabolomics and transcriptomics profiles reveal the dysregulation of the tricarboxylic acid cycle and related mechanisms in prostate cancer.

PubMed

Shao, Yaping; Ye, Guozhu; Ren, Shancheng; Piao, Hai-Long; Zhao, Xinjie; Lu, Xin; Wang, Fubo; Ma, Wang; Li, Jia; Yin, Peiyuan; Xia, Tian; Xu, Chuanliang; Yu, Jane J; Sun, Yinghao; Xu, Guowang

2018-07-15

Genetic alterations drive metabolic reprograming to meet increased biosynthetic precursor and energy demands for cancer cell proliferation and survival in unfavorable environments. A systematic study of gene-metabolite regulatory networks and metabolic dysregulation should reveal the molecular mechanisms underlying prostate cancer (PCa) pathogenesis. Herein, we performed gas chromatography-mass spectrometry (GC-MS)-based metabolomics and RNA-seq analyses in prostate tumors and matched adjacent normal tissues (ANTs) to elucidate the molecular alterations and potential underlying regulatory mechanisms in PCa. Significant accumulation of metabolic intermediates and enrichment of genes in the tricarboxylic acid (TCA) cycle were observed in tumor tissues, indicating TCA cycle hyperactivation in PCa tissues. In addition, the levels of fumarate and malate were highly correlated with the Gleason score, tumor stage and expression of genes encoding related enzymes and were significantly related to the expression of genes involved in branched chain amino acid degradation. Using an integrated omics approach, we further revealed the potential anaplerotic routes from pyruvate, glutamine catabolism and branched chain amino acid (BCAA) degradation contributing to replenishing metabolites for TCA cycle. Integrated omics techniques enable the performance of network-based analyses to gain a comprehensive and in-depth understanding of PCa pathophysiology and may facilitate the development of new and effective therapeutic strategies. © 2018 UICC.

Alteration mapping at Goldfield, Nevada, by cluster and discriminant analysis of Landsat digital data. [mapping of hydrothermally altered volcanic rocks

NASA Technical Reports Server (NTRS)

Ballew, G.

1977-01-01

The ability of Landsat multispectral digital data to differentiate among 62 combinations of rock and alteration types at the Goldfield mining district of Western Nevada was investigated by using statistical techniques of cluster and discriminant analysis. Multivariate discriminant analysis was not effective in classifying each of the 62 groups, with classification results essentially the same whether data of four channels alone or combined with six ratios of channels were used. Bivariate plots of group means revealed a cluster of three groups including mill tailings, basalt and all other rock and alteration types. Automatic hierarchical clustering based on the fourth dimensional Mahalanobis distance between group means of 30 groups having five or more samples was performed using Johnson's HICLUS program. The results of the cluster analysis revealed hierarchies of mill tailings vs. natural materials, basalt vs. non-basalt, highly reflectant rocks vs. other rocks and exclusively unaltered rocks vs. predominantly altered rocks. The hierarchies were used to determine the order in which sets of multiple discriminant analyses were to be performed and the resulting discriminant functions were used to produce a map of geology and alteration which has an overall accuracy of 70 percent for discriminating exclusively altered rocks from predominantly altered rocks.

Early somatosensory processing in individuals at risk for developing psychoses.

PubMed

Hagenmuller, Florence; Heekeren, Karsten; Theodoridou, Anastasia; Walitza, Susanne; Haker, Helene; Rössler, Wulf; Kawohl, Wolfram

2014-01-01

Human cortical somatosensory evoked potentials (SEPs) allow an accurate investigation of thalamocortical and early cortical processing. SEPs reveal a burst of superimposed early (N20) high-frequency oscillations around 600 Hz. Previous studies reported alterations of SEPs in patients with schizophrenia. This study addresses the question whether those alterations are also observable in populations at risk for developing schizophrenia or bipolar disorders. To our knowledge to date, this is the first study investigating SEPs in a population at risk for developing psychoses. Median nerve SEPs were investigated using multichannel EEG in individuals at risk for developing bipolar disorders (n = 25), individuals with high-risk status (n = 59) and ultra-high-risk status for schizophrenia (n = 73) and a gender and age-matched control group (n = 45). Strengths and latencies of low- and high-frequency components as estimated by dipole source analysis were compared between groups. Low- and high-frequency source activity was reduced in both groups at risk for schizophrenia, in comparison to the group at risk for bipolar disorders. HFO amplitudes were also significant reduced in subjects with high-risk status for schizophrenia compared to healthy controls. These differences were accentuated among cannabis non-users. Reduced N20 source strengths were related to higher positive symptom load. These results suggest that the risk for schizophrenia, in contrast to bipolar disorders, may involve an impairment of early cerebral somatosensory processing. Neurophysiologic alterations in schizophrenia precede the onset of initial psychotic episode and may serve as indicator of vulnerability for developing schizophrenia.

Early somatosensory processing in individuals at risk for developing psychoses

PubMed Central

Hagenmuller, Florence; Heekeren, Karsten; Theodoridou, Anastasia; Walitza, Susanne; Haker, Helene; Rössler, Wulf; Kawohl, Wolfram

2014-01-01

Human cortical somatosensory evoked potentials (SEPs) allow an accurate investigation of thalamocortical and early cortical processing. SEPs reveal a burst of superimposed early (N20) high-frequency oscillations around 600 Hz. Previous studies reported alterations of SEPs in patients with schizophrenia. This study addresses the question whether those alterations are also observable in populations at risk for developing schizophrenia or bipolar disorders. To our knowledge to date, this is the first study investigating SEPs in a population at risk for developing psychoses. Median nerve SEPs were investigated using multichannel EEG in individuals at risk for developing bipolar disorders (n = 25), individuals with high-risk status (n = 59) and ultra-high-risk status for schizophrenia (n = 73) and a gender and age-matched control group (n = 45). Strengths and latencies of low- and high-frequency components as estimated by dipole source analysis were compared between groups. Low- and high-frequency source activity was reduced in both groups at risk for schizophrenia, in comparison to the group at risk for bipolar disorders. HFO amplitudes were also significant reduced in subjects with high-risk status for schizophrenia compared to healthy controls. These differences were accentuated among cannabis non-users. Reduced N20 source strengths were related to higher positive symptom load. These results suggest that the risk for schizophrenia, in contrast to bipolar disorders, may involve an impairment of early cerebral somatosensory processing. Neurophysiologic alterations in schizophrenia precede the onset of initial psychotic episode and may serve as indicator of vulnerability for developing schizophrenia. PMID:25309363

Brain Connectivity Alterations Are Associated with the Development of Dementia in Parkinson's Disease.

PubMed

Bertrand, Josie-Anne; McIntosh, Anthony R; Postuma, Ronald B; Kovacevic, Natasha; Latreille, Véronique; Panisset, Michel; Chouinard, Sylvain; Gagnon, Jean-François

2016-04-01

Dementia affects a high proportion of Parkinson's disease (PD) patients and poses a burden on caregivers and healthcare services. Electroencephalography (EEG) is a common nonevasive and nonexpensive technique that can easily be used in clinical settings to identify brain functional abnormalities. Only few studies had identified EEG abnormalities that can predict PD patients at higher risk for dementia. Brain connectivity EEG measures, such as multiscale entropy (MSE) and phase-locking value (PLV) analyses, may be more informative and sensitive to brain alterations leading to dementia than previously used methods. This study followed 62 dementia-free PD patients for a mean of 3.4 years to identify cerebral alterations that are associated with dementia. Baseline resting state EEG of patients who developed dementia (N = 18) was compared to those of patients who remained dementia-free (N = 44) and of 37 healthy subjects. MSE and PLV analyses were performed. Partial least squares statistical analysis revealed group differences associated with the development of dementia. Patients who developed dementia showed higher signal complexity and lower PLVs in low frequencies (mainly in delta frequency) than patients who remained dementia-free and controls. Conversely, both patient groups showed lower signal variability and higher PLVs in high frequencies (mainly in gamma frequency) compared to controls, with the strongest effect in patients who developed dementia. These findings suggest that specific disruptions of brain communication can be measured before PD patients develop dementia, providing a new potential marker to identify patients at highest risk of developing dementia and who are the best candidates for neuroprotective trials.

Kynurenine 3-Monooxygenase: An Influential Mediator of Neuropathology.

PubMed

Parrott, Jennifer M; O'Connor, Jason C

2015-01-01

Mounting evidence demonstrates that kynurenine metabolism may play an important pathogenic role in the development of multiple neurological and neuropsychiatric disorders. The kynurenine pathway consists of two functionally distinct branches that generate both neuroactive and oxidatively reactive metabolites. In the brain, the rate-limiting enzyme for one of these branches, kynurenine 3-monooxygenase (KMO), is predominantly expressed in microglia and has emerged as a pivotal point of metabolic regulation. KMO substrate and expression levels are upregulated by pro-inflammatory cytokines and altered by functional genetic mutations. Increased KMO metabolism results in the formation of metabolites that activate glutamate receptors and elevate oxidative stress, while recent evidence has revealed neurodevelopmental consequences of reduced KMO activity. Together, the evidence suggests that KMO is positioned at a critical metabolic junction to influence the development or trajectory of a myriad of neurological diseases. Understanding the mechanism(s) by which alterations in KMO activity are able to impair neuronal function, and viability will enhance our knowledge of related disease pathology and provide insight into novel therapeutic opportunities. This review will discuss the influence of KMO on brain kynurenine metabolism and the current understanding of molecular mechanisms by which altered KMO activity may contribute to neurodevelopment, neurodegenerative, and neuropsychiatric diseases.

Kynurenine 3-Monooxygenase: An Influential Mediator of Neuropathology

PubMed Central

Parrott, Jennifer M.; O’Connor, Jason C.

2015-01-01

Mounting evidence demonstrates that kynurenine metabolism may play an important pathogenic role in the development of multiple neurological and neuropsychiatric disorders. The kynurenine pathway consists of two functionally distinct branches that generate both neuroactive and oxidatively reactive metabolites. In the brain, the rate-limiting enzyme for one of these branches, kynurenine 3-monooxygenase (KMO), is predominantly expressed in microglia and has emerged as a pivotal point of metabolic regulation. KMO substrate and expression levels are upregulated by pro-inflammatory cytokines and altered by functional genetic mutations. Increased KMO metabolism results in the formation of metabolites that activate glutamate receptors and elevate oxidative stress, while recent evidence has revealed neurodevelopmental consequences of reduced KMO activity. Together, the evidence suggests that KMO is positioned at a critical metabolic junction to influence the development or trajectory of a myriad of neurological diseases. Understanding the mechanism(s) by which alterations in KMO activity are able to impair neuronal function, and viability will enhance our knowledge of related disease pathology and provide insight into novel therapeutic opportunities. This review will discuss the influence of KMO on brain kynurenine metabolism and the current understanding of molecular mechanisms by which altered KMO activity may contribute to neurodevelopment, neurodegenerative, and neuropsychiatric diseases. PMID:26347662

Proteomic analysis of altered proteins in lymphoid organ of yellow head virus infected Penaeus monodon.

PubMed

Bourchookarn, Apichai; Havanapan, Phattara-Orn; Thongboonkerd, Visith; Krittanai, Chartchai

2008-03-01

A comparative proteomic analysis was employed to identify altered proteins in the yellow head virus (YHV) infected lymphoid organ (LO) of Penaeus monodon. At 24 h post-infection, the infected shrimps showed obvious signs of infection, while the control shrimps remained healthy. Two-dimensional electrophoresis of proteins extracted from the LO revealed significant alterations in abundance of several proteins in the infected group. Protein identification by MALDI-TOF MS and nanoLC-ESI-MS/MS revealed significant increase of transglutaminase, protein disulfide isomerase, ATP synthase beta subunit, V-ATPase subunit A, and hemocyanin fragments. A significant decrease was also identified for Rab GDP-dissociation inhibitor, 6-phosphogluconate dehydrogenase, actin, fast tropomyosin isoform, and hemolymph clottable protein. Some of these altered proteins were further investigated at the mRNA level using real-time RT-PCR, which confirmed the proteomic data. Identification of these altered proteins in the YHV-infected shrimps may provide novel insights into the molecular responses of P. monodon to YHV infection.

Integrated metabolomic and transcriptome analyses reveal finishing forage affects metabolic pathways related to beef quality and animal welfare

PubMed Central

Carrillo, José A.; He, Yanghua; Li, Yaokun; Liu, Jianan; Erdman, Richard A.; Sonstegard, Tad S.; Song, Jiuzhou

2016-01-01

Beef represents a major dietary component and source of protein in many countries. With an increasing demand for beef, the industry is currently undergoing changes towards naturally produced beef. However, the true differences between the feeding systems, especially the biochemical and nutritional aspects, are still unclear. Using transcriptome and metabolome profiles, we identified biological pathways related to the differences between grass- and grain-fed Angus steers. In the latissimus dorsi muscle, we have recognized 241 differentially expressed genes (FDR < 0.1). The metabolome examinations of muscle and blood revealed 163 and 179 altered compounds in each tissue (P < 0.05), respectively. Accordingly, alterations in glucose metabolism, divergences in free fatty acids and carnitine conjugated lipid levels, and altered β-oxidation have been observed. The anti-inflammatory n3 polyunsaturated fatty acids are enriched in grass finished beef, while higher levels of n6 PUFAs in grain finished animals may promote inflammation and oxidative stress. Furthermore, grass-fed animals produce tender beef with lower total fat and a higher omega3/omega6 ratio than grain-fed ones, which could potentially benefit consumer health. Most importantly, blood cortisol levels strongly indicate that grass-fed animals may experience less stress than the grain-fed individuals. These results will provide deeper insights into the merits and mechanisms of muscle development. PMID:27185157

Integrated metabolomic and transcriptome analyses reveal finishing forage affects metabolic pathways related to beef quality and animal welfare.

PubMed

Carrillo, José A; He, Yanghua; Li, Yaokun; Liu, Jianan; Erdman, Richard A; Sonstegard, Tad S; Song, Jiuzhou

2016-05-17

Beef represents a major dietary component and source of protein in many countries. With an increasing demand for beef, the industry is currently undergoing changes towards naturally produced beef. However, the true differences between the feeding systems, especially the biochemical and nutritional aspects, are still unclear. Using transcriptome and metabolome profiles, we identified biological pathways related to the differences between grass- and grain-fed Angus steers. In the latissimus dorsi muscle, we have recognized 241 differentially expressed genes (FDR < 0.1). The metabolome examinations of muscle and blood revealed 163 and 179 altered compounds in each tissue (P < 0.05), respectively. Accordingly, alterations in glucose metabolism, divergences in free fatty acids and carnitine conjugated lipid levels, and altered β-oxidation have been observed. The anti-inflammatory n3 polyunsaturated fatty acids are enriched in grass finished beef, while higher levels of n6 PUFAs in grain finished animals may promote inflammation and oxidative stress. Furthermore, grass-fed animals produce tender beef with lower total fat and a higher omega3/omega6 ratio than grain-fed ones, which could potentially benefit consumer health. Most importantly, blood cortisol levels strongly indicate that grass-fed animals may experience less stress than the grain-fed individuals. These results will provide deeper insights into the merits and mechanisms of muscle development.

Endophytic fungus Phomopsis liquidambari and different doses of N-fertilizer alter microbial community structure and function in rhizosphere of rice

PubMed Central

Siddikee, Md. Ashaduzzaman; Zereen, Mst Israt; Li, Cai-Feng; Dai, Chuan-Chao

2016-01-01

Microbial community structure and functions of rhizosphere soil of rice were investigated after applying low and high doses of nitrogenous fertilizer and Phomopsis liquidambari. Average well color development, substrate richness, catabolic diversity and soil enzymes activities varied after applying N-fertilizer and P. liquidambari and were greater in P. liquidambari treated soil than only N-fertilization. Multivariate analysis distinctly separated the catabolic and enzymes activity profile which statistically proved alteration of microbial functional diversity. Nitrogen fertilizer altered microbial community structure revealed by the increased content of total PLFAs, specific subgroup marker PLFAs except fungal PLFAs and by the decreased ratio of G+/G−, sat/monunsat, iso/anteiso, F/B except trans/cis while P. liquidambari inoculation enhanced N-fertilization effect except increased fungal PLFA and decreased trans/cis. PCA using identified marker PLFAs revealed definite discrimination among the treatments which further statistically confirmed structural changed of microbial community. Nitrogenase activity representative of N-fixing community decreased in N-fertilizer treatment while P. liquidambari inoculation increased. In short, application of P. liquidambari with low doses of N-fertilizer improved rice growth and reduced N-fertilizer requirement by increasing enzymes activities involved in C, N and P cycling, structural and functional diversity of microbes, nitrogenase activity involved in N2 fixation and accumulation of total-N. PMID:27596935

Genomic analysis reveals secondary glioblastoma after radiotherapy in a subset of recurrent medulloblastomas.

PubMed

Phi, Ji Hoon; Park, Ae Kyung; Lee, Semin; Choi, Seung Ah; Baek, In-Pyo; Kim, Pora; Kim, Eun-Hye; Park, Hee Chul; Kim, Byung Chul; Bhak, Jong; Park, Sung-Hye; Lee, Ji Yeoun; Wang, Kyu-Chang; Kim, Dong-Seok; Shim, Kyu Won; Kim, Se Hoon; Kim, Chae-Yong; Kim, Seung-Ki

2018-06-01

Despite great advances in understanding of molecular pathogenesis and achievement of a high cure rate in medulloblastoma, recurrent medulloblastomas are still dismal. Additionally, misidentification of secondary malignancies due to histological ambiguity leads to misdiagnosis and eventually to inappropriate treatment. Nevertheless, the genomic characteristics of recurrent medulloblastomas are poorly understood, largely due to a lack of matched primary and recurrent tumor tissues. We performed a genomic analysis of recurrent tumors from 17 pediatric medulloblastoma patients. Whole transcriptome sequencing revealed that a subset of recurrent tumors initially diagnosed as locally recurrent medulloblastomas are secondary glioblastomas after radiotherapy, showing high similarity to the non-G-CIMP proneural subtype of glioblastoma. Further analysis, including whole exome sequencing, revealed missense mutations or complex gene fusion events in PDGFRA with augmented expression in the secondary glioblastomas after radiotherapy, implicating PDGFRA as a putative driver in the development of secondary glioblastomas after treatment exposure. This result provides insight into the possible application of PDGFRA-targeted therapy in these second malignancies. Furthermore, genomic alterations of TP53 including 17p loss or germline/somatic mutations were also found in most of the secondary glioblastomas after radiotherapy, indicating a crucial role of TP53 alteration in the process. On the other hand, analysis of recurrent medulloblastomas revealed that the most prevalent alterations are the loss of 17p region including TP53 and gain of 7q region containing EZH2 which already exist in primary tumors. The 7q gain events are frequently accompanied by high expression levels of EZH2 in both primary and recurrent medulloblastomas, which provides a clue to a new therapeutic target to prevent recurrence. Considering the fact that it is often challenging to differentiate between recurrent medulloblastomas and secondary glioblastomas after radiotherapy, our findings have major clinical implications both for correct diagnosis and for potential therapeutic interventions in these devastating diseases.

Proteomic alterations in root tips of Arabidopsis thaliana seedlings under altered gravity conditions

NASA Astrophysics Data System (ADS)

Zheng, H. Q.; Wang, H.

Gravity has a profound influence on plant growth and development Removed the influence of gravitational acceleration by spaceflight caused a wide range of cellular changes in plant Whole seedling that germinated and grown on clinostats showed the absent of gravitropism At the cellular level clinostat treatment has specific effects on plant cells such as induce alterations in cell wall composition increase production of heat-soluble proteins impact on the cellular energy metabolism facilitate a uniform distribution of plastids amyloplasts and increase number and volume of nucleoli A number of recent studies have shown that the exposure of Arabidopsis seedlings and callus cells to gravity stimulation hyper g-forces or clinostat rotation induces alterations in gene expression In our previous study the proteome of the Arabidopsis thaliana callus cells were separated by high resolution two-dimensional electrophoresis 2-DE Image analysis revealed that 80 protein spots showed quantitative and qualitative variations after exposure to clinostat rotation treatment We report here a systematic proteomic approach to investigate the altered gravity responsive proteins in root tip of Arabidopsis thaliana cv Landsberg erecta Three-day-old seedlings were exposed for 12h to a horizontal clinostat rotation H simulated weightlessness altered g-forces by centrifugation 7g hypergravity a vertical clinostat rotation V clinostat control or a stationary control grown conditions Total proteins of roots were extracted

CDKL5 alterations lead to early epileptic encephalopathy in both genders.

PubMed

Liang, Jao-Shwann; Shimojima, Keiko; Takayama, Rumiko; Natsume, Jun; Shichiji, Minobu; Hirasawa, Kyoko; Imai, Kaoru; Okanishi, Tohru; Mizuno, Seiji; Okumura, Akihisa; Sugawara, Midori; Ito, Tomoshiro; Ikeda, Hiroko; Takahashi, Yukitoshi; Oguni, Hirokazu; Imai, Katsumi; Osawa, Makiko; Yamamoto, Toshiyuki

2011-10-01

Genetic mutations of the cyclin-dependent kinase-like 5 gene (CDKL5) have been reported in patients with epileptic encephalopathy, which is characterized by intractable seizures and severe-to-profound developmental delay. We investigated the clinical relevance of CDKL5 alterations in both genders. A total of 125 patients with epileptic encephalopathy were examined for genomic copy number aberrations, and 119 patients with no such aberrations were further examined for CDKL5 mutations. Five patients with Rett syndrome, who did not show methyl CpG-binding protein 2 gene (MECP2) mutations, were also examined for CDKL5 mutations. One male and three female patients showed submicroscopic deletions including CDKL5, and two male and six female patients showed CDKL5 nucleotide alterations. Development of early onset seizure was a characteristic clinical feature for the patients with CDKL5 alterations in both genders despite polymorphous seizure types, including myoclonic seizures, tonic seizures, and spasms. Severe developmental delays and mild frontal lobe atrophies revealed by brain magnetic resonance imaging (MRI) were observed in almost all patients, and there was no gender difference in phenotypic features. We observed that 5% of the male patients and 14% of the female patients with epileptic encephalopathy had CDKL5 alterations. These findings indicate that alterations in CDKL5 are associated with early epileptic encephalopathy in both female and male patients. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

Kinetic Analysis of Mouse Brain Proteome Alterations Following Chikungunya Virus Infection before and after Appearance of Clinical Symptoms

PubMed Central

Fraisier, Christophe; Koraka, Penelope; Belghazi, Maya; Bakli, Mahfoud; Granjeaud, Samuel; Pophillat, Matthieu; Lim, Stephanie M.; Osterhaus, Albert; Martina, Byron; Camoin, Luc; Almeras, Lionel

2014-01-01

Recent outbreaks of Chikungunya virus (CHIKV) infection have been characterized by an increasing number of severe cases with atypical manifestations including neurological complications. In parallel, the risk map of CHIKV outbreaks has expanded because of improved vector competence. These features make CHIKV infection a major public health concern that requires a better understanding of the underlying physiopathological processes for the development of antiviral strategies to protect individuals from severe disease. To decipher the mechanisms of CHIKV infection in the nervous system, a kinetic analysis on the host proteome modifications in the brain of CHIKV-infected mice sampled before and after the onset of clinical symptoms was performed. The combination of 2D-DIGE and iTRAQ proteomic approaches, followed by mass spectrometry protein identification revealed 177 significantly differentially expressed proteins. This kinetic analysis revealed a dramatic down-regulation of proteins before the appearance of the clinical symptoms followed by the increased expression of most of these proteins in the acute symptomatic phase. Bioinformatic analyses of the protein datasets enabled the identification of the major biological processes that were altered during the time course of CHIKV infection, such as integrin signaling and cytoskeleton dynamics, endosome machinery and receptor recycling related to virus transport and synapse function, regulation of gene expression, and the ubiquitin-proteasome pathway. These results reveal the putative mechanisms associated with severe CHIKV infection-mediated neurological disease and highlight the potential markers or targets that can be used to develop diagnostic and/or antiviral tools. PMID:24618821

Type 1 diabetes mellitus effects on dental enamel formation revealed by microscopy and microanalysis.

PubMed

Silva, Bruna Larissa Lago; Medeiros, Danila Lima; Soares, Ana Prates; Line, Sérgio Roberto Peres; Pinto, Maria das Graças Farias; Soares, Telma de Jesus; do Espírito Santo, Alexandre Ribeiro

2018-03-01

Type 1 diabetes mellitus (T1DM) largely affects children, occurring therefore at the same period of deciduous and permanent teeth development. The aim of this work was to investigate birefringence and morphology of the secretory stage enamel organic extracellular matrix (EOECM), and structural and mechanical features of mature enamel from T1DM rats. Adult Wistar rats were maintained alive for a period of 56 days after the induction of experimental T1DM with a single dose of streptozotocin (60 mg/kg). After proper euthanasia of the animals, fixed upper incisors were accurately processed, and secretory stage EOECM and mature enamel were analyzed by transmitted polarizing and bright field light microscopies (TPLM and BFLM), energy-dispersive x-ray (EDX) analysis, scanning electron microscopy (SEM), and microhardness testing. Bright field light microscopies and transmitted polarizing light microscopies showed slight morphological changes in the secretory stage EOECM from diabetic rats, which also did not exhibit statistically significant alterations in birefringence brightness when compared to control animals (P > .05). EDX analysis showed that T1DM induced statistically significant little increases in the amount of calcium and phosphorus in outer mature enamel (P < .01) with preservation of calcium/phosphorus ratio in that structure (P > .05). T1DM also caused important ultrastructural alterations in mature enamel as revealed by SEM and induced a statistically significant reduction of about 13.67% in its microhardness at 80 μm from dentin-enamel junction (P < .01). This study shows that T1DM may disturb enamel development, leading to alterations in mature enamel ultrastructure and in its mechanical features. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effects of neonatal allopregnanolone manipulations and early maternal separation on adult alcohol intake and monoamine levels in ventral striatum of male rats.

PubMed

Llidó, Anna; Bartolomé, Iris; Darbra, Sònia; Pallarès, Marc

2016-06-01

Changes in endogenous neonatal levels of the neurosteroid allopregnanolone (AlloP) as well as a single 24h period of early maternal separation (EMS) on postnatal day (PND) 9 affect the development of the central nervous system (CNS), causing adolescent/adult alterations including systems and behavioural traits that could be related to vulnerability to drug abuse. In rats, some behavioural alterations caused by EMS can be neutralised by previous administration of AlloP. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP could increase adult alcohol consumption, and if EMS could change these effects. We administered AlloP or finasteride, a 5α-reductase inhibitor, from PND5 to PND9, followed by 24h of EMS at PND9. At PND70 we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v)+glucose 3% (w/v), and glucose 3% (w/v)) for 15days. Ventral striatum samples were obtained to determine monoamine levels. Results revealed that neonatal finasteride increased both ethanol and glucose consumption, and AlloP increased alcohol intake compared with neonatal vehicle-injected animals. The differences between neonatal groups in alcohol consumption were not found in EMS animals. In accordance, both finasteride and AlloP animals that did not suffer EMS showed lower levels of dopamine and serotonin in ventral striatum. Taken together, these results reveal that neonatal neurosteroids alterations affect alcohol intake; an effect which can be modified by subsequent EMS. Thus, these data corroborate the importance of the relationship between neonatal neurosteroids and neonatal stress for the correct CNS development. Copyright © 2016 Elsevier Inc. All rights reserved.

Striatal Synaptic Dysfunction and Hippocampal Plasticity Deficits in the Hu97/18 Mouse Model of Huntington Disease

PubMed Central

Kolodziejczyk, Karolina; Parsons, Matthew P.; Southwell, Amber L.; Hayden, Michael R.; Raymond, Lynn A.

2014-01-01

Huntington disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the gene (HTT) encoding the huntingtin protein (HTT). This mutation leads to multiple cellular and synaptic alterations that are mimicked in many current HD animal models. However, the most commonly used, well-characterized HD models do not accurately reproduce the genetics of human disease. Recently, a new ‘humanized’ mouse model, termed Hu97/18, has been developed that genetically recapitulates human HD, including two human HTT alleles, no mouse Hdh alleles and heterozygosity of the HD mutation. Previously, behavioral and neuropathological testing in Hu97/18 mice revealed many features of HD, yet no electrophysiological measures were employed to investigate possible synaptic alterations. Here, we describe electrophysiological changes in the striatum and hippocampus of the Hu97/18 mice. At 9 months of age, a stage when cognitive deficits are fully developed and motor dysfunction is also evident, Hu97/18 striatal spiny projection neurons (SPNs) exhibited small changes in membrane properties and lower amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs); however, release probability from presynaptic terminals was unaltered. Strikingly, these mice also exhibited a profound deficiency in long-term potentiation (LTP) at CA3-to-CA1 synapses. In contrast, at 6 months of age we found only subtle alterations in SPN synaptic transmission, while 3-month old animals did not display any electrophysiologically detectable changes in the striatum and CA1 LTP was intact. Together, these data reveal robust, progressive deficits in synaptic function and plasticity in Hu97/18 mice, consistent with previously reported behavioral abnormalities, and suggest an optimal age (9 months) for future electrophysiological assessment in preclinical studies of HD. PMID:24728353

The histone H2A deubiquitinase Usp16 regulates hematopoiesis and hematopoietic stem cell function.

PubMed

Gu, Yue; Jones, Amanda E; Yang, Wei; Liu, Shanrun; Dai, Qian; Liu, Yudong; Swindle, C Scott; Zhou, Dewang; Zhang, Zhuo; Ryan, Thomas M; Townes, Tim M; Klug, Christopher A; Chen, Dongquan; Wang, Hengbin

2016-01-05

Epigenetic mechanisms play important regulatory roles in hematopoiesis and hematopoietic stem cell (HSC) function. Subunits of polycomb repressive complex 1 (PRC1), the major histone H2A ubiquitin ligase, are critical for both normal and pathological hematopoiesis; however, it is unclear which of the several counteracting H2A deubiquitinases functions along with PRC1 to control H2A ubiquitination (ubH2A) level and regulates hematopoiesis in vivo. Here we investigated the function of Usp16 in mouse hematopoiesis. Conditional deletion of Usp16 in bone marrow resulted in a significant increase of global ubH2A level and lethality. Usp16 deletion did not change HSC number but was associated with a dramatic reduction of mature and progenitor cell populations, revealing a role in governing HSC lineage commitment. ChIP- and RNA-sequencing studies in HSC and progenitor cells revealed that Usp16 bound to many important hematopoietic regulators and that Usp16 deletion altered the expression of genes in transcription/chromosome organization, immune response, hematopoietic/lymphoid organ development, and myeloid/leukocyte differentiation. The altered gene expression was partly rescued by knockdown of PRC1 subunits, suggesting that Usp16 and PRC1 counterbalance each other to regulate cellular ubH2A level and gene expression in the hematopoietic system. We further discovered that knocking down Cdkn1a (p21cip1), a Usp16 target and regulated gene, rescued the altered cell cycle profile and differentiation defect of Usp16-deleted HSCs. Collectively, these studies identified Usp16 as one of the histone H2A deubiquitinases, which coordinates with the H2A ubiquitin ligase PRC1 to regulate hematopoiesis, and revealed cell cycle regulation by Usp16 as key for HSC differentiation.

Novel mouse model recapitulates genome and transcriptome alterations in human colorectal carcinomas.

PubMed

McNeil, Nicole E; Padilla-Nash, Hesed M; Buishand, Floryne O; Hue, Yue; Ried, Thomas

2017-03-01

Human colorectal carcinomas are defined by a nonrandom distribution of genomic imbalances that are characteristic for this disease. Often, these imbalances affect entire chromosomes. Understanding the role of these aneuploidies for carcinogenesis is of utmost importance. Currently, established transgenic mice do not recapitulate the pathognonomic genome aberration profile of human colorectal carcinomas. We have developed a novel model based on the spontaneous transformation of murine colon epithelial cells. During this process, cells progress through stages of pre-immortalization, immortalization and, finally, transformation, and result in tumors when injected into immunocompromised mice. We analyzed our model for genome and transcriptome alterations using ArrayCGH, spectral karyotyping (SKY), and array based gene expression profiling. ArrayCGH revealed a recurrent pattern of genomic imbalances. These results were confirmed by SKY. Comparing these imbalances with orthologous maps of human chromosomes revealed a remarkable overlap. We observed focal deletions of the tumor suppressor genes Trp53 and Cdkn2a/p16. High-level focal genomic amplification included the locus harboring the oncogene Mdm2, which was confirmed by FISH in the form of double minute chromosomes. Array-based global gene expression revealed distinct differences between the sequential steps of spontaneous transformation. Gene expression changes showed significant similarities with human colorectal carcinomas. Pathways most prominently affected included genes involved in chromosomal instability and in epithelial to mesenchymal transition. Our novel mouse model therefore recapitulates the most prominent genome and transcriptome alterations in human colorectal cancer, and might serve as a valuable tool for understanding the dynamic process of tumorigenesis, and for preclinical drug testing. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Targeted Metabolomics Reveals Early Dominant Optic Atrophy Signature in Optic Nerves of Opa1delTTAG/+ Mice.

PubMed

Chao de la Barca, Juan Manuel; Simard, Gilles; Sarzi, Emmanuelle; Chaumette, Tanguy; Rousseau, Guillaume; Chupin, Stéphanie; Gadras, Cédric; Tessier, Lydie; Ferré, Marc; Chevrollier, Arnaud; Desquiret-Dumas, Valérie; Gueguen, Naïg; Leruez, Stéphanie; Verny, Christophe; Miléa, Dan; Bonneau, Dominique; Amati-Bonneau, Patrizia; Procaccio, Vincent; Hamel, Christian; Lenaers, Guy; Reynier, Pascal; Prunier-Mirebeau, Delphine

2017-02-01

Dominant optic atrophy (MIM No. 165500) is a blinding condition related to mutations in OPA1, a gene encoding a large GTPase involved in mitochondrial inner membrane dynamics. Although several mouse models mimicking the disease have been developed, the pathophysiological mechanisms responsible for retinal ganglion cell degeneration remain poorly understood. Using a targeted metabolomic approach, we measured the concentrations of 188 metabolites in nine tissues, that is, brain, three types of skeletal muscle, heart, liver, retina, optic nerve, and plasma in symptomatic 11-month-old Opa1delTTAG/+ mice. Significant metabolic signatures were found only in the optic nerve and plasma of female mice. The optic nerve signature was characterized by altered concentrations of phospholipids, amino acids, acylcarnitines, and carnosine, whereas the plasma signature showed decreased concentrations of amino acids and sarcosine associated with increased concentrations of several phospholipids. In contrast, the investigation of 3-month-old presymptomatic Opa1delTTAG/+ mice showed no specific plasma signature but revealed a significant optic nerve signature in both sexes, although with a sex effect. The Opa1delTTAG/+ versus wild-type optic nerve signature was characterized by the decreased concentrations of 10 sphingomyelins and 10 lysophosphatidylcholines, suggestive of myelin sheath alteration, and by alteration in the concentrations of metabolites involved in neuroprotection, such as dimethylarginine, carnitine, spermine, spermidine, carnosine, and glutamate, suggesting a concomitant axonal metabolic dysfunction. Our comprehensive metabolomic investigations revealed in symptomatic as well as in presymptomatic Opa1delTTAG/+ mice, a specific sensitiveness of the optic nerve to Opa1 insufficiency, opening new routes for protective therapeutic strategies.

Deciphering transcriptional and metabolic networks associated with lysine metabolism during Arabidopsis seed development.

PubMed

Angelovici, Ruthie; Fait, Aaron; Zhu, Xiaohong; Szymanski, Jedrzej; Feldmesser, Ester; Fernie, Alisdair R; Galili, Gad

2009-12-01

In order to elucidate transcriptional and metabolic networks associated with lysine (Lys) metabolism, we utilized developing Arabidopsis (Arabidopsis thaliana) seeds as a system in which Lys synthesis could be stimulated developmentally without application of chemicals and coupled this to a T-DNA insertion knockout mutation impaired in Lys catabolism. This seed-specific metabolic perturbation stimulated Lys accumulation starting from the initiation of storage reserve accumulation. Our results revealed that the response of seed metabolism to the inducible alteration of Lys metabolism was relatively minor; however, that which was observable operated in a modular manner. They also demonstrated that Lys metabolism is strongly associated with the operation of the tricarboxylic acid cycle while largely disconnected from other metabolic networks. In contrast, the inducible alteration of Lys metabolism was strongly associated with gene networks, stimulating the expression of hundreds of genes controlling anabolic processes that are associated with plant performance and vigor while suppressing a small number of genes associated with plant stress interactions. The most pronounced effect of the developmentally inducible alteration of Lys metabolism was an induction of expression of a large set of genes encoding ribosomal proteins as well as genes encoding translation initiation and elongation factors, all of which are associated with protein synthesis. With respect to metabolic regulation, the inducible alteration of Lys metabolism was primarily associated with altered expression of genes belonging to networks of amino acids and sugar metabolism. The combined data are discussed within the context of network interactions both between and within metabolic and transcriptional control systems.

Unique mutation portraits and frequent COL2A1 gene alteration in chondrosarcoma

PubMed Central

Totoki, Yasushi; Yoshida, Akihiko; Hosoda, Fumie; Nakamura, Hiromi; Hama, Natsuko; Ogura, Koichi; Yoshida, Aki; Fujiwara, Tomohiro; Arai, Yasuhito; Toguchida, Junya; Tsuda, Hitoshi; Miyano, Satoru; Kawai, Akira

2014-01-01

Chondrosarcoma is the second most frequent malignant bone tumor. However, the etiological background of chondrosarcomagenesis remains largely unknown, along with details on molecular alterations and potential therapeutic targets. Massively parallel paired-end sequencing of whole genomes of 10 primary chondrosarcomas revealed that the process of accumulation of somatic mutations is homogeneous irrespective of the pathological subtype or the presence of IDH1 mutations, is unique among a range of cancer types, and shares significant commonalities with that of prostate cancer. Clusters of structural alterations localized within a single chromosome were observed in four cases. Combined with targeted resequencing of additional cartilaginous tumor cohorts, we identified somatic alterations of the COL2A1 gene, which encodes an essential extracellular matrix protein in chondroskeletal development, in 19.3% of chondrosarcoma and 31.7% of enchondroma cases. Epigenetic regulators (IDH1 and YEATS2) and an activin/BMP signal component (ACVR2A) were recurrently altered. Furthermore, a novel FN1-ACVR2A fusion transcript was observed in both chondrosarcoma and osteochondromatosis cases. With the characteristic accumulative process of somatic changes as a background, molecular defects in chondrogenesis and aberrant epigenetic control are primarily causative of both benign and malignant cartilaginous tumors. PMID:25024164

Expression of SMARCB1 (INI1) mutations in familial schwannomatosis.

PubMed

Smith, Miriam J; Walker, James A; Shen, Yiping; Stemmer-Rachamimov, Anat; Gusella, James F; Plotkin, Scott R

2012-12-15

Genetic changes in the SMARCB1 tumor suppressor gene have recently been reported in tumors and blood from families with schwannomatosis. Exon scanning of all nine SMARCB1 exons in genomic DNA from our cohort of families meeting the criteria for 'definite' or 'presumptive' schwannomatosis previously revealed constitutional alterations in 13 of 19 families (68%). Screening of four new familial schwannomatosis probands identified one additional constitutional alteration. We confirmed the presence of mRNA transcripts for two missense alterations, four mutations of conserved splice motifs and two additional mutations, in less conserved sequences, which also affect splicing. Furthermore, we found that transcripts for a rare 3'-untranslated region (c.*82C > T) alteration shared by four unrelated families did not produce splice variants but did show unequal allelic expression, suggesting that the alteration is either causative itself or linked to an unidentified causative mutation. Overexpression studies in cells lacking SMARCB1 suggest that mutant SMARCB1 proteins, like wild-type SMARCB1 protein, retain the ability to suppress cyclin D1 activity. These data, together with the expression of SMARCB1 protein in a proportion of cells from schwannomatosis-related schwannomas, suggest that these tumors develop through a mechanism that is distinct from that of rhabdoid tumors in which SMARCB1 protein is completely absent in tumor cells.

Simulated climate warming alters phenological synchrony between an outbreak insect herbivore and host trees.

PubMed

Schwartzberg, Ezra G; Jamieson, Mary A; Raffa, Kenneth F; Reich, Peter B; Montgomery, Rebecca A; Lindroth, Richard L

2014-07-01

As the world's climate warms, the phenologies of interacting organisms in seasonally cold environments may advance at differing rates, leading to alterations in phenological synchrony that can have important ecological consequences. For temperate and boreal species, the timing of early spring development plays a key role in plant-herbivore interactions and can influence insect performance, outbreak dynamics, and plant damage. We used a field-based, meso-scale free-air forest warming experiment (B4WarmED) to examine the effects of elevated temperature on the phenology and performance of forest tent caterpillar (Malacosoma disstria) in relation to the phenology of two host trees, aspen (Populus tremuloides) and birch (Betula papyrifera). Results of our 2-year study demonstrated that spring phenology advanced for both insects and trees, with experimentally manipulated increases in temperature of 1.7 and 3.4 °C. However, tree phenology advanced more than insect phenology, resulting in altered phenological synchrony. Specifically, we observed a decrease in the time interval between herbivore egg hatch and budbreak of aspen in both years and birch in one year. Moreover, warming decreased larval development time from egg hatch to pupation, but did not affect pupal mass. Larvae developed more quickly on aspen than birch, but pupal mass was not affected by host species. Our study reveals that warming-induced phenological shifts can alter the timing of ecological interactions across trophic levels. These findings illustrate one mechanism by which climate warming could mediate insect herbivore outbreaks, and also highlights the importance of climate change effects on trophic interactions.

Developmental Ethanol Exposure Causes Reduced Feeding and Reveals a Critical Role for Neuropeptide F in Survival

PubMed Central

Guevara, Amanda; Gates, Hillary; Urbina, Brianna; French, Rachael

2018-01-01

Food intake is necessary for survival, and natural reward circuitry has evolved to help ensure that animals ingest sufficient food to maintain development, growth, and survival. Drugs of abuse, including alcohol, co-opt the natural reward circuitry in the brain, and this is a major factor in the reinforcement of drug behaviors leading to addiction. At the junction of these two aspects of reward are alterations in feeding behavior due to alcohol consumption. In particular, developmental alcohol exposure (DAE) results in a collection of physical and neurobehavioral disorders collectively referred to as Fetal Alcohol Spectrum Disorder (FASD). The deleterious effects of DAE include intellectual disabilities and other neurobehavioral changes, including altered feeding behaviors. Here we use Drosophila melanogaster as a genetic model organism to study the effects of DAE on feeding behavior and the expression and function of Neuropeptide F. We show that addition of a defined concentration of ethanol to food leads to reduced feeding at all stages of development. Further, genetic conditions that reduce or eliminate NPF signaling combine with ethanol exposure to further reduce feeding, and the distribution of NPF is altered in the brains of ethanol-supplemented larvae. Most strikingly, we find that the vast majority of flies with a null mutation in the NPF receptor die early in larval development when reared in ethanol, and provide evidence that this lethality is due to voluntary starvation. Collectively, we find a critical role for NPF signaling in protecting against altered feeding behavior induced by developmental ethanol exposure. PMID:29623043

In-Silico Integration Approach to Identify a Key miRNA Regulating a Gene Network in Aggressive Prostate Cancer

PubMed Central

Colaprico, Antonio; Bontempi, Gianluca; Castiglioni, Isabella

2018-01-01

Like other cancer diseases, prostate cancer (PC) is caused by the accumulation of genetic alterations in the cells that drives malignant growth. These alterations are revealed by gene profiling and copy number alteration (CNA) analysis. Moreover, recent evidence suggests that also microRNAs have an important role in PC development. Despite efforts to profile PC, the alterations (gene, CNA, and miRNA) and biological processes that correlate with disease development and progression remain partially elusive. Many gene signatures proposed as diagnostic or prognostic tools in cancer poorly overlap. The identification of co-expressed genes, that are functionally related, can identify a core network of genes associated with PC with a better reproducibility. By combining different approaches, including the integration of mRNA expression profiles, CNAs, and miRNA expression levels, we identified a gene signature of four genes overlapping with other published gene signatures and able to distinguish, in silico, high Gleason-scored PC from normal human tissue, which was further enriched to 19 genes by gene co-expression analysis. From the analysis of miRNAs possibly regulating this network, we found that hsa-miR-153 was highly connected to the genes in the network. Our results identify a four-gene signature with diagnostic and prognostic value in PC and suggest an interesting gene network that could play a key regulatory role in PC development and progression. Furthermore, hsa-miR-153, controlling this network, could be a potential biomarker for theranostics in high Gleason-scored PC. PMID:29562723

Identification and Phenotypic Characterization of ZEBRA LEAF16 Encoding a β-Hydroxyacyl-ACP Dehydratase in Rice

PubMed Central

Liu, Ziwen; Wang, Zhiyuan; Gu, Han; You, Jia; Hu, Manman; Zhang, Yujun; Zhu, Ze; Wang, Yihua; Liu, Shijia; Chen, Liangming; Liu, Xi; Tian, Yunlu; Zhou, Shirong; Jiang, Ling; Liu, Linglong; Wan, Jianmin

2018-01-01

The chloroplast is a self-independent organelle and contains its own transcription and translation systems. The establishment of genetic systems is vital for normal plant growth and development. We isolated a rice zebra leaf 16 (zl16) mutant derived from rice cultivar 9311. The zl16 mutant showed chlorotic abnormalities in the transverse sectors of the young leaves of seedlings. The use of transmission electron microscopy (TEM) demonstrated that dramatic defects occurred in variegated zl16 leaves during the early development of a chloroplast. Map-based cloning revealed that ZL16 encodes a β-hydroxyacyl-ACP dehydratase (HAD) involved in de novo fatty acid synthesis. Compared with the wild type, a missense mutation (Arg164Trp) in the zl16 mutant was identified, which significantly reduced enzymatic activity and altered the three-dimensional modeling structure of the putative protein. ZL16 was ubiquitously expressed in various plant organs, with a pronounced level in the young leaf. A subcellular localization experiment indicated that ZL16 was targeted in the chloroplast. Furthermore, we analyzed the expression of some nuclear genes involved in chloroplast development, and found they were altered in the zl16 mutant. RNA-Seq analysis indicated that some genes related to cell membrane constituents were downregulated in the mutant. An in vivo metabolic assay revealed that the total fatty acid content in the mutant was significantly decreased relative to the wild type. Our results indicate that HAD is essential for the development of chloroplasts by regulating the synthesis of fatty acids in rice. PMID:29946330

Thymidine kinase 2 deficiency-induced mitochondrial DNA depletion causes abnormal development of adipose tissues and adipokine levels in mice.

PubMed

Villarroya, Joan; Dorado, Beatriz; Vilà, Maya R; Garcia-Arumí, Elena; Domingo, Pere; Giralt, Marta; Hirano, Michio; Villarroya, Francesc

2011-01-01

Mammal adipose tissues require mitochondrial activity for proper development and differentiation. The components of the mitochondrial respiratory chain/oxidative phosphorylation system (OXPHOS) are encoded by both mitochondrial and nuclear genomes. The maintenance of mitochondrial DNA (mtDNA) is a key element for a functional mitochondrial oxidative activity in mammalian cells. To ascertain the role of mtDNA levels in adipose tissue, we have analyzed the alterations in white (WAT) and brown (BAT) adipose tissues in thymidine kinase 2 (Tk2) H126N knockin mice, a model of TK2 deficiency-induced mtDNA depletion. We observed respectively severe and moderate mtDNA depletion in TK2-deficient BAT and WAT, showing both tissues moderate hypotrophy and reduced fat accumulation. Electron microscopy revealed altered mitochondrial morphology in brown but not in white adipocytes from TK2-deficient mice. Although significant reduction in mtDNA-encoded transcripts was observed both in WAT and BAT, protein levels from distinct OXPHOS complexes were significantly reduced only in TK2-deficient BAT. Accordingly, the activity of cytochrome c oxidase was significantly lowered only in BAT from TK2-deficient mice. The analysis of transcripts encoding up to fourteen components of specific adipose tissue functions revealed that, in both TK2-deficient WAT and BAT, there was a consistent reduction of thermogenesis related gene expression and a severe reduction in leptin mRNA. Reduced levels of resistin mRNA were found in BAT from TK2-deficient mice. Analysis of serum indicated a dramatic reduction in circulating levels of leptin and resistin. In summary, our present study establishes that mtDNA depletion leads to a moderate impairment in mitochondrial respiratory function, especially in BAT, causes substantial alterations in WAT and BAT development, and has a profound impact in the endocrine properties of adipose tissues. © 2011 Villarroya et al.

Thymidine Kinase 2 Deficiency-Induced Mitochondrial DNA Depletion Causes Abnormal Development of Adipose Tissues and Adipokine Levels in Mice

PubMed Central

Villarroya, Joan; Dorado, Beatriz; Vilà, Maya R.; Garcia-Arumí, Elena; Domingo, Pere; Giralt, Marta; Hirano, Michio; Villarroya, Francesc

2011-01-01

Mammal adipose tissues require mitochondrial activity for proper development and differentiation. The components of the mitochondrial respiratory chain/oxidative phosphorylation system (OXPHOS) are encoded by both mitochondrial and nuclear genomes. The maintenance of mitochondrial DNA (mtDNA) is a key element for a functional mitochondrial oxidative activity in mammalian cells. To ascertain the role of mtDNA levels in adipose tissue, we have analyzed the alterations in white (WAT) and brown (BAT) adipose tissues in thymidine kinase 2 (Tk2) H126N knockin mice, a model of TK2 deficiency-induced mtDNA depletion. We observed respectively severe and moderate mtDNA depletion in TK2-deficient BAT and WAT, showing both tissues moderate hypotrophy and reduced fat accumulation. Electron microscopy revealed altered mitochondrial morphology in brown but not in white adipocytes from TK2-deficient mice. Although significant reduction in mtDNA-encoded transcripts was observed both in WAT and BAT, protein levels from distinct OXPHOS complexes were significantly reduced only in TK2-deficient BAT. Accordingly, the activity of cytochrome c oxidase was significantly lowered only in BAT from TK2-deficient mice. The analysis of transcripts encoding up to fourteen components of specific adipose tissue functions revealed that, in both TK2-deficient WAT and BAT, there was a consistent reduction of thermogenesis related gene expression and a severe reduction in leptin mRNA. Reduced levels of resistin mRNA were found in BAT from TK2-deficient mice. Analysis of serum indicated a dramatic reduction in circulating levels of leptin and resistin. In summary, our present study establishes that mtDNA depletion leads to a moderate impairment in mitochondrial respiratory function, especially in BAT, causes substantial alterations in WAT and BAT development, and has a profound impact in the endocrine properties of adipose tissues. PMID:22216345

Exercise Is More Effective at Altering Gut Microbial Composition and Producing Stable Changes in Lean Mass in Juvenile versus Adult Male F344 Rats

PubMed Central

Mika, Agnieszka; Van Treuren, Will; González, Antonio; Herrera, Jonathan J.; Knight, Rob; Fleshner, Monika

2015-01-01

The mammalian intestine harbors a complex microbial ecosystem that influences many aspects of host physiology. Exposure to specific microbes early in development affects host metabolism, immune function, and behavior across the lifespan. Just as the physiology of the developing organism undergoes a period of plasticity, the developing microbial ecosystem is characterized by instability and may also be more sensitive to change. Early life thus presents a window of opportunity for manipulations that produce adaptive changes in microbial composition. Recent insights have revealed that increasing physical activity can increase the abundance of beneficial microbial species. We therefore investigated whether six weeks of wheel running initiated in the juvenile period (postnatal day 24) would produce more robust and stable changes in microbial communities versus exercise initiated in adulthood (postnatal day 70) in male F344 rats. 16S rRNA gene sequencing was used to characterize the microbial composition of juvenile versus adult runners and their sedentary counterparts across multiple time points during exercise and following exercise cessation. Alpha diversity measures revealed that the microbial communities of young runners were less even and diverse, a community structure that reflects volatility and malleability. Juvenile onset exercise altered several phyla and, notably, increased Bacteroidetes and decreased Firmicutes, a configuration associated with leanness. At the genus level of taxonomy, exercise altered more genera in juveniles than in the adults and produced patterns associated with adaptive metabolic consequences. Given the potential of these changes to contribute to a lean phenotype, we examined body composition in juvenile versus adult runners. Interestingly, exercise produced persistent increases in lean body mass in juvenile but not adult runners. Taken together, these results indicate that the impact of exercise on gut microbiota composition as well as body composition may depend on the developmental stage during which exercise is initiated. PMID:26016739

Lack of broad functional differences in immunity in fully vaccinated vs. unvaccinated children.

PubMed

Sherrid, Ashley M; Ruck, Candice E; Sutherland, Darren; Cai, Bing; Kollmann, Tobias R

2017-04-01

Concerns have been raised that with an increase in the number of vaccines administered early in life, immune development could be altered, leading to either increased or decreased immune reactivity. We investigated the impact of vaccination on immune status, contrasting the immune response to general, nonantigen-specific stimuli in a cohort of entirely unvaccinated vs. fully vaccinated children at 3-5 y of age. Innate immunity was assessed by quantifying bulk and cell-type-specific cytokine production in response to stimulation with pathogen associated microbial patterns. Adaptive immune status was characterized by assessing lymphocyte proliferation and cytokine production in response to generic T cell stimuli. Our investigations failed to reveal a broadly evident alteration of either innate or adaptive immunity in vaccinated children. Equivalently robust innate and adaptive responses to pathogen associated microbial patterns and generic T cell stimulants were observed in both groups. Although our sample size was small, our data suggest that standard childhood vaccinations do not lead to long-lasting gross alterations of the immune system.

A survey of Australian adult users of altered auditory feedback devices for stuttering: use patterns, perceived effectiveness and satisfaction.

PubMed

Lincoln, Michelle; Walker, Clare

2007-10-15

Small portable devices that provide delayed auditory feedback (DAF) and/or frequency altered feedback (FAF) have been developed and marketed to clinicians and people who stutter as fluency enhancing aids for use in everyday speaking situations. The literature contains many laboratory-based reports about the impact of altered auditory feedback (AAF) on the speech of people who stutter but few reports about its use in everyday speaking situations. This paper investigates use patterns and perceptions of the effectiveness and satisfaction with AAF devices. The current study surveys 14 Australian AAF users. The survey responses revealed varied opinions about AAF devices and their use and effectiveness in everyday speaking situations. Opinions were somewhat related to the type of device used. The results of this study provide some important directions for future research. In particular there is need to investigate the effectiveness of AAF devices when used in conjunction with other traditional treatments.

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma.

PubMed

Ricketts, Christopher J; De Cubas, Aguirre A; Fan, Huihui; Smith, Christof C; Lang, Martin; Reznik, Ed; Bowlby, Reanne; Gibb, Ewan A; Akbani, Rehan; Beroukhim, Rameen; Bottaro, Donald P; Choueiri, Toni K; Gibbs, Richard A; Godwin, Andrew K; Haake, Scott; Hakimi, A Ari; Henske, Elizabeth P; Hsieh, James J; Ho, Thai H; Kanchi, Rupa S; Krishnan, Bhavani; Kwiatkowski, David J; Lui, Wembin; Merino, Maria J; Mills, Gordon B; Myers, Jerome; Nickerson, Michael L; Reuter, Victor E; Schmidt, Laura S; Shelley, C Simon; Shen, Hui; Shuch, Brian; Signoretti, Sabina; Srinivasan, Ramaprasad; Tamboli, Pheroze; Thomas, George; Vincent, Benjamin G; Vocke, Cathy D; Wheeler, David A; Yang, Lixing; Kim, William Y; Robertson, A Gordon; Spellman, Paul T; Rathmell, W Kimryn; Linehan, W Marston

2018-04-03

Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival. Published by Elsevier Inc.

Data-driven modeling of background and mine-related acidity and metals in river basins

USGS Publications Warehouse

Friedel, Michael J

2013-01-01

A novel application of self-organizing map (SOM) and multivariate statistical techniques is used to model the nonlinear interaction among basin mineral-resources, mining activity, and surface-water quality. First, the SOM is trained using sparse measurements from 228 sample sites in the Animas River Basin, Colorado. The model performance is validated by comparing stochastic predictions of basin-alteration assemblages and mining activity at 104 independent sites. The SOM correctly predicts (>98%) the predominant type of basin hydrothermal alteration and presence (or absence) of mining activity. Second, application of the Davies–Bouldin criteria to k-means clustering of SOM neurons identified ten unique environmental groups. Median statistics of these groups define a nonlinear water-quality response along the spatiotemporal hydrothermal alteration-mining gradient. These results reveal that it is possible to differentiate among the continuum between inputs of background and mine-related acidity and metals, and it provides a basis for future research and empirical model development.

Extracting genetic alteration information for personalized cancer therapy from ClinicalTrials.gov

PubMed Central

Xu, Jun; Lee, Hee-Jin; Zeng, Jia; Wu, Yonghui; Zhang, Yaoyun; Huang, Liang-Chin; Johnson, Amber; Holla, Vijaykumar; Bailey, Ann M; Cohen, Trevor; Meric-Bernstam, Funda; Bernstam, Elmer V

2016-01-01

Objective: Clinical trials investigating drugs that target specific genetic alterations in tumors are important for promoting personalized cancer therapy. The goal of this project is to create a knowledge base of cancer treatment trials with annotations about genetic alterations from ClinicalTrials.gov. Methods: We developed a semi-automatic framework that combines advanced text-processing techniques with manual review to curate genetic alteration information in cancer trials. The framework consists of a document classification system to identify cancer treatment trials from ClinicalTrials.gov and an information extraction system to extract gene and alteration pairs from the Title and Eligibility Criteria sections of clinical trials. By applying the framework to trials at ClinicalTrials.gov, we created a knowledge base of cancer treatment trials with genetic alteration annotations. We then evaluated each component of the framework against manually reviewed sets of clinical trials and generated descriptive statistics of the knowledge base. Results and Discussion: The automated cancer treatment trial identification system achieved a high precision of 0.9944. Together with the manual review process, it identified 20 193 cancer treatment trials from ClinicalTrials.gov. The automated gene-alteration extraction system achieved a precision of 0.8300 and a recall of 0.6803. After validation by manual review, we generated a knowledge base of 2024 cancer trials that are labeled with specific genetic alteration information. Analysis of the knowledge base revealed the trend of increased use of targeted therapy for cancer, as well as top frequent gene-alteration pairs of interest. We expect this knowledge base to be a valuable resource for physicians and patients who are seeking information about personalized cancer therapy. PMID:27013523

Extracting genetic alteration information for personalized cancer therapy from ClinicalTrials.gov.

PubMed

Xu, Jun; Lee, Hee-Jin; Zeng, Jia; Wu, Yonghui; Zhang, Yaoyun; Huang, Liang-Chin; Johnson, Amber; Holla, Vijaykumar; Bailey, Ann M; Cohen, Trevor; Meric-Bernstam, Funda; Bernstam, Elmer V; Xu, Hua

2016-07-01

Clinical trials investigating drugs that target specific genetic alterations in tumors are important for promoting personalized cancer therapy. The goal of this project is to create a knowledge base of cancer treatment trials with annotations about genetic alterations from ClinicalTrials.gov. We developed a semi-automatic framework that combines advanced text-processing techniques with manual review to curate genetic alteration information in cancer trials. The framework consists of a document classification system to identify cancer treatment trials from ClinicalTrials.gov and an information extraction system to extract gene and alteration pairs from the Title and Eligibility Criteria sections of clinical trials. By applying the framework to trials at ClinicalTrials.gov, we created a knowledge base of cancer treatment trials with genetic alteration annotations. We then evaluated each component of the framework against manually reviewed sets of clinical trials and generated descriptive statistics of the knowledge base. The automated cancer treatment trial identification system achieved a high precision of 0.9944. Together with the manual review process, it identified 20 193 cancer treatment trials from ClinicalTrials.gov. The automated gene-alteration extraction system achieved a precision of 0.8300 and a recall of 0.6803. After validation by manual review, we generated a knowledge base of 2024 cancer trials that are labeled with specific genetic alteration information. Analysis of the knowledge base revealed the trend of increased use of targeted therapy for cancer, as well as top frequent gene-alteration pairs of interest. We expect this knowledge base to be a valuable resource for physicians and patients who are seeking information about personalized cancer therapy. © The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Prevalence of plasmid-mediated qnr determinants and gyrase alteration in Klebsiella pneumoniae isolated from a university teaching hospital in Malaysia.

PubMed

Saiful Anuar, A S; Mohd Yusof, M Y; Tay, S T

2013-07-01

The ciprofloxacin resistance of Klebsiella (K.) pneumoniae is mediated primarily through alterations in type II topoisomerase (gyrA) gene and plasmid-mediated quinolone resistance-conferring genes (qnr). This study aimed to define the prevalence of plasmid-mediated quinolone resistance-conferring genes (qnr) and type II topoisomerase (gyrA) alterations of a population of ciprofloxacin-resistant (n = 21), intermediate (n = 8), and sensitive (n = 18) K. pneumoniae isolates obtained from a teaching hospital at Kuala Lumpur, Malaysia. A multiplex PCR assay was performed for simultaneous detection of qnrA, qnrB and qnrS. Sequence analysis of the amplified gyrA and gyrB regions of the isolates were performed. The findings in this study revealed the emergence of a high prevalence (48.9%) of qnr determinants in our isolates. Four variants of plasmid-mediated qnr determinants (qnrB1, qnrB6, qnrB10 and qnrS1) were detected from 11 (52.4%) ciprofloxacin-resistant, 5 (62.5%) intermediate and 7 (38.9%) sensitive isolates. gyrA alterations were detected from 18 (85.7%) ciprofloxacin-resistant isolates. Single gyrA alterations, Ser83→Tyr, Ser83→Ile, and Asp87→Gly, and double alterations, Ser83→Phe plus Asp87→Ala and Ser83→Tyr plus Asp87→Asn were detected. While ciprofloxacin resistance was significantly associated with gyrA alteration (Ser83, p = 0.003; Asp87, p = 0.005; double alteration, p = 0.016), no significant association of ciprofloxacin resistance was noted with the presence of qnr determinants (p = 0.283). The findings in this study demonstrate the emergence of qnr determinants and gyrA alterations contributed to the development and spread of fluoroquinolone resistance in the Malaysian isolates.

[Circadian rhythm disruption and human development].

PubMed

Kohyama, Jun

2013-12-01

Ontogenetic developments of rest-activity, sleep-wakefulness, temperature and several hormone rhythms in humans were reviewed. The reported effects of environment on these alterations were also summarized. Then, disorders or conditions which often encounter during early stage of life and reveal circadian rhythm disruptions were described. These disorders or conditions included severe brain damage, visual disturbance, developmental disorders(autistic spectrum disorder and attention deficit/hyperactivity disorder), Rett syndrome, Angelman syndrome, Smith-Magenis syndrome, epilepsy, Yonaki, and inadequate sleep hygiene. Finally, it was emphasized that we should pay special attention on the development of youngsters who showed sleep disturbance during early stage of life with special reference to the later occurrence of developmental disorders.

Early alcohol exposure impairs ocular dominance plasticity throughout the critical period.

PubMed

Medina, Alexandre E; Ramoa, Ary S

2005-06-09

Animal models of fetal alcohol syndrome (FAS) have revealed an impairment of sensory neocortex plasticity. Here, we examine whether early alcohol exposure leads to a permanent impairment of ocular dominance plasticity (OD) or to an alteration in the timing of the critical period. Ferrets were exposed to alcohol during a brief period of development prior to eye opening and effects of monocular deprivation examined during early, mid and late critical period. Single-unit electrophysiology revealed markedly reduced OD plasticity at every age examined. This finding provides evidence that early alcohol exposure does not affect the timing or duration of the critical period of OD plasticity and suggests an enduring impairment of neural plasticity in FAS.

Altered Neural Oscillations During Multisensory Integration in Adolescents with Fetal Alcohol Spectrum Disorder.

PubMed

Bolaños, Alfredo D; Coffman, Brian A; Candelaria-Cook, Felicha T; Kodituwakku, Piyadasa; Stephen, Julia M

2017-12-01

Children with fetal alcohol spectrum disorder (FASD), who were exposed to alcohol in utero, display a broad range of sensory, cognitive, and behavioral deficits, which are broadly theorized to be rooted in altered brain function and structure. Based on the role of neural oscillations in multisensory integration from past studies, we hypothesized that adolescents with FASD would show a decrease in oscillatory power during event-related gamma oscillatory activity (30 to 100 Hz), when compared to typically developing healthy controls (HC), and that such decrease in oscillatory power would predict behavioral performance. We measured sensory neurophysiology using magnetoencephalography (MEG) during passive auditory, somatosensory, and multisensory (synchronous) stimulation in 19 adolescents (12 to 21 years) with FASD and 23 age- and gender-matched HC. We employed a cross-hemisphere multisensory paradigm to assess interhemispheric connectivity deficits in children with FASD. Time-frequency analysis of MEG data revealed a significant decrease in gamma oscillatory power for both unisensory and multisensory conditions in the FASD group relative to HC, based on permutation testing of significant group differences. Greater beta oscillatory power (15 to 30 Hz) was also noted in the FASD group compared to HC in both unisensory and multisensory conditions. Regression analysis revealed greater predictive power of multisensory oscillations from unisensory oscillations in the FASD group compared to the HC group. Furthermore, multisensory oscillatory power, for both groups, predicted performance on the Intra-Extradimensional Set Shift Task and the Cambridge Gambling Task. Altered oscillatory power in the FASD group may reflect a restricted ability to process somatosensory and multisensory stimuli during day-to-day interactions. These alterations in neural oscillations may be associated with the neurobehavioral deficits experienced by adolescents with FASD and may carry over to adulthood. Copyright © 2017 by the Research Society on Alcoholism.

Shrinkage of X cells in the lateral geniculate nucleus after monocular deprivation revealed by FoxP2 labeling.

PubMed

Duffy, Kevin R; Holman, Kaitlyn D; Mitchell, Donald E

2014-05-01

The parallel processing of visual features by distinct neuron populations is a central characteristic of the mammalian visual system. In the A laminae of the cat dorsal lateral geniculate nucleus (dLGN), parallel processing streams originate from two principal neuron types, called X and Y cells. Disruption of visual experience early in life by monocular deprivation has been shown to alter the structure and function of Y cells, but the extent to which deprivation influences X cells remains less clear. A transcription factor, FoxP2, has recently been shown to selectively label X cells in the ferret dLGN and thus provides an opportunity to examine whether monocular deprivation alters the soma size of X cells. In this study, FoxP2 labeling was examined in the dLGN of normal and monocularly deprived cats. The characteristics of neurons labeled for FoxP2 were consistent with FoxP2 being a marker for X cells in the cat dLGN. Monocular deprivation for either a short (7 days) or long (7 weeks) duration did not alter the density of FoxP2-positive neurons between nondeprived and deprived dLGN layers. However, for each deprived animal examined, measurement of the cross-sectional area of FoxP2-positive neurons (X cells) revealed that within deprived layers, X cells were smaller by approximately 20% after 7 days of deprivation, and by approximately 28% after 7 weeks of deprivation. The observed alteration to the cross-sectional area of X cells indicates that perturbation of this major pathway contributes to the functional impairments that develop from monocular deprivation.

Altered Brain Network Segregation in Fragile X Syndrome Revealed by Structural Connectomics.

PubMed

Bruno, Jennifer Lynn; Hosseini, S M Hadi; Saggar, Manish; Quintin, Eve-Marie; Raman, Mira Michelle; Reiss, Allan L

2017-03-01

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism spectrum disorder, is associated with significant behavioral, social, and neurocognitive deficits. Understanding structural brain network topology in FXS provides an important link between neurobiological and behavioral/cognitive symptoms of this disorder. We investigated the connectome via whole-brain structural networks created from group-level morphological correlations. Participants included 100 individuals: 50 with FXS and 50 with typical development, age 11-23 years. Results indicated alterations in topological properties of structural brain networks in individuals with FXS. Significantly reduced small-world index indicates a shift in the balance between network segregation and integration and significantly reduced clustering coefficient suggests that reduced local segregation shifted this balance. Caudate and amygdala were less interactive in the FXS network further highlighting the importance of subcortical region alterations in the neurobiological signature of FXS. Modularity analysis indicates that FXS and typically developing groups' networks decompose into different sets of interconnected sub networks, potentially indicative of aberrant local interconnectivity in individuals with FXS. These findings advance our understanding of the effects of fragile X mental retardation protein on large-scale brain networks and could be used to develop a connectome-level biological signature for FXS. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Prenatal Ethanol Exposure and Neocortical Development: A Transgenerational Model of FASD.

PubMed

Abbott, Charles W; Rohac, David J; Bottom, Riley T; Patadia, Sahil; Huffman, Kelly J

2017-07-06

Fetal Alcohol Spectrum Disorders, or FASD, represent a range of adverse developmental conditions caused by prenatal ethanol exposure (PrEE) from maternal consumption of alcohol. PrEE induces neurobiological damage in the developing brain leading to cognitive-perceptual and behavioral deficits in the offspring. Alcohol-mediated alterations to epigenetic function may underlie PrEE-related brain dysfunction, with these changes potentially carried across generations to unexposed offspring. To determine the transgenerational impact of PrEE on neocortical development, we generated a mouse model of FASD and identified numerous stable phenotypes transmitted via the male germline to the unexposed third generation. These include alterations in ectopic intraneocortical connectivity, upregulation of neocortical Rzrβ and Id2 expression accompanied by both promoter hypomethylation of these genes and decreased global DNA methylation levels. DNMT expression was also suppressed in newborn PrEE cortex, providing further insight into how ethanol perturbs DNA methylation leading to altered regulation of gene transcription. These PrEE-induced, transgenerational phenotypes may be responsible for cognitive, sensorimotor, and behavioral deficits seen in humans with FASD. Thus, understanding the possible epigenetic mechanisms by which these phenotypes are generated may reveal novel targets for therapeutic intervention of FASD and lead to advances in human health. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Investigating the Microstructural Correlation of White Matter in Autism Spectrum Disorder.

PubMed

Dean, Douglas C; Travers, Brittany G; Adluru, Nagesh; Tromp, Do P M; Destiche, Daniel J; Samsin, Danica; Prigge, Molly B; Zielinski, Brandon A; Fletcher, P Thomas; Anderson, Jeffrey S; Froehlich, Alyson L; Bigler, Erin D; Lange, Nicholas; Lainhart, Janet E; Alexander, Andrew L

2016-06-01

White matter microstructure forms a complex and dynamical system that is critical for efficient and synchronized brain function. Neuroimaging findings in children with autism spectrum disorder (ASD) suggest this condition is associated with altered white matter microstructure, which may lead to atypical macroscale brain connectivity. In this study, we used diffusion tensor imaging measures to examine the extent that white matter tracts are interrelated within ASD and typical development. We assessed the strength of inter-regional white matter correlations between typically developing and ASD diagnosed individuals. Using hierarchical clustering analysis, clustering patterns of the pairwise white matter correlations were constructed and revealed to be different between the two groups. Additionally, we explored the use of graph theory analysis to examine the characteristics of the patterns formed by inter-regional white matter correlations and compared these properties between ASD and typical development. We demonstrate that the ASD sample has significantly less coherence in white matter microstructure across the brain compared to that in the typical development sample. The ASD group also presented altered topological characteristics, which may implicate less efficient brain networking in ASD. These findings highlight the potential of graph theory based network characteristics to describe the underlying networks as measured by diffusion magnetic resonance imaging and furthermore indicates that ASD may be associated with altered brain network characteristics. Our findings are consistent with those of a growing number of studies and hypotheses that have suggested disrupted brain connectivity in ASD.

Investigating the Microstructural Correlation of White Matter in Autism Spectrum Disorder

PubMed Central

Travers, Brittany G.; Adluru, Nagesh; Tromp, Do P.M.; Destiche, Daniel J.; Samsin, Danica; Prigge, Molly B.; Zielinski, Brandon A.; Fletcher, P. Thomas; Anderson, Jeffrey S.; Froehlich, Alyson L.; Bigler, Erin D.; Lange, Nicholas; Lainhart, Janet E.; Alexander, Andrew L.

2016-01-01

Abstract White matter microstructure forms a complex and dynamical system that is critical for efficient and synchronized brain function. Neuroimaging findings in children with autism spectrum disorder (ASD) suggest this condition is associated with altered white matter microstructure, which may lead to atypical macroscale brain connectivity. In this study, we used diffusion tensor imaging measures to examine the extent that white matter tracts are interrelated within ASD and typical development. We assessed the strength of inter-regional white matter correlations between typically developing and ASD diagnosed individuals. Using hierarchical clustering analysis, clustering patterns of the pairwise white matter correlations were constructed and revealed to be different between the two groups. Additionally, we explored the use of graph theory analysis to examine the characteristics of the patterns formed by inter-regional white matter correlations and compared these properties between ASD and typical development. We demonstrate that the ASD sample has significantly less coherence in white matter microstructure across the brain compared to that in the typical development sample. The ASD group also presented altered topological characteristics, which may implicate less efficient brain networking in ASD. These findings highlight the potential of graph theory based network characteristics to describe the underlying networks as measured by diffusion magnetic resonance imaging and furthermore indicates that ASD may be associated with altered brain network characteristics. Our findings are consistent with those of a growing number of studies and hypotheses that have suggested disrupted brain connectivity in ASD. PMID:27021440

Adulthood stress responses in rats are variably altered as a factor of adolescent stress exposure.

PubMed

Moore, Nicole L T; Altman, Daniel E; Gauchan, Sangeeta; Genovese, Raymond F

2016-05-01

Stress exposure during development may influence adulthood stress response severity. The present study investigates persisting effects of two adolescent stressors upon adulthood response to predator exposure (PE). Rats were exposed to underwater trauma (UWT) or PE during adolescence, then to PE after reaching adulthood. Rats were then exposed to predator odor (PO) to test responses to predator cues alone. Behavioral and neuroendocrine assessments were conducted to determine acute effects of each stress experience. Adolescent stress altered behavioral response to adulthood PE. Acoustic startle response was blunted. Bidirectional changes in plus maze exploration were revealed as a factor of adolescent stress type. Neuroendocrine response magnitude did not predict severity of adolescent or adult stress response, suggesting that different adolescent stress events may differentially alter developmental outcomes regardless of acute behavioral or neuroendocrine response. We report that exposure to two different stressors in adolescence may differentially affect stress response outcomes in adulthood. Acute response to an adolescent stressor may not be consistent across all stressors or all dependent measures, and may not predict alterations in developmental outcomes pertaining to adulthood stress exposure. Further studies are needed to characterize factors underlying long-term effects of a developmental stressor.

Multi-Omics Reveals that Lead Exposure Disturbs Gut Microbiome Development, Key Metabolites, and Metabolic Pathways.

PubMed

Gao, Bei; Chi, Liang; Mahbub, Ridwan; Bian, Xiaoming; Tu, Pengcheng; Ru, Hongyu; Lu, Kun

2017-04-17

Lead exposure remains a global public health issue, and the recent Flint water crisis has renewed public concern about lead toxicity. The toxicity of lead has been well established in a variety of systems and organs. The gut microbiome has been shown to be highly involved in many critical physiological processes, including food digestion, immune system development, and metabolic homeostasis. However, despite the key role of the gut microbiome in human health, the functional impact of lead exposure on the gut microbiome has not been studied. The aim of this study is to define gut microbiome toxicity induced by lead exposure in C57BL/6 mice using multiomics approaches, including 16S rRNA sequencing, whole genome metagenomics sequencing, and gas chromatography-mass spectrometry (GC-MS) metabolomics. 16S rRNA sequencing revealed that lead exposure altered the gut microbiome trajectory and phylogenetic diversity. Metagenomics sequencing and metabolomics profiling showed that numerous metabolic pathways, including vitamin E, bile acids, nitrogen metabolism, energy metabolism, oxidative stress, and the defense/detoxification mechanism, were significantly disturbed by lead exposure. These perturbed molecules and pathways may have important implications for lead toxicity in the host. Taken together, these results demonstrated that lead exposure not only altered the gut microbiome community structures/diversity but also greatly affected metabolic functions, leading to gut microbiome toxicity.

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas.

PubMed

Schaub, Franz X; Dhankani, Varsha; Berger, Ashton C; Trivedi, Mihir; Richardson, Anne B; Shaw, Reid; Zhao, Wei; Zhang, Xiaoyang; Ventura, Andrea; Liu, Yuexin; Ayer, Donald E; Hurlin, Peter J; Cherniack, Andrew D; Eisenman, Robert N; Bernard, Brady; Grandori, Carla

2018-03-28

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior

PubMed Central

Leclercq, Sophie; Mian, Firoz M.; Stanisz, Andrew M.; Bindels, Laure B.; Cambier, Emmanuel; Ben-Amram, Hila; Koren, Omry; Forsythe, Paul; Bienenstock, John

2017-01-01

There is increasing concern about potential long-term effects of antibiotics on children's health. Epidemiological studies have revealed that early-life antibiotic exposure can increase the risk of developing immune and metabolic diseases, and rodent studies have shown that administration of high doses of antibiotics has long-term effects on brain neurochemistry and behaviour. Here we investigate whether low-dose penicillin in late pregnancy and early postnatal life induces long-term effects in the offspring of mice. We find that penicillin has lasting effects in both sexes on gut microbiota, increases cytokine expression in frontal cortex, modifies blood–brain barrier integrity and alters behaviour. The antibiotic-treated mice exhibit impaired anxiety-like and social behaviours, and display aggression. Concurrent supplementation with Lactobacillus rhamnosus JB-1 prevents some of these alterations. These results warrant further studies on the potential role of early-life antibiotic use in the development of neuropsychiatric disorders, and the possible attenuation of these by beneficial bacteria. PMID:28375200

Childhood poverty and recruitment of adult emotion regulatory neurocircuitry

PubMed Central

Ma, Sean T.; Okada, Go; Shaun Ho, S.; Swain, James E.; Evans, Gary W.

2015-01-01

One in five American children grows up in poverty. Childhood poverty has far-reaching adverse impacts on cognitive, social and emotional development. Altered development of neurocircuits, subserving emotion regulation, is one possible pathway for childhood poverty’s ill effects. Children exposed to poverty were followed into young adulthood and then studied using functional brain imaging with an implicit emotion regulation task focused. Implicit emotion regulation involved attention shifting and appraisal components. Early poverty reduced left dorsolateral prefrontal cortex recruitment in the context of emotional regulation. Furthermore, this emotion regulation associated brain activation mediated the effects of poverty on adult task performance. Moreover, childhood poverty also predicted enhanced insula and reduced hippocampal activation, following exposure to acute stress. These results demonstrate that childhood poverty can alter adult emotion regulation neurocircuitry, revealing specific brain mechanisms that may underlie long-term effects of social inequalities on health. The role of poverty-related emotion regulatory neurocircuitry appears to be particularly salient during stressful conditions. PMID:25939653

Transcriptome Analysis in Prenatal IGF1-Deficient Mice Identifies Molecular Pathways and Target Genes Involved in Distal Lung Differentiation

PubMed Central

Hernández-Porras, Isabel; López, Icíar Paula; De Las Rivas, Javier; Pichel, José García

2013-01-01

Background Insulin-like Growth Factor 1 (IGF1) is a multifunctional regulator of somatic growth and development throughout evolution. IGF1 signaling through IGF type 1 receptor (IGF1R) controls cell proliferation, survival and differentiation in multiple cell types. IGF1 deficiency in mice disrupts lung morphogenesis, causing altered prenatal pulmonary alveologenesis. Nevertheless, little is known about the cellular and molecular basis of IGF1 activity during lung development. Methods/Principal Findings Prenatal Igf1−/− mutant mice with a C57Bl/6J genetic background displayed severe disproportional lung hypoplasia, leading to lethal neonatal respiratory distress. Immuno-histological analysis of their lungs showed a thickened mesenchyme, alterations in extracellular matrix deposition, thinner smooth muscles and dilated blood vessels, which indicated immature and delayed distal pulmonary organogenesis. Transcriptomic analysis of Igf1−/− E18.5 lungs using RNA microarrays identified deregulated genes related to vascularization, morphogenesis and cellular growth, and to MAP-kinase, Wnt and cell-adhesion pathways. Up-regulation of immunity-related genes was verified by an increase in inflammatory markers. Increased expression of Nfib and reduced expression of Klf2, Egr1 and Ctgf regulatory proteins as well as activation of ERK2 MAP-kinase were corroborated by Western blot. Among IGF-system genes only IGFBP2 revealed a reduction in mRNA expression in mutant lungs. Immuno-staining patterns for IGF1R and IGF2, similar in both genotypes, correlated to alterations found in specific cell compartments of Igf1−/− lungs. IGF1 addition to Igf1−/− embryonic lungs cultured ex vivo increased airway septa remodeling and distal epithelium maturation, processes accompanied by up-regulation of Nfib and Klf2 transcription factors and Cyr61 matricellular protein. Conclusions/Significance We demonstrated the functional tissue specific implication of IGF1 on fetal lung development in mice. Results revealed novel target genes and gene networks mediators of IGF1 action on pulmonary cellular proliferation, differentiation, adhesion and immunity, and on vascular and distal epithelium maturation during prenatal lung development. PMID:24391734

Altered topography of intrinsic functional connectivity in childhood risk for social anxiety

PubMed Central

Taber-Thomas, Bradley C.; Morales, Santiago; Hillary, Frank G.; Pérez-Edgar, Koraly E.

2016-01-01

Background Extreme shyness in childhood arising from behavioral inhibition (BI) is among the strongest risk factors for developing social anxiety. Although no imaging studies of intrinsic brain networks in BI children have been reported, adults with a history of BI exhibit altered functioning of frontolimbic circuits and enhanced processing of salient, personally-relevant information. BI in childhood may be marked by increased coupling of salience (insula) and default (ventromedial prefrontal cortex) network hubs. Methods We tested this potential relation in 42 children ages 9 to 12, oversampled for high-BI. Participants provided resting-state functional magnetic resonance imaging. A novel topographical pattern analysis of salience network intrinsic functional connectivity was conducted, and the impact of salience-default coupling on the relation between BI and social anxiety symptoms was assessed via moderation analysis. Results High-BI children exhibit altered salience network topography, marked by reduced insula connectivity to dorsal anterior cingulate and increased insula connectivity to ventromedial prefrontal cortex. Whole-brain analyses revealed increased connectivity of salience, executive, and sensory networks with default network hubs in children higher in BI. Finally, the relation between insula-ventromedial prefrontal connectivity and social anxiety symptoms was strongest among the highest BI children. Conclusions BI is associated with an increase in connectivity to default network hubs that may bias processing toward personally-relevant information during development. These altered patterns of connectivity point to potential biomarkers of the neural profile of risk for anxiety in childhood. PMID:27093074

Understanding the mechanisms of Si-K-Ca glass alteration using silicon isotopes

NASA Astrophysics Data System (ADS)

Verney-Carron, Aurélie; Sessegolo, Loryelle; Saheb, Mandana; Valle, Nathalie; Ausset, Patrick; Losno, Rémi; Mangin, Denis; Lombardo, Tiziana; Chabas, Anne; Loisel, Claudine

2017-04-01

It is important to understand glass alteration mechanisms and to determine their associated kinetics in order to develop models able to predict the alteration of nuclear, basaltic or archaeological glasses. Recent studies revealed that the respective contributions of diffusion, dissolution, condensation and precipitation processes in alteration are still a matter for debate. In this work, the alteration of a medieval-type glass (Si-K-Ca) was investigated as it presents a specific composition (without B and with low Al). Experiments were performed using a dynamic device, at 30 °C, at pH 8 and 9 and during 1 month in order to simulate alteration in contact with water (rainfall or condensation). The solution was doped in 29Si to discriminate between the silicon from glass (mainly 28Si) and from solution. The results showed that the external region of the alteration layer is devoid of modifier cations (K, Ca) and presents a 29Si/28Si ratio close to the solution one. This excludes that the alteration layer is a glass skeleton and highlights a progressive hydrolysis/condensation process, even if non-hydrolyzed silica tetrahedra could remain when the Si isotopic equilibrium is not reached. The internal zone appears to be gradually depleted in modifier cations and partly enriched in 29Si, but the thickness of this zone is overestimated using SEM-EDS and SIMS techniques. Even if in these experiments the dissolution mechanism is favored, the contribution of interdiffusion cannot be neglected to explain the weathering of ancient stained glassed windows in the atmosphere. The respective contribution of diffusion and dissolution are also discussed as a function of glass composition and surface texture, as well as of experimental conditions (alkaline pH, renewal of the solution).

Are histological alterations observed in the gallbladder precancerous lesions?

PubMed Central

Meirelles-Costa, Adriana Lúcia Agnelli; Bresciani, Claudio José Caldas; Perez, Rodrigo Oliva; Bresciani, Barbara Helou; Siqueira, Sheila Aparecida C.; Cecconello, Ivan

2010-01-01

INTRODUCTION Gallbladder cancer, which is characterized by rapid progression and a poor prognosis, is a complex disease to treat. Unfortunately, little is known currently about its etiology or pathogenesis. A better understanding of its carcinogenesis and determining risk factors that lead to its development could help improve the available treatment options. METHOD Based on this better understanding, the histological alterations (such as acute cholecystitis, adenomyomatosis, xanthogranulomatous cholecystitis, polyps, pyloric metaplasia, intestinal metaplasia, dysplasia, cancer and others) in gallbladders from 1,689 patients who underwent laparoscopic cholecystectomy for cholecystolithiasis were analyzed. The association of these gallbladder histological alterations with clinical data was studied. RESULTS Gender analysis revealed a greater incidence of inflammatory changes in males, while dysplasia and cancer were only found in women. The incidence of cholesterolosis was greater in the patients 60 years of age and under, and the incidence of adenomyomatosis and gangrene was greater in the elderly patients. A progressive increase in the average age was observed as alterations progressed through pyloric metaplasia, intestinal metaplasia, dysplasia and then cancer, suggesting that the metaplasia-dysplasia-carcinoma sequence may occur in gallbladder cancer. Gallbladder histological alterations were also observed in asymptomatic patients. CONCLUSION The results of this study suggest that there could be an association between some histological alterations of gallbladder and cancer, and they also suggest that the metaplasia-dysplasia-carcinoma sequence could in fact be true in the case of gallbladder cancer. Nevertheless, further studies directed towards a perfect understanding of gallbladder carcinogenesis are required. PMID:20186297

Altered social behavior and neuronal development in mice lacking the Uba6-Use1 ubiquitin transfer system

PubMed Central

Lee, Peter C. W.; Dodart, Jean-Cosme; Aron, Liviu; Finley, Lydia W.; Bronson, Roderick T.; Haigis, Marcia C.; Yankner, Bruce A.; Harper, J. Wade

2013-01-01

The Uba6 (E1)-Use1 (E2) ubiquitin transfer cascade is a poorly understood alternative arm of the ubiquitin proteasome system (UPS) required for mouse embryonic development, independent of the canonical Uba1-E2-E3 pathway. Loss of neuronal Uba6 during embryonic development results in altered patterning of neurons in the hippocampus and the amygdala, decreased dendritic spine density, and numerous behavioral disorders. The levels of the E3 ubiquitin ligase Ube3a (E6-AP) and Shank3, both linked with dendritic spine function, are elevated in the amygdala of Uba6-deficient mice, while levels of the Ube3a substrate Arc are reduced. Uba6 and Use1 promote proteasomal turnover of Ube3a in mouse embryo fibroblasts (MEFs) and catalyze Ube3a ubiquitylation in vitro. These activities occur in parallel with an independent pathway involving Uba1-UbcH7, but in a spatially distinct manner in MEFs. These data reveal an unanticipated role for Uba6 in neuronal development, spine architecture, mouse behavior, and turnover of Ube3a. PMID:23499007

Misexpression of BRE gene in the developing chick neural tube affects neurulation and somitogenesis

PubMed Central

Wang, Guang; Li, Yan; Wang, Xiao-Yu; Chuai, Manli; Yeuk-Hon Chan, John; Lei, Jian; Münsterberg, Andrea; Lee, Kenneth Ka Ho; Yang, Xuesong

2015-01-01

The brain and reproductive expression (BRE) gene is expressed in numerous adult tissues and especially in the nervous and reproductive systems. However, little is known about BRE expression in the developing embryo or about its role in embryonic development. In this study, we used in situ hybridization to reveal the spatiotemporal expression pattern for BRE in chick embryo during development. To determine the importance of BRE in neurogenesis, we overexpressed BRE and also silenced BRE expression specifically in the neural tube. We established that overexpressing BRE in the neural tube indirectly accelerated Pax7+ somite development and directly increased HNK-1+ neural crest cell (NCC) migration and TuJ-1+ neurite outgrowth. These altered morphogenetic processes were associated with changes in the cell cycle of NCCs and neural tube cells. The inverse effect was obtained when BRE expression was silenced in the neural tube. We also determined that BMP4 and Shh expression in the neural tube was affected by misexpression of BRE. This provides a possible mechanism for how altering BRE expression was able to affect somitogenesis, neurogenesis, and NCC migration. In summary, our results demonstrate that BRE plays an important role in regulating neurogenesis and indirectly somite differentiation during early chick embryo development. PMID:25568339

Csf2 null mutation alters placental gene expression and trophoblast glycogen cell and giant cell abundance in mice.

PubMed

Sferruzzi-Perri, Amanda N; Macpherson, Anne M; Roberts, Claire T; Robertson, Sarah A

2009-07-01

Genetic deficiency in granulocyte-macrophage colony-stimulating factor (CSF2, GM-CSF) results in altered placental structure in mice. To investigate the mechanism of action of CSF2 in placental morphogenesis, the placental gene expression and cell composition were examined in Csf2 null mutant and wild-type mice. Microarray and quantitative RT-PCR analyses on Embryonic Day (E) 13 placentae revealed that the Csf2 null mutation caused altered expression of 17 genes not previously known to be associated with placental development, including Mid1, Cd24a, Tnfrsf11b, and Wdfy1. Genes controlling trophoblast differentiation (Ascl2, Tcfeb, Itgav, and Socs3) were also differentially expressed. The CSF2 ligand and the CSF2 receptor alpha subunit were predominantly synthesized in the placental junctional zone. Altered placental structure in Csf2 null mice at E15 was characterized by an expanded junctional zone and by increased Cx31(+) glycogen cells and cyclin-dependent kinase inhibitor 1C (CDKN1C(+), P57(Kip2+)) giant cells, accompanied by elevated junctional zone transcription of genes controlling spongiotrophoblast and giant cell differentiation and secretory function (Ascl2, Hand1, Prl3d1, and Prl2c2). Granzyme genes implicated in tissue remodeling and potentially in trophoblast invasion (Gzmc, Gzme, and Gzmf) were downregulated in the junctional zone of Csf2 null mutant placentae. These data demonstrate aberrant placental gene expression in Csf2 null mutant mice that is associated with altered differentiation and/or functional maturation of junctional zone trophoblast lineages, glycogen cells, and giant cells. We conclude that CSF2 is a regulator of trophoblast differentiation and placental development, which potentially influences the functional capacity of the placenta to support optimal fetal growth in pregnancy.

Comparative proteomics as a tool for identifying specific alterations within interferon response pathways in human glioblastoma multiforme cells

PubMed Central

Lobas, Anna A; Solovyeva, Elizaveta M; Sidorenko, Alena S; Gorshkov, Vladimir; Kjeldsen, Frank; Bubis, Julia A; Ivanov, Mark V; Ilina, Irina Y; Moshkovskii, Sergei A; Chumakov, Peter M; Gorshkov, Mikhail V

2018-01-01

An acquisition of increased sensitivity of cancer cells to viruses is a common outcome of malignant progression that justifies the development of oncolytic viruses as anticancer therapeutics. Studying molecular changes that underlie the sensitivity to viruses would help to identify cases where oncolytic virus therapy would be most effective. We quantified changes in protein abundances in two glioblastoma multiforme (GBM) cell lines that differ in the ability to induce resistance to vesicular stomatitis virus (VSV) infection in response to type I interferon (IFN) treatment. In IFN-treated samples we observed an up-regulation of protein products of some IFN-regulated genes (IRGs). In total, the proteome analysis revealed up to 20% more proteins encoded by IRGs in the glioblastoma cell line, which develops resistance to VSV infection after pre-treatment with IFN. In both cell lines protein-protein interaction and signaling pathway analyses have revealed a significant stimulation of processes related to type I IFN signaling and defense responses to viruses. However, we observed a deficiency in STAT2 protein in the VSV-sensitive cell line that suggests a de-regulation of the JAK/STAT/IRF9 signaling. The study has shown that the up-regulation of IRG proteins induced by the IFNα treatment of GBM cells can be detected at the proteome level. Similar analyses could be applied for revealing functional alterations within the antiviral mechanisms in glioblastoma samples, accompanying by acquisition of sensitivity to oncolytic viruses. The approach can be useful for discovering the biomarkers that predict a potential sensitivity of individual glioblastoma tumors to oncolytic virus therapy. PMID:29416731

No pain, no gain: lack of exercise obstructs neurogenesis.

PubMed

Watson, Nate; Ji, Xunming; Yasuhara, Takao; Date, Isao; Kaneko, Yuji; Tajiri, Naoki; Borlongan, Cesar V

2015-01-01

Bedridden patients develop atrophied muscles, their daily activities greatly reduced, and some display a depressive mood. Patients who are able to receive physical rehabilitation sometimes show surprising clinical improvements, including reduced depression and attenuation of other stress-related behaviors. Regenerative medicine has advanced two major stem cell-based therapies for CNS disorders, namely, transplantation of exogenous stem cells and amplification of endogenous neurogenesis. The latter strategy embraces a natural way of reinnervating the damaged brain and correcting the neurological impairments. In this study, we discussed how immobilization-induced disuse atrophy, using the hindlimb suspension model, affects neurogenesis in rats. The overarching hypothesis is that immobilization suppresses neurogenesis by reducing the circulating growth or trophic factors, such as vascular endothelial growth factor or brain-derived neurotrophic factor. That immobilization alters neurogenesis and stem cell differentiation in the CNS requires characterization of the stem cell microenvironment by examining the trophic and growth factors, as well as stress-related proteins that have been implicated in exercise-induced neurogenesis. Although accumulating evidence has revealed the contribution of "increased" exercise on neurogenesis, the reverse paradigm involving "lack of exercise," which mimics pathological states (e.g., stroke patients are often immobile), remains underexplored. This novel paradigm will enable us to examine the effects on neurogenesis by a nonpermissive stem cell microenvironment likely produced by lack of exercise. BrdU labeling of proliferative cells, biochemical assays of serum, cerebrospinal fluid and brain levels of trophic factors, growth factors, and stress-related proteins are proposed as indices of neurogenesis, while quantitative measurements of spontaneous movements will reveal psychomotor components of immobilization. Studies designed to reveal how in vivo stimulation, or lack thereof, alters the stem cell microenvironment are needed to begin to develop treatment strategies for enhancing neurogenesis in bedridden patients.

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

Perkins, Timothy N.; Dentener, Mieke A.

Growth and development of the mature lung is a complex process orchestrated by a number of intricate developmental signaling pathways. Wingless-type MMTV-integration site (WNT) signaling plays critical roles in controlling branching morphogenesis cell differentiation, and formation of the conducting and respiratory airways. In addition, WNT pathways are often re-activated in mature lungs during repair and regeneration. WNT- signaling has been elucidated as a crucial contributor to the development of idiopathic pulmonary fibrosis as well as other hyper-proliferative lung diseases. Silicosis, a detrimental occupational lung disease caused by excessive inhalation of crystalline silica dust, is hallmarked by repeated cycles of damagingmore » inflammation, epithelial hyperplasia, and formation of dense, hyalinized nodules of whorled collagen. However, mechanisms of epithelial cell hyperplasia and matrix deposition are not well understood, as most research efforts have focused on the pronounced inflammatory response. Microarray data from our previous studies has revealed a number of WNT-signaling and WNT-target genes altered by crystalline silica in human lung epithelial cells. In the present study, we utilize pathway analysis to designate connections between genes altered by silica in WNT-signaling networks. Furthermore, we confirm microarray findings by QRT-PCR and demonstrate both activation of canonical (β-catenin) and down-regulation of non-canonical (WNT5A) signaling in immortalized (BEAS-2B) and primary (PBEC) human bronchial epithelial cells. These findings suggest that WNT-signaling and cross-talk with other pathways (e.g. Notch), may contribute to proliferative, fibrogenic and inflammatory responses to silica in lung epithelial cells. - Highlights: • Pathway analysis reveals silica-induced WNT-signaling in lung epithelial cells. • Silica-induced canonical WNT-signaling is mediated by autocrine/paracrine signals. • Crystalline silica decreases non-canonical WNT5A signaling. • Microarray reveals WNT as a novel complex signaling network in silica-mediated injury.« less

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

PubMed Central

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

2005-01-01

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

Oncogene-induced senescence results in marked metabolic and bioenergetic alterations

PubMed Central

Quijano, Celia; Cao, Liu; Fergusson, Maria M; Romero, Hector; Liu, Jie; Gutkind, Sarah; Rovira, Ilsa I; Mohney, Robert P; Karoly, Edward D

2012-01-01

Oncogene-induced senescence (OIS) is characterized by permanent growth arrest and the acquisition of a secretory, pro-inflammatory state. Increasingly, OIS is viewed as an important barrier to tumorgenesis. Surprisingly, relatively little is known about the metabolic changes that accompany and therefore may contribute to OIS. Here, we have performed a metabolomic and bioenergetic analysis of Ras-induced senescence. Profiling approximately 300 different intracellular metabolites reveals that cells that have undergone OIS develop a unique metabolic signature that differs markedly from cells undergoing replicative senescence. A number of lipid metabolites appear uniquely increased in OIS cells, including a marked increase in the level of certain intracellular long chain fatty acids. Functional studies reveal that this alteration in the metabolome reflects substantial changes in overall lipid metabolism. In particular, Ras-induced senescent cells manifest a decline in lipid synthesis and a significant increase in fatty acid oxidation. Increased fatty acid oxidation results in an unexpectedly high rate of basal oxygen consumption in cells that have undergone OIS. Pharmacological or genetic inhibition of carnitine palmitoyltransferase 1, the rate-limiting step in mitochondrial fatty acid oxidation, restores a presenescent metabolic rate and, surprisingly, selectively inhibits the secretory, pro-inflammatory state that accompanies OIS. Thus, Ras-induced senescent cells demonstrate profound alterations in their metabolic and bioenergetic profiles, particularly with regards to the levels, synthesis and oxidation of free fatty acids. Furthermore, the inflammatory phenotype that accompanies OIS appears to be related to these underlying changes in cellular metabolism. PMID:22421146

Methylphenidate and the Juvenile Brain: Enhancement of Attention at the Expense of Cortical Plasticity?

PubMed Central

Urban, Kimberly R.; Gao, Wen-Jun

2013-01-01

Methylphenidate (Ritalin) is the most commonly prescribed psychoactive drug for juveniles and adolescents. Used to treat attention-deficit/hyperactivity disorder (ADHD) and for cognitive enhancement in healthy individuals, it has been regarded as a relatively safe medication for the past several decades. However, a thorough review of the literature reveals that the age-dependent activities of the drug, as well as potential developmental effects, are largely ignored. In addition, the diagnosis of ADHD is subjective, leaving open the possibility of misdiagnosis and excessive prescription of the drug. Recent studies have suggested that early life exposure of healthy rodent models to methylphenidate resulted in altered sleep/wake cycle, heightened stress reactivity, and, in fact, a dosage previously thought of as therapeutic depressed neuronal function in juvenile rats. Furthermore, juvenile rats exposed to low-dose methylphenidate displayed alterations in neural markers of plasticity, indicating that the drug might alter the basic properties of prefrontal cortical circuits. In this review of the current literature, we propose that juvenile exposure to methylphenidate may cause abnormal prefrontal function and impaired plasticity in the healthy brain, strengthening the case for developing a more thorough understanding of methylphenidate’s actions on the developing, juvenile brain, as well as better diagnostic measures for ADHD. PMID:24095262

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

PubMed Central

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

2014-01-01

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

Alteration in Auxin Homeostasis and Signaling by Overexpression Of PINOID Kinase Causes Leaf Growth Defects in Arabidopsis thaliana

PubMed Central

Saini, Kumud; Markakis, Marios N.; Zdanio, Malgorzata; Balcerowicz, Daria M.; Beeckman, Tom; De Veylder, Lieven; Prinsen, Els; Beemster, Gerrit T. S.; Vissenberg, Kris

2017-01-01

In plants many developmental processes are regulated by auxin and its directional transport. PINOID (PID) kinase helps to regulate this transport by influencing polar recruitment of PIN efflux proteins on the cellular membranes. We investigated how altered auxin levels affect leaf growth in Arabidopsis thaliana. Arabidopsis mutants and transgenic plants with altered PID expression levels were used to study the effect on auxin distribution and leaf development. Single knockouts showed small pleiotropic growth defects. Contrastingly, several leaf phenotypes related to changes in auxin concentrations and transcriptional activity were observed in PID overexpression (PIDOE) lines. Unlike in the knockout lines, the leaves of PIDOE lines showed an elevation in total indole-3-acetic acid (IAA). Accordingly, enhanced DR5-visualized auxin responses were detected, especially along the leaf margins. Kinematic analysis revealed that ectopic expression of PID negatively affects cell proliferation and expansion rates, yielding reduced cell numbers and small-sized cells in the PIDOE leaves. We used PIDOE lines as a tool to study auxin dose effects on leaf development and demonstrate that auxin, above a certain threshold, has a negative affect on leaf growth. RNA sequencing further showed how subtle PIDOE-related changes in auxin levels lead to transcriptional reprogramming of cellular processes. PMID:28659952

Quantitative proteomic profiling of paired cancerous and normal colon epithelial cells isolated freshly from colorectal cancer patients.

PubMed

Tu, Chengjian; Mojica, Wilfrido; Straubinger, Robert M; Li, Jun; Shen, Shichen; Qu, Miao; Nie, Lei; Roberts, Rick; An, Bo; Qu, Jun

2017-05-01

The heterogeneous structure in tumor tissues from colorectal cancer (CRC) patients excludes an informative comparison between tumors and adjacent normal tissues. Here, we develop and apply a strategy to compare paired cancerous (CEC) versus normal (NEC) epithelial cells enriched from patients and discover potential biomarkers and therapeutic targets for CRC. CEC and NEC cells are respectively isolated from five different tumor and normal locations in the resected colon tissue from each patient (N = 12 patients) using an optimized epithelial cell adhesion molecule (EpCAM)-based enrichment approach. An ion current-based quantitative method is employed to perform comparative proteomic analysis for each patient. A total of 458 altered proteins that are common among >75% of patients are observed and selected for further investigation. Besides known findings such as deregulation of mitochondrial function, tricarboxylic acid cycle, and RNA post-transcriptional modification, functional analysis further revealed RAN signaling pathway, small nucleolar ribonucleoproteins (snoRNPs), and infection by RNA viruses are altered in CEC cells. A selection of the altered proteins of interest is validated by immunohistochemistry analyses. The informative comparison between matched CEC and NEC enhances our understanding of molecular mechanisms of CRC development and provides biomarker candidates and new pathways for therapeutic intervention. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Identification and suppression of the p-coumaroyl CoA:hydroxycinnamyl alcohol transferase in Zea mays L.

PubMed Central

Marita, Jane M; Hatfield, Ronald D; Rancour, David M; Frost, Kenneth E

2014-01-01

Grasses, such as Zea mays L. (maize), contain relatively high levels of p-coumarates (pCA) within their cell walls. Incorporation of pCA into cell walls is believed to be due to a hydroxycinnamyl transferase that couples pCA to monolignols. To understand the role of pCA in maize development, the p-coumaroyl CoA:hydroxycinnamyl alcohol transferase (pCAT) was isolated and purified from maize stems. Purified pCAT was subjected to partial trypsin digestion, and peptides were sequenced by tandem mass spectrometry. TBLASTN analysis of the acquired peptide sequences identified a single full-length maize cDNA clone encoding all the peptide sequences obtained from the purified enzyme. The cDNA clone was obtained and used to generate an RNAi construct for suppressing pCAT expression in maize. Here we describe the effects of suppression of pCAT in maize. Primary screening of transgenic maize seedling leaves using a new rapid analytical platform was used to identify plants with decreased amounts of pCA. Using this screening method, mature leaves from fully developed plants were analyzed, confirming reduced pCA levels throughout plant development. Complete analysis of isolated cell walls from mature transgenic stems and leaves revealed that lignin levels did not change, but pCA levels decreased and the lignin composition was altered. Transgenic plants with the lowest levels of pCA had decreased levels of syringyl units in the lignin. Thus, altering the levels of pCAT expression in maize leads to altered lignin composition, but does not appear to alter the total amount of lignin present in the cell walls. PMID:24654730

Identification and suppression of the p-coumaroyl CoA:hydroxycinnamyl alcohol transferase in Zea mays L.

PubMed

Marita, Jane M; Hatfield, Ronald D; Rancour, David M; Frost, Kenneth E

2014-06-01

Grasses, such as Zea mays L. (maize), contain relatively high levels of p-coumarates (pCA) within their cell walls. Incorporation of pCA into cell walls is believed to be due to a hydroxycinnamyl transferase that couples pCA to monolignols. To understand the role of pCA in maize development, the p-coumaroyl CoA:hydroxycinnamyl alcohol transferase (pCAT) was isolated and purified from maize stems. Purified pCAT was subjected to partial trypsin digestion, and peptides were sequenced by tandem mass spectrometry. TBLASTN analysis of the acquired peptide sequences identified a single full-length maize cDNA clone encoding all the peptide sequences obtained from the purified enzyme. The cDNA clone was obtained and used to generate an RNAi construct for suppressing pCAT expression in maize. Here we describe the effects of suppression of pCAT in maize. Primary screening of transgenic maize seedling leaves using a new rapid analytical platform was used to identify plants with decreased amounts of pCA. Using this screening method, mature leaves from fully developed plants were analyzed, confirming reduced pCA levels throughout plant development. Complete analysis of isolated cell walls from mature transgenic stems and leaves revealed that lignin levels did not change, but pCA levels decreased and the lignin composition was altered. Transgenic plants with the lowest levels of pCA had decreased levels of syringyl units in the lignin. Thus, altering the levels of pCAT expression in maize leads to altered lignin composition, but does not appear to alter the total amount of lignin present in the cell walls. © 2014 The Authors The Plant Journal © 2014 John Wiley & Sons Ltd.

Comparative study of cell alterations in oral lichen planus and epidermoid carcinoma of the mouth mucosa.

PubMed

Sousa, Fernando Augusto Cervantes Garcia de; Paradella, Thaís Cachuté; Brandão, Adriana Aigotti Haberbeck; Rosa, Luiz Eduardo Blumer

2009-01-01

Currently, much is discussed regarding the pre-malignant nature of mouth mucosa lichen planus. The present study aims at analyzing the alterations found in the epithelial cells present in the oral cavity lichen planus, comparing them to those found in epidermoid carcinoma. Histological cross-sections of oral lichen planus and epidermoid carcinoma, dyed by hematoxylineosin, were analyzed through light microscopy. The most frequently found alterations in oral lichen planus were: an increase in the nucleus/cytoplasm relation (93.33%), nucleus membrane thickness (86.67%) and bi-nucleus or multinucleous (86.67%). The Student t test (alpha=5%) revealed a statistically significant difference between the average number of cell alterations in oral lichen planus (5.87+/-1.57) and in epidermoid carcinoma (7.60+/-1.81). As to the types of alterations, the chi-squared test also revealed statistically significant differences among the lesions assessed in relation to the following cell alterations: nuclear excess chromatism, atypical mitoses, cellular pleomorphism and abnormal cell differentiation (p<0.05). Despite the fact that in some cases, some pathologists may make mistakes in the histopathological diagnosis of oral lichen planus, the results obtained in this study show that the alterations present in oral lichen planus differ considerably from those seen in epidermoid carcinoma, thus showing how distinct these two diseases are.

Lipidomics reveals dramatic lipid compositional changes in the maturing postnatal lung

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

Dautel, Sydney E.; Kyle, Jennifer E.; Clair, Geremy

Lung immaturity is a major cause of morbidity and mortality in premature infants. Understanding the molecular mechanisms driving normal lung development could provide insights on how to ameliorate disrupted development. While transcriptomic and proteomic analyses of normal lung development have been previously reported, characterization of changes in the lipidome is lacking. Lipids play significant roles in the lung, such as dipalmitoylcholine in pulmonary surfactant; however, many of the roles of specific lipid species in normal lung development, as well as in disease states, are not well defined. In this study, we used liquid chromatography-mass spectrometry (LC-MS/MS) to investigate the murinemore » lipidome during normal postnatal lung development. Lipidomics analysis of lungs from post-natal day 7, day 14 and 6-8 week mice (adult) identified 928 unique lipids across 21 lipid subclasses, with dramatic alterations in the lipidome across developmental stages. Our data confirmed previously recognized aspects of post-natal lung development and revealed several insights, including in sphingolipid-mediated apoptosis, inflammation and energy storage/usage. Complementary proteomics, metabolomics and chemical imaging corroborated these observations. Finally, this multi-omic view provides a unique resource and deeper insight into normal pulmonary development.« less

Lipidomics reveals dramatic lipid compositional changes in the maturing postnatal lung

DOE PAGES

Dautel, Sydney E.; Kyle, Jennifer E.; Clair, Geremy; ...

2017-02-01

Lung immaturity is a major cause of morbidity and mortality in premature infants. Understanding the molecular mechanisms driving normal lung development could provide insights on how to ameliorate disrupted development. While transcriptomic and proteomic analyses of normal lung development have been previously reported, characterization of changes in the lipidome is lacking. Lipids play significant roles in the lung, such as dipalmitoylcholine in pulmonary surfactant; however, many of the roles of specific lipid species in normal lung development, as well as in disease states, are not well defined. In this study, we used liquid chromatography-mass spectrometry (LC-MS/MS) to investigate the murinemore » lipidome during normal postnatal lung development. Lipidomics analysis of lungs from post-natal day 7, day 14 and 6-8 week mice (adult) identified 928 unique lipids across 21 lipid subclasses, with dramatic alterations in the lipidome across developmental stages. Our data confirmed previously recognized aspects of post-natal lung development and revealed several insights, including in sphingolipid-mediated apoptosis, inflammation and energy storage/usage. Complementary proteomics, metabolomics and chemical imaging corroborated these observations. Finally, this multi-omic view provides a unique resource and deeper insight into normal pulmonary development.« less

Expression of SMARCB1 (INI1) mutations in familial schwannomatosis

PubMed Central

Smith, Miriam J.; Walker, James A.; Shen, Yiping; Stemmer-Rachamimov, Anat; Gusella, James F.; Plotkin, Scott R.

2012-01-01

Genetic changes in the SMARCB1 tumor suppressor gene have recently been reported in tumors and blood from families with schwannomatosis. Exon scanning of all nine SMARCB1 exons in genomic DNA from our cohort of families meeting the criteria for ‘definite’ or ‘presumptive’ schwannomatosis previously revealed constitutional alterations in 13 of 19 families (68%). Screening of four new familial schwannomatosis probands identified one additional constitutional alteration. We confirmed the presence of mRNA transcripts for two missense alterations, four mutations of conserved splice motifs and two additional mutations, in less conserved sequences, which also affect splicing. Furthermore, we found that transcripts for a rare 3′-untranslated region (c.*82C > T) alteration shared by four unrelated families did not produce splice variants but did show unequal allelic expression, suggesting that the alteration is either causative itself or linked to an unidentified causative mutation. Overexpression studies in cells lacking SMARCB1 suggest that mutant SMARCB1 proteins, like wild-type SMARCB1 protein, retain the ability to suppress cyclin D1 activity. These data, together with the expression of SMARCB1 protein in a proportion of cells from schwannomatosis-related schwannomas, suggest that these tumors develop through a mechanism that is distinct from that of rhabdoid tumors in which SMARCB1 protein is completely absent in tumor cells. PMID:22949514

Zebrafish Bone and General Physiology Are Differently Affected by Hormones or Changes in Gravity.

PubMed

Aceto, Jessica; Nourizadeh-Lillabadi, Rasoul; Marée, Raphael; Dardenne, Nadia; Jeanray, Nathalie; Wehenkel, Louis; Aleström, Peter; van Loon, Jack J W A; Muller, Marc

2015-01-01

Teleost fish such as zebrafish (Danio rerio) are increasingly used for physiological, genetic and developmental studies. Our understanding of the physiological consequences of altered gravity in an entire organism is still incomplete. We used altered gravity and drug treatment experiments to evaluate their effects specifically on bone formation and more generally on whole genome gene expression. By combining morphometric tools with an objective scoring system for the state of development for each element in the head skeleton and specific gene expression analysis, we confirmed and characterized in detail the decrease or increase of bone formation caused by a 5 day treatment (from 5dpf to 10 dpf) of, respectively parathyroid hormone (PTH) or vitamin D3 (VitD3). Microarray transcriptome analysis after 24 hours treatment reveals a general effect on physiology upon VitD3 treatment, while PTH causes more specifically developmental effects. Hypergravity (3g from 5dpf to 9 dpf) exposure results in a significantly larger head and a significant increase in bone formation for a subset of the cranial bones. Gene expression analysis after 24 hrs at 3g revealed differential expression of genes involved in the development and function of the skeletal, muscular, nervous, endocrine and cardiovascular systems. Finally, we propose a novel type of experimental approach, the "Reduced Gravity Paradigm", by keeping the developing larvae at 3g hypergravity for the first 5 days before returning them to 1g for one additional day. 5 days exposure to 3g during these early stages also caused increased bone formation, while gene expression analysis revealed a central network of regulatory genes (hes5, sox10, lgals3bp, egr1, edn1, fos, fosb, klf2, gadd45ba and socs3a) whose expression was consistently affected by the transition from hyper- to normal gravity.

Zebrafish Bone and General Physiology Are Differently Affected by Hormones or Changes in Gravity

PubMed Central

Aceto, Jessica; Nourizadeh-Lillabadi, Rasoul; Marée, Raphael; Dardenne, Nadia; Jeanray, Nathalie; Wehenkel, Louis; Aleström, Peter

2015-01-01

Teleost fish such as zebrafish (Danio rerio) are increasingly used for physiological, genetic and developmental studies. Our understanding of the physiological consequences of altered gravity in an entire organism is still incomplete. We used altered gravity and drug treatment experiments to evaluate their effects specifically on bone formation and more generally on whole genome gene expression. By combining morphometric tools with an objective scoring system for the state of development for each element in the head skeleton and specific gene expression analysis, we confirmed and characterized in detail the decrease or increase of bone formation caused by a 5 day treatment (from 5dpf to 10 dpf) of, respectively parathyroid hormone (PTH) or vitamin D3 (VitD3). Microarray transcriptome analysis after 24 hours treatment reveals a general effect on physiology upon VitD3 treatment, while PTH causes more specifically developmental effects. Hypergravity (3g from 5dpf to 9 dpf) exposure results in a significantly larger head and a significant increase in bone formation for a subset of the cranial bones. Gene expression analysis after 24 hrs at 3g revealed differential expression of genes involved in the development and function of the skeletal, muscular, nervous, endocrine and cardiovascular systems. Finally, we propose a novel type of experimental approach, the "Reduced Gravity Paradigm", by keeping the developing larvae at 3g hypergravity for the first 5 days before returning them to 1g for one additional day. 5 days exposure to 3g during these early stages also caused increased bone formation, while gene expression analysis revealed a central network of regulatory genes (hes5, sox10, lgals3bp, egr1, edn1, fos, fosb, klf2, gadd45ba and socs3a) whose expression was consistently affected by the transition from hyper- to normal gravity. PMID:26061167

Rapid Postnatal Expansion of Neural Networks Occurs in an Environment of Altered Neurovascular and Neurometabolic Coupling.

PubMed

Kozberg, Mariel G; Ma, Ying; Shaik, Mohammed A; Kim, Sharon H; Hillman, Elizabeth M C

2016-06-22

In the adult brain, increases in neural activity lead to increases in local blood flow. However, many prior measurements of functional hemodynamics in the neonatal brain, including functional magnetic resonance imaging (fMRI) in human infants, have noted altered and even inverted hemodynamic responses to stimuli. Here, we demonstrate that localized neural activity in early postnatal mice does not evoke blood flow increases as in the adult brain, and elucidate the neural and metabolic correlates of these altered functional hemodynamics as a function of developmental age. Using wide-field GCaMP imaging, the development of neural responses to somatosensory stimulus is visualized over the entire bilaterally exposed cortex. Neural responses are observed to progress from tightly localized, unilateral maps to bilateral responses as interhemispheric connectivity becomes established. Simultaneous hemodynamic imaging confirms that spatiotemporally coupled functional hyperemia is not present during these early stages of postnatal brain development, and develops gradually as cortical connectivity is established. Exploring the consequences of this lack of functional hyperemia, measurements of oxidative metabolism via flavoprotein fluorescence suggest that neural activity depletes local oxygen to below baseline levels at early developmental stages. Analysis of hemoglobin oxygenation dynamics at the same age confirms oxygen depletion for both stimulus-evoked and resting-state neural activity. This state of unmet metabolic demand during neural network development poses new questions about the mechanisms of neurovascular development and its role in both normal and abnormal brain development. These results also provide important insights for the interpretation of fMRI studies of the developing brain. This work demonstrates that the postnatal development of neuronal connectivity is accompanied by development of the mechanisms that regulate local blood flow in response to neural activity. Novel in vivo imaging reveals that, in the developing mouse brain, strong and localized GCaMP neural responses to stimulus fail to evoke local blood flow increases, leading to a state in which oxygen levels become locally depleted. These results demonstrate that the development of cortical connectivity occurs in an environment of altered energy availability that itself may play a role in shaping normal brain development. These findings have important implications for understanding the pathophysiology of abnormal developmental trajectories, and for the interpretation of functional magnetic resonance imaging data acquired in the developing brain. Copyright © 2016 the authors 0270-6474/16/366704-14$15.00/0.

Inhibition of RAS activation due to a homozygous ezrin variant in patients with profound intellectual disability.

PubMed

Riecken, Lars Björn; Tawamie, Hasan; Dornblut, Carsten; Buchert, Rebecca; Ismayel, Amina; Schulz, Alexander; Schumacher, Johannes; Sticht, Heinrich; Pohl, Katja J; Cui, Yan; Reis, André; Morrison, Helen; Abou Jamra, Rami

2015-02-01

Gain-of-function alterations in several components and modulators of the Ras-MAPK pathway lead to dysregulation of the pathway and cause a broad spectrum of autosomal dominant developmental disorders, collectively known as RASopathies. These findings demonstrate the importance of tight multilevel Ras regulation to safeguard signaling output and prevent aberrant activity. We have recently identified ezrin as a novel regulatory element required for Ras activation. Homozygosity mapping and exome sequencing have now revealed the first presumably disease-causing variant in the coding gene EZR in two siblings with a profound intellectual disability. Localization and membrane targeting of the altered ezrin protein appeared normal but molecular modeling suggested protein interaction surfaces to be disturbed. Functional analysis revealed that the altered ezrin protein is no longer able to bind Ras and facilitate its activation. Furthermore, expression of the altered ezrin protein in different cell lines resulted in abnormal cellular processes, including reduced proliferation and neuritogenesis, thus revealing a possible mechanism for its phenotype in humans. To our knowledge, this is the first report of an autosomal recessively inherited loss-of-function mutation causing reduced Ras activity and thus extends and complements the pathogenicity spectrum of known Ras-MAPK pathway disturbances. © 2014 WILEY PERIODICALS, INC.

Oncogenic signalling pathways in benign odontogenic cysts and tumours.

PubMed

Diniz, Marina Gonçalves; Gomes, Carolina Cavalieri; de Sousa, Sílvia Ferreira; Xavier, Guilherme Machado; Gomez, Ricardo Santiago

2017-09-01

The first step towards the prevention of cancer is to develop an in-depth understanding of tumourigenesis and the molecular basis of malignant transformation. What drives tumour initiation? Why do most benign tumours fail to metastasize? Oncogenic mutations, previously considered to be the hallmark drivers of cancers, are reported in benign cysts and tumours, including those that have an odontogenic origin. Despite the presence of such alterations, the vast majority of odontogenic lesions are benign and never progress to the stage of malignant transformation. As these lesions are likely to develop due to developmental defects, it is possible that they harbour quiet genomes. Now the question arises - do they result from DNA replication errors? Specific candidate genes have been sequenced in odontogenic lesions, revealing recurrent BRAF mutation in the case of ameloblastoma, KRAS mutation in adenomatoid odontogenic tumours, PTCH1 mutation in odontogenic keratocysts, and CTNNB1 (Beta-catenin) mutation in calcifying odontogenic cysts. Studies on these benign and rare entities might reveal important information about the tumorigenic process and the mechanisms that hinder/halt neoplastic progression. This is because the role of relatively common oncogenic mutations seems to be context dependent. In this review, each mutation signature of the odontogenic lesion and the affected signalling pathways are discussed in the context of tooth development and tumorigenesis. Furthermore, behavioural differences between different types of odontogenic lesions are explored and discussed based on the molecular alteration described. This review also includes the employment of molecular results for guiding therapeutic approaches towards odontogenic lesions. Copyright © 2017 Elsevier Ltd. All rights reserved.

ENPP1 Mutation Causes Recessive Cole Disease by Altering Melanogenesis.

PubMed

Chourabi, Marwa; Liew, Mei Shan; Lim, Shawn; H'mida-Ben Brahim, Dorra; Boussofara, Lobna; Dai, Liang; Wong, Pui Mun; Foo, Jia Nee; Sriha, Badreddine; Robinson, Kim Samirah; Denil, Simon; Common, John Ea; Mamaï, Ons; Ben Khalifa, Youcef; Bollen, Mathieu; Liu, Jianjun; Denguezli, Mohamed; Bonnard, Carine; Saad, Ali; Reversade, Bruno

2018-02-01

Cole disease is a genodermatosis of pigmentation following a strict dominant mode of inheritance. In this study, we investigated eight patients affected with an overlapping genodermatosis after recessive inheritance. The patients presented with hypo- and hyperpigmented macules over the body, resembling dyschromatosis universalis hereditaria in addition to punctuate palmoplantar keratosis. By homozygosity mapping and whole-exome sequencing, a biallelic p.Cys120Arg mutation in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was identified in all patients. We found that this mutation, like those causing dominant Cole disease, impairs homodimerization of the ENPP1 enzyme that is mediated by its two somatomedin-B-like domains. Histological analysis revealed structural and molecular changes in affected skin that were likely to originate from defective melanocytes because keratinocytes do not express ENPP1. Consistently, RNA-sequencing analysis of patient-derived primary melanocytes revealed alterations in melanocyte development and in pigmentation signaling pathways. We therefore conclude that germline ENPP1 cysteine-specific mutations, primarily affecting the melanocyte lineage, cause a clinical spectrum of dyschromatosis, in which the p.Cys120Arg allele represents a recessive and more severe form of Cole disease. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Significance of 5,10-methylenetetrahydrofolate reductase gene variants in acute lymphoblastic leukemia in Indian population: an experimental, computational and meta-analysis.

PubMed

Bellampalli, Ravishankara; Phani, Nagaraja M; Bhat, Kamalakshi G; Prasad, Krishna; Bhaskaranand, Nalini; Guruprasad, Kanive P; Rai, Padmalatha S; Satyamoorthy, Kapaettu

2015-05-01

Acute lymphoblastic leukemia (ALL) arises due to several genetic alterations in progenitor cells, and methotrexate is frequently used as part of the treatment regimen. Although there is evidence for an effect of 5,10-methylenetetrahydrofolate reductase gene (MTHFR) C677T and A1298C variations on drug response in ALL, its risk association for ALL is still unresolved. In a case-control study of 203 patients with ALL and 246 controls and meta-analysis in the Indian population, we showed an insignificant association of MTHFR C677T and A1298C genotypes with childhood and adult ALL. Comprehensive in silico characterization of non-synonymous single nucleotide polymorphisms (nsSNPs) and SNPs of the 3' untranslated region (UTR) revealed nine nsSNPs as deleterious, and three SNPs in the 3'UTR could possibly alter the binding of miRNAs. The study revealed that several overlooked SNPs may contribute to the risk of ALL susceptibility and further studies of these SNPs with functional characterization in a large sample size are required to understand the significant role of MTHFR in ALL development.

Aberrant functioning of the theory-of-mind network in children and adolescents with autism.

PubMed

Kana, Rajesh K; Maximo, Jose O; Williams, Diane L; Keller, Timothy A; Schipul, Sarah E; Cherkassky, Vladimir L; Minshew, Nancy J; Just, Marcel Adam

2015-01-01

Theory-of-mind (ToM), the ability to infer people's thoughts and feelings, is a pivotal skill in effective social interactions. Individuals with autism spectrum disorders (ASD) have been found to have altered ToM skills, which significantly impacts the quality of their social interactions. Neuroimaging studies have reported altered activation of the ToM cortical network, especially in adults with autism, yet little is known about the brain responses underlying ToM in younger individuals with ASD. This functional magnetic resonance imaging (fMRI) study investigated the neural mechanisms underlying ToM in high-functioning children and adolescents with ASD and matched typically developing (TD) peers. fMRI data were acquired from 13 participants with ASD and 13 TD control participants while they watched animations involving two "interacting" geometrical shapes. Participants with ASD showed significantly reduced activation, relative to TD controls, in regions considered part of the ToM network, the mirror network, and the cerebellum. Functional connectivity analyses revealed underconnectivity between frontal and posterior regions during task performance in the ASD participants. Overall, the findings of this study reveal disruptions in the brain circuitry underlying ToM in ASD at multiple levels, including decreased activation and decreased functional connectivity.

[Mycoplasma pneumoniae meningoencephalitis].

PubMed

Cambonie, G; Sarran, N; Leboucq, N; Luc, F; Bongrand, A F; Slim, G; Lassus, P; Fournier-Favre, S; Montoya, F; Astruc, J; Rieu, D

1999-03-01

Severe central nervous system diseases, such as encephalitis, have been reported in association with Mycoplasma pneumoniae infections. After an ENT infection, a 9-year-old boy with Down's syndrome developed encephalitis revealed by an acute alteration in consciousness. Head computed tomography showed, after 2 weeks, an infiltration in the basal ganglia region. The diagnosis of Mycoplasma pneumoniae encephalitis was made; recovery was complete in a few weeks. Mycoplasma pneumoniae infection should be considered in all cases of acute encephalopathy; yet the pathogenesis of the disorder is unknown and the treatment uncertain.

What Hayabusa2 Will Find at Asteroid Ryugu, and What It Will Reveal About the Source of Earth's Water

NASA Technical Reports Server (NTRS)

Zolensky, Michael; Martinez, James E.

2017-01-01

Water-rich carbonaceous chondrites contain evidence of aqueous alteration in the early solar system. To see this one must look carefully at the meteorites, and see past the later alteration which has generally obscured mineral textures. We suggest that these materials will dominate, be detectable, and be sampled on the surfaces of C-class asteroids, initially by the Hayabusa2 spacecraft. Thus, hydrous samples returned by this mission will help to reveal the source of water on earth.

Metabolomic analysis reveals altered metabolic pathways in a rat model of gastric carcinogenesis.

PubMed

Gu, Jinping; Hu, Xiaomin; Shao, Wei; Ji, Tianhai; Yang, Wensheng; Zhuo, Huiqin; Jin, Zeyu; Huang, Huiying; Chen, Jiacheng; Huang, Caihua; Lin, Donghai

2016-09-13

Gastric cancer (GC) is one of the most malignant tumors with a poor prognosis. Alterations in metabolic pathways are inextricably linked to GC progression. However, the underlying molecular mechanisms remain elusive. We performed NMR-based metabolomic analysis of sera derived from a rat model of gastric carcinogenesis, revealed significantly altered metabolic pathways correlated with the progression of gastric carcinogenesis. Rats were histologically classified into four pathological groups (gastritis, GS; low-grade gastric dysplasia, LGD; high-grade gastric dysplasia, HGD; GC) and the normal control group (CON). The metabolic profiles of the five groups were clearly distinguished from each other. Furthermore, significant inter-metabolite correlations were extracted and used to reconstruct perturbed metabolic networks associated with the four pathological stages compared with the normal stage. Then, significantly altered metabolic pathways were identified by pathway analysis. Our results showed that oxidative stress-related metabolic pathways, choline phosphorylation and fatty acid degradation were continually disturbed during gastric carcinogenesis. Moreover, amino acid metabolism was perturbed dramatically in gastric dysplasia and GC. The GC stage showed more changed metabolite levels and more altered metabolic pathways. Two activated pathways (glycolysis; glycine, serine and threonine metabolism) substantially contributed to the metabolic alterations in GC. These results lay the basis for addressing the molecular mechanisms underlying gastric carcinogenesis and extend our understanding of GC progression.

Modulation of invasive phenotype by interstitial pressure-driven convection in aggregates of human breast cancer cells.

PubMed

Tien, Joe; Truslow, James G; Nelson, Celeste M

2012-01-01

This paper reports the effect of elevated pressure on the invasive phenotype of patterned three-dimensional (3D) aggregates of MDA-MB-231 human breast cancer cells. We found that the directionality of the interstitial pressure profile altered the frequency of invasion by cells located at the surface of an aggregate. In particular, application of pressure at one end of an aggregate suppressed invasion at the opposite end. Experimental alteration of the configuration of cell aggregates and computational modeling of the resulting flow and solute concentration profiles revealed that elevated pressure inhibited invasion by altering the chemical composition of the interstitial fluid near the surface of the aggregate. Our data reveal a link between hydrostatic pressure, interstitial convection, and invasion.

Alterations of 3p21.31 tumor suppressor genes in head and neck squamous cell carcinoma: Correlation with progression and prognosis.

PubMed

Ghosh, Susmita; Ghosh, Amlan; Maiti, Guru Prasad; Alam, Neyaz; Roy, Anup; Roy, Bidyut; Roychoudhury, Susanta; Panda, Chinmay Kumar

2008-12-01

The aim of our study was to analyze the alterations of some candidate tumor suppressor genes (TSGs) viz. LIMD1, LTF, CDC25A, SCOTIN, RASSF1A and CACNA2D2 located in the chromosomal region 3p21.31 associated with the development of early dysplastic lesions of head and neck. In analysis of 72 dysplastic lesions and 116 squamous cell carcinoma of head and neck, both deletion and promoter methylation have been seen in these genes except for CDC25A and SCOTIN where no methylation has been detected. The alteration of LIMD1 was highest (50%) in the mild dysplastic lesions and did not change significantly during progression of tumor indicating its association with this stage of the disease. It was evident that alterations of LTF, CDC25A and CACNA2D2 were associated with development of moderate dysplastic lesions, while alterations in RASSF1A and CACNA2D2 were needed for progression. Novel somatic mutations were seen in exon 1 of LIMD1 (7%), intron 3/exon4 splice junction of LTF (2%) and exon 7 of cdc25A (10%). Quantitative RT-PCR analysis revealed mean reduced expression of the genes in the following order: LTF (67.6 +/- 16.8) > LIMD1 (53.2 +/- 20.1) > CACNA2D2 (23.7 +/- 7.1) > RASSF1A (15.1 +/- 5.6) > CDC25A (5.3 +/- 2.3) > SCOTIN (0.58 +/- 0.54). Immunohistochemical analysis of CDC25A showed its localization both in cytoplasm and nucleus in primary lesions and oral cancer cell lines. In absence of HPV infection, LTF and RASSF1A alterations jointly have adverse impact on survival of tobacco addicted patients. Thus, our data suggested that multiple candidate TSGs in the chromosomal 3p21.31 region were differentially associated with the early dysplastic lesions of head and neck. (c) 2008 Wiley-Liss, Inc.

Increased levels of N(ε)- Carboxy methyl lysine (N(ε)-CML) are associated with topographic alterations in retinal pigment epithelium: A preliminary study.

PubMed

Mishra, Nibha; Saxena, Sandeep; Ruia, Surabhi; Prasad, Senthamizh; Singh, Vinita; Khanna, Vinay; Staffa, Robert; Gaspar, Ludovit; Kruzliak, Peter

2016-07-01

To evaluate the association of serum levels of N(ε)- Carboxy methyl lysine (N(ε)-CML), an advanced glycation end product with topographic alterations in retinal pigment epithelium (RPE) in diabetic retinopathy on spectral domain optical coherence tomography (SD-OCT). Consecutive cases of type 2 diabetes mellitus with no retinopathy (n=20); non-proliferative diabetic retinopathy (n=20); proliferative diabetic retinopathy (n=20) and healthy controls (n=20) between the ages of 40 and 65years were included. RPE alterations were graded on segmentation map of SD-OCT: grade 0, No RPE alterations; grade 1, RPE alterations in up to two quadrants and grade 2, RPE alterations in more than two quadrants. Serum level of N(ε)-CML and glycated hemoglobin (HbA1c) was analyzed using the standard protocol. Statistical analysis was done. Significant increase in N(ε)-CML was observed with increased severity of diabetic retinopathy (F=34.1; p<0.0001). Fisher exact test revealed significant increase in grades of RPE alterations with increased severity of diabetic retinopathy (p<0.001). Univariate ordinal regression analysis was done to calculate the risk of progression in grades of RPE alteration with individual changes in variables like duration of diabetes (odds ratio=1.37; p=0.001), HbA1c (odds ratio=1.37; p=0.002) and Nε-CML (odds ratio=1.37; p<0.0001). Multivariate ordinal regression analysis for predicting progression in grades of RPE alteration revealed Nε-CML to be an independent predictor of increase in grades of RPE alteration (adjusted odds ratio=1.07; p<0.01) when duration of diabetes and HbA1c were held constant. Increase in serum levels of N(ε)- Carboxy methyl lysine is significantly associated with topographic alterations in RPE. Grades of RPE alteration increase significantly with increased severity of diabetic retinopathy. Copyright © 2016 Elsevier Inc. All rights reserved.

Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation

PubMed Central

Rihel, Jason; Prober, David A.; Arvanites, Anthony; Lam, Kelvin; Zimmerman, Steven; Jang, Sumin; Haggarty, Stephen J.; Kokel, David; Rubin, Lee L.; Peterson, Randall T.; Schier, Alexander F.

2010-01-01

A major obstacle for the discovery of psychoactive drugs is the inability to predict how small molecules will alter complex behaviors. We report the development and application of a high-throughput, quantitative screen for drugs that alter the behavior of larval zebrafish. We found that the multi-dimensional nature of observed phenotypes enabled the hierarchical clustering of molecules according to shared behaviors. Behavioral profiling revealed conserved functions of psychotropic molecules and predicted the mechanisms of action of poorly characterized compounds. In addition, behavioral profiling implicated new factors such as ether-a-go-go-related gene (ERG) potassium channels and immunomodulators in the control of rest and locomotor activity. These results demonstrate the power of high-throughput behavioral profiling in zebrafish to discover and characterize psychotropic drugs and to dissect the pharmacology of complex behaviors. PMID:20075256

Mapping the CgrA regulon of Rhodospirillum centenum reveals a hierarchal network controlling Gram-negative cyst development.

PubMed

Dong, Qian; Fang, Mingxu; Roychowdhury, Sugata; Bauer, Carl E

2015-12-16

Several Gram-negative species undergo development leading to the formation of metabolically dormant desiccation resistant cysts. Recent analysis of cyst development has revealed that ~20 % of the Rhodospirillum centenum transcriptome undergo temporal changes in expression as cells transition from vegetative to cyst forms. It has also been established that one trigger for cyst formation is the synthesis of the signaling nucleotide 3', 5'- cyclic guanosine monophosphate (cGMP) that is sensed by a homolog of the catabolite repressor protein called CgrA. CgrA in the presence of cGMP initiate a cascade of gene expression leading to the development of cysts. In this study, we have used RNA-seq and chromatin immunoprecipitation (ChIP-Seq) techniques to define the CgrA-cGMP regulon. Our results indicate that disruption of CgrA leads to altered expression of 258 genes, 131 of which have been previously reported to be involved in cyst development. ChIP-seq analysis combined with transcriptome data also demonstrates that CgrA directly regulates the expression of numerous sigma factors and transcription factors several of which are known to be involved in cyst cell development. This analysis reveals the presence of CgrA binding sites upstream of many developmentally regulated genes including many transcription factors and signal transduction components. CgrA thus functions as master controller of the cyst development by initiating a hierarchal cascade of downstream transcription factors that induces temporal expression of encystment genes.

Altering carbon allocation in hybrid poplar ( Populus alba × grandidentata ) impacts cell wall growth and development

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

Unda, Faride; Kim, Hoon; Hefer, Charles

Galactinol synthase is a pivotal enzyme involved in the synthesis of the raffinose family of oligosaccharides (RFOs) that function as transport carbohydrates in the phloem, as storage compounds in sink tissues and as soluble metabolites that combat both abiotic and biotic stress in several plant species. For hybrid poplar (Populus alba 9 grandidentata) overexpressing the Arabidopsis thaliana GolS3 (AtGolS3) gene showed clear effects on development; the extreme overexpressing lines were stunted and had cell wall traits characteristic of tension wood, whereas lines with only moderate up-regulation grew normally and had moderately altered secondary cell wall composition and ultrastructure. Stem cross-sectionsmore » of the developing xylem revealed a significant increase in the number of vessels, as well as the clear presence of a G-layer in the fibres. Furthermore, AtGolS3-OE lines possessed higher cellulose and lower lignin contents, an increase in cellulose crystallinity, and significantly altered hemicellulose-derived carbohydrates, notably manifested by their mannose and xylose contents. Additionally, the transgenic plants displayed elevated xylem starch content. Transcriptome interrogation of the transgenic plants showed a significant up-regulation of genes involved in the synthesis of myo-inositol, along with genes involved in sucrose degradation. Our results suggest that the over expression of GolS and its product galactinol may serve as a molecular signal that initiates metabolic changes, culminating in a change in cell wall development and potentially the formation of tension wood.« less

Altering carbon allocation in hybrid poplar ( Populus alba × grandidentata ) impacts cell wall growth and development

DOE PAGES

Unda, Faride; Kim, Hoon; Hefer, Charles; ...

2017-03-04

Galactinol synthase is a pivotal enzyme involved in the synthesis of the raffinose family of oligosaccharides (RFOs) that function as transport carbohydrates in the phloem, as storage compounds in sink tissues and as soluble metabolites that combat both abiotic and biotic stress in several plant species. For hybrid poplar (Populus alba 9 grandidentata) overexpressing the Arabidopsis thaliana GolS3 (AtGolS3) gene showed clear effects on development; the extreme overexpressing lines were stunted and had cell wall traits characteristic of tension wood, whereas lines with only moderate up-regulation grew normally and had moderately altered secondary cell wall composition and ultrastructure. Stem cross-sectionsmore » of the developing xylem revealed a significant increase in the number of vessels, as well as the clear presence of a G-layer in the fibres. Furthermore, AtGolS3-OE lines possessed higher cellulose and lower lignin contents, an increase in cellulose crystallinity, and significantly altered hemicellulose-derived carbohydrates, notably manifested by their mannose and xylose contents. Additionally, the transgenic plants displayed elevated xylem starch content. Transcriptome interrogation of the transgenic plants showed a significant up-regulation of genes involved in the synthesis of myo-inositol, along with genes involved in sucrose degradation. Our results suggest that the over expression of GolS and its product galactinol may serve as a molecular signal that initiates metabolic changes, culminating in a change in cell wall development and potentially the formation of tension wood.« less

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

PubMed

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

2014-04-01

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

Chronic In Vivo Load Alteration Induces Degenerative Changes in the Rat Tibiofemoral Joint

PubMed Central

Roemhildt, M. L.; Beynnon, B. D.; Gauthier, A. E.; Gardner-Morse, M.; Ertem, F.; Badger, G. J.

2012-01-01

Objective We investigated the relationship between the magnitude and duration of sustained compressive load alteration and the development of degenerative changes in the rat tibiofemoral joint. Methods A varus loading device was attached to the left hind limb of mature rats to apply increased compression to the medial compartment and decreased compression to the lateral compartment of the tibiofemoral joint of either 0% or 100% body weight for 0, 6 or 20 weeks. Compartment-specific assessment of the tibial plateaus included biomechanical measures (articular cartilage aggregate modulus, permeability and Poisson’s ratio, and subchondral bone modulus) and histological assessments (articular cartilage, calcified cartilage, and subchondral bone thicknesses, degenerative scoring parameters, and articular cartilage cellularity). Results Increased compression in the medial compartment produced significant degenerative changes consistent with the development of osteoarthritis including a progressive decrease in cartilage aggregate modulus (43% and 77% at 6 and 20 weeks), diminished cellularity (38% and 51% at 6 and 20 weeks), and increased histological degeneration. At 20 weeks, medial compartment articular cartilage thickness deceased 30% while subchondral bone thickness increased 32% and subchondral bone modulus increased 99%. Decreased compression in the lateral compartment increased calcified cartilage thickness, diminished region-specific subchondral bone thickness and revealed trends for reduced cellularity and decreased articular cartilage thickness at 20 weeks. Conclusions Altered chronic joint loading produced degenerative changes consistent with those observed clinically with the development of osteoarthritis and may replicate the slow development of non-traumatic osteoarthritis in which mechanical loads play a primary etiological role. PMID:23123358

Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory

PubMed Central

Okuda, Kosuke; Takao, Keizo; Watanabe, Aya; Miyakawa, Tsuyoshi; Mizuguchi, Masashi

2018-01-01

Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 -/Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the specific mechanisms of these deficits in the CDKL5 deficiency disorder. PMID:29702698

Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory.

PubMed

Okuda, Kosuke; Takao, Keizo; Watanabe, Aya; Miyakawa, Tsuyoshi; Mizuguchi, Masashi; Tanaka, Teruyuki

2018-01-01

Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 -/Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the specific mechanisms of these deficits in the CDKL5 deficiency disorder.

Application of a quantitative histological health index for Antarctic rock cod (Trematomus bernacchii) from Davis Station, East Antarctica.

PubMed

Corbett, Patricia A; King, Catherine K; Mondon, Julie A

2015-08-01

A quantitative Histological Health Index (HHI) was applied to Antarctic rock cod (Trematomus bernacchii) using gill, liver, spleen, kidney and gonad to assess the impact of wastewater effluent from Davis Station, East Antarctica. A total of 120 fish were collected from 6 sites in the Prydz Bay region of East Antarctica at varying distances from the wastewater outfall. The HHI revealed a greater severity of alteration in fish at the wastewater outfall, which decreased stepwise with distance. Gill and liver displayed the greatest severity of alteration in fish occurring in close proximity to the wastewater outfall, showing severe and pronounced alteration respectively. Findings of the HHI add to a growing weight of evidence indicating that the current level of wastewater treatment at Davis Station is insufficient to prevent impact to the surrounding environment. The HHI for T. bernacchii developed in this study is recommended as a useful risk assessment tool for assessing in situ, sub-lethal impacts from station-derived contamination in coastal regions throughout Antarctica. Copyright © 2015 Elsevier Ltd. All rights reserved.

Adaptations of the vestibular system to short and long-term exposures to altered gravity

NASA Astrophysics Data System (ADS)

Bruce, L. L.

2003-10-01

Long-term space flight creates unique environmental conditions to which the vestibular system must adapt for optimal survival of a given organism. The development and maintenance of vestibular connections are controlled by environmental gravitational stimulation as well as genetically controlled molecular interactions. This paper describes the effects of hypergravity on axonal growth and dendritic morphology, respectively. Two aspects of this vestibular adaptation are examined: (1) How does long-term exposure to hypergravity affect the development of vestibular axons? (2) How does short-term exposure to extremely rapid changes in gravity, such as those that occur during shuttle launch and landing, affect dendrites of the vestibulocerebellar system? To study the effects of longterm exposures to altered gravity, embryonic rats that developed in hypergravity were compared to microgravity-exposed and control rats. Examination of the vestibular projections from epithelia devoted to linear and angular acceleration revealed that the terminal fields segregate differently in rat embryos that gestated in each of the gravitational environments.To study the effects of short-term exposures to altered gravity, mice were exposed briefly to strong vestibular stimuli and the vestibulocerebellum was examined for any resulting morphological changes. My data show that these stimuli cause intense vestibular excitation of cerebellar Purkinje cells, which induce up-regulation of clathrin-mediated endocytosis and other morphological changes that are comparable to those seen in long-term depression. This system provides a basis for studying how the vestibular environment can modify cerebellar function, allowing animals to adapt to new environments.

Immune dysregulation may contribute to disease pathogenesis in spinal muscular atrophy mice

PubMed Central

Deguise, Marc-Olivier; De Repentigny, Yves; McFall, Emily; Auclair, Nicole; Sad, Subash

2017-01-01

Abstract Spinal muscular atrophy (SMA) has long been solely considered a neurodegenerative disorder. However, recent work has highlighted defects in many other cell types that could contribute to disease aetiology. Interestingly, the immune system has never been extensively studied in SMA. Defects in lymphoid organs could exacerbate disease progression by neuroinflammation or immunodeficiency. Smn depletion led to severe alterations in the thymus and spleen of two different mouse models of SMA. The spleen from Smn depleted mice was dramatically smaller at a very young age and its histological architecture was marked by mislocalization of immune cells in the Smn2B/- model mice. In comparison, the thymus was relatively spared in gross morphology but showed many histological alterations including cortex thinning in both mouse models at symptomatic ages. Thymocyte development was also impaired as evidenced by abnormal population frequencies in the Smn2B/- thymus. Cytokine profiling revealed major changes in different tissues of both mouse models. Consistent with our observations, we found that survival motor neuron (Smn) protein levels were relatively high in lymphoid organs compared to skeletal muscle and spinal cord during postnatal development in wild type mice. Genetic introduction of one copy of the human SMN2 transgene was enough to rescue splenic and thymic defects in Smn2B/- mice. Thus, Smn is required for the normal development of lymphoid organs, and altered immune function may contribute to SMA disease pathogenesis. PMID:28108555

Characterization of the human gut microbiome during travelers' diarrhea

PubMed Central

Youmans, Bonnie P; Ajami, Nadim J; Jiang, Zhi-Dong; Campbell, Frederick; Wadsworth, W Duncan; Petrosino, Joseph F; DuPont, Herbert L; Highlander, Sarah K

2015-01-01

Alterations in the gut microbiota are correlated with ailments such as obesity, inflammatory bowel disease, and diarrhea. Up to 60% of individuals traveling from industrialized to developing countries acquire a form of secretory diarrhea known as travelers' diarrhea (TD), and enterotoxigenic Escherichia coli (ETEC) and norovirus (NoV) are the leading causative pathogens. Presumably, TD alters the gut microbiome, however the effect of TD on gut communities has not been studied. We report the first analysis of bacterial gut populations associated with TD. We examined and compared the gut microbiomes of individuals who developed TD associated with ETEC, NoV, or mixed pathogens, and TD with no pathogen identified, to healthy travelers. We observed a signature dysbiotic gut microbiome profile of high Firmicutes:Bacteroidetes ratios in the travelers who developed diarrhea, regardless of etiologic agent or presence of a pathogen. There was no significant difference in α-diversity among travelers. The bacterial composition of the microbiota of the healthy travelers was similar to the diarrheal groups, however the β-diversity of the healthy travelers was significantly different than any pathogen-associated TD group. Further comparison of the healthy traveler microbiota to those from healthy subjects who were part of the Human Microbiome Project also revealed a significantly higher Firmicutes:Bacteriodetes ratio in the healthy travelers and significantly different β-diversity. Thus, the composition of the gut microbiome in healthy, diarrhea-free travelers has characteristics of a dysbiotic gut, suggesting that these alterations could be associated with factors such as travel. PMID:25695334

Characterization of the human gut microbiome during travelers' diarrhea.

PubMed

Youmans, Bonnie P; Ajami, Nadim J; Jiang, Zhi-Dong; Campbell, Frederick; Wadsworth, W Duncan; Petrosino, Joseph F; DuPont, Herbert L; Highlander, Sarah K

2015-01-01

Alterations in the gut microbiota are correlated with ailments such as obesity, inflammatory bowel disease, and diarrhea. Up to 60% of individuals traveling from industrialized to developing countries acquire a form of secretory diarrhea known as travelers' diarrhea (TD), and enterotoxigenic Escherichia coli (ETEC) and norovirus (NoV) are the leading causative pathogens. Presumably, TD alters the gut microbiome, however the effect of TD on gut communities has not been studied. We report the first analysis of bacterial gut populations associated with TD. We examined and compared the gut microbiomes of individuals who developed TD associated with ETEC, NoV, or mixed pathogens, and TD with no pathogen identified, to healthy travelers. We observed a signature dysbiotic gut microbiome profile of high Firmicutes:Bacteroidetes ratios in the travelers who developed diarrhea, regardless of etiologic agent or presence of a pathogen. There was no significant difference in α-diversity among travelers. The bacterial composition of the microbiota of the healthy travelers was similar to the diarrheal groups, however the β-diversity of the healthy travelers was significantly different than any pathogen-associated TD group. Further comparison of the healthy traveler microbiota to those from healthy subjects who were part of the Human Microbiome Project also revealed a significantly higher Firmicutes:Bacteriodetes ratio in the healthy travelers and significantly different β-diversity. Thus, the composition of the gut microbiome in healthy, diarrhea-free travelers has characteristics of a dysbiotic gut, suggesting that these alterations could be associated with factors such as travel.

Biochemical and hematological effects of lead ingestion in nestling American kestrels (Falco sparverius)

USGS Publications Warehouse

Hoffman, D.J.; Franson, J.C.; Pattee, O.H.; Bunck, C.M.; Murray, H.C.

1985-01-01

1. One-day old American kestrel (Faico sparverius) nestlings were orally dosed daily with 5 μl/g of corn oil (controls), 25, 125 or 625 mg/kg of metallic lead in corn oil for 10 days.2. Forty per cent of the nestlings receiving 625 mg/kg of lead died after 6 days and growth rates were significantly depressed in the two highest lead dosed groups. At 10 days hematocrit values were significantly lower in the two highest lead treated groups, and hemoglobin content and red blood cell (δ-aminolevulinic acid dehydratase (ALAD) activity was depressed in all lead treated groups. Plasma creatine phosphokinase decreased in the two highest treatment groups.3. Brain, liver and kidney ALAD activities, brain RNA to protein ratio and liver protein concentration decreased after lead exposure whereas liver DNA, DNA to RNA ratio and DNA to protein ratio increased. Brain monoamine oxidase and ATPase were not significantly altered.4. Measurements of the ontogeny of hematological variants and enzymes in normal development, using additional untreated nestlings, revealed decreases in red blood cell ALAD, plasma aspartate amino transferase, lactate dehydrogenase, brain DNA and RNA and liver DNA, whereas hematocrit, hemoglobin, plasma alkaline phosphatase, brain monoamine oxidase, brain ALAD and liver ALAD increased during the first 10 days of posthatching development.5. Biochemical and hematological alterations were more severe than those reported in adult kestrels or precocial young birds exposed to lead. Alterations may be due in part to delayed development.

Altering Neurospora crassa MOB2A exposes its functions in development and affects its interaction with the NDR kinase COT1.

PubMed

Aharoni-Kats, Liran; Zelinger, Einat; Chen, She; Yarden, Oded

2018-06-01

The Neurospora crassa Mps One Binder (MOB) proteins MOB2A and MOB2B physically interact with the Nuclear Dbf2 Related (NDR) kinase COT1 and have been shown to have overlapping functions in various aspects of asexual development. Here, we identified two N. crassa MOB2A residues, Tyr117 and Tyr119, which are potentially phosphorylated. Using phosphomimetic mob-2a mutants we have been able to establish that apart from their previously described roles, MOB2A/B are involved in additional developmental processes. Enhanced conidial germination, accompanied by conidial agglutination, in the phosphomimetic mutants indicated that MOB2A is a negative regulator of germination. Thick-section imaging of perithecia revealed slow maturation and a lack of asci alignment in the mutant strains demonstrating a role for MOB2A in sexual development. We demonstrate that even though MOB2A and MOB2B have some overlapping functions, MOB2B cannot compensate for the roles MOB2A has in conidiation and germination. Altering Tyr residues 117 and 119 impaired the physical interactions between MOB2A and COT1, most likely contributing to some of the observed effects. As cot-1 and the phosphomimetic mutants share an extragenic suppressor (gul-1), we concluded that at least some of the effects imposed by altering Tyr117 and Tyr119 are mediated by the NDR kinase. © 2018 John Wiley & Sons Ltd.

Blanching of paint and varnish layers in easel paintings: contribution to the understanding of the alteration

NASA Astrophysics Data System (ADS)

Genty-Vincent, Anaïs; Eveno, Myriam; Nowik, Witold; Bastian, Gilles; Ravaud, Elisabeth; Cabillic, Isabelle; Uziel, Jacques; Lubin-Germain, Nadège; Menu, Michel

2015-11-01

The blanching of easel paintings can affect the varnish layer and also the paint layer with a blurring effect. The understanding of the physicochemical and optical phenomena involved in the whitening process remains an important challenge for the painting conservation. A set of ca. 50 microsamples from French, Flemish, and Italian blanched oil paintings, from sixteenth to nineteenth century, have been collected for in deep investigations. In parallel, the reproduction of the alteration was achieved by preparing some paint layers according to historical treatises and altering them in a climatic chamber in a humid environment or directly by immersing in ultrapure water. The observation of raw samples with a field-emission gun scanning electron microscope revealed for the first time that the altered layers have an unexpected highly porous structure with a pore size ranging from ca. 40 nm to 2 μm. The formation mechanism of these pores should mostly be physical as the supplementary analyses (Fourier transform infrared spectroscopy, gas chromatography-mass spectrometry) do not reveal any noticeable molecular modification. Considering the tiny size of the pores, the alteration can be explained by the Rayleigh or Mie light scattering.

Modeling Gene-Wise Dependencies Improves the Identification of Drug Response Biomarkers in Cancer Studies | Office of Cancer Genomics

Cancer.gov

Recent advances in biomedical and sequencing technologies have revealed the genomic landscape of common forms of human cancer in unprecedented detail. Of the genes that drive tumorigenesis when altered, for most cancers it is believed that there exist a small number of “mountains” (genes altered at high frequencies across the population), and a much larger number of “hills” (much less frequently altered genes).

Pore Pressure Distribution and Flank Instability in Hydrothermally Altered Stratovolcanoes

NASA Astrophysics Data System (ADS)

Ball, J. L.; Taron, J.; Hurwitz, S.; Reid, M. E.

2015-12-01

Field and geophysical investigations of stratovolcanoes with long-lived hydrothermal systems commonly reveal that initially permeable regions (such as brecciated layers of pyroclastic material) can become both altered and water-bearing. Hydrothermal alteration in these regions, including clay formation, can turn them into low-permeability barriers to fluid flow, which could increase pore fluid pressures resulting in flank slope instability. We examined elevated pore pressure conditions using numerical models of hydrothermal flow in stratovolcanoes, informed by geophysical data about internal structures and deposits. Idealized radially symmetric meshes were developed based on cross-sectional profiles and alteration/permeability structures of Cascade Range stratovolcanoes. We used the OpenGeoSys model to simulate variably saturated conditions in volcanoes heated only by regional heat fluxes, as well as 650°C intrusions at two km depth below the surface. Meteoric recharge was estimated from precipitation rates in the Cascade Range. Preliminary results indicate zones of elevated pore pressures form: 1) where slopes are underlain by continuous low-permeability altered layers, or 2) when the edifice has an altered core with saturated, less permeable limbs. The first scenario might control shallow collapses on the slopes above the altered layers. The second could promote deeper flank collapses that are initially limited to the summit and upper slopes, but could progress to the core of an edifice. In both scenarios, pore pressures can be further elevated by shallow intrusions, or evolve over longer time scales under forcing from regional heat flux. Geometries without confining low-permeability layers do not show these pressure effects. Our initial scenarios use radially symmetric models, but we are also simulating hydrothermal flow under real 3D geometries with asymmetric subsurface structures (Mount Adams). Simulation results will be used to inform 3D slope-stability models.

Sayama CM2 Chondrite: Fresh but Heavily Altered

NASA Technical Reports Server (NTRS)

Takaoka, N.; Nakamura, T.; Noguchi, T.; Tonui, E.; Gounelle, M.; Zolensky, M. E.; Ebisawa, N.; Osawa, T.; Okazaki, R.; Nagao, K.;

Maternal exposure to fish oil primes offspring to harbor intestinal pathobionts associated with altered immune cell balance.

PubMed

Gibson, D L; Gill, S K; Brown, K; Tasnim, N; Ghosh, S; Innis, S; Jacobson, K

2015-01-01

Our previous studies revealed that offspring from rat dams fed fish oil (at 8% and 18% energy), developed impaired intestinal barriers sensitizing the colon to exacerbated injury later in life. To discern the mechanism, we hypothesized that in utero exposure to fish oil, rich in n-3 polyunsaturated fatty acid (PUFA), caused abnormal intestinal reparative responses to mucosal injury through differences in intestinal microbiota and the presence of naïve immune cells. To identify such mechanisms, gut microbes and naïve immune cells were compared between rat pups born to dams fed either n-6 PUFA, n-3 PUFA or breeder chow. Maternal exposure to either of the PUFA rich diets altered the development of the intestinal microbiota with an overall reduction in microbial density. Using qPCR, we found that each type of PUFA differentially altered the major gut phyla; fish oil increased Bacteroidetes and safflower oil increased Firmicutes. Both PUFA diets reduced microbes known to dominate the infant gut like Enterobacteriaceae and Bifidobacteria spp. when compared to the chow group. Uniquely, maternal fish oil diets resulted in offspring showing blooms of opportunistic pathogens like Bilophila wadsworthia, Enterococcus faecium and Bacteroides fragilis in their gut microbiota. As well, fish oil groups showed a reduction in colonic CD8+ T cells, CD4+ Foxp3+ T cells and arginase+ M2 macrophages. In conclusion, fish oil supplementation in pharmacological excess, at 18% by energy as shown in this study, provides an example where excess dosing in utero can prime offspring to harbor intestinal pathobionts and alter immune cell homeostasis.

Excess fertilizer responsive miRNAs revealed in Linum usitatissimum L.

PubMed

Melnikova, Nataliya V; Dmitriev, Alexey A; Belenikin, Maxim S; Speranskaya, Anna S; Krinitsina, Anastasia A; Rachinskaia, Olga A; Lakunina, Valentina A; Krasnov, George S; Snezhkina, Anastasiya V; Sadritdinova, Asiya F; Uroshlev, Leonid A; Koroban, Nadezda V; Samatadze, Tatiana E; Amosova, Alexandra V; Zelenin, Alexander V; Muravenko, Olga V; Bolsheva, Nadezhda L; Kudryavtseva, Anna V

2015-02-01

Effective fertilizer application is necessary to increase crop yields and reduce risk of plant overdosing. It is known that expression level of microRNAs (miRNAs) alters in plants under different nutrient concentrations in soil. The aim of our study was to identify and characterize miRNAs with expression alterations under excessive fertilizer in agriculturally important crop - flax (Linum usitatissimum L.). We have sequenced small RNAs in flax grown under normal and excessive fertilizer using Illumina GAIIx. Over 14 million raw reads was obtained for two small RNA libraries. 84 conserved miRNAs from 20 families were identified. Differential expression was revealed for several flax miRNAs under excessive fertilizer according to high-throughput sequencing data. For 6 miRNA families (miR395, miR169, miR408, miR399, miR398 and miR168) expression level alterations were evaluated on the extended sampling using qPCR. Statistically significant up-regulation was revealed for miR395 under excessive fertilizer. It is known that target genes of miR395 are involved in sulfate uptake and assimilation. However, according to our data alterations of the expression level of miR395 could be associated not only with excess sulfur application, but also with redundancy of other macro- and micronutrients. Furthermore expression level was evaluated for miRNAs and their predicted targets. The negative correlation between miR399 expression and expression of its predicted target ubiquitin-conjugating enzyme E2 gene was shown in flax for the first time. So we suggested miR399 involvement in phosphate regulation in L. usitatissimum. Revealed in our study expression alterations contribute to miRNA role in flax response to excessive fertilizer. Copyright © 2014 Elsevier B.V. and Société française de biochimie et biologie Moléculaire (SFBBM). All rights reserved.

Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress

PubMed Central

Papale, Ligia A.; Li, Sisi; Madrid, Andy; Zhang, Qi; Chen, Li; Chopra, Pankaj; Jin, Peng; Keleş, Sündüz; Alisch, Reid S.

2016-01-01

Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders. While it is well known that acute environmental stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive epigenetic modification that is highly enriched in neurons and is associated with active neuronal transcription. Recently, we reported a genome-wide disruption of hippocampal 5hmC in male mice following acute stress that was correlated to altered transcript levels of genes in known stress related pathways. Since sex-specific endocrine mechanisms respond to environmental stimulus by altering the neuronal epigenome, we examined the genome-wide profile of hippocampal 5hmC in female mice following exposure to acute stress and identified 363 differentially hydroxymethylated regions (DhMRs) linked to known (e.g., Nr3c1 and Ntrk2) and potentially novel genes associated with stress response and psychiatric disorders. Integration of hippocampal expression data from the same female mice found stress-related hydroxymethylation correlated to altered transcript levels. Finally, characterization of stress-induced sex-specific 5hmC profiles in the hippocampus revealed 778 sex-specific acute stress-induced DhMRs some of which were correlated to altered transcript levels that produce sex-specific isoforms in response to stress. Together, the alterations in 5hmC presented here provide a possible molecular mechanism for the adaptive sex-specific response to stress that may augment the design of novel therapeutic agents that will have optimal effectiveness in each sex. PMID:27576189

Circuits of cancer drivers revealed by convergent misregulation of transcription factor targets across tumor types.

PubMed

Gonzalez-Perez, Abel

2016-01-20

Large tumor genome sequencing projects have now uncovered a few hundred genes involved in the onset of tumorigenesis, or drivers, in some two dozen malignancies. One of the main challenges emerging from this catalog of drivers is how to make sense of their heterogeneity in most cancer types. This is key not only to understand how carcinogenesis appears and develops in these malignancies to be able to early diagnose them, but also to open up the possibility to employ therapeutic strategies targeting a driver protein to counteract the alteration of another connected driver. Here, I focus on driver transcription factors and their connection to tumorigensis in several tumor types through the alteration of the expression of their targets. First, I explore their involvement in tumorigenesis as mutational drivers in 28 different tumor types. Then, I collect a list of downstream targets of the all driver transcription factors (TFs), and identify which of them exhibit a differential expression upon alterations of driver transcription factors. I identify the subset of targets of each TF most likely mediating the tumorigenic effect of their driver alterations in each tumor type, and explore their overlap. Furthermore, I am able to identify other driver genes that cause tumorigenesis through the alteration of very similar sets of targets. I thus uncover these circuits of connected drivers which cause tumorigenesis through the perturbation of overlapping cellular pathways in a pan-cancer manner across 15 malignancies. The systematic detection of these circuits may be key to propose novel therapeutic strategies indirectly targeting driver alterations in tumors.

[Numeric alterations in the dys gene and their association with clinical features].

PubMed

Mampel, Alejandra; Echeverría, María Inés; Vargas, Ana Lía; Roque, María

2011-01-01

The Duchenne/Becker muscular dystrophy is a hereditary miopathy with a recessive sex-linked pattern. The related gene is called DYS and the coded protein plays a crucial role in the anchorage between the cytoskeleton and the cellular membrane in muscle cells. Different clinical manifestations are observed depending on the impact of the genetic alteration on the protein. The global register of mutations reveals an enhanced frequency for deletions/duplications of one or more exons affecting the DYS gene. In the present work, numeric alterations have been studied in the 79 exons of the DYS gene. The study has been performed on 59 individuals, including 31 independent cases and 28 cases with a familial link. The applied methodology was Multiplex Ligation Dependent Probe Amplification (MLPA). In the 31 independent cases clinical data were established: i.e. the clinical score, the Raven test percentiles, and the creatininphosphokinase (CPK) blood values. Our results reveal a 61.3% frequency of numeric alterations affecting the DYS gene in our population, provoking all of them a reading frame shift. The rate for de novo mutations was identified as 35.2%. Alterations involving a specific region of one exon were observed with high frequency, affecting a specific region. A significant association was found between numeric alterations and a low percentile for the Raven test. These data contribute to the local knowledge of genetic alterations and their phenotypic impact for the Duchenne/Becker disease.

Magnesium Uptake by CorA Transporters Is Essential for Growth, Development and Infection in the Rice Blast Fungus Magnaporthe oryzae

PubMed Central

Reza, Md. Hashim; Shah, Hiral; Manjrekar, Johannes; Chattoo, Bharat B.

2016-01-01

Magnaporthe oryzae, the causative organism of rice blast, infects cereal crops and grasses at various stages of plant development. A comprehensive understanding of its metabolism and the implications on pathogenesis is necessary for countering this devastating crop disease. We present the role of the CorA magnesium transporters, MoAlr2 and MoMnr2, in development and pathogenicity of M. oryzae. The MoALR2 and MoMNR2 genes individually complement the Mg2+ uptake defects of a S. cerevisiae CorA transporter double mutant. MoALR2 and MoMNR2 respond to extracellular Mg2+ and Ca2+ levels and their expression is elevated under Mg2+ scarce conditions. RNA silencing mediated knockdown of MoALR2 (WT+siALR2, Δmnr2+siALR2 and ALR2+MNR2 simultaneous silencing) drastically alters intracellular cation concentrations and sensitivity to metal ions. MoALR2 silencing is detrimental to vegetative growth and surface hydrophobicity of mycelia, and the transformants display loss of cell wall integrity. MoALR2 is required for conidiogenesis and appressorium development, and is essential for infection. Investigation of knockdown transformants reveal low cAMP levels and altered expression of genes encoding proteins involved in MoMps1 cell wall integrity and cAMP MoPmk1 driven MAP Kinase signaling pathways. In contrast to MoALR2 knockdowns, the MoMNR2 deletion (Δmnr2) shows increased sensitivity to CorA inhibitors as well as altered cation sensitivity, but has limited effect on surface hydrophobicity and severity of plant infection. Interestingly, MoALR2 expression is elevated in Δmnr2. Impairment of development and infectivity of knockdown transformants and altered intracellular cation composition suggest that CorA transporters are essential for Mg2+ homeostasis within the cell, and are crucial to maintaining normal gene expression associated with cell structure, signal transduction and surface hydrophobicity in M. oryzae. We suggest that CorA transporters, and especially MoALR2, constitute an attractive target for the development of antifungal agents against this pathogen. PMID:27416318

Androgen receptor (AR) cistrome in prostate differentiation and cancer progression.

PubMed

Wang, Fengtian; Koul, Hari K

2017-01-01

Despite the progress in development of better AR-targeted therapies for prostate cancer (PCa), there is no curative therapy for castration-resistant prostate cancer (CRPC). Therapeutic resistance in PCa can be characterized in two broad categories of AR therapy resistance: the first and most prevalent one involves restoration of AR activity despite AR targeted therapy, and the second one involves tumor progression despite blockade of AR activity. As such AR remains the most attractive drug target for CRPC. Despite its oncogenic role, AR signaling also contributes to the maturation and differentiation of prostate luminal cells during development. Recent evidence suggests that AR cistrome is altered in advanced PCa. Alteration in AR may result from AR amplification, alternative splicing, mutations, post-translational modification of AR, and altered expression of AR co-factors. We reasoned that such alterations would result in the transcription of disparate AR target genes and as such may contribute to the emergence of castration-resistance. In the present study, we evaluated the expression of genes associated with canonical or non-canonical AR cistrome in relationship with PCa progression and prostate development by analyzing publicly available datasets. We discovered a transcription switch from canonical AR cistrome target genes to the non-canonical AR cistrome target genes during PCa progression. Using Gene Set Enrichment Analysis (GSEA), we discovered that canonical AR cistrome target genes are enriched in indolent PCa patients and the loss of canonical AR cistrome is associated with tumor metastasis and poor clinical outcome. Analysis of the datasets involving prostate development, revealed that canonical AR cistrome target genes are significantly enriched in prostate luminal cells and can distinguish luminal cells from basal cells, suggesting a pivotal role for canonical AR cistrome driven genes in prostate development. These data suggest that the expression of canonical AR cistrome related genes play an important role in maintaining the prostate luminal cell identity and might restrict the lineage plasticity observed in lethal PCa. Understanding the molecular mechanisms that dictate AR cistrome may lead to development of new therapeutic strategies aimed at restoring canonical AR cistrome, rewiring the oncogenic AR signaling and overcome resistance to AR targeted therapies.

Copy number alterations in small intestinal neuroendocrine tumors determined by array comparative genomic hybridization.

PubMed

Hashemi, Jamileh; Fotouhi, Omid; Sulaiman, Luqman; Kjellman, Magnus; Höög, Anders; Zedenius, Jan; Larsson, Catharina

2013-10-29

Small intestinal neuroendocrine tumors (SI-NETs) are typically slow-growing tumors that have metastasized already at the time of diagnosis. The purpose of the present study was to further refine and define regions of recurrent copy number (CN) alterations (CNA) in SI-NETs. Genome-wide CNAs was determined by applying array CGH (a-CGH) on SI-NETs including 18 primary tumors and 12 metastases. Quantitative PCR analysis (qPCR) was used to confirm CNAs detected by a-CGH as well as to detect CNAs in an extended panel of SI-NETs. Unsupervised hierarchical clustering was used to detect tumor groups with similar patterns of chromosomal alterations based on recurrent regions of CN loss or gain. The log rank test was used to calculate overall survival. Mann-Whitney U test or Fisher's exact test were used to evaluate associations between tumor groups and recurrent CNAs or clinical parameters. The most frequent abnormality was loss of chromosome 18 observed in 70% of the cases. CN losses were also frequently found of chromosomes 11 (23%), 16 (20%), and 9 (20%), with regions of recurrent CN loss identified in 11q23.1-qter, 16q12.2-qter, 9pter-p13.2 and 9p13.1-11.2. Gains were most frequently detected in chromosomes 14 (43%), 20 (37%), 4 (27%), and 5 (23%) with recurrent regions of CN gain located to 14q11.2, 14q32.2-32.31, 20pter-p11.21, 20q11.1-11.21, 20q12-qter, 4 and 5. qPCR analysis confirmed most CNAs detected by a-CGH as well as revealed CNAs in an extended panel of SI-NETs. Unsupervised hierarchical clustering of recurrent regions of CNAs revealed two separate tumor groups and 5 chromosomal clusters. Loss of chromosomes 18, 16 and 11 and gain of chromosome 20 were found in both tumor groups. Tumor group II was enriched for alterations in chromosome cluster-d, including gain of chromosomes 4, 5, 7, 14 and gain of 20 in chromosome cluster-b. Gain in 20pter-p11.21 was associated with short survival. Statistically significant differences were observed between primary tumors and metastases for loss of 16q and gain of 7. Our results revealed recurrent CNAs in several candidate regions with a potential role in SI-NET development. Distinct genetic alterations and pathways are involved in tumorigenesis of SI-NETs.

UBIAD1 Mutation Alters a Mitochondrial Prenyltransferase to Cause Schnyder Corneal Dystrophy

PubMed Central

Nickerson, Michael L.; Kostiha, Brittany N.; Brandt, Wolfgang; Fredericks, William; Xu, Ke-Ping; Yu, Fu-Shin; Gold, Bert; Chodosh, James; Goldberg, Marc; Lu, Da Wen; Yamada, Masakazu; Tervo, Timo M.; Grutzmacher, Richard; Croasdale, Chris; Hoeltzenbein, Maria; Sutphin, John; Malkowicz, S. Bruce; Wessjohann, Ludger; Kruth, Howard S.; Dean, Michael; Weiss, Jayne S.

2010-01-01

Background Mutations in a novel gene, UBIAD1, were recently found to cause the autosomal dominant eye disease Schnyder corneal dystrophy (SCD). SCD is characterized by an abnormal deposition of cholesterol and phospholipids in the cornea resulting in progressive corneal opacification and visual loss. We characterized lesions in the UBIAD1 gene in new SCD families and examined protein homology, localization, and structure. Methodology/Principal Findings We characterized five novel mutations in the UBIAD1 gene in ten SCD families, including a first SCD family of Native American ethnicity. Examination of protein homology revealed that SCD altered amino acids which were highly conserved across species. Cell lines were established from patients including keratocytes obtained after corneal transplant surgery and lymphoblastoid cell lines from Epstein-Barr virus immortalized peripheral blood mononuclear cells. These were used to determine the subcellular localization of mutant and wild type protein, and to examine cholesterol metabolite ratios. Immunohistochemistry using antibodies specific for UBIAD1 protein in keratocytes revealed that both wild type and N102S protein were localized sub-cellularly to mitochondria. Analysis of cholesterol metabolites in patient cell line extracts showed no significant alteration in the presence of mutant protein indicating a potentially novel function of the UBIAD1 protein in cholesterol biochemistry. Molecular modeling was used to develop a model of human UBIAD1 protein in a membrane and revealed potentially critical roles for amino acids mutated in SCD. Potential primary and secondary substrate binding sites were identified and docking simulations indicated likely substrates including prenyl and phenolic molecules. Conclusions/Significance Accumulating evidence from the SCD familial mutation spectrum, protein homology across species, and molecular modeling suggest that protein function is likely down-regulated by SCD mutations. Mitochondrial UBIAD1 protein appears to have a highly conserved function that, at least in humans, is involved in cholesterol metabolism in a novel manner. PMID:20505825

Phototropic growth in a reef flat acroporid branching coral species.

PubMed

Kaniewska, Paulina; Campbell, Paul R; Fine, Maoz; Hoegh-Guldberg, Ove

2009-03-01

Many terrestrial plants form complex morphological structures and will alter these growth patterns in response to light direction. Similarly reef building corals have high morphological variation across coral families, with many species also displaying phenotypic plasticity across environmental gradients. In particular, the colony geometry in branching corals is altered by the frequency, location and direction of branch initiation and growth. This study demonstrates that for the branching species Acropora pulchra, light plays a key role in axial polyp differentiation and therefore axial corallite development--the basis for new branch formation. A. pulchra branches exhibited a directional growth response, with axial corallites only developing when light was available, and towards the incident light. Field experimentation revealed that there was a light intensity threshold of 45 micromol m(-2) s(-1), below which axial corallites would not develop and this response was blue light (408-508 nm) dependent. There was a twofold increase in axial corallite growth above this light intensity threshold and a fourfold increase in axial corallite growth under the blue light treatment. These features of coral branch growth are highly reminiscent of the initiation of phototropic branch growth in terrestrial plants, which is directed by the blue light component of sunlight.

Crickets in space: morphological, physiological and behavioral alterations induced by space flight and hypergravity

NASA Astrophysics Data System (ADS)

Horn, E.; Agricola, H.; Böser, S.; Förster, S.; Kämper, G.; Riewe, P.; Sebastian, C.

"Crickets in Space" was a Neurolab experiment by which the balance between genetic programs and the gravitational environment for the development of a gravity sensitive neuronal system was studied. The model character of crickets was justified by their external gravity receptors, identified position-sensitive interneurons (PSI) and gravity-related compensatory head response, and by the specific relation of this behavior to neuronal arousal systems activated by locomotion. These advantages allowed to study the impact of modified gravity on cellular processes in a complex organism. Eggs, 1st, 4th and 6th stage larvae of Acheta domesticus were used. Post-flight experiments revealed a low susceptibility of the behavior to micro- and hypergravity while the physiology of the PSI was significantly affected. Immunocytological investigations revealed a stage-dependent sensitivity of thoracic GABAergic motoneurons to 3g-conditions concerning their soma sizes but not their topographical arrangement. The morphology of neuromuscular junctions was not affected by 3g-hypergravity. Peptidergic neurons from cerebral sensorimotor centers revealed no significant modifications by microgravity (μg). The contrary physiological and behavioral results indicate a facilitation of 1g-readaptation originating from accessory gravity, proprioceptive and visual sense organs. Absence of anatomical modifications point to an effective time window of μg- or 3g-expo-sure related to the period of neuronal proliferation. The analysis of basic mechanisms of how animals and man adapt to altered gravitational conditions will profit from a continuation of the project "Crickets in Space".

Biomechanical evaluation of two types of short-stemmed hip prostheses compared to the trust plate prosthesis by three-dimensional measurement of micromotions.

PubMed

Fottner, Andreas; Schmid, Markus; Birkenmaier, Christof; Mazoochian, Farhad; Plitz, Wolfgang; Volkmar, Jansson

2009-06-01

Stemless and short-stemmed hip prostheses have been developed to preserve femoral bone stock. While all these prostheses claim a more or less physiological load transfer, clinical long-term results are only available for the stemless thrust plate prosthesis. In this study, the in vitro primary stability of the thrust plate prosthesis was compared to two types of short-stemmed prostheses. In addition to the well-established Mayo prosthesis, the modular Metha prosthesis was tested using cone adapters with 130 degrees and 140 degrees neck-shaft-angles. The prostheses were implanted in composite femurs and loaded dynamically (300-1700 N). Three-dimensional micromotions at the bone-prosthesis interface were measured. In addition, the three-dimensional deformations at the surface of the composite femur were measured to gain data on the strain distribution. For all tested prostheses, the micromotions did not exceed 150 microm, the critical value for osteointegration. The thrust plate prosthesis revealed similar motions as the short-stemmed prostheses. The short-stemmed prosthesis with the 130 degrees cone tended to have the highest micromotions of all tested short-stemmed prostheses. The thrust plate prosthesis revealed the lowest alteration of bone surface deformation after implantation. The comparably low micromotions of the thrust plate prosthesis and the short-stemmed prostheses should be conducive to osseous integration. The higher alteration of load transmission after implantation reveals a higher risk of stress shielding for the short-stemmed prostheses.

Behavioral and neural correlates of disrupted orienting attention in posttraumatic stress disorder.

PubMed

Russman Block, Stefanie; King, Anthony P; Sripada, Rebecca K; Weissman, Daniel H; Welsh, Robert; Liberzon, Israel

2017-04-01

Prior work has revealed that posttraumatic stress disorder (PTSD) is associated with altered (a) attentional performance and (b) resting-state functional connectivity (rsFC) in brain networks linked to attention. Here, we sought to characterize and link these behavioral and brain-based alterations in the context of Posner and Peterson's tripartite model of attention. Male military veterans with PTSD (N = 49; all deployed to Iraq or Afghanistan) and healthy age-and-gender-matched community controls (N = 26) completed the Attention Network Task. A subset of these individuals (36 PTSD and 21 controls) also underwent functional magnetic resonance imaging (fMRI) to assess rsFC. The behavioral measures revealed that the PTSD group was impaired at disengaging spatial attention, relative to the control group. FMRI measures further revealed that, relative to the control group, the PTSD group exhibited greater rsFC between the salience network and (a) the default mode network, (b) the dorsal attention network, and (c) the ventral attention network. Moreover, problems with disengaging spatial attention increased the rsFC between the networks above in the control group, but not in the PTSD group. The present findings link PTSD to both altered orienting of spatial attention and altered relationships between spatial orienting and functional connectivity involving the salience network. Interventions that target orienting and disengaging spatial attention may be a new avenue for PTSD research.

Urine peptidome analysis predicts risk of end-stage renal disease and reveals proteolytic pathways involved in autosomal dominant polycystic kidney disease progression.

PubMed

Pejchinovski, Martin; Siwy, Justyna; Metzger, Jochen; Dakna, Mohammed; Mischak, Harald; Klein, Julie; Jankowski, Vera; Bae, Kyongtae T; Chapman, Arlene B; Kistler, Andreas D

2017-03-01

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by slowly progressive bilateral renal cyst growth ultimately resulting in loss of kidney function and end-stage renal disease (ESRD). Disease progression rate and age at ESRD are highly variable. Therapeutic interventions therefore require early risk stratification of patients and monitoring of disease progression in response to treatment. We used a urine peptidomic approach based on capillary electrophoresis-mass-spectrometry (CE-MS) to identify potential biomarkers reflecting the risk for early progression to ESRD in the Consortium of Radiologic Imaging in Polycystic Kidney Disease (CRISP) cohort. A biomarker-based classifier consisting of 20 urinary peptides allowed the prediction of ESRD within 10-13 years of follow-up in patients 24-46 years of age at baseline. The performance of the biomarker score approached that of height-adjusted total kidney volume (htTKV) and the combination of the biomarker panel with htTKV improved prediction over either one alone. In young patients (<24 years at baseline), the same biomarker model predicted a 30 mL/min/1.73 m 2 glomerular filtration rate decline over 8 years. Sequence analysis of the altered urinary peptides and the prediction of the involved proteases by in silico analysis revealed alterations in distinct proteolytic pathways, in particular matrix metalloproteinases and cathepsins. We developed a urinary test that accurately predicts relevant clinical outcomes in ADPKD patients and suggests altered proteolytic pathways involved in disease progression. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Chronic nandrolone administration induces dysfunction of the reward pathway in rats.

PubMed

Zotti, Margherita; Tucci, Paolo; Colaianna, Marilena; Morgese, Maria Grazia; Mhillaj, Emanuela; Schiavone, Stefania; Scaccianoce, Sergio; Cuomo, Vincenzo; Trabace, Luigia

2014-01-01

Data in animal models and surveys in humans have revealed psychiatric complications of long-term anabolic androgenic steroid abuse. However, the neurobiochemical mechanisms behind the observed behavioral changes are poorly understood. The aim of the present study was to investigate the effects of nandrolone decanoate on emotional behavior and neurochemical brain alterations in gonadally intact male rats. The behavioral reactivity to the elevated plus maze and the social interaction test was used to assess anxiety-related symptoms, and the sucrose preference test was used to evaluate anhedonia. Dopaminergic, serotonergic and noradrenergic transmissions were also evaluated in selected brain areas. The chronic administration of nandrolone, at 5 mg kg(-1) injected daily for 4 weeks, induced the loss of sweet taste preference, a sign of anhedonia and dysfunction of the reward pathway. The behavioral outcomes were accompanied by reductions in the dopamine, serotonin and noradrenaline contents in the nucleus accumbens. Alterations in the time spent in the open arms and in the social interaction test were not found, suggesting that nandrolone did not induce an anxiogenic profile. No differences were revealed between the experimental groups in the amygdala in terms of the neurotransmitters measured. Our data suggest that nandrolone-treated rats have a depressive, but not anxiogenic-like, profile, accompanied by brain region-dependent changes in dopaminergic, serotonergic and noradrenergic neurotransmission. As anabolic androgenic steroid dependence is plausibly the major form of worldwide substance dependence that remains largely unexplored, it should be highlighted that our data could contribute to a better understanding of the altered rewards induced by nandrolone treatment and to the development of appropriate treatments.

Biomechanical properties of bone in a mouse model of Rett syndrome

PubMed Central

Kamal, Bushra; Russell, David; Payne, Anthony; Constante, Diogo; Tanner, K. Elizabeth; Isaksson, Hanna; Mathavan, Neashan; Cobb, Stuart R.

2015-01-01

Rett syndrome (RTT) is an X-linked genetic disorder and a major cause of intellectual disability in girls. Mutations in the methyl-CpG binding protein 2 (MECP2) gene are the primary cause of the disorder. Despite the dominant neurological phenotypes, MECP2 is expressed ubiquitously throughout the body and a number of peripheral phenotypes such as scoliosis, reduced bone mineral density and skeletal fractures are also common and important clinical features of the disorder. In order to explore whether MeCP2 protein deficiency results in altered structural and functional properties of bone and to test the potential reversibility of any defects, we have conducted a series of histological, imaging and biomechanical tests of bone in a functional knockout mouse model of RTT. Both hemizygous Mecp2stop/y male mice in which Mecp2 is silenced in all cells and female Mecp2stop/+ mice in which Mecp2 is silenced in ~ 50% of cells as a consequence of random X-chromosome inactivation, revealed significant reductions in cortical bone stiffness, microhardness and tensile modulus. Microstructural analysis also revealed alterations in both cortical and cancellous femoral bone between wild-type and MeCP2-deficient mice. Furthermore, unsilencing of Mecp2 in adult mice cre-mediated stop cassette deletion resulted in a restoration of biomechanical properties (stiffness, microhardness) towards wild-type levels. These results show that MeCP2-deficiency results in overt, but potentially reversible, alterations in the biomechanical integrity of bone and highlights the importance of targeting skeletal phenotypes in considering the development of pharmacological and gene-based therapies. PMID:25445449

Studies Toward Birth and Early Mammalian Development in Space

NASA Technical Reports Server (NTRS)

Ronca, April E.; Dalton, Bonnie (Technical Monitor)

2002-01-01

Successful reproduction is the hallmark of a species' ability to adapt to its environment and must be realized to sustain life beyond Earth. Before taking this immense step, we need to understand the effects of altered gravity on critical phases of mammalian reproduction, viz., those events surrounding pregnancy, birth and the early development of offspring. No mammal has yet undergone birth in space. however studies spanning the gravity continuum from 0 to 2-g are revealing insights into how birth and early postnatal development will proceed in space. In this presentation, I will report the results of behavioral studies of rat mothers and offspring exposed from mid- to late pregnancy to either hypogravity (0-g) or hypergravity (1.5 or 2-g).

Rice putative methyltransferase gene OsTSD2 is required for root development involving pectin modification

PubMed Central

Qu, Lianghuan; Wu, Chunyan; Zhang, Fei; Wu, Yangyang; Fang, Chuanying; Jin, Cheng; Liu, Xianqing; Luo, Jie

2016-01-01

Pectin synthesis and modification are vital for plant development, although the underlying mechanisms are still not well understood. Here, we report the functional characterization of the OsTSD2 gene, which encodes a putative methyltransferase in rice. All three independent T-DNA insertion lines of OsTSD2 displayed dwarf phenotypes and serial alterations in different zones of the root. These alterations included abnormal cellular adhesion and schizogenous aerenchyma formation in the meristematic zone, inhibited root elongation in the elongation zone, and higher lateral root density in the mature zone. Immunofluorescence (with LM19) and Ruthenium Red staining of the roots showed that unesterified homogalacturonan (HG) was increased in Ostsd2 mutants. Biochemical analysis of cell wall pectin polysaccharides revealed that both the monosaccharide composition and the uronic acid content were decreased in Ostsd2 mutants. Increased endogenous ABA content and opposite roles performed by ABA and IAA in regulating cellular adhesion in the Ostsd2 mutants suggested that OsTSD2 is required for root development in rice through a pathway involving pectin synthesis/modification. A hypothesis to explain the relationship among OsTSD2, pectin methylesterification, and root development is proposed, based on pectin’s function in regional cell extension/division in a zone-dependent manner. PMID:27497286

Altered sucrose synthase and invertase expression affects the local and systemic sugar metabolism of nematode-infected Arabidopsis thaliana plants.

PubMed

Cabello, Susana; Lorenz, Cindy; Crespo, Sara; Cabrera, Javier; Ludwig, Roland; Escobar, Carolina; Hofmann, Julia

2014-01-01

Sedentary endoparasitic nematodes of plants induce highly specific feeding cells in the root central cylinder. From these, the obligate parasites withdraw all required nutrients. The feeding cells were described as sink tissues in the plant's circulation system that are supplied with phloem-derived solutes such as sugars. Currently, there are several publications describing mechanisms of sugar import into the feeding cells. However, sugar processing has not been studied so far. Thus, in the present work, the roles of the sucrose-cleaving enzymes sucrose synthases (SUS) and invertases (INV) in the development of Heterodera schachtii were studied. Gene expression analyses indicate that both enzymes are regulated transcriptionally. Nematode development was enhanced on multiple INV and SUS mutants. Syncytia of these mutants were characterized by altered enzyme activity and changing sugar pool sizes. Further, the analyses revealed systemically affected sugar levels and enzyme activities in the shoots of the tested mutants, suggesting changes in the source-sink relationship. Finally, the development of the root-knot nematode Meloidogyne javanica was studied in different INV and SUS mutants and wild-type Arabidopsis plants. Similar effects on the development of both sedentary endoparasitic nematode species (root-knot and cyst nematode) were observed, suggesting a more general role of sucrose-degrading enzymes during plant-nematode interactions.

Altered dopaminergic regulation of the dorsal striatum is able to induce tic-like movements in juvenile rats

PubMed Central

Rizzo, Francesca; Boeckers, Tobias; Schulze, Ulrike

2018-01-01

Motor tics are sudden, repetitive, involuntary movements representing the hallmark behaviors of the neurodevelopmental disease Tourette’s syndrome (TS). The primary cause of TS remains unclear. The initial observation that dopaminergic antagonists alleviate tics led to the development of a dopaminergic theory of TS etiology which is supported by post mortem and in vivo studies indicating that non-physiological activation of the striatum could generate tics. The striatum controls movement execution through the balanced activity of dopamine receptor D1 and D2-expressing medium spiny neurons of the direct and indirect pathway, respectively. Different neurotransmitters can activate or repress striatal activity and among them, dopamine plays a major role. In this study we introduced a chronic dopaminergic alteration in juvenile rats, in order to modify the delicate balance between direct and indirect pathway. This manipulation was done in the dorsal striatum, that had been associated with tic-like movements generation in animal models. The results were movements resembling tics, which were categorized and scored according to a newly developed rating scale and were reduced by clonidine and riluzole treatment. Finally, post mortem analyses revealed altered RNA expression of dopaminergic receptors D1 and D2, suggesting an imbalanced dopaminergic regulation of medium spiny neuron activity as being causally related to the observed phenotype. PMID:29698507

Altered brain activity for phonological manipulation in dyslexic Japanese children.

PubMed

Kita, Yosuke; Yamamoto, Hisako; Oba, Kentaro; Terasawa, Yuri; Moriguchi, Yoshiya; Uchiyama, Hitoshi; Seki, Ayumi; Koeda, Tatsuya; Inagaki, Masumi

2013-12-01

Because of unique linguistic characteristics, the prevalence rate of developmental dyslexia is relatively low in the Japanese language. Paradoxically, Japanese children have serious difficulty analysing phonological processes when they have dyslexia. Neurobiological deficits in Japanese dyslexia remain unclear and need to be identified, and may lead to better understanding of the commonality and diversity in the disorder among different linguistic systems. The present study investigated brain activity that underlies deficits in phonological awareness in Japanese dyslexic children using functional magnetic resonance imaging. We developed and conducted a phonological manipulation task to extract phonological processing skills and to minimize the influence of auditory working memory on healthy adults, typically developing children, and dyslexic children. Current experiments revealed that several brain regions participated in manipulating the phonological information including left inferior and middle frontal gyrus, left superior temporal gyrus, and bilateral basal ganglia. Moreover, dyslexic children showed altered activity in two brain regions. They showed hyperactivity in the basal ganglia compared with the two other groups, which reflects inefficient phonological processing. Hypoactivity in the left superior temporal gyrus was also found, suggesting difficulty in composing and processing phonological information. The altered brain activity shares similarity with those of dyslexic children in countries speaking alphabetical languages, but disparity also occurs between these two populations. These are initial findings concerning the neurobiological impairments in dyslexic Japanese children.

Ambient Ultrafine Particle Ingestion Alters Gut Microbiota in Association with Increased Atherogenic Lipid Metabolites

PubMed Central

Li, Rongsong; Yang, Jieping; Saffari, Arian; Jacobs, Jonathan; Baek, Kyung In; Hough, Greg; Larauche, Muriel H.; Ma, Jianguo; Jen, Nelson; Moussaoui, Nabila; Zhou, Bill; Kang, Hanul; Reddy, Srinivasa; Henning, Susanne M.; Campen, Matthew J.; Pisegna, Joseph; Li, Zhaoping; Fogelman, Alan M.; Sioutas, Constantinos; Navab, Mohamad; Hsiai, Tzung K.

2017-01-01

Ambient particulate matter (PM) exposure is associated with atherosclerosis and inflammatory bowel disease. Ultrafine particles (UFP, dp < 0.1–0.2 μm) are redox active components of PM. We hypothesized that orally ingested UFP promoted atherogenic lipid metabolites in both the intestine and plasma via altered gut microbiota composition. Low density lipoprotein receptor-null (Ldlr−/−) mice on a high-fat diet were orally administered with vehicle control or UFP (40 μg/mouse/day) for 3 days a week. After 10 weeks, UFP ingested mice developed macrophage and neutrophil infiltration in the intestinal villi, accompanied by elevated cholesterol but reduced coprostanol levels in the cecum, as well as elevated atherogenic lysophosphatidylcholine (LPC 18:1) and lysophosphatidic acids (LPAs) in the intestine and plasma. At the phylum level, Principle Component Analysis revealed significant segregation of microbiota compositions which was validated by Beta diversity analysis. UFP-exposed mice developed increased abundance in Verrocomicrobia but decreased Actinobacteria, Cyanobacteria, and Firmicutes as well as a reduced diversity in microbiome. Spearman’s analysis negatively correlated Actinobacteria with cecal cholesterol, intestinal and plasma LPC18:1, and Firmicutes and Cyanobacteria with plasma LPC 18:1. Thus, ultrafine particles ingestion alters gut microbiota composition, accompanied by increased atherogenic lipid metabolites. These findings implicate the gut-vascular axis in a atherosclerosis model. PMID:28211537

Altered brain activity for phonological manipulation in dyslexic Japanese children

PubMed Central

Yamamoto, Hisako; Oba, Kentaro; Terasawa, Yuri; Moriguchi, Yoshiya; Uchiyama, Hitoshi; Seki, Ayumi; Koeda, Tatsuya; Inagaki, Masumi

2013-01-01

Because of unique linguistic characteristics, the prevalence rate of developmental dyslexia is relatively low in the Japanese language. Paradoxically, Japanese children have serious difficulty analysing phonological processes when they have dyslexia. Neurobiological deficits in Japanese dyslexia remain unclear and need to be identified, and may lead to better understanding of the commonality and diversity in the disorder among different linguistic systems. The present study investigated brain activity that underlies deficits in phonological awareness in Japanese dyslexic children using functional magnetic resonance imaging. We developed and conducted a phonological manipulation task to extract phonological processing skills and to minimize the influence of auditory working memory on healthy adults, typically developing children, and dyslexic children. Current experiments revealed that several brain regions participated in manipulating the phonological information including left inferior and middle frontal gyrus, left superior temporal gyrus, and bilateral basal ganglia. Moreover, dyslexic children showed altered activity in two brain regions. They showed hyperactivity in the basal ganglia compared with the two other groups, which reflects inefficient phonological processing. Hypoactivity in the left superior temporal gyrus was also found, suggesting difficulty in composing and processing phonological information. The altered brain activity shares similarity with those of dyslexic children in countries speaking alphabetical languages, but disparity also occurs between these two populations. These are initial findings concerning the neurobiological impairments in dyslexic Japanese children. PMID:24052613

Evidences of early aqueous Mars: Implications on the origin of branched valleys in the Ius Chasma, Mars

NASA Astrophysics Data System (ADS)

Martha, Tapas R.; Jain, Nirmala; Vamshi, Gasiganti T.; Vinod Kumar, K.

2017-11-01

This study shows results of morphological and spectroscopic analyses of Ius Chasma and its southern branched valleys using Orbiter datasets such as Mars Reconnaissance Orbiter (MRO)-Compact Reconnaissance Imaging Spectrometer for Mars (CRISM), High Resolution Imaging Science Experiment (MRO-HiRISE) and digital terrain model (HRSC-DTM). Result of the spectral analysis reveals presence of hydrated minerals such as opal, nontronite and vermiculite in the floor and wall rock areas Ius Chasma indicating alteration of parent rock in an water rich environment of early Mars. Topographic gradient and morphological evidences such as V-shaped valleys with theatre shaped stubby channels, dendritic drainage and river piracy indicate that these valleys were initially developed by surface runoff due to episodic floods and further expanded due to groundwater sapping controlled by faults and fractures. Minerals formed by aqueous alteration during valley formation and their intricate association with different morphological domains suggest that surface runoff played a key role in the development of branched valleys south of Ius Chasma on Mars.

Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour.

PubMed

Bacon, C; Schneider, M; Le Magueresse, C; Froehlich, H; Sticht, C; Gluch, C; Monyer, H; Rappold, G A

2015-05-01

Neurodevelopmental disorders are multi-faceted and can lead to intellectual disability, autism spectrum disorder and language impairment. Mutations in the Forkhead box FOXP1 gene have been linked to all these disorders, suggesting that it may play a central role in various cognitive and social processes. To understand the role of Foxp1 in the context of neurodevelopment leading to alterations in cognition and behaviour, we generated mice with a brain-specific Foxp1 deletion (Nestin-Cre(Foxp1-/-)mice). The mutant mice were viable and allowed for the first time the analysis of pre- and postnatal neurodevelopmental phenotypes, which included a pronounced disruption of the developing striatum and more subtle alterations in the hippocampus. More detailed analysis in the CA1 region revealed abnormal neuronal morphogenesis that was associated with reduced excitability and an imbalance of excitatory to inhibitory input in CA1 hippocampal neurons in Nestin-Cre(Foxp1-/-) mice. Foxp1 ablation was also associated with various cognitive and social deficits, providing new insights into its behavioural importance.

Impaired angiogenesis in aminopeptidase N-null mice

PubMed Central

Rangel, Roberto; Sun, Yan; Guzman-Rojas, Liliana; Ozawa, Michael G.; Sun, Jessica; Giordano, Ricardo J.; Van Pelt, Carolyn S.; Tinkey, Peggy T.; Behringer, Richard R.; Sidman, Richard L.; Arap, Wadih; Pasqualini, Renata

2007-01-01

Aminopeptidase N (APN, CD13; EC 3.4.11.2) is a transmembrane metalloprotease with several functions, depending on the cell type and tissue environment. In tumor vasculature, APN is overexpressed in the endothelium and promotes angiogenesis. However, there have been no reports of in vivo inactivation of the APN gene to validate these findings. Here we evaluated, by targeted disruption of the APN gene, whether APN participates in blood vessel formation and function under normal conditions. Surprisingly, APN-null mice developed with no gross or histological abnormalities. Standard neurological, cardiovascular, metabolic, locomotor, and hematological studies revealed no alterations. Nonetheless, in oxygen-induced retinopathy experiments, APN-deficient mice had a marked and dose-dependent deficiency of the expected retinal neovascularization. Moreover, gelfoams embedded with growth factors failed to induce functional blood vessel formation in APN-null mice. These findings establish that APN-null mice develop normally without physiological alterations and can undergo physiological angiogenesis but show a severely impaired angiogenic response under pathological conditions. Finally, in addition to vascular biology research, APN-null mice may be useful reagents in other medical fields such as malignant, cardiovascular, immunological, or infectious diseases. PMID:17360568

Proteomic identification of altered cerebral proteins in the complex regional pain syndrome animal model.

PubMed

Nahm, Francis Sahngun; Park, Zee-Yong; Nahm, Sang-Soep; Kim, Yong Chul; Lee, Pyung Bok

2014-01-01

Complex regional pain syndrome (CRPS) is a rare but debilitating pain disorder. Although the exact pathophysiology of CRPS is not fully understood, central and peripheral mechanisms might be involved in the development of this disorder. To reveal the central mechanism of CRPS, we conducted a proteomic analysis of rat cerebrum using the chronic postischemia pain (CPIP) model, a novel experimental model of CRPS. After generating the CPIP animal model, we performed a proteomic analysis of the rat cerebrum using a multidimensional protein identification technology, and screened the proteins differentially expressed between the CPIP and control groups. Results. A total of 155 proteins were differentially expressed between the CPIP and control groups: 125 increased and 30 decreased; expressions of proteins related to cell signaling, synaptic plasticity, regulation of cell proliferation, and cytoskeletal formation were increased in the CPIP group. However, proenkephalin A, cereblon, and neuroserpin were decreased in CPIP group. Altered expression of cerebral proteins in the CPIP model indicates cerebral involvement in the pathogenesis of CRPS. Further study is required to elucidate the roles of these proteins in the development and maintenance of CRPS.

Progesterone action in breast, uterine, and ovarian cancers

PubMed Central

Diep, Caroline H.; Daniel, Andrea R.; Mauro, Laura J.; Knutson, Todd P.; Lange, Carol A.

2015-01-01

Progesterone and progesterone receptors (PR) are essential for the development and cyclical regulation of hormone-responsive tissues including the breast and reproductive tract. Altered functions of PR isoforms contribute to the pathogenesis of tumors that arise in these tissues. In the breast, progesterone acts in concert with estrogen to promote proliferative and pro-survival gene programs. In sharp contrast, progesterone inhibits estrogen-driven growth in the uterus and protects the ovary from neoplastic transformation. Progesterone-dependent actions and associated biology in diverse tissues and tumors are mediated by two progesterone receptor isoforms, PR-A and PR-B. These isoforms are subject to altered transcriptional activity or expression levels, differential cross-talk with growth factor signaling pathways, and distinct post-translational modifications and cofactor binding partners. Herein, we summarize and discuss the recent literature focused on progesterone and PR isoform-specific actions in breast, uterine, and ovarian cancers. Understanding the complexity of context-dependent PR actions in these tissues is critical to developing new models that will allow us to advance our knowledge base with the goal of revealing novel and efficacious therapeutic regimens for these hormone-responsive diseases. PMID:25587053

Automated array-based genomic profiling in chronic lymphocytic leukemia: Development of a clinical tool and discovery of recurrent genomic alterations

PubMed Central

Schwaenen, Carsten; Nessling, Michelle; Wessendorf, Swen; Salvi, Tatjana; Wrobel, Gunnar; Radlwimmer, Bernhard; Kestler, Hans A.; Haslinger, Christian; Stilgenbauer, Stephan; Döhner, Hartmut; Bentz, Martin; Lichter, Peter

2004-01-01

B cell chronic lymphocytic leukemia (B-CLL) is characterized by a highly variable clinical course. Recurrent chromosomal imbalances provide significant prognostic markers. Risk-adapted therapy based on genomic alterations has become an option that is currently being tested in clinical trials. To supply a robust tool for such large scale studies, we developed a comprehensive DNA microarray dedicated to the automated analysis of recurrent genomic imbalances in B-CLL by array-based comparative genomic hybridization (matrix–CGH). Validation of this chip in a series of 106 B-CLL cases revealed a high specificity and sensitivity that fulfils the criteria for application in clinical oncology. This chip is immediately applicable within clinical B-CLL treatment trials that evaluate whether B-CLL cases with distinct chromosomal abnormalities should be treated with chemotherapy of different intensities and/or stem cell transplantation. Through the control set of DNA fragments equally distributed over the genome, recurrent genomic imbalances were discovered: trisomy of chromosome 19 and gain of the MYCN oncogene correlating with an elevation of MYCN mRNA expression. PMID:14730057

Childhood poverty and recruitment of adult emotion regulatory neurocircuitry.

PubMed

Liberzon, Israel; Ma, Sean T; Okada, Go; Ho, S Shaun; Swain, James E; Evans, Gary W

2015-11-01

One in five American children grows up in poverty. Childhood poverty has far-reaching adverse impacts on cognitive, social and emotional development. Altered development of neurocircuits, subserving emotion regulation, is one possible pathway for childhood poverty's ill effects. Children exposed to poverty were followed into young adulthood and then studied using functional brain imaging with an implicit emotion regulation task focused. Implicit emotion regulation involved attention shifting and appraisal components. Early poverty reduced left dorsolateral prefrontal cortex recruitment in the context of emotional regulation. Furthermore, this emotion regulation associated brain activation mediated the effects of poverty on adult task performance. Moreover, childhood poverty also predicted enhanced insula and reduced hippocampal activation, following exposure to acute stress. These results demonstrate that childhood poverty can alter adult emotion regulation neurocircuitry, revealing specific brain mechanisms that may underlie long-term effects of social inequalities on health. The role of poverty-related emotion regulatory neurocircuitry appears to be particularly salient during stressful conditions. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

PSD-95 expression controls l-DOPA dyskinesia through dopamine D1 receptor trafficking

PubMed Central

Porras, Gregory; Berthet, Amandine; Dehay, Benjamin; Li, Qin; Ladepeche, Laurent; Normand, Elisabeth; Dovero, Sandra; Martinez, Audrey; Doudnikoff, Evelyne; Martin-Négrier, Marie-Laure; Chuan, Qin; Bloch, Bertrand; Choquet, Daniel; Boué-Grabot, Eric; Groc, Laurent; Bezard, Erwan

2012-01-01

l-DOPA–induced dyskinesia (LID), a detrimental consequence of dopamine replacement therapy for Parkinson’s disease, is associated with an alteration in dopamine D1 receptor (D1R) and glutamate receptor interactions. We hypothesized that the synaptic scaffolding protein PSD-95 plays a pivotal role in this process, as it interacts with D1R, regulates its trafficking and function, and is overexpressed in LID. Here, we demonstrate in rat and macaque models that disrupting the interaction between D1R and PSD-95 in the striatum reduces LID development and severity. Single quantum dot imaging revealed that this benefit was achieved primarily by destabilizing D1R localization, via increased lateral diffusion followed by increased internalization and diminished surface expression. These findings indicate that altering D1R trafficking via synapse-associated scaffolding proteins may be useful in the treatment of dyskinesia in Parkinson’s patients. PMID:23041629

Microarray analysis reveals overlapping and specific transcriptional responses to different plant hormones in rice

PubMed Central

Garg, Rohini; Tyagi, Akhilesh K.; Jain, Mukesh

2012-01-01

Hormones exert pleiotropic effects on plant growth and development throughout the life cycle. Many of these effects are mediated at molecular level via altering gene expression. In this study, we investigated the exogenous effect of plant hormones, including auxin, cytokinin, abscisic acid, ethylene, salicylic acid and jasmonic acid, on the transcription of rice genes at whole genome level using microarray. Our analysis identified a total of 4171 genes involved in several biological processes, whose expression was altered significantly in the presence of different hormones. Further, 28% of these genes exhibited overlapping transcriptional responses in the presence of any two hormones, indicating crosstalk among plant hormones. In addition, we identified genes showing only a particular hormone-specific response, which can be used as hormone-specific markers. The results of this study will facilitate further studies in hormone biology in rice. PMID:22827941

DNA Fingerprinting of Lactic Acid Bacteria in Sauerkraut Fermentations▿ † ‡

PubMed Central

Plengvidhya, Vethachai; Breidt, Fredrick; Lu, Zhongjing; Fleming, Henry P.

2007-01-01

Previous studies using traditional biochemical identification methods to study the ecology of commercial sauerkraut fermentations revealed that four species of lactic acid bacteria, Leuconostoc mesenteroides, Lactobacillus plantarum, Pediococcus pentosaceus, and Lactobacillus brevis, were the primary microorganisms in these fermentations. In this study, 686 isolates were collected from four commercial fermentations and analyzed by DNA fingerprinting. The results indicate that the species of lactic acid bacteria present in sauerkraut fermentations are more diverse than previously reported and include Leuconostoc citreum, Leuconostoc argentinum, Lactobacillus paraplantarum, Lactobacillus coryniformis, and Weissella sp. The newly identified species Leuconostoc fallax was also found. Unexpectedly, only two isolates of P. pentosaceus and 15 isolates of L. brevis were recovered during this study. A better understanding of the microbiota may aid in the development of low-salt fermentations, which may have altered microflora and altered sensory characteristics. PMID:17921264

An atypical case of neuroleptic malignant syndrome precipitated by valproate.

PubMed

Verma, Rajesh; Junewar, Vivek; Rathaur, Bhanu Pratap Singh

2014-03-06

Neuroleptic malignant syndrome (NMS) can be caused by various drugs. We report a case of a 60-year-old woman who presented with high-grade fever, muscular rigidity, tachycardia, tachypnoea and altered sensorium along with seizures. She had been taking olanzapine for the past 2 years for psychosis. For the last month valproate was added to her treatment. Her blood investigations revealed hyponatraemia and raised serum ammonia and creatinine phosphokinase (CPK) levels. In view of hyperthermia, muscular rigidity, autonomic disturbances, altered mental status and raised CPK, a diagnosis of NMS was made. Valproate could have probably precipitated NMS; although the patient was taking antipsychotics for a long time, it was only with the addition of valproate that she developed these symptoms. Raised serum ammonia levels also indicated the presence of valproate toxicity. Seizures were probably due to electrolyte disturbances. Offending drugs were withdrawn. The patient improved with treatment by dopamine agonist and other supportive treatments.

Keratin 17 null mice exhibit age- and strain-dependent alopecia.

PubMed

McGowan, Kevin M; Tong, Xuemei; Colucci-Guyon, Emma; Langa, Francina; Babinet, Charles; Coulombe, Pierre A

2002-06-01

Onset of type I keratin 17 (K17) synthesis marks the adoption of an appendageal fate within embryonic ectoderm, and its expression persists in specific cell types within mature hair, glands, and nail. We report that K17 null mice develop severe alopecia during the first week postbirth, correlating with hair fragility, alterations in follicular histology, and apoptosis in matrix cells. These alterations are incompletely penetrant and normalize starting with the first postnatal cycle. Absence of a hair phenotype correlates with a genetic strain-dependent compensation by related keratins, including K16. These findings reveal a crucial role for K17 in the structural integrity of the first hair produced and the survival of hair-producing cells. Given that identical inherited mutations in this gene can cause either pachyonychia congenita or steatocystoma multiplex, the features of this mouse model suggest that this clinical heterogeneity arises from a cell type-specific, genetically determined compensation by related keratins.

Antibacterial Activity Affected by the Conformational Flexibility in Glycine-Lysine Based α-Helical Antimicrobial Peptides.

PubMed

Rončević, Tomislav; Vukičević, Damir; Ilić, Nada; Krce, Lucija; Gajski, Goran; Tonkić, Marija; Goić-Barišić, Ivana; Zoranić, Larisa; Sonavane, Yogesh; Benincasa, Monica; Juretić, Davor; Maravić, Ana; Tossi, Alessandro

2018-04-12

Antimicrobial peptides often show broad-spectrum activity due to a mechanism based on bacterial membrane disruption, which also reduces development of permanent resistance, a desirable characteristic in view of the escalating multidrug resistance problem. Host cell toxicity however requires design of artificial variants of natural AMPs to increase selectivity and reduce side effects. Kiadins were designed using rules obtained from natural peptides active against E. coli and a validated computational algorithm based on a training set of such peptides, followed by rational conformational alterations. In vitro activity, tested against ESKAPE strains (ATCC and clinical isolates), revealed a varied activity spectrum and cytotoxicity that only in part correlated with conformational flexibility. Peptides with a higher proportion of Gly were generally less potent and caused less bacterial membrane alteration, as observed by flow cytometry and AFM, which correlate to structural characteristics as observed by circular dichroism spectroscopy and predicted by molecular dynamics calculations.

Epigenetic regulation in human melanoma: past and future.

PubMed

Sarkar, Debina; Leung, Euphemia Y; Baguley, Bruce C; Finlay, Graeme J; Askarian-Amiri, Marjan E

2015-01-01

The development and progression of melanoma have been attributed to independent or combined genetic and epigenetic events. There has been remarkable progress in understanding melanoma pathogenesis in terms of genetic alterations. However, recent studies have revealed a complex involvement of epigenetic mechanisms in the regulation of gene expression, including methylation, chromatin modification and remodeling, and the diverse activities of non-coding RNAs. The roles of gene methylation and miRNAs have been relatively well studied in melanoma, but other studies have shown that changes in chromatin status and in the differential expression of long non-coding RNAs can lead to altered regulation of key genes. Taken together, they affect the functioning of signaling pathways that influence each other, intersect, and form networks in which local perturbations disturb the activity of the whole system. Here, we focus on how epigenetic events intertwine with these pathways and contribute to the molecular pathogenesis of melanoma.

Design rules for biomolecular adhesion: lessons from force measurements.

PubMed

Leckband, Deborah

2010-01-01

Cell adhesion to matrix, other cells, or pathogens plays a pivotal role in many processes in biomolecular engineering. Early macroscopic methods of quantifying adhesion led to the development of quantitative models of cell adhesion and migration. The more recent use of sensitive probes to quantify the forces that alter or manipulate adhesion proteins has revealed much greater functional diversity than was apparent from population average measurements of cell adhesion. This review highlights theoretical and experimental methods that identified force-dependent molecular properties that are central to the biological activity of adhesion proteins. Experimental and theoretical methods emphasized in this review include the surface force apparatus, atomic force microscopy, and vesicle-based probes. Specific examples given illustrate how these tools have revealed unique properties of adhesion proteins and their structural origins.

Two Mind-Altering Curriculums: Contemplation, Mindfulness, and the Educational Question Whether "To Think or Not to Think?"

ERIC Educational Resources Information Center

Ergas, Oren

2013-01-01

Findings "from" neuroscience and psychological research reveal that the mind's "default" state is "wandering" bearing directly on our well-being. These findings raise difficult questions as to the premises underlying the curriculum rendered as a "mind-altering device" (Eisner, 1993). This article analyzes…

Spectral, mineralogical, and geochemical variations across Home Plate, Gusev Crater, Mars indicate high and low temperature alteration

USGS Publications Warehouse

Schmidt, M.E.; Farrand, W. H.; Johnson, J. R.; Schroder, C.; Hurowitz, J.A.; McCoy, T.J.; Ruff, S.W.; Arvidson, R. E.; Des Marais, D.J.; Lewis, K.W.; Ming, D. W.; Squyres, S. W.; De Souza, P.A.

2009-01-01

Over the last ~ 3??years in Gusev Crater, Mars, the Spirit rover observed coherent variations in color, mineralogy, and geochemistry across Home Plate, an ~ 80??m-diameter outcrop of basaltic tephra. Observations of Home Plate from orbit and from the summit of Husband Hill reveal clear differences in visible/near-infrared (VNIR) colors between its eastern and western regions that are consistent with mineralogical compositions indicated by M??ssbauer spectrometer (MB) and by Miniature Thermal Emission Spectrometer (Mini-TES). Pyroxene and magnetite dominate the east side, while olivine, nanophase Fe oxide (npOx) and glass are more abundant on the western side. Alpha Particle X-Ray Spectrometer (APXS) observations reveal that eastern Home Plate has higher Si/Mg, Al, Zn, Ni, and K, while Cl and Br are higher in the west. We propose that these variations are the result of two distinct alteration regimes that may or may not be temporally related: a localized, higher temperature recrystallization and alteration of the east side of Home Plate and lower temperature alteration of the western side that produced npOx.

Metabolic Reprogramming in Amyotrophic Lateral Sclerosis.

PubMed

Szelechowski, M; Amoedo, N; Obre, E; Léger, C; Allard, L; Bonneu, M; Claverol, S; Lacombe, D; Oliet, S; Chevallier, S; Le Masson, G; Rossignol, R

2018-03-02

Mitochondrial dysfunction in the spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the neurometabolic alterations during early stages of the disease remain unknown. Here, we investigated the bioenergetic and proteomic changes in ALS mouse motor neurons and patients' skin fibroblasts. We first observed that SODG93A mice presymptomatic motor neurons display alterations in the coupling efficiency of oxidative phosphorylation, along with fragmentation of the mitochondrial network. The proteome of presymptomatic ALS mice motor neurons also revealed a peculiar metabolic signature with upregulation of most energy-transducing enzymes, including the fatty acid oxidation (FAO) and the ketogenic components HADHA and ACAT2, respectively. Accordingly, FAO inhibition altered cell viability specifically in ALS mice motor neurons, while uncoupling protein 2 (UCP2) inhibition recovered cellular ATP levels and mitochondrial network morphology. These findings suggest a novel hypothesis of ALS bioenergetics linking FAO and UCP2. Lastly, we provide a unique set of data comparing the molecular alterations found in human ALS patients' skin fibroblasts and SODG93A mouse motor neurons, revealing conserved changes in protein translation, folding and assembly, tRNA aminoacylation and cell adhesion processes.

Combined metabolomic and correlation networks analyses reveal fumarase insufficiency altered amino acid metabolism.

PubMed

Hou, Entai; Li, Xian; Liu, Zerong; Zhang, Fuchang; Tian, Zhongmin

2018-04-01

Fumarase catalyzes the interconversion of fumarate and l-malate in the tricarboxylic acid cycle. Fumarase insufficiencies were associated with increased levels of fumarate, decreased levels of malate and exacerbated salt-induced hypertension. To gain insights into the metabolism profiles induced by fumarase insufficiency and identify key regulatory metabolites, we applied a GC-MS based metabolomics platform coupled with a network approach to analyze fumarase insufficient human umbilical vein endothelial cells (HUVEC) and negative controls. A total of 24 altered metabolites involved in seven metabolic pathways were identified as significantly altered, and enriched for the biological module of amino acids metabolism. In addition, Pearson correlation network analysis revealed that fumaric acid, l-malic acid, l-aspartic acid, glycine and l-glutamic acid were hub metabolites according to Pagerank based on their three centrality indices. Alanine aminotransferase and glutamate dehydrogenase activities increased significantly in fumarase deficiency HUVEC. These results confirmed that fumarase insufficiency altered amino acid metabolism. The combination of metabolomics and network methods would provide another perspective on expounding the molecular mechanism at metabolomics level. Copyright © 2017 John Wiley & Sons, Ltd.

Iron deficiency alters megakaryopoiesis and platelet phenotype independent of thrombopoietin.

PubMed

Evstatiev, Rayko; Bukaty, Adam; Jimenez, Kristine; Kulnigg-Dabsch, Stefanie; Surman, Lidia; Schmid, Werner; Eferl, Robert; Lippert, Kathrin; Scheiber-Mojdehkar, Barbara; Kvasnicka, Hans Michael; Khare, Vineeta; Gasche, Christoph

2014-05-01

Iron deficiency is a common cause of reactive thrombocytosis, however, the exact pathways have not been revealed. Here we aimed to study the mechanisms behind iron deficiency-induced thrombocytosis. Within few weeks, iron-depleted diet caused iron deficiency in young Sprague-Dawley rats, as reflected by a drop in hemoglobin, mean corpuscular volume, hepatic iron content and hepcidin mRNA in the liver. Thrombocytosis established in parallel. Moreover, platelets produced in iron deficient animals displayed a higher mean platelet volume and increased aggregation. Bone marrow studies revealed subtle alterations that are suggestive of expansion of megakaryocyte progenitors, an increase in megakaryocyte ploidy and accelerated megakaryocyte differentiation. Iron deficiency did not alter the production of hematopoietic growth factors such as thrombopoietin, interleukin 6 or interleukin 11. Megakaryocytic cell lines grown in iron-depleted conditions exhibited reduced proliferation but increased ploidy and cell size. Our data suggest that iron deficiency increases megakaryopoietic differentiation and alters platelet phenotype without changes in megakaryocyte growth factors, specifically TPO. Iron deficiency-induced thrombocytosis may have evolved to maintain or increase the coagulation capacity in conditions with chronic bleeding. Copyright © 2014 Wiley Periodicals, Inc.

Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations

PubMed Central

Wankhade, Umesh D.; Zhong, Ying; Kang, Ping; Alfaro, Maria; Chintapalli, Sree V.; Thakali, Keshari M.

2017-01-01

Objective Non-alcoholic fatty liver disease (NAFLD) is an important co-morbidity associated with obesity and a precursor to steatohepatitis. However, the contributions of gestational and early life influences on development of NAFLD and NASH remain poorly appreciated. Methods Two independent studies were performed to examine whether maternal over-nutrition via exposure to high fat diet (HFD) leads to exacerbated hepatic responses to post-natal HFD and methionine choline deficient (MCD) diets in the offspring. Offspring of both control diet- and HFD-fed dams were weaned onto control and HFD, creating four groups. Results When compared to their control diet-fed littermates, offspring of HF-dams weaned onto HFD gained greater body weight; had increased relative liver weight and showed hepatic steatosis and inflammation. Similarly, this group revealed significantly greater immune response and pro-fibrogenic gene expression via RNA-seq. In parallel, 7–8 week old offspring were challenged with either control or MCD diets for 3 weeks. Responses to MCD diets were also exacerbated due to maternal HFD as seen by gene expression of classical pro-fibrogenic genes. Quantitative genome-scale DNA methylation analysis of over 1 million CpGs showed persistent epigenetic changes in key genes in tissue development and metabolism (Fgf21, Ppargc1β) with maternal HFD and in cell adhesion and communication (VWF, Ephb2) in the combination of maternal HFD and offspring MCD diets. Maternal HFD also influenced gut microbiome profiles in offspring leading to a decrease in α-diversity. Linear regression analysis revealed association between serum ALT levels and Coprococcus, Coriobacteriacae, Helicobacterioceae and Allobaculum. Conclusion Our findings indicate that maternal HFD detrimentally alters epigenetic and gut microbiome pathways to favor development of fatty liver disease and its progressive sequelae. PMID:28414763

Drosophila small heat shock protein CryAB ensures structural integrity of developing muscles, and proper muscle and heart performance.

PubMed

Wójtowicz, Inga; Jabłońska, Jadwiga; Zmojdzian, Monika; Taghli-Lamallem, Ouarda; Renaud, Yoan; Junion, Guillaume; Daczewska, Malgorzata; Huelsmann, Sven; Jagla, Krzysztof; Jagla, Teresa

2015-03-01

Molecular chaperones, such as the small heat shock proteins (sHsps), maintain normal cellular function by controlling protein homeostasis in stress conditions. However, sHsps are not only activated in response to environmental insults, but also exert developmental and tissue-specific functions that are much less known. Here, we show that during normal development the Drosophila sHsp CryAB [L(2)efl] is specifically expressed in larval body wall muscles and accumulates at the level of Z-bands and around myonuclei. CryAB features a conserved actin-binding domain and, when attenuated, leads to clustering of myonuclei and an altered pattern of sarcomeric actin and the Z-band-associated actin crosslinker Cheerio (filamin). Our data suggest that CryAB and Cheerio form a complex essential for muscle integrity: CryAB colocalizes with Cheerio and, as revealed by mass spectrometry and co-immunoprecipitation experiments, binds to Cheerio, and the muscle-specific attenuation of cheerio leads to CryAB-like sarcomeric phenotypes. Furthermore, muscle-targeted expression of CryAB(R120G), which carries a mutation associated with desmin-related myopathy (DRM), results in an altered sarcomeric actin pattern, in affected myofibrillar integrity and in Z-band breaks, leading to reduced muscle performance and to marked cardiac arrhythmia. Taken together, we demonstrate that CryAB ensures myofibrillar integrity in Drosophila muscles during development and propose that it does so by interacting with the actin crosslinker Cheerio. The evidence that a DRM-causing mutation affects CryAB muscle function and leads to DRM-like phenotypes in the fly reveals a conserved stress-independent role of CryAB in maintaining muscle cell cytoarchitecture. © 2015. Published by The Company of Biologists Ltd.

Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations.

PubMed

Wankhade, Umesh D; Zhong, Ying; Kang, Ping; Alfaro, Maria; Chintapalli, Sree V; Thakali, Keshari M; Shankar, Kartik

2017-01-01

Non-alcoholic fatty liver disease (NAFLD) is an important co-morbidity associated with obesity and a precursor to steatohepatitis. However, the contributions of gestational and early life influences on development of NAFLD and NASH remain poorly appreciated. Two independent studies were performed to examine whether maternal over-nutrition via exposure to high fat diet (HFD) leads to exacerbated hepatic responses to post-natal HFD and methionine choline deficient (MCD) diets in the offspring. Offspring of both control diet- and HFD-fed dams were weaned onto control and HFD, creating four groups. When compared to their control diet-fed littermates, offspring of HF-dams weaned onto HFD gained greater body weight; had increased relative liver weight and showed hepatic steatosis and inflammation. Similarly, this group revealed significantly greater immune response and pro-fibrogenic gene expression via RNA-seq. In parallel, 7-8 week old offspring were challenged with either control or MCD diets for 3 weeks. Responses to MCD diets were also exacerbated due to maternal HFD as seen by gene expression of classical pro-fibrogenic genes. Quantitative genome-scale DNA methylation analysis of over 1 million CpGs showed persistent epigenetic changes in key genes in tissue development and metabolism (Fgf21, Ppargc1β) with maternal HFD and in cell adhesion and communication (VWF, Ephb2) in the combination of maternal HFD and offspring MCD diets. Maternal HFD also influenced gut microbiome profiles in offspring leading to a decrease in α-diversity. Linear regression analysis revealed association between serum ALT levels and Coprococcus, Coriobacteriacae, Helicobacterioceae and Allobaculum. Our findings indicate that maternal HFD detrimentally alters epigenetic and gut microbiome pathways to favor development of fatty liver disease and its progressive sequelae.

Serum Metabolomic Profiling in Acute Alcoholic Hepatitis Identifies Multiple Dysregulated Pathways

PubMed Central

Rachakonda, Vikrant; Gabbert, Charles; Raina, Amit; Bell, Lauren N.; Cooper, Sara; Malik, Shahid; Behari, Jaideep

2014-01-01

Background and Objectives While animal studies have implicated derangements of global energy homeostasis in the pathogenesis of acute alcoholic hepatitis (AAH), the relevance of these findings to the development of human AAH remains unclear. Using global, unbiased serum metabolomics analysis, we sought to characterize alterations in metabolic pathways associated with severe AAH and identify potential biomarkers for disease prognosis. Methods This prospective, case-control study design included 25 patients with severe AAH and 25 ambulatory patients with alcoholic cirrhosis. Serum samples were collected within 24 hours of the index clinical encounter. Global, unbiased metabolomics profiling was performed. Patients were followed for 180 days after enrollment to determine survival. Results Levels of 234 biochemicals were altered in subjects with severe AAH. Random-forest analysis, principal component analysis, and integrated hierarchical clustering methods demonstrated that metabolomics profiles separated the two cohorts with 100% accuracy. Severe AAH was associated with enhanced triglyceride lipolysis, impaired mitochondrial fatty acid beta oxidation, and upregulated omega oxidation. Low levels of multiple lysolipids and related metabolites suggested decreased plasma membrane remodeling in severe AAH. While most measured bile acids were increased in severe AAH, low deoxycholate and glycodeoxycholate levels indicated intestinal dysbiosis. Several changes in substrate utilization for energy homeostasis were identified in severe AAH, including increased glucose consumption by the pentose phosphate pathway, altered tricarboxylic acid (TCA) cycle activity, and enhanced peptide catabolism. Finally, altered levels of small molecules related to glutathione metabolism and antioxidant vitamin depletion were observed in patients with severe AAH. Univariable logistic regression revealed 15 metabolites associated with 180-day survival in severe AAH. Conclusion Severe AAH is characterized by a distinct metabolic phenotype spanning multiple pathways. Metabolomics profiling revealed a panel of biomarkers for disease prognosis, and future studies are planned to validate these findings in larger cohorts of patients with severe AAH. PMID:25461442

The Triangle of Death in Alzheimer's Disease Brain: The Aberrant Cross-Talk Among Energy Metabolism, Mammalian Target of Rapamycin Signaling, and Protein Homeostasis Revealed by Redox Proteomics.

PubMed

Di Domenico, Fabio; Barone, Eugenio; Perluigi, Marzia; Butterfield, D Allan

2017-03-10

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and represents one of the most disabling conditions. AD shares many features in common with systemic insulin resistance diseases, suggesting that it can be considered as a metabolic disease, characterized by reduced insulin-stimulated growth and survival signaling, increased oxidative stress (OS), proinflammatory cytokine activation, mitochondrial dysfunction, impaired energy metabolism, and altered protein homeostasis. Recent Advances: Reduced glucose utilization and energy metabolism in AD have been associated with the buildup of amyloid-β peptide and hyperphosphorylated tau, increased OS, and the accumulation of unfolded/misfolded proteins. Mammalian target of rapamycin (mTOR), which is aberrantly activated in AD since early stages, plays a key role during AD neurodegeneration by, on one side, inhibiting insulin signaling as a negative feedback mechanism and, on the other side, regulating protein homeostasis (synthesis/clearance). It is likely that the concomitant and mutual alterations of energy metabolism-mTOR signaling-protein homeostasis might represent a self-sustaining triangle of harmful events that trigger the degeneration and death of neurons and the development and progression of AD. Intriguingly, the altered cross-talk between the components of such a triangle of death, beyond altering the redox homeostasis of the neuron, is further exacerbated by increased levels of OS that target and impair key components of the pathways involved. Redox proteomic studies in human samples and animal models of AD-like dementia led to identification of oxidatively modified components of the pathways composing the triangle of death, therefore revealing the crucial role of OS in fueling this aberrant vicious cycle. The identification of compounds able to restore the function of the pathways targeted by oxidative damage might represent a valuable therapeutic approach to slow or delay AD. Antioxid. Redox Signal. 26, 364-387.

Assessment of flow regime alterations over a spectrum of temporal scales using wavelet-based approaches

NASA Astrophysics Data System (ADS)

Wu, Fu-Chun; Chang, Ching-Fu; Shiau, Jenq-Tzong

2015-05-01

The full range of natural flow regime is essential for sustaining the riverine ecosystems and biodiversity, yet there are still limited tools available for assessment of flow regime alterations over a spectrum of temporal scales. Wavelet analysis has proven useful for detecting hydrologic alterations at multiple scales via the wavelet power spectrum (WPS) series. The existing approach based on the global WPS (GWPS) ratio tends to be dominated by the rare high-power flows so that alterations of the more frequent low-power flows are often underrepresented. We devise a new approach based on individual deviations between WPS (DWPS) that are root-mean-squared to yield the global DWPS (GDWPS). We test these two approaches on the three reaches of the Feitsui Reservoir system (Taiwan) that are subjected to different classes of anthropogenic interventions. The GDWPS reveal unique features that are not detected with the GWPS ratios. We also segregate the effects of individual subflow components on the overall flow regime alterations using the subflow GDWPS. The results show that the daily hydropeaking waves below the reservoir not only intensified the flow oscillations at daily scale but most significantly eliminated subweekly flow variability. Alterations of flow regime were most severe below the diversion weir, where the residual hydropeaking resulted in a maximum impact at daily scale while the postdiversion null flows led to large hydrologic alterations over submonthly scales. The smallest impacts below the confluence reveal that the hydrologic alterations at scales longer than 2 days were substantially mitigated with the joining of the unregulated tributary flows, whereas the daily-scale hydrologic alteration was retained because of the hydropeaking inherited from the reservoir releases. The proposed DWPS approach unravels for the first time the details of flow regime alterations at these intermediate scales that are overridden by the low-frequency high-power flows when the long-term averaged GWPS are used.

Homeodomain protein Otp affects developmental neuropeptide switching in oxytocin neurons associated with a long-term effect on social behavior

PubMed Central

Wircer, Einav; Blechman, Janna; Borodovsky, Nataliya; Tsoory, Michael; Nunes, Ana Rita; Oliveira, Rui F; Levkowitz, Gil

2017-01-01

Proper response to stress and social stimuli depends on orchestrated development of hypothalamic neuronal circuits. Here we address the effects of the developmental transcription factor orthopedia (Otp) on hypothalamic development and function. We show that developmental mutations in the zebrafish paralogous gene otpa but not otpb affect both stress response and social preference. These behavioral phenotypes were associated with developmental alterations in oxytocinergic (OXT) neurons. Thus, otpa and otpb differentially regulate neuropeptide switching in a newly identified subset of OXT neurons that co-express the corticotropin-releasing hormone (CRH). Single-cell analysis revealed that these neurons project mostly to the hindbrain and spinal cord. Ablation of this neuronal subset specifically reduced adult social preference without affecting stress behavior, thereby uncoupling the contribution of a specific OXT cluster to social behavior from the general otpa−/− deficits. Our findings reveal a new role for Otp in controlling developmental neuropeptide balance in a discrete OXT circuit whose disrupted development affects social behavior. DOI: http://dx.doi.org/10.7554/eLife.22170.001 PMID:28094761

Investigations of potential endocrine disruption and sexual dimorphism in nestling tree swallows (Tachycineta bicolor) with a range of PCB body burdens

USGS Publications Warehouse

Yorks, A.L.; Rattner, B.A.; Melancon, M.J.; Bakst, M.R.

1998-01-01

Polychlorinated biphenyls (PCBs) elicit endocrine disruptive effects in many species, including birds. Tree swallows (Tachycineta bicolor) were studied at eight sites, located in Maryland, Pennsylvania, and New York, with a range of PCB contamination to determine effects on gender and gonadal development of nestling offipring. Blood samples were collected from nestlings and genetic sex was determined by polymerase chain reaction amplification of sex chromatin in nucleated red blood cells. Gonads were excised and fixed for subsequent gross and histologic examination. PCB analyses of twelve-day old nestlings indicated that residue concentrations varied considerably among the eight sites. Of the 145 nestlings examined anatomically, the phenotypic sex ratio was 53% female and 47% male. No intersexes were observed. Histological observations revealed some variation such as numbers of spermatogonia and stages of follicular development among individuals. Genotypic evaluation of the 145 nestlings revealed complete concordance with phenotypic observations. Although there were significant differences in PCB exposure among study sites, there was no evidence of abnormal gonadal development or anatomical gender alteration in nestling Tree swallows.

The importance of proper bioinformatics analysis and clinical interpretation of tumor genomic profiling: a case study of undifferentiated sarcoma and a constitutional pathogenic BRCA2 mutation and an MLH1 variant of uncertain significance.

PubMed

Varga, Elizabeth; Chao, Elizabeth C; Yeager, Nicholas D

2015-09-01

Next-generation sequencing (NGS) technology is increasingly utilized to identify therapeutic targets for patients with malignancy. This technology also has the capability to reveal the presence of constitutional genetic alterations, which may have significant implications for patients and their family members. Here we present the case of a 23 year old Caucasian patient with recurrent undifferentiated sarcoma who had NGS-based tumor analysis using an assay which simultaneously analyzed the entire coding sequence of 236 cancer-related genes (3769 exons) plus 47 introns from 19 genes often rearranged or altered in cancer. Pathogenic alterations were reported in tumor as the predicted protein alterations, BRCA2 "R645fs*15″ and MLH1 "E694*". Because constitutional BRCA2 and MLH1 gene mutations are associated with Hereditary Breast Ovarian Cancer Syndrome (HBOCS) and Lynch syndrome respectively, sequence analysis of DNA isolated from peripheral blood was performed. The presence of the alterations, BRCA2 c.1929delG and MLH1 c.2080G>T, corresponding to the previously reported predicted protein alterations, were confirmed by Sanger sequencing in the constitutional DNA. An additional DNA finding was reported in this analysis, MLH1 c.2081A>C at the neighboring nucleotide. Further evaluation of the family revealed that all alterations were paternally inherited and the two MLH1 substitutions were in cis, more appropriately referred to as MLH1 c.2080_2081delGAinsTC, which is classified as a variant of uncertain significance. This case illustrates important considerations related to appropriate interpretation of NGS tumor results and follow-up of patients with potentially deleterious constitutional alterations.

Clinically Relevant Cytotoxic Immune Cell Signatures and Clonal Expansion of T Cell Receptors in High-risk MYCN-not-amplified Human Neuroblastoma | Office of Cancer Genomics

Cancer.gov

Purpose: High-risk neuroblastoma is an aggressive disease. DNA sequencing studies have revealed a paucity of actionable genomic alterations and a low mutation burden, posing challenges to develop effective novel therapies. We used RNA sequencing (RNA-seq) to investigate the biology of this disease including a focus on tumor-infiltrating lymphocytes (TILs). Experimental Design: We performed deep RNA-seq on pre-treatment diagnostic tumors from 129 high-risk and 21 low- or intermediate-risk patients with neuroblastomas.

Intra-tumor heterogeneity of cancer cells and its implications for cancer treatment

PubMed Central

Sun, Xiao-xiao; Yu, Qiang

2015-01-01

Recent studies have revealed extensive genetic and non-genetic variation across different geographical regions of a tumor or throughout different stages of tumor progression, which is referred to as intra-tumor heterogeneity. Several causes contribute to this phenomenon, including genomic instability, epigenetic alteration, plastic gene expression, signal transduction, and microenvironmental differences. These variables may affect key signaling pathways that regulate cancer cell growth, drive phenotypic diversity, and pose challenges to cancer treatment. Understanding the mechanisms underlying this heterogeneity will support the development of effective therapeutic strategies. PMID:26388155

Sultr4;1 mutant seeds of Arabidopsis have an enhanced sulphate content and modified proteome suggesting metabolic adaptations to altered sulphate compartmentalization

PubMed Central

2010-01-01

Background Sulphur is an essential macronutrient needed for the synthesis of many cellular components. Sulphur containing amino acids and stress response-related compounds, such as glutathione, are derived from reduction of root-absorbed sulphate. Sulphate distribution in cell compartments necessitates specific transport systems. The low-affinity sulphate transporters SULTR4;1 and SULTR4;2 have been localized to the vacuolar membrane, where they may facilitate sulphate efflux from the vacuole. Results In the present study, we demonstrated that the Sultr4;1 gene is expressed in developing Arabidopsis seeds to a level over 10-fold higher than the Sultr4;2 gene. A characterization of dry mature seeds from a Sultr4;1 T-DNA mutant revealed a higher sulphate content, implying a function for this transporter in developing seeds. A fine dissection of the Sultr4;1 seed proteome identified 29 spots whose abundance varied compared to wild-type. Specific metabolic features characteristic of an adaptive response were revealed, such as an up-accumulation of various proteins involved in sugar metabolism and in detoxification processes. Conclusions This study revealed a role for SULTR4;1 in determining sulphate content of mature Arabidopsis seeds. Moreover, the adaptive response of sultr4;1 mutant seeds as revealed by proteomics suggests a function of SULTR4;1 in redox homeostasis, a mechanism that has to be tightly controlled during development of orthodox seeds. PMID:20426829

Use of the electrosurgical unit in a carbon dioxide atmosphere.

PubMed

Culp, William C; Kimbrough, Bradly A; Luna, Sarah; Maguddayao, Aris J; Eidson, Jack L; Paolino, David V

2016-01-01

The electrosurgical unit (ESU) utilizes an electrical discharge to cut and coagulate tissue and is often held above the surgical site, causing a spark to form. The voltage at which the spark is created, termed the breakdown voltage, is governed by the surrounding gaseous environment. Surgeons are now utilizing the ESU laparoscopically with carbon dioxide insufflation, potentially altering ESU operating characteristics. This study examines the clinical implications of altering gas composition by measuring the spark gap distance as a marker of breakdown voltage and use of the ESU on a biologic model, both in room air and carbon dioxide. Paschen's Law predicted a 35% decrease in gap distance in carbon dioxide, while testing revealed an average drop of 37-47% as compared to air. However, surgical model testing revealed no perceivable clinical difference. Electrosurgery can be performed in carbon dioxide environments, although surgeons should be aware of potentially altered ESU performance.

Rare-earth element fractionation in uranium ore and its U(VI) alteration minerals

DOE PAGES

Balboni, Enrica; Spano, T; Cook, N; ...

2017-10-20

We developed a cation exchange chromatography method employing sulfonated polysterene cation resin (DOWEX AG50-X8) in order to separate rare-earth elements (REEs) from uranium-rich materials. The chemical separation scheme is designed to reduce matrix effects and consequently yield enhanced ionization efficiencies for concentration determinations of REEs without significant fractionation using solution mode-inductively coupled plasma mass spectrometry (ICP-MS) analysis. This method was then applied to determine REE abundances in four uraninite (ideally UO 2) samples and their associated U(VI) alteration minerals. In three of the samples analyzed, the concentration of REEs for primary uraninite are higher than those for their corresponding secondarymore » uranium alteration phases. The results for U(VI) alteration minerals of two samples indicate enrichment of the light REEs (LREEs) over the heavy REEs (HREEs). This differential mobilization is attributed to differences in the mineralogical composition of the U(VI) alteration. There is a lack of fractionation of the LREEs in the uraninite alteration rind that is composed of U(VI) minerals containing Ca 2+ as the interlayer cation (uranophane and bequerelite); contrarily, U(VI) alteration minerals containing K + and Pb 2+ as interlayer cations (fourmarierite, dumontite) indicate fractionation (enrichment) of the LREEs. Our results have implications for nuclear forensic analyses since a comparison is reported between the REE abundances for the CUP-2 (processed uranium ore) certified reference material and previously determined values for uranium ore concentrate (UOC) produced from the same U deposit (Blind River/Elliott Lake, Canada). UOCs represent the most common form of interdicted nuclear material and consequently is material frequently targeted for forensic analysis. The comparison reveals similar chondrite normalized REE signatures but variable absolute abundances. Based on the results reported here, the latter may be attributed to the differing REE abundances between primary ore and associated alteration phases, and/or is related to varying fabrication processes adopted during production of UOC.« less

Rare-earth element fractionation in uranium ore and its U(VI) alteration minerals

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

Balboni, Enrica; Spano, T; Cook, N

We developed a cation exchange chromatography method employing sulfonated polysterene cation resin (DOWEX AG50-X8) in order to separate rare-earth elements (REEs) from uranium-rich materials. The chemical separation scheme is designed to reduce matrix effects and consequently yield enhanced ionization efficiencies for concentration determinations of REEs without significant fractionation using solution mode-inductively coupled plasma mass spectrometry (ICP-MS) analysis. This method was then applied to determine REE abundances in four uraninite (ideally UO 2) samples and their associated U(VI) alteration minerals. In three of the samples analyzed, the concentration of REEs for primary uraninite are higher than those for their corresponding secondarymore » uranium alteration phases. The results for U(VI) alteration minerals of two samples indicate enrichment of the light REEs (LREEs) over the heavy REEs (HREEs). This differential mobilization is attributed to differences in the mineralogical composition of the U(VI) alteration. There is a lack of fractionation of the LREEs in the uraninite alteration rind that is composed of U(VI) minerals containing Ca 2+ as the interlayer cation (uranophane and bequerelite); contrarily, U(VI) alteration minerals containing K + and Pb 2+ as interlayer cations (fourmarierite, dumontite) indicate fractionation (enrichment) of the LREEs. Our results have implications for nuclear forensic analyses since a comparison is reported between the REE abundances for the CUP-2 (processed uranium ore) certified reference material and previously determined values for uranium ore concentrate (UOC) produced from the same U deposit (Blind River/Elliott Lake, Canada). UOCs represent the most common form of interdicted nuclear material and consequently is material frequently targeted for forensic analysis. The comparison reveals similar chondrite normalized REE signatures but variable absolute abundances. Based on the results reported here, the latter may be attributed to the differing REE abundances between primary ore and associated alteration phases, and/or is related to varying fabrication processes adopted during production of UOC.« less

Multiple Roles of Integrin-Linked Kinase in Epidermal Development, Maturation and Pigmentation Revealed by Molecular Profiling

PubMed Central

Judah, David; Rudkouskaya, Alena; Wilson, Ryan; Carter, David E.; Dagnino, Lina

2012-01-01

Integrin-linked kinase (ILK) is an important scaffold protein that mediates a variety of cellular responses to integrin stimulation by extracellular matrix proteins. Mice with epidermis-restricted inactivation of the Ilk gene exhibit pleiotropic phenotypic defects, including impaired hair follicle morphogenesis, reduced epidermal adhesion to the basement membrane, compromised epidermal integrity, as well as wasting and failure to thrive leading to perinatal death. To better understand the underlying molecular mechanisms that cause such a broad range of alterations, we investigated the impact of Ilk gene inactivation on the epidermis transcriptome. Microarray analysis showed over 700 differentially regulated mRNAs encoding proteins involved in multiple aspects of epidermal function, including keratinocyte differentiation and barrier formation, inflammation, regeneration after injury, and fundamental epidermal developmental pathways. These studies also revealed potential effects on genes not previously implicated in ILK functions, including those important for melanocyte and melanoblast development and function, regulation of cytoskeletal dynamics, and homeobox genes. This study shows that ILK is a critical regulator of multiple aspects of epidermal function and homeostasis, and reveals the previously unreported involvement of ILK not only in epidermal differentiation and barrier formation, but also in melanocyte genesis and function. PMID:22574216

Multiple roles of integrin-linked kinase in epidermal development, maturation and pigmentation revealed by molecular profiling.

PubMed

Judah, David; Rudkouskaya, Alena; Wilson, Ryan; Carter, David E; Dagnino, Lina

2012-01-01

Integrin-linked kinase (ILK) is an important scaffold protein that mediates a variety of cellular responses to integrin stimulation by extracellular matrix proteins. Mice with epidermis-restricted inactivation of the Ilk gene exhibit pleiotropic phenotypic defects, including impaired hair follicle morphogenesis, reduced epidermal adhesion to the basement membrane, compromised epidermal integrity, as well as wasting and failure to thrive leading to perinatal death. To better understand the underlying molecular mechanisms that cause such a broad range of alterations, we investigated the impact of Ilk gene inactivation on the epidermis transcriptome. Microarray analysis showed over 700 differentially regulated mRNAs encoding proteins involved in multiple aspects of epidermal function, including keratinocyte differentiation and barrier formation, inflammation, regeneration after injury, and fundamental epidermal developmental pathways. These studies also revealed potential effects on genes not previously implicated in ILK functions, including those important for melanocyte and melanoblast development and function, regulation of cytoskeletal dynamics, and homeobox genes. This study shows that ILK is a critical regulator of multiple aspects of epidermal function and homeostasis, and reveals the previously unreported involvement of ILK not only in epidermal differentiation and barrier formation, but also in melanocyte genesis and function.

Hypnosis as a model of functional neurologic disorders.

PubMed

Deeley, Q

2016-01-01

In the 19th century it was recognized that neurologic symptoms could be caused by "morbid ideation" as well as organic lesions. The subsequent observation that hysteric (now called "functional") symptoms could be produced and removed by hypnotic suggestion led Charcot to hypothesize that suggestion mediated the effects of ideas on hysteric symptoms through as yet unknown effects on brain activity. The advent of neuroimaging 100 years later revealed strikingly similar neural correlates in experiments matching functional symptoms with clinical analogs created by suggestion. Integrative models of suggested and functional symptoms regard these alterations in brain function as the endpoint of a broader set of changes in information processing due to suggestion. These accounts consider that suggestions alter experience by mobilizing representations from memory systems, and altering causal attributions, during preconscious processing which alters the content of what is provided to our highly edited subjective version of the world. Hypnosis as a model for functional symptoms draws attention to how radical alterations in experience and behavior can conform to the content of mental representations through effects on cognition and brain function. Experimental study of functional symptoms and their suggested counterparts in hypnosis reveals the distinct and shared processes through which this can occur. © 2016 Elsevier B.V. All rights reserved.

MGMT DNA repair gene promoter/enhancer haplotypes alter transcription factor binding and gene expression.

PubMed

Xu, Meixiang; Cross, Courtney E; Speidel, Jordan T; Abdel-Rahman, Sherif Z

2016-10-01

The O 6 -methylguanine-DNA methyltransferase (MGMT) protein removes O 6 -alkyl-guanine adducts from DNA. MGMT expression can thus alter the sensitivity of cells and tissues to environmental and chemotherapeutic alkylating agents. Previously, we defined the haplotype structure encompassing single nucleotide polymorphisms (SNPs) in the MGMT promoter/enhancer (P/E) region and found that haplotypes, rather than individual SNPs, alter MGMT promoter activity. The exact mechanism(s) by which these haplotypes exert their effect on MGMT promoter activity is currently unknown, but we noted that many of the SNPs comprising the MGMT P/E haplotypes are located within or in close proximity to putative transcription factor binding sites. Thus, these haplotypes could potentially affect transcription factor binding and, subsequently, alter MGMT promoter activity. In this study, we test the hypothesis that MGMT P/E haplotypes affect MGMT promoter activity by altering transcription factor (TF) binding to the P/E region. We used a promoter binding TF profiling array and a reporter assay to evaluate the effect of different P/E haplotypes on TF binding and MGMT expression, respectively. Our data revealed a significant difference in TF binding profiles between the different haplotypes evaluated. We identified TFs that consistently showed significant haplotype-dependent binding alterations (p ≤ 0.01) and revealed their role in regulating MGMT expression using siRNAs and a dual-luciferase reporter assay system. The data generated support our hypothesis that promoter haplotypes alter the binding of TFs to the MGMT P/E and, subsequently, affect their regulatory function on MGMT promoter activity and expression level.

Assessment of collective impact of upstream watershed development and basin-wide successive droughts on downstream flow regime: The Lesser Zab transboundary basin

NASA Astrophysics Data System (ADS)

Al-Faraj, Furat A. M.; Al-Dabbagh, Bassam N. S.

2015-11-01

Rapid population growth and socio-economic development coupled with climate change and variability have observably impaired the natural characteristics of hydrological regimes of most of large rivers worldwide. The Lesser Zab shared between Iraq and Iran was one of the few remaining rather intact transboundary river watersheds. The unregulated natural flow pattern, however, has been shifted mainly due to recent upstream anthropogenic factors incorporated with successive droughts. A new generic approach was introduced through integrating a subset of the Indicators of Hydrologic Alteration (IHA) into three generic empirical equations coupled with the application of two universally endorsed drought indices to assess the changes in hydrological patterns prior to, and after upstream watershed development twinned with consecutive drought spells. A departure of about -16% was detected in the long-term median annual runoff in the artificially impaired periods. Alterations ranged from -3.4% to -41.7% were linked to monthly medians. The 1- to 90-day minimum runoffs were dropped between -33.3% and -53.8% over the regulated period. More substantial shifts were perceived between 1999 and 2013. The rates of anomaly ranged from -55.6% to -73.1%. The extreme minimum flows were experienced low to high alterations, while low to moderate degree of anomalies were associated with 1- to 90-day maximum flows. This rate of increased water withdrawal is anticipated to develop and the vulnerability degree of the downstream riparian country is projected to increase. Findings reveal that the impact of successive basin-wide drought episodes has considerably outweighed the effect of current recent upstream damming and water withdrawals.

Altering carbon allocation in hybrid poplar (Populus alba × grandidentata) impacts cell wall growth and development.

PubMed

Unda, Faride; Kim, Hoon; Hefer, Charles; Ralph, John; Mansfield, Shawn D

2017-07-01

Galactinol synthase is a pivotal enzyme involved in the synthesis of the raffinose family of oligosaccharides (RFOs) that function as transport carbohydrates in the phloem, as storage compounds in sink tissues and as soluble metabolites that combat both abiotic and biotic stress in several plant species. Hybrid poplar (Populus alba × grandidentata) overexpressing the Arabidopsis thaliana GolS3 (AtGolS3) gene showed clear effects on development; the extreme overexpressing lines were stunted and had cell wall traits characteristic of tension wood, whereas lines with only moderate up-regulation grew normally and had moderately altered secondary cell wall composition and ultrastructure. Stem cross-sections of the developing xylem revealed a significant increase in the number of vessels, as well as the clear presence of a G-layer in the fibres. Furthermore, AtGolS3-OE lines possessed higher cellulose and lower lignin contents, an increase in cellulose crystallinity, and significantly altered hemicellulose-derived carbohydrates, notably manifested by their mannose and xylose contents. In addition, the transgenic plants displayed elevated xylem starch content. Transcriptome interrogation of the transgenic plants showed a significant up-regulation of genes involved in the synthesis of myo-inositol, along with genes involved in sucrose degradation. The results suggest that the overexpression of GolS and its product galactinol may serve as a molecular signal that initiates metabolic changes, culminating in a change in cell wall development and potentially the formation of tension wood. © 2016 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

Genome-wide methylation profiling and the PI3K-AKT pathway analysis associated with smoking in urothelial cell carcinoma.

PubMed

Brait, Mariana; Munari, Enrico; LeBron, Cynthia; Noordhuis, Maartje G; Begum, Shahnaz; Michailidi, Christina; Gonzalez-Roibon, Nilda; Maldonado, Leonel; Sen, Tanusree; Guerrero-Preston, Rafael; Cope, Leslie; Parrella, Paola; Fazio, Vito Michele; Ha, Patrick K; Netto, George J; Sidransky, David; Hoque, Mohammad O

2013-04-01

Urothelial cell carcinoma (UCC) is the second most common genitourinary malignant disease in the USA, and tobacco smoking is the major known risk factor for UCC development. Exposure to carcinogens, such as those contained in tobacco smoke, is known to directly or indirectly damage DNA, causing mutations, chromosomal deletion events and epigenetic alterations in UCC. Molecular studies have shown that chromosome 9 alterations and P53, RAS, RB and PTEN mutations are among the most frequent events in UCC. Recent studies suggested that continuous tobacco carcinogen exposure drives and enhances the selection of epigenetically altered cells in UCC, predominantly in the invasive form of the disease. However, the sequence of molecular events that leads to UCC after exposure to tobacco smoke is not well understood. To elucidate molecular events that lead to UCC oncogenesis and progression after tobacco exposure, we developed an in vitro cellular model for smoking-induced UCC. SV-40 immortalized normal HUC1 human bladder epithelial cells were continuously exposed to 0.1% cigarette smoke extract (CSE) until transformation occurred. Morphological alterations and increased cell proliferation of non-malignant urothelial cells were observed after 4 months (mo) of treatment with CSE. Anchorage-independent growth assessed by soft agar assay and increase in the migratory and invasive potential was observed in urothelial cells after 6 mo of CSE treatment. By performing a PCR mRNA expression array specific to the PI3K-AKT pathway, we found that 26 genes were upregulated and 22 genes were downregulated after 6 mo of CSE exposure of HUC1 cells. Among the altered genes, PTEN, FOXO1, MAPK1 and PDK1 were downregulated in the transformed cells, while AKT1, AKT2, HRAS, RAC1 were upregulated. Validation by RT-PCR and western blot analysis was then performed. Furthermore, genome-wide methylation analysis revealed MCAM, DCC and HIC1 are hypermethylated in CSE-treated urothelial cells when compared with non-CSE exposed cells. The methylation status of these genes was validated using quantitative methylation-specific PCR (QMSP), confirming an increase in methylation of CSE-treated urothelial cells compared to untreated controls. Therefore, our findings suggest that a tobacco signature could emerge from distinctive patterns of genetic and epigenetic alterations and can be identified using an in vitro cellular model for the development of smoking-induced cancer.

Genome-wide methylation profiling and the PI3K-AKT pathway analysis associated with smoking in urothelial cell carcinoma

PubMed Central

Brait, Mariana; Munari, Enrico; LeBron, Cynthia; Noordhuis, Maartje G.; Begum, Shahnaz; Michailidi, Christina; Gonzalez-Roibon, Nilda; Maldonado, Leonel; Sen, Tanusree; Guerrero-Preston, Rafael; Cope, Leslie; Parrella, Paola; Fazio, Vito Michele; Ha, Patrick K.; Netto, George J.; Sidransky, David; Hoque, Mohammad O.

2013-01-01

Urothelial cell carcinoma (UCC) is the second most common genitourinary malignant disease in the USA, and tobacco smoking is the major known risk factor for UCC development. Exposure to carcinogens, such as those contained in tobacco smoke, is known to directly or indirectly damage DNA, causing mutations, chromosomal deletion events and epigenetic alterations in UCC. Molecular studies have shown that chromosome 9 alterations and P53, RAS, RB and PTEN mutations are among the most frequent events in UCC. Recent studies suggested that continuous tobacco carcinogen exposure drives and enhances the selection of epigenetically altered cells in UCC, predominantly in the invasive form of the disease. However, the sequence of molecular events that leads to UCC after exposure to tobacco smoke is not well understood. To elucidate molecular events that lead to UCC oncogenesis and progression after tobacco exposure, we developed an in vitro cellular model for smoking-induced UCC. SV-40 immortalized normal HUC1 human bladder epithelial cells were continuously exposed to 0.1% cigarette smoke extract (CSE) until transformation occurred. Morphological alterations and increased cell proliferation of non-malignant urothelial cells were observed after 4 months (mo) of treatment with CSE. Anchorage-independent growth assessed by soft agar assay and increase in the migratory and invasive potential was observed in urothelial cells after 6 mo of CSE treatment. By performing a PCR mRNA expression array specific to the PI3K-AKT pathway, we found that 26 genes were upregulated and 22 genes were downregulated after 6 mo of CSE exposure of HUC1 cells. Among the altered genes, PTEN, FOXO1, MAPK1 and PDK1 were downregulated in the transformed cells, while AKT1, AKT2, HRAS, RAC1 were upregulated. Validation by RT-PCR and western blot analysis was then performed. Furthermore, genome-wide methylation analysis revealed MCAM, DCC and HIC1 are hypermethylated in CSE-treated urothelial cells when compared with non-CSE exposed cells. The methylation status of these genes was validated using quantitative methylation-specific PCR (QMSP), confirming an increase in methylation of CSE-treated urothelial cells compared to untreated controls. Therefore, our findings suggest that a tobacco signature could emerge from distinctive patterns of genetic and epigenetic alterations and can be identified using an in vitro cellular model for the development of smoking-induced cancer. PMID:23435205

Metabonomics reveals metabolite changes in biliary atresia infants.

PubMed

Zhou, Kejun; Xie, Guoxiang; Wang, Jun; Zhao, Aihua; Liu, Jiajian; Su, Mingming; Ni, Yan; Zhou, Ying; Pan, Weihua; Che, Yanran; Zhang, Ting; Xiao, Yongtao; Wang, Yang; Wen, Jie; Jia, Wei; Cai, Wei

2015-06-05

Biliary atresia (BA) is a rare neonatal cholestatic disorder caused by obstruction of extra- and intra-hepatic bile ducts. If untreated, progressive liver cirrhosis will lead to death within 2 years. Early diagnosis and operation improve the outcome significantly. Infants with neonatal hepatitis syndrome (NHS) present similar symptoms, confounding the early diagnosis of BA. The lack of noninvasive diagnostic methods to differentiate BA from NHS greatly delays the surgery of BA infants, thus deteriorating the outcome. Here we performed a metabolomics study in plasma of BA, NHS, and healthy infants using gas chromatography-time-of-flight mass spectrometry. Scores plots of orthogonal partial least-squares discriminant analysis clearly separated BA from NHS and healthy infants. Eighteen metabolites were found to be differentially expressed between BA and NHS, among which seven (l-glutamic acid, l-ornithine, l-isoleucine, l-lysine, l-valine, l-tryptophan, and l-serine) were amino acids. The altered amino acids were quantitatively verified using ultraperformance liquid chromatography-tandem mass spectrometry. Ingenuity pathway analysis revealed the network of "Cellular Function and Maintenance, Hepatic System Development and Function, Neurological Disease" was altered most significantly. This study suggests that plasma metabolic profiling has great potential in differentiating BA from NHS, and amino acid metabolism is significantly different between the two diseases.

High temperatures reveal cryptic genetic variation in a polymorphic female sperm storage organ.

PubMed

Berger, David; Bauerfeind, Stephanie Sandra; Blanckenhorn, Wolf Ulrich; Schäfer, Martin Andreas

2011-10-01

Variation in female reproductive morphology may play a decisive role in reproductive isolation by affecting the relative fertilization success of alternative male phenotypes. Yet, knowledge of how environmental variation may influence the development of the female reproductive tract and thus alter the arena of postcopulatory sexual selection is limited. Yellow dung fly females possess either three or four sperm storage compartments, a polymorphism with documented influence on sperm precedence. We performed a quantitative genetics study including 12 populations reared at three developmental temperatures complemented by extensive field data to show that warm developmental temperatures increase the frequency of females with four compartments, revealing striking hidden genetic variation for the polymorphism. Systematic genetic differentiation in growth rate and spermathecal number along latitude, and phenotypic covariance between the traits across temperature treatments suggest that the genetic architecture underlying the polymorphism is shaped by selection on metabolic rate. Our findings illustrate how temperature can modulate the preconditions for sexual selection by differentially exposing novel variation in reproductive morphology. This implies that environmental change may substantially alter the dynamics of sexual selection. We further discuss how temperature-dependent developmental plasticity may have contributed to observed rapid evolutionary transitions in spermathecal morphology. © 2011 The Author(s). Evolution© 2011 The Society for the Study of Evolution.

Neurobehavioral changes in response to alterations in gene expression profiles in the brains of mice exposed to low and high levels of mercury vapor during postnatal development.

PubMed

Yoshida, Minoru; Honda, Akiko; Watanabe, Chiho; Satoh, Masahiko; Yasutake, Akira

2014-08-01

This study examined the relationship between neurobehavioral changes and alterations in gene expression profiles in the brains of mice exposed to different levels of Hg(0) during postnatal development. Neonatal mice were repeatedly exposed to mercury vapor (Hg(0)) at a concentration of 0.057 mg/m(3) (low level), which was close to the current threshold value (TLV), and 0.197 mg/m(3) (high level) for 24 hr until the 20(th) day postpartum. Behavioral responses were evaluated based on changes in locomotor activity in the open field test (OPF), learning ability in the passive avoidance response test (PA), and spatial learning ability in the Morris water maze (MM) at 12 weeks of age. No significant differences were observed in the three behavioral measurements between mice exposed to the low level of Hg(0) and control mice. On the other hand, total locomotive activity in mice exposed to the high level of Hg(0) was significantly decreased and central locomotion was reduced in the OPF task. Mercury concentrations were approximately 0.4 μg/g and 1.9 μg/g in the brains of mice exposed to the low and high levels of Hg(0), respectively. Genomic analysis revealed that the expression of 2 genes was up-regulated and 18 genes was down-regulated in the low-level exposure group, while the expression of 3 genes was up-regulated and 70 genes was down-regulated in the high-level exposure group. Similar alterations in the expression of seven genes, six down-regulated genes and one up-regulated gene, were observed in both groups. The results indicate that an increase in the number of altered genes in the brain may be involved in the emergence of neurobehavioral effects, which may be associated with the concentration of mercury in the brain. Moreover, some of the commonly altered genes following exposure to both concentrations of Hg(0) with and without neurobehavioral effects may be candidates as sensitive biomarker genes for assessing behavioral effects in the early stages of development.

Sex differences in associations between white matter microstructure and gonadal hormones in children and adolescents with prenatal alcohol exposure.

PubMed

Uban, K A; Herting, M M; Wozniak, J R; Sowell, E R

2017-09-01

Despite accumulating evidence from animal models demonstrating that prenatal alcohol exposure (PAE) results in life-long neuroendocrine dysregulation, very little is known on this topic among humans with fetal alcohol spectrum disorders (FASD). We expected that alterations in gonadal hormones might interfere with the typical development of white matter (WM) myelination, and in a sex-dependent manner, in human adolescents with FASD. In order to investigate this hypothesis, we used diffusion tensor imaging (DTI) to assess: 1) whether or not sex moderates the impact of PAE on WM microstructure; and 2) how gonadal hormones relate to alterations in WM microstructure in children and adolescents affected by PAE. 61 youth (9 to 16 yrs.; 49% girls; 50% PAE) participated as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD). DTI scans and passive drool samples were obtained to examine neurodevelopmental associations with testosterone (T) and dehydroepiandrosterone (DHEA) levels in boys and girls, and estradiol (E2) and progesterone (P) levels in girls. Tract-based spatial statistics were utilized to generate fractional anisotropy (FA) and mean diffusivity (MD) for 9 a priori WM regions of interest (ROIs). As predicted, alterations in FA were observed in adolescents with PAE relative to controls, and these differences varied by sex. Girls with PAE exhibited lower FA (Inferior fronto-occipital and Uncinate fasciculi) while boys with PAE exhibited higher FA (Callosal body, Cingulum, Corticospinal tract, Optic radiation, Superior longitudinal fasciculus) relative to age-matched controls. When gonadal hormone levels were examined in relation to DTI measures, additional group differences in FA were revealed, demonstrating that neuroendocrine factors are associated with PAE-related brain alterations. These findings provide human evidence that PAE relates to sex-specific differences in WM microstructure, and underlying alterations in gonadal hormone function may, in part, contribute to these effects. Determining PAE-effects on neuroendocrine function among humans is an essential first step towards developing novel clinical (e.g., assessment or intervention) tools that target hormone systems to improve on-going brain development among children and adolescents with FASD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Identification of proteins in the aqueous humor associated with cataract development using iTRAQ methodology.

PubMed

Xiang, Minhong; Zhang, Xingru; Li, Qingsong; Wang, Hanmin; Zhang, Zhenyong; Han, Zhumei; Ke, Meiqing; Chen, Xingxing

2017-05-01

Proteins in the aqueous humor (AH) are important in the induction of cataract development. The identification of cataract-associated proteins assists in identifying patients and predisposed to the condition and improve treatment efficacy. Proteomics analysis has previously been used for identifying protein markers associated with eye diseases; however, few studies have examined the proteomic alterations in cataract development due to high myopia, glaucoma and diabetes. The present study, using the isobaric tagging for relative and absolute protein quantification methodology, aimed to examine cataract-associated proteins in the AH from patients with high myopia, glaucoma or diabetes, and controls. The results revealed that 445 proteins were identified in the AH groups, compared with the control groups, and 146, 264 and 130 proteins were differentially expressed in the three groups of patients, respectively. In addition, 44 of these proteins were determined to be cataract‑associated, and the alterations of five randomly selected proteins were confirmed using enzyme-linked immunosorbent assays. The biological functions of these 44 cataract-associated proteins were analyzed using Gen Ontology/pathways annotation, in addition to protein‑protein interaction network analysis. The results aimed to expand current knowledge of the pathophysiologic characteristics of cataract development and provided a panel of candidates for biomarkers of the disease, which may assist in further diagnosis and the monitoring of cataract development.

Sociotechnical challenges to developing technologies for patient access to health information exchange data

PubMed Central

Ancker, Jessica S; Miller, Melissa C; Patel, Vaishali; Kaushal, Rainu

2014-01-01

Background Providing patients with access to their medical data is widely expected to help educate and empower them to manage their own health. Health information exchange (HIE) infrastructures could potentially help patients access records across multiple healthcare providers. We studied three HIE organizations as they developed portals to give consumers access to HIE data previously exchanged only among healthcare organizations. Objective To follow the development of new consumer portal technologies, and to identify barriers and facilitators to patient access to HIE data. Methods Semistructured interviews of 15 key informants over a 2-year period spanning the development and early implementation of three new projects, coded according to a sociotechnical framework. Results As the organizations tried to develop functionality that fully served the needs of both providers and patients, plans were altered by technical barriers (primarily related to data standardization) and cultural and legal issues surrounding data access. Organizational changes also played an important role in altering project plans. In all three cases, patient access to data was significantly scaled back from initial plans. Conclusions This prospective study revealed how sociotechnical factors previously identified as important in health information technology success and failure helped to shape the evolution of three novel consumer informatics projects. Barriers to providing patients with seamless access to their HIE data were multifactorial. Remedies will have to address technical, organizational, cultural, and other factors. PMID:24064443

Identification of Serum Metabolites Associated With Incident Hypertension in the European Prospective Investigation into Cancer and Nutrition-Potsdam Study.

PubMed

Dietrich, Stefan; Floegel, Anna; Weikert, Cornelia; Prehn, Cornelia; Adamski, Jerzy; Pischon, Tobias; Boeing, Heiner; Drogan, Dagmar

2016-08-01

Metabolomics is a promising tool to gain new insights into early metabolic alterations preceding the development of hypertension in humans. We therefore aimed to identify metabolites associated with incident hypertension using measured data of serum metabolites of the European Prospective Investigation Into Cancer and Nutrition (EPIC)-Potsdam study. Targeted metabolic profiling was conducted on serum blood samples of a randomly drawn EPIC-Potsdam subcohort consisting of 135 cases and 981 noncases of incident hypertension, all of them being free of hypertension and not on antihypertensive therapy at the time of blood sampling. Mean follow-up was 9.9 years. A validated set of 127 metabolites was statistically analyzed with a random survival forest backward selection algorithm to identify predictive metabolites of incident hypertension taking into account important epidemiological hypertension risk markers. Six metabolites were identified to be most predictive for the development of hypertension. Higher concentrations of serine, glycine, and acyl-alkyl-phosphatidylcholines C42:4 and C44:3 tended to be associated with higher and diacyl-phosphatidylcholines C38:4 and C38:3 with lower predicted 10-year hypertension-free survival, although visualization by partial plots revealed some nonlinearity in the above associations. The identified metabolites improved prediction of incident hypertension when used together with known risk markers of hypertension. In conclusion, these findings indicate that metabolic alterations occur early in the development of hypertension. However, these alterations are confined to a few members of the amino acid or phosphatidylcholine metabolism, respectively. © 2016 American Heart Association, Inc.

Cell periphery-related proteins as major genomic targets behind the adaptive evolution of an industrial Saccharomyces cerevisiae strain to combined heat and hydrolysate stress.

PubMed

Wallace-Salinas, Valeria; Brink, Daniel P; Ahrén, Dag; Gorwa-Grauslund, Marie F

2015-07-09

Laboratory evolution is an important tool for developing robust yeast strains for bioethanol production since the biological basis behind combined tolerance requires complex alterations whose proper regulation is difficult to achieve by rational metabolic engineering. Previously, we reported on the evolved industrial Saccharomyces cerevisiae strain ISO12 that had acquired improved tolerance to grow and ferment in the presence of lignocellulose-derived inhibitors at high temperature (39 °C). In the current study, we used comparative genomics to uncover the extent of the genomic alterations that occurred during the evolution process and investigated possible associations between the mutations and the phenotypic traits in ISO12. Through whole-genome sequencing and variant calling we identified a high number of strain-unique SNPs and INDELs in both ISO12 and the parental strain Ethanol Red. The variants were predicted to have 760 non-synonymous effects in both strains combined and were significantly enriched in Gene Ontology terms related to cell periphery, membranes and cell wall. Eleven genes, including MTL1, FLO9/FLO11, and CYC3 were found to be under positive selection in ISO12. Additionally, the FLO genes exhibited changes in copy number, and the alterations to this gene family were correlated with experimental results of multicellularity and invasive growth in the adapted strain. An independent lipidomic analysis revealed further differences between the strains in the content of nine lipid species. Finally, ISO12 displayed improved viability in undiluted spruce hydrolysate that was unrelated to reduction of inhibitors and changes in cell wall integrity, as shown by HPLC and lyticase assays. Together, the results of the sequence comparison and the physiological characterisations indicate that cell-periphery proteins (e.g. extracellular sensors such as MTL1) and peripheral lipids/membranes are important evolutionary targets in the process of adaptation to the combined stresses. The capacity of ISO12 to develop complex colony formation also revealed multicellularity as a possible evolutionary strategy to improve competitiveness and tolerance to environmental stresses (also reflected by the FLO genes). Although a panel of altered genes with high relevance to the novel phenotype was detected, this study also demonstrates that the observed long-term molecular effects of thermal and inhibitor stress have polygenetic basis.

EVALUATION OF LOW-SUN ILLUMINATED LANDSAT-4 THEMATIC MAPPER DATA FOR MAPPING HYDROTHERMALLY ALTERED ROCKS IN SOUTHERN NEVADA.

USGS Publications Warehouse

Podwysocki, Melvin H.; Power, Marty S.; Salisbury, Jack; Jones, O.D.

1984-01-01

Landsat-4 Thematic Mapper (TM) data of southern Nevada collected under conditions of low-angle solar illumination were digitally processed to identify hydroxyl-bearing minerals commonly associated with hydrothermal alteration in volcanic terrains. Digital masking procedures were used to exclude shadow areas and vegetation and thus to produce a CRC image suitable for testing the new TM bands as a means to map hydrothermally altered rocks. Field examination of a masked CRC image revealed that several different types of altered rocks displayed hues associated with spectral characteristics common to hydroxyl-bearing minerals. Several types of unaltered rocks also displayed similar hues.

Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress.

PubMed

Papale, Ligia A; Li, Sisi; Madrid, Andy; Zhang, Qi; Chen, Li; Chopra, Pankaj; Jin, Peng; Keleş, Sündüz; Alisch, Reid S

2016-12-01

Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders. While it is well known that acute environmental stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive epigenetic modification that is highly enriched in neurons and is associated with active neuronal transcription. Recently, we reported a genome-wide disruption of hippocampal 5hmC in male mice following acute stress that was correlated to altered transcript levels of genes in known stress related pathways. Since sex-specific endocrine mechanisms respond to environmental stimulus by altering the neuronal epigenome, we examined the genome-wide profile of hippocampal 5hmC in female mice following exposure to acute stress and identified 363 differentially hydroxymethylated regions (DhMRs) linked to known (e.g., Nr3c1 and Ntrk2) and potentially novel genes associated with stress response and psychiatric disorders. Integration of hippocampal expression data from the same female mice found stress-related hydroxymethylation correlated to altered transcript levels. Finally, characterization of stress-induced sex-specific 5hmC profiles in the hippocampus revealed 778 sex-specific acute stress-induced DhMRs some of which were correlated to altered transcript levels that produce sex-specific isoforms in response to stress. Together, the alterations in 5hmC presented here provide a possible molecular mechanism for the adaptive sex-specific response to stress that may augment the design of novel therapeutic agents that will have optimal effectiveness in each sex. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

The correlations between alteration of p16 gene and clinicopathological factors and prognosis in squamous cell carcinomas of the buccal mucosa.

PubMed

Dong, Yuying; Wang, Jie; Dong, Fusheng; Wang, Xu; Zhang, Yinghuai

2012-07-01

To evaluate relationships between the alteration of p16 gene and the clinical status and prognosis of the patients with squamous cell carcinoma of the buccal mucosa. Thirty buccal cancers were included in the analysis. Deletion analysis was performed by PCR. Point mutation analysis was used by PCR-SSCP and direct sequencing. Methylation-specific PCR methods were adopted for the evaluation of p16 methylation. The correlation between alteration of p16 gene and clinicopathological factors buccal cancer was evaluated by Fisher's exact test. Kaplan-Meier and Cox regression were used to investigate the relationship between p16 alteration and survival time. The frequency of p16 alteration was 63.3% in buccal carcinomas. P16 deletion was associated significantly with tumor size (P = 0.01). P16 point mutation was associated significantly with differentiation (P = 0.006). P16 methylation was associated significantly with nodes metastasis (P = 0.027). The overall survival rate of 30 buccal carcinomas was 53.3%. The Log-rank test (P = 0.021) and univariate Cox regression analysis (P = 0.030) revealed that p16 methylation was significantly associated with the overall survival rate. Multivariate analysis showed that p16 deletion, p16 mutation, and p16 methylation were not statistically significant. The alterations of p16 gene may play a major role in malignancy and development and metastases of buccal carcinoma and may be an excellent marker of aggressive clinical behavior. P16 methylation has a prognostic value in buccal carcinoma but not an independent prognosis factor. P16 point mutation and p16 deletion have not prognostic significance in buccal carcinoma. © 2012 John Wiley & Sons A/S.

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

PubMed

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

2018-03-01

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

The legacy of land-use is revealed in the biogeochemistry of urban streams

EPA Science Inventory

Urban streams are among the most profoundly impacted aquatic ecosystems, characterized by altered hydrology or burial, increased sediment input, and myriad pollutants. We present results from a series of urban stream studies that revealed unique geochemical and biochemical patte...

Teacher Interactions within the Physical Environment: How Teachers Alter Their Space and/or Routines Because of Classroom Character.

ERIC Educational Resources Information Center

Lang, Dale Christopher

Through questionnaires, observations, and interviews, this study revealed the degree to which 31 high school teachers altered their classroom spaces and/or adjusted their routines to meet their pedagogical goals at a temporary school site. Teachers emphatically desired: (1) an appropriate amount of space to rearrange student furniture, enabling…

Visual Circuit Development Requires Patterned Activity Mediated by Retinal Acetylcholine Receptors

PubMed Central

Burbridge, Timothy J.; Xu, Hong-Ping; Ackman, James B.; Ge, Xinxin; Zhang, Yueyi; Ye, Mei-Jun; Zhou, Z. Jimmy; Xu, Jian; Contractor, Anis; Crair, Michael C.

2014-01-01

SUMMARY The elaboration of nascent synaptic connections into highly ordered neural circuits is an integral feature of the developing vertebrate nervous system. In sensory systems, patterned spontaneous activity before the onset of sensation is thought to influence this process, but this conclusion remains controversial largely due to the inherent difficulty recording neural activity in early development. Here, we describe novel genetic and pharmacological manipulations of spontaneous retinal activity, assayed in vivo, that demonstrate a causal link between retinal waves and visual circuit refinement. We also report a de-coupling of downstream activity in retinorecipient regions of the developing brain after retinal wave disruption. Significantly, we show that the spatiotemporal characteristics of retinal waves affect the development of specific visual circuits. These results conclusively establish retinal waves as necessary and instructive for circuit refinement in the developing nervous system and reveal how neural circuits adjust to altered patterns of activity prior to experience. PMID:25466916

14 CFR 26.45 - Holders of type certificates-Alterations and repairs to alterations.

Code of Federal Regulations, 2012 CFR

2012-01-01

... AIRPLANES Aging Airplane Safety-Damage Tolerance Data for Repairs and Alterations § 26.45 Holders of type... alteration data developed by the holder of a type certificate, the holder must— (1) Review alteration data... Repairs Made to Alterations. For existing and future repair data developed by a holder of a type...

14 CFR 26.45 - Holders of type certificates-Alterations and repairs to alterations.

Code of Federal Regulations, 2014 CFR

2014-01-01

... AIRPLANES Aging Airplane Safety-Damage Tolerance Data for Repairs and Alterations § 26.45 Holders of type... alteration data developed by the holder of a type certificate, the holder must— (1) Review alteration data... Repairs Made to Alterations. For existing and future repair data developed by a holder of a type...

14 CFR 26.45 - Holders of type certificates-Alterations and repairs to alterations.

Code of Federal Regulations, 2013 CFR

2013-01-01

... AIRPLANES Aging Airplane Safety-Damage Tolerance Data for Repairs and Alterations § 26.45 Holders of type... alteration data developed by the holder of a type certificate, the holder must— (1) Review alteration data... Repairs Made to Alterations. For existing and future repair data developed by a holder of a type...

Short-term withdrawal from developmental exposure to cocaine activates the glucocorticoid receptor and alters spine dynamics.

PubMed

Caffino, Lucia; Giannotti, Giuseppe; Malpighi, Chiara; Racagni, Giorgio; Fumagalli, Fabio

2015-10-01

Although glucocorticoid receptors (GRs) contribute to the action of cocaine, their role following developmental exposure to the psychostimulant is still unknown. To address this issue, we exposed adolescent male rats to cocaine (20mg/kg/day) from post-natal day (PND) 28 to PND 42 and sacrificed them at PND 45 or 90. We studied the medial prefrontal cortex (mPFC), a brain region that is still developing during adolescence. In PND 45 rats we found enhanced GR transcription and translation as well as increased trafficking toward the nucleus of the receptor, with no alteration in plasma corticosterone levels. We also showed reduced expression of the GR co-chaperone FKBP51, that normally keeps the receptor in the cytoplasm, and increased expression of Src1, which cooperates in the activation of GR transcriptional activity, revealing that short withdrawal alters the finely tuned mechanisms regulating GR action. Since activation of GRs regulate dendritic spine morphology, we next investigated spine dynamics in cocaine-withdrawn rats. We found that PSD95, cofilin and F-actin, molecules regulating spine actin network, are reduced in the mPFC of PND 45 rats suggesting reduced spine density, confirmed by confocal imaging. Further, formation of filopodia, i.e. the inactive spines, is enhanced suggesting the formation of non-functional spines. Of note, no changes were found in molecules related to GR machinery or spine dynamics following long-term abstinence, i.e. in adult rats (PND 90). These findings demonstrate that short withdrawal promotes plastic changes in the developing brain via the dysregulation of the GR system and alterations in the spine network. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Cytokine and Chemokine Expression in Kidneys during Chronic Leptospirosis in Reservoir and Susceptible Animal Models

PubMed Central

Matsui, Mariko; Roche, Louise; Geroult, Sophie; Soupé-Gilbert, Marie-Estelle; Monchy, Didier; Huerre, Michel; Goarant, Cyrille

2016-01-01

Leptospirosis is caused by pathogenic spirochetes of the genus Leptospira. Humans can be infected after exposure to contaminated urine of reservoir animals, usually rodents, regarded as typical asymptomatic carriers of leptospires. In contrast, accidental hosts may present an acute form of leptospirosis with a range of clinical symptoms including the development of Acute Kidney Injury (AKI). Chronic Kidney Disease (CKD) is considered as a possible AKI-residual sequela but little is known about the renal pathophysiology consequent to leptospirosis infection. Herein, we studied the renal morphological alterations in relation with the regulation of inflammatory cytokines and chemokines, comparing two experimental models of chronic leptospirosis, the golden Syrian hamster that survived the infection, becoming carrier of virulent leptospires, and the OF1 mouse, a usual reservoir of the bacteria. Animals were monitored until 28 days after injection with a virulent L. borgpetersenii serogroup Ballum to assess chronic infection. Hamsters developed morphological alterations in the kidneys with tubulointerstitial nephritis and fibrosis. Grading of lesions revealed higher scores in hamsters compared to the slight alterations observed in the mouse kidneys, irrespective of the bacterial load. Interestingly, pro-fibrotic TGF-β was downregulated in mouse kidneys. Moreover, cytokines IL-1β and IL-10, and chemokines MIP-1α/CCL3 and IP-10/CXCL-10 were significantly upregulated in hamster kidneys compared to mice. These results suggest a possible maintenance of inflammatory processes in the hamster kidneys with the infiltration of inflammatory cells in response to bacterial carriage, resulting in alterations of renal tissues. In contrast, lower expression levels in mouse kidneys indicated a better regulation of the inflammatory response and possible resolution processes likely related to resistance mechanisms. PMID:27219334

Structural alterations of the mucosa stroma in the Barrett's esophagus metaplasia-dysplasia-adenocarcinoma sequence.

PubMed

Bobryshev, Yuri V; Killingsworth, Murray C; Lord, Reginald V N

2012-09-01

Accumulating evidence suggests that the extracellular matrix play important roles in intercellular communications and contribute to the development of a number of diseases, including diseases of the gastrointestinal tract. The present study examined the structural characteristics and alterations of the extracellular matrix of the mucosa stroma in the Barrett's esophagus metaplasia-dysplasia-adenocarcinoma sequence. A total of 41 esophageal tissue specimens (15 esophageal adenocarcinoma, 10 Barrett's esophagus intestinal metaplasia, seven dysplasia and nine normal esophagus) were studied. The present study used transmission electron microscopy and computerized quantitative electron-microscopic analysis in order to investigate the characteristics of the extracellular matrix of the mucosa. The study revealed that marked structural alterations of the mucosa stroma, relating to changes in the distribution and appearance of collagen fibers as well as to changes in numbers of matrix microvesicles, occur in Barrett's esophagus and esophageal adenocarcinoma. It was found that there were 3.1 times more microvesicles in the stroma in Barrett's esophagus than in the stroma of the normal esophagus (P<0.0001) and that there were 5.8 times more microvesicles in esophageal adenocarcinoma than in the normal esophagus (P<0.0001). There were 1.9 times more microvesicles in esophageal adenocarcinoma than in Barrett's esophagus (P=0.0043). The study demonstrates distinctive alterations of the mucosa stroma extracellular matrix in the metaplasia-dysplasia-adenocarcinoma sequence. The findings suggest that the redistribution of collagen fibers and increases in numbers of matrix microvesicles may play roles in the formation of specialized intestinal metaplasia and the development of adenocarcinoma. © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Voxel-based morphometry analysis reveals frontal brain differences in participants with ADHD and their unaffected siblings.

PubMed

Bralten, Janita; Greven, Corina U; Franke, Barbara; Mennes, Maarten; Zwiers, Marcel P; Rommelse, Nanda N J; Hartman, Catharina; van der Meer, Dennis; O'Dwyer, Laurence; Oosterlaan, Jaap; Hoekstra, Pieter J; Heslenfeld, Dirk; Arias-Vasquez, Alejandro; Buitelaar, Jan K

2016-06-01

Data on structural brain alterations in patients with attention-deficit/hyperactivity disorder (ADHD) have been inconsistent. Both ADHD and brain volumes have a strong genetic loading, but whether brain alterations in patients with ADHD are familial has been underexplored. We aimed to detect structural brain alterations in adolescents and young adults with ADHD compared with healthy controls. We examined whether these alterations were also found in their unaffected siblings, using a uniquely large sample. We performed voxel-based morphometry analyses on MRI scans of patients with ADHD, their unaffected siblings and typically developing controls. We identified brain areas that differed between participants with ADHD and controls and investigated whether these areas were different in unaffected siblings. Influences of medication use, age, sex and IQ were considered. Our sample included 307 patients with ADHD, 169 unaffected siblings and 196 typically developing controls (mean age 17.2 [range 8-30] yr). Compared with controls, participants with ADHD had significantly smaller grey matter volume in 5 clusters located in the precentral gyrus, medial and orbitofrontal cortex, and (para)cingulate cortices. Unaffected siblings showed intermediate volumes significantly different from controls in 4 of these clusters (all except the precentral gyrus). Medication use, age, sex and IQ did not have an undue influence on the results. Our sample was heterogeneous, most participants with ADHD were taking medication, and the comparison was cross-sectional. Brain areas involved in decision making, motivation, cognitive control and motor functioning were smaller in participants with ADHD than in controls. Investigation of unaffected siblings indicated familiality of 4 of the structural brain differences, supporting their potential in molecular genetic analyses in ADHD research.

Maternal exposure to fish oil primes offspring to harbor intestinal pathobionts associated with altered immune cell balance

PubMed Central

Gibson, DL; Gill, SK; Brown, K; Tasnim, N; Ghosh, S; Innis, S; Jacobson, K

2015-01-01

Our previous studies revealed that offspring from rat dams fed fish oil (at 8% and 18% energy), developed impaired intestinal barriers sensitizing the colon to exacerbated injury later in life. To discern the mechanism, we hypothesized that in utero exposure to fish oil, rich in n-3 polyunsaturated fatty acid (PUFA), caused abnormal intestinal reparative responses to mucosal injury through differences in intestinal microbiota and the presence of naïve immune cells. To identify such mechanisms, gut microbes and naïve immune cells were compared between rat pups born to dams fed either n-6 PUFA, n-3 PUFA or breeder chow. Maternal exposure to either of the PUFA rich diets altered the development of the intestinal microbiota with an overall reduction in microbial density. Using qPCR, we found that each type of PUFA differentially altered the major gut phyla; fish oil increased Bacteroidetes and safflower oil increased Firmicutes. Both PUFA diets reduced microbes known to dominate the infant gut like Enterobacteriaceae and Bifidobacteria spp. when compared to the chow group. Uniquely, maternal fish oil diets resulted in offspring showing blooms of opportunistic pathogens like Bilophila wadsworthia, Enterococcus faecium and Bacteroides fragilis in their gut microbiota. As well, fish oil groups showed a reduction in colonic CD8+ T cells, CD4+ Foxp3+ T cells and arginase+ M2 macrophages. In conclusion, fish oil supplementation in pharmacological excess, at 18% by energy as shown in this study, provides an example where excess dosing in utero can prime offspring to harbor intestinal pathobionts and alter immune cell homeostasis. PMID:25559197

Voxel-based morphometry analysis reveals frontal brain differences in participants with ADHD and their unaffected siblings

PubMed Central

Bralten, Janita; Greven, Corina U.; Franke, Barbara; Mennes, Maarten; Zwiers, Marcel P.; Rommelse, Nanda N.J.; Hartman, Catharina; van der Meer, Dennis; O’Dwyer, Laurence; Oosterlaan, Jaap; Hoekstra, Pieter J.; Heslenfeld, Dirk; Arias-Vasquez, Alejandro; Buitelaar, Jan K.

2016-01-01

Background Data on structural brain alterations in patients with attention-deficit/hyperactivity disorder (ADHD) have been inconsistent. Both ADHD and brain volumes have a strong genetic loading, but whether brain alterations in patients with ADHD are familial has been underexplored. We aimed to detect structural brain alterations in adolescents and young adults with ADHD compared with healthy controls. We examined whether these alterations were also found in their unaffected siblings, using a uniquely large sample. Methods We performed voxel-based morphometry analyses on MRI scans of patients with ADHD, their unaffected siblings and typically developing controls. We identified brain areas that differed between participants with ADHD and controls and investigated whether these areas were different in unaffected siblings. Influences of medication use, age, sex and IQ were considered. Results Our sample included 307 patients with ADHD, 169 unaffected siblings and 196 typically developing controls (mean age 17.2 [range 8–30] yr). Compared with controls, participants with ADHD had significantly smaller grey matter volume in 5 clusters located in the precentral gyrus, medial and orbitofrontal cortex, and (para)cingulate cortices. Unaffected siblings showed intermediate volumes significantly different from controls in 4 of these clusters (all except the precentral gyrus). Medication use, age, sex and IQ did not have an undue influence on the results. Limitations Our sample was heterogeneous, most participants with ADHD were taking medication, and the comparison was cross-sectional. Conclusion Brain areas involved in decision making, motivation, cognitive control and motor functioning were smaller in participants with ADHD than in controls. Investigation of unaffected siblings indicated familiality of 4 of the structural brain differences, supporting their potential in molecular genetic analyses in ADHD research. PMID:26679925

Beta/Gamma Oscillations and Event-Related Potentials Indicate Aberrant Multisensory Processing in Schizophrenia

PubMed Central

Balz, Johanna; Roa Romero, Yadira; Keil, Julian; Krebber, Martin; Niedeggen, Michael; Gallinat, Jürgen; Senkowski, Daniel

2016-01-01

Recent behavioral and neuroimaging studies have suggested multisensory processing deficits in patients with schizophrenia (SCZ). Thus far, the neural mechanisms underlying these deficits are not well understood. Previous studies with unisensory stimulation have shown altered neural oscillations in SCZ. As such, altered oscillations could contribute to aberrant multisensory processing in this patient group. To test this assumption, we conducted an electroencephalography (EEG) study in 15 SCZ and 15 control participants in whom we examined neural oscillations and event-related potentials (ERPs) in the sound-induced flash illusion (SIFI). In the SIFI multiple auditory stimuli that are presented alongside a single visual stimulus can induce the illusory percept of multiple visual stimuli. In SCZ and control participants we compared ERPs and neural oscillations between trials that induced an illusion and trials that did not induce an illusion. On the behavioral level, SCZ (55.7%) and control participants (55.4%) did not significantly differ in illusion rates. The analysis of ERPs revealed diminished amplitudes and altered multisensory processing in SCZ compared to controls around 135 ms after stimulus onset. Moreover, the analysis of neural oscillations revealed altered 25–35 Hz power after 100 to 150 ms over occipital scalp for SCZ compared to controls. Our findings extend previous observations of aberrant neural oscillations in unisensory perception paradigms. They suggest that altered ERPs and altered occipital beta/gamma band power reflect aberrant multisensory processing in SCZ. PMID:27999553

The first imported case of Rift Valley fever in China reveals a genetic reassortment of different viral lineages.

PubMed

Liu, Jingyuan; Sun, Yulan; Shi, Weifeng; Tan, Shuguang; Pan, Yang; Cui, Shujuan; Zhang, Qingchao; Dou, Xiangfeng; Lv, Yanning; Li, Xinyu; Li, Xitai; Chen, Lijuan; Quan, Chuansong; Wang, Qianli; Zhao, Yingze; Lv, Qiang; Hua, Wenhao; Zeng, Hui; Chen, Zhihai; Xiong, Haofeng; Jiang, Chengyu; Pang, Xinghuo; Zhang, Fujie; Liang, Mifang; Wu, Guizhen; Gao, George F; Liu, William J; Li, Ang; Wang, Quanyi

2017-01-18

We report the first imported case of Rift Valley fever (RVF) in China. The patient returned from Angola, a non-epidemic country, with an infection of a new reassortant from different lineages of Rift Valley fever viruses (RVFVs). The patient developed multiorgan dysfunction and gradually recovered with continuous renal replacement therapy and a short regimen of methylprednisolone treatment. The disordered cytokines and chemokines in the plasma of the patient revealed hypercytokinemia, but the levels of protective cytokines were low upon admission and fluctuated as the disease improved. Whole-genome sequencing and phylogenetic analysis revealed that the imported strain was a reassortant comprising the L and M genes from lineage E and the S gene from lineage A. This case highlights that RVFV had undergone genetic reassortment, which could potentially alter its biological properties, cause large outbreaks and pose a serious threat to global public health as well as the livestock breeding industry.

Cardiac electrical defects in progeroid mice and Hutchinson-Gilford progeria syndrome patients with nuclear lamina alterations.

PubMed

Rivera-Torres, José; Calvo, Conrado J; Llach, Anna; Guzmán-Martínez, Gabriela; Caballero, Ricardo; González-Gómez, Cristina; Jiménez-Borreguero, Luis J; Guadix, Juan A; Osorio, Fernando G; López-Otín, Carlos; Herraiz-Martínez, Adela; Cabello, Nuria; Vallmitjana, Alex; Benítez, Raul; Gordon, Leslie B; Jalife, José; Pérez-Pomares, José M; Tamargo, Juan; Delpón, Eva; Hove-Madsen, Leif; Filgueiras-Rama, David; Andrés, Vicente

2016-11-15

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by defective prelamin A processing, leading to nuclear lamina alterations, severe cardiovascular pathology, and premature death. Prelamin A alterations also occur in physiological aging. It remains unknown how defective prelamin A processing affects the cardiac rhythm. We show age-dependent cardiac repolarization abnormalities in HGPS patients that are also present in the Zmpste24 -/- mouse model of HGPS. Challenge of Zmpste24 -/- mice with the β-adrenergic agonist isoproterenol did not trigger ventricular arrhythmia but caused bradycardia-related premature ventricular complexes and slow-rate polymorphic ventricular rhythms during recovery. Patch-clamping in Zmpste24 -/- cardiomyocytes revealed prolonged calcium-transient duration and reduced sarcoplasmic reticulum calcium loading and release, consistent with the absence of isoproterenol-induced ventricular arrhythmia. Zmpste24 -/- progeroid mice also developed severe fibrosis-unrelated bradycardia and PQ interval and QRS complex prolongation. These conduction defects were accompanied by overt mislocalization of the gap junction protein connexin43 (Cx43). Remarkably, Cx43 mislocalization was also evident in autopsied left ventricle tissue from HGPS patients, suggesting intercellular connectivity alterations at late stages of the disease. The similarities between HGPS patients and progeroid mice reported here strongly suggest that defective cardiac repolarization and cardiomyocyte connectivity are important abnormalities in the HGPS pathogenesis that increase the risk of arrhythmia and premature death.

Is it Worth the Effort? Novel Insights into Obesity-Associated Alterations in Cost-Benefit Decision-Making

PubMed Central

Mathar, David; Horstmann, Annette; Pleger, Burkhard; Villringer, Arno; Neumann, Jane

2016-01-01

Cost-benefit decision-making entails the process of evaluating potential actions according to the trade-off between the expected reward (benefit) and the anticipated effort (costs). Recent research revealed that dopaminergic transmission within the fronto-striatal circuitry strongly modulates cost-benefit decision-making. Alterations within the dopaminergic fronto-striatal system have been associated with obesity, but little is known about cost-benefit decision-making differences in obese compared with lean individuals. With a newly developed experimental task we investigate obesity-associated alterations in cost-benefit decision-making, utilizing physical effort by handgrip-force exertion and both food and non-food rewards. We relate our behavioral findings to alterations in local gray matter volume assessed by structural MRI. Obese compared with lean subjects were less willing to engage in physical effort in particular for high-caloric sweet snack food. Further, self-reported body dissatisfaction negatively correlated with the willingness to invest effort for sweet snacks in obese men. On a structural level, obesity was associated with reductions in gray matter volume in bilateral prefrontal cortex. Nucleus accumbens volume positively correlated with task induced implicit food craving. Our results challenge the common notion that obese individuals are willing to work harder to obtain high-caloric food and emphasize the need for further exploration of the underlying neural mechanisms regarding cost-benefit decision-making differences in obesity. PMID:26793079

Molecular Inversion Probe Analysis of Gene Copy Alterations Reveals Distinct Categories of Colorectal Carcinoma

PubMed Central

Ji, Hanlee; Kumm, Jochen; Zhang, Michael; Farnam, Kyle; Salari, Keyan; Faham, Malek; Ford, James M.; Davis, Ronald W.

2006-01-01

Genomic instability is a major feature of neoplastic development in colorectal carcinoma and other cancers. Specific genomic instability events, such as deletions in chromosomes and other alterations in gene copy number, have potential utility as biologically relevant prognostic biomarkers. For example, genomic deletions on chromosome arm 18q are an indicator of colorectal carcinoma behavior and potentially useful as a prognostic indicator. Adapting a novel genomic technology called molecular inversion probes which can determine gene copy alterations, such as genomic deletions, we designed a set of probes to interrogate several hundred individual exons of >200 cancer genes with an overall distribution covering all chromosome arms. In addition, >100 probes were designed in close proximity of microsatellite markers on chromosome arm 18q. We analyzed a set of colorectal carcinoma cell lines and primary colorectal tumor samples for gene copy alterations and deletion mutations in exons. Based on clustering analysis, we distinguished the different categories of genomic instability among the colorectal cancer cell lines. Our analysis of primary tumors uncovered several distinct categories of colorectal carcinoma, each with specific patterns of 18q deletions and deletion mutations in specific genes. This finding has potential clinical ramifications given the application of 18q loss of heterozygosity events as a potential indicator for adjuvant treatment in stage II colorectal carcinoma. PMID:16912164

Visual impairment in FOXG1-mutated individuals and mice.

PubMed

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

2016-06-02

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

Is it Worth the Effort? Novel Insights into Obesity-Associated Alterations in Cost-Benefit Decision-Making.

PubMed

Mathar, David; Horstmann, Annette; Pleger, Burkhard; Villringer, Arno; Neumann, Jane

2015-01-01

Cost-benefit decision-making entails the process of evaluating potential actions according to the trade-off between the expected reward (benefit) and the anticipated effort (costs). Recent research revealed that dopaminergic transmission within the fronto-striatal circuitry strongly modulates cost-benefit decision-making. Alterations within the dopaminergic fronto-striatal system have been associated with obesity, but little is known about cost-benefit decision-making differences in obese compared with lean individuals. With a newly developed experimental task we investigate obesity-associated alterations in cost-benefit decision-making, utilizing physical effort by handgrip-force exertion and both food and non-food rewards. We relate our behavioral findings to alterations in local gray matter volume assessed by structural MRI. Obese compared with lean subjects were less willing to engage in physical effort in particular for high-caloric sweet snack food. Further, self-reported body dissatisfaction negatively correlated with the willingness to invest effort for sweet snacks in obese men. On a structural level, obesity was associated with reductions in gray matter volume in bilateral prefrontal cortex. Nucleus accumbens volume positively correlated with task induced implicit food craving. Our results challenge the common notion that obese individuals are willing to work harder to obtain high-caloric food and emphasize the need for further exploration of the underlying neural mechanisms regarding cost-benefit decision-making differences in obesity.

HIT'nDRIVE: patient-specific multidriver gene prioritization for precision oncology

PubMed Central

Hodzic, Ermin; Sauerwald, Thomas; Dao, Phuong; Wang, Kendric; Yeung, Jake; Anderson, Shawn; Vandin, Fabio; Haffari, Gholamreza; Collins, Colin C.; Sahinalp, S. Cenk

2017-01-01

Prioritizing molecular alterations that act as drivers of cancer remains a crucial bottleneck in therapeutic development. Here we introduce HIT'nDRIVE, a computational method that integrates genomic and transcriptomic data to identify a set of patient-specific, sequence-altered genes, with sufficient collective influence over dysregulated transcripts. HIT'nDRIVE aims to solve the “random walk facility location” (RWFL) problem in a gene (or protein) interaction network, which differs from the standard facility location problem by its use of an alternative distance measure: “multihitting time,” the expected length of the shortest random walk from any one of the set of sequence-altered genes to an expression-altered target gene. When applied to 2200 tumors from four major cancer types, HIT'nDRIVE revealed many potentially clinically actionable driver genes. We also demonstrated that it is possible to perform accurate phenotype prediction for tumor samples by only using HIT'nDRIVE-seeded driver gene modules from gene interaction networks. In addition, we identified a number of breast cancer subtype-specific driver modules that are associated with patients’ survival outcome. Furthermore, HIT'nDRIVE, when applied to a large panel of pan-cancer cell lines, accurately predicted drug efficacy using the driver genes and their seeded gene modules. Overall, HIT'nDRIVE may help clinicians contextualize massive multiomics data in therapeutic decision making, enabling widespread implementation of precision oncology. PMID:28768687

Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution

PubMed Central

Kim, Hoon; Zheng, Siyuan; Amini, Seyed S.; Virk, Selene M.; Mikkelsen, Tom; Brat, Daniel J.; Grimsby, Jonna; Sougnez, Carrie; Muller, Florian; Hu, Jian; Sloan, Andrew E.; Cohen, Mark L.; Van Meir, Erwin G.; Scarpace, Lisa; Laird, Peter W.; Weinstein, John N.; Lander, Eric S.; Gabriel, Stacey; Getz, Gad; Meyerson, Matthew; Chin, Lynda; Barnholtz-Sloan, Jill S.

2015-01-01

Glioblastoma (GBM) is a prototypical heterogeneous brain tumor refractory to conventional therapy. A small residual population of cells escapes surgery and chemoradiation, resulting in a typically fatal tumor recurrence ∼7 mo after diagnosis. Understanding the molecular architecture of this residual population is critical for the development of successful therapies. We used whole-genome sequencing and whole-exome sequencing of multiple sectors from primary and paired recurrent GBM tumors to reconstruct the genomic profile of residual, therapy resistant tumor initiating cells. We found that genetic alteration of the p53 pathway is a primary molecular event predictive of a high number of subclonal mutations in glioblastoma. The genomic road leading to recurrence is highly idiosyncratic but can be broadly classified into linear recurrences that share extensive genetic similarity with the primary tumor and can be directly traced to one of its specific sectors, and divergent recurrences that share few genetic alterations with the primary tumor and originate from cells that branched off early during tumorigenesis. Our study provides mechanistic insights into how genetic alterations in primary tumors impact the ensuing evolution of tumor cells and the emergence of subclonal heterogeneity. PMID:25650244

Ultrastructure of neurovascular changes in human diabetic retinopathy.

PubMed

Fehér, János; Taurone, Samanta; Spoletini, Marialuisa; Biró, Zsolt; Varsányi, Balázs; Scuderi, Gianluca; Orlando, Maria Patrizia; Turchetta, Rosaria; Micera, Alessandra; Artico, Marco

2018-01-01

The previous concept regarding diabetic retinopathy assigned a primary role to hyperglycemia-induced microvascular alterations, while neuronal and glial abnormalities were considered to be secondary to either ischemia or exudation. The aim of this study was to reveal the potential role of neuronal and glial cells in initial and advanced alterations of the retinopathy in human type 2 diabetes. Electron microscopy and histochemical studies were performed on 38 surgically removed human eyes (28 obtained from diabetic patients and 10 from non-diabetic patients). Morphometric analysis of basement membrane material and lipids was performed. An accumulation of metabolic by-products was found in the capillary wall with aging: this aspect was significantly more pronounced in diabetics. Müller glial cells were found to contribute to alterations of the capillary wall and to occlusion, as well as to the development of proliferative retinopathy and cystoid degeneration of the retina. Our results showed morphological evidence regarding the role of neuronal and glial cells in the pathology of diabetic retinopathy, prior and in addition to microangiopathy. These morphological findings support a neurovascular pathogenesis at the origin of diabetic retinopathy, thus the current treatment approach should be completed by neuroprotective measures.

Spanwise structure of the flow past a fixed or freely vibrating cylinder in the early turbulent regime

NASA Astrophysics Data System (ADS)

Bourguet, Remi; Gsell, Simon; Braza, Marianna

2017-11-01

The flow patterns developing downstream of slender bodies with bluff cross-section have been the object of intense research in the past decades. Particular attention was paid to the vortex patterns emerging in the plane perpendicular to the body axis. In the present study, focus is placed on the spanwise structure of the flow, in the early turbulent regime. The existence of dominant spanwise wavelengths had already been reported. However, many aspects remained to be explored, among others, the streamwise evolution of the spanwise patterns and their possible alteration when the body oscillates. These aspects are examined here on the basis of direct numerical simulations of the flow past a circular cylinder at Reynolds number 3900. The body is either fixed or subjected to vortex-induced vibrations. A systematic analysis of the spanwise patterns reveals persistent trends of their amplitude and wavelength in the different compartments of the flow, i.e. the separating shear layer and wake regions. Physical mechanisms are proposed to explain these trends. It is also found that the spanwise structure of the flow is differently altered in these two regions once the cylinder vibrates, the alteration being concentrated in the separating shear layers.

Alterations in Striatal Circuits Underlying Addiction-Like Behaviors.

PubMed

Kim, Hyun Jin; Lee, Joo Han; Yun, Kyunghwa; Kim, Joung-Hun

2017-06-30

Drug addiction is a severe psychiatric disorder characterized by the compulsive pursuit of drugs of abuse despite potential adverse consequences. Although several decades of studies have revealed that psychostimulant use can result in extensive alterations of neural circuits and physiology, no effective therapeutic strategies or medicines for drug addiction currently exist. Changes in neuronal connectivity and regulation occurring after repeated drug exposure contribute to addiction-like behaviors in animal models. Among the involved brain areas, including those of the reward system, the striatum is the major area of convergence for glutamate, GABA, and dopamine transmission, and this brain region potentially determines stereotyped behaviors. Although the physiological consequences of striatal neurons after drug exposure have been relatively well documented, it remains to be clarified how changes in striatal connectivity underlie and modulate the expression of addiction-like behaviors. Understanding how striatal circuits contribute to addiction-like behaviors may lead to the development of strategies that successfully attenuate drug-induced behavioral changes. In this review, we summarize the results of recent studies that have examined striatal circuitry and pathway-specific alterations leading to addiction-like behaviors to provide an updated framework for future investigations.

Assessment of the structural brain network reveals altered connectivity in children with unilateral cerebral palsy due to periventricular white matter lesions.

PubMed

Pannek, Kerstin; Boyd, Roslyn N; Fiori, Simona; Guzzetta, Andrea; Rose, Stephen E

2014-01-01

Cerebral palsy (CP) is a term to describe the spectrum of disorders of impaired motor and sensory function caused by a brain lesion occurring early during development. Diffusion MRI and tractography have been shown to be useful in the study of white matter (WM) microstructure in tracts likely to be impacted by the static brain lesion. The purpose of this study was to identify WM pathways with altered connectivity in children with unilateral CP caused by periventricular white matter lesions using a whole-brain connectivity approach. Data of 50 children with unilateral CP caused by periventricular white matter lesions (5-17 years; manual ability classification system [MACS] I = 25/II = 25) and 17 children with typical development (CTD; 7-16 years) were analysed. Structural and High Angular Resolution Diffusion weighted Images (HARDI; 64 directions, b = 3000 s/mm(2)) were acquired at 3 T. Connectomes were calculated using whole-brain probabilistic tractography in combination with structural parcellation of the cortex and subcortical structures. Connections with altered fractional anisotropy (FA) in children with unilateral CP compared to CTD were identified using network-based statistics (NBS). The relationship between FA and performance of the impaired hand in bimanual tasks (Assisting Hand Assessment-AHA) was assessed in connections that showed significant differences in FA compared to CTD. FA was reduced in children with unilateral CP compared to CTD. Seven pathways, including the corticospinal, thalamocortical, and fronto-parietal association pathways were identified simultaneously in children with left and right unilateral CP. There was a positive relationship between performance of the impaired hand in bimanual tasks and FA within the cortico-spinal and thalamo-cortical pathways (r(2) = 0.16-0.44; p < 0.05). This study shows that network-based analysis of structural connectivity can identify alterations in FA in unilateral CP, and that these alterations in FA are related to clinical function. Application of this connectome-based analysis to investigate alterations in connectivity following treatment may elucidate the neurological correlates of improved functioning due to intervention.

Tissue metabolic changes for effects of pirfenidone in rats of acute paraquat poisoning by GC-MS.

PubMed

Ma, Jianshe; Sun, Fa; Chen, Bingbao; Tu, Xiaoting; Peng, Xiufa; Wen, Congcong; Hu, Lufeng; Wang, Xianqin

2017-12-01

We developed a metabolomic method to evaluate the effect of pirfenidone on rats with acute paraquat (PQ) poisoning, through the analysis of various tissues (lung, liver, kidney, and heart), by gas chromatography-mass spectrometry (GC-MS). Thirty-eight rats were randomly divided into a control group, an acute PQ (20 mg kg -1 ) poisoning group, a pirfenidone (20 mg kg -1 ) treatment group, and a pirfenidone (40 mg kg -1 ) treatment group. Partial least squares-discriminate analysis (PLS-DA) revealed metabolic alterations in rat tissue samples from the two pirfenidone treatment groups after acute PQ poisoning. The PLS-DA 3D score chart showed that the rats in the acute PQ poisoning group were clearly distinguished from the rats in the control group. Also, the two pirfenidone treatment groups were distinguished from the acute PQ poisoning group and control group. Additionally, the pirfenidone (40 mg kg -1 ) treatment group was separated farther than the pirfenidone (20 mg kg -1 ) treatment group from the acute PQ poisoning group. Evaluation of the pathological changes in the rat tissues revealed that treatment with pirfenidone appeared to decrease pulmonary fibrosis in the acute PQ poisoning rats. The results indicate that pirfenidone induced beneficial metabolic alterations in the tissues of rats with acute PQ poisoning. Rats with acute PQ poisoning exhibited a certain reduction in biochemical indicators after treatment with pirfenidone, indicating that pirfenidone could protect liver and kidney function. Accordingly, the developed metabolomic approach proved to be useful to elucidate the effect of pirfenidone in rats of acute PQ poisoning.

Assessing biological effects of fluoxetine in developing zebrafish embryos using gas chromatography-mass spectrometry based metabolomics.

PubMed

Mishra, Priti; Gong, Zhiyuan; Kelly, Barry C

2017-12-01

Continuous low-dose exposure of pharmaceutically active compounds (PhACs) in aquatic ecosystems is a concern worldwide. In this study, we utilized a gas chromatography mass spectrometry (GC-MS) based metabolomics approach to assess endogenous metabolite changes in developing zebrafish embryos exposed to different concentrations of the widely used antidepressant, fluoxetine. Embryos were exposed from 2 h post fertilization (hpf) until 96 hpf. Using the Fiehn GC-MS library, a total of 31 metabolites were positively identified in embryos. Statistical analyses revealed significant dysregulation of 11 metabolites in fluoxetine exposed embryos. Metabolite classes that were significantly altered included, amino acids, monosaccharides, glycerophosphates, fatty acids, carboxylic acid derivatives and sugars. Concentrations of amino acids, maltose, d-malic acid, 3-phosphoglycerate and d-glucose were significantly reduced in exposed embryos. Conversely, concentrations of citric acid were in some cases significantly elevated in exposed embryos. Metabolic pathway analysis revealed perturbation of five main pathways, including (i) alanine, aspartate and glutamate metabolism, (ii) phenylalanine, tyrosine and tryptophan biosynthesis, (iii) phenylalanine metabolism. (iv) tyrosine metabolism and (v) starch and sucrose metabolism. The results indicate fluoxetine exposure causes perturbation of energy and amino acid metabolism, which may adversely impact embryogenesis due to depletion of energy reserves during this period. Also, the observed alterations in aspartic acid, phenylalanine and tyrosine in fluoxetine exposed embryos suggests potential disruption of normal neurobehavioral and liver function. The results further demonstrate that GC-MS based metabolomics is an effective approach for assessing toxicodynamics and threshold effect levels of environmental pollutants in aquatic organisms. Copyright © 2017 Elsevier Ltd. All rights reserved.

The legacy of land-use is revealed in the biogeochemistry of urban streams - 3-4-2014

EPA Science Inventory

Urban streams are among the most profoundly impacted aquatic ecosystems, characterized by altered hydrology or burial, increased sediment input, and myriad pollutants. We present results from a series of urban stream studies that revealed unique geochemical and biochemical patte...

Responses to Interpersonal Stress: Normative Changes Across Childhood and the Impact of Peer Victimization.

PubMed

Troop-Gordon, Wendy; Sugimura, Niwako; Rudolph, Karen D

2017-03-01

This research examined the development of stress responses across second to sixth grades and whether exposure to peer victimization alters stress response trajectories. Youth (338 girls; 298 boys; M age  = 7.97 years, SD = .37) reported on stress responses; teachers and youth reported on peer victimization. Latent growth curve modeling revealed an increase in effortful engagement responses and a decrease in disengagement and involuntary engagement responses during this period. Peer victimization disrupted these normative trajectories, resulting in less effortful engagement and more effortful disengagement and involuntary stress responses in early adolescence. These findings suggest that early peer victimization sensitizes youth to stress by interfering with the development of effective coping and fostering maladaptive stress responses. © 2016 The Authors. Child Development © 2016 Society for Research in Child Development, Inc.

Production of cross-kingdom oxylipins by pathogenic fungi: An update on their role in development and pathogenicity.

PubMed

Fischer, Gregory J; Keller, Nancy P

2016-03-01

Oxylipins are a class of molecules derived from the incorporation of oxygen into polyunsaturated fatty acid substrates through the action of oxygenases. While extensively investigated in the context of mammalian immune responses, over the last decade it has become apparent that oxylipins are a common means of communication among and between plants, animals, and fungi to control development and alter host-microbe interactions. In fungi, some oxylipins are derived nonenzymatically while others are produced by lipoxygenases, cyclooxygenases, and monooxygenases with homology to plant and human enzymes. Recent investigations of numerous plant and human fungal pathogens have revealed oxylipins to be involved in the establishment and progression of disease. This review highlights oxylipin production by pathogenic fungi and their role in fungal development and pathogen/host interactions.

A Gene Module-Based eQTL Analysis Prioritizing Disease Genes and Pathways in Kidney Cancer.

PubMed

Yang, Mary Qu; Li, Dan; Yang, William; Zhang, Yifan; Liu, Jun; Tong, Weida

2017-01-01

Clear cell renal cell carcinoma (ccRCC) is the most common and most aggressive form of renal cell cancer (RCC). The incidence of RCC has increased steadily in recent years. The pathogenesis of renal cell cancer remains poorly understood. Many of the tumor suppressor genes, oncogenes, and dysregulated pathways in ccRCC need to be revealed for improvement of the overall clinical outlook of the disease. Here, we developed a systems biology approach to prioritize the somatic mutated genes that lead to dysregulation of pathways in ccRCC. The method integrated multi-layer information to infer causative mutations and disease genes. First, we identified differential gene modules in ccRCC by coupling transcriptome and protein-protein interactions. Each of these modules consisted of interacting genes that were involved in similar biological processes and their combined expression alterations were significantly associated with disease type. Then, subsequent gene module-based eQTL analysis revealed somatic mutated genes that had driven the expression alterations of differential gene modules. Our study yielded a list of candidate disease genes, including several known ccRCC causative genes such as BAP1 and PBRM1 , as well as novel genes such as NOD2, RRM1, CSRNP1, SLC4A2, TTLL1 and CNTN1. The differential gene modules and their driver genes revealed by our study provided a new perspective for understanding the molecular mechanisms underlying the disease. Moreover, we validated the results in independent ccRCC patient datasets. Our study provided a new method for prioritizing disease genes and pathways.

Volumetric imaging of oral epithelial neoplasia by MPM-SHGM: epithelial connective tissue interface (Conference Presentation)

NASA Astrophysics Data System (ADS)

Pal, Rahul; Yang, Jinping; Qiu, Suimin; Resto, Vicente; McCammon, Susan; Vargas, Gracie

2016-03-01

The majority of oral cancers are comprised of oral squamous cell carcinoma in which neoplastic epithelial cells invade across the epithelial connective tissue interface (ECTI). Invasion is preceded by a multi-component process including epithelial hyperproliferation, loss of cell polarity, and remodeling of the extracellular matrix. Multiphoton Autofluorescence Microscopy (MPAM) and Second Harmonic Generation Microscopy (SHGM) show promise for revealing indicators of neoplasia. In particular, volumetric imaging by these methods can reveal aspects of the 3D microstructure that are not possible by other methods and which could both further our understanding of neoplastic transformation and be explored for development of diagnostic approaches in this disease having only 55% 5-year survival rate. MPAM-SHG were applied to reveal the 3D structure of the critical ECTI interface that plays an integral part toward invasion. Epithelial dysplasia was induced in an established hamster model. MPAM-SHGM was applied to lesion sites, using 780 nm excitation (450-600nm emission) for autofluroescence of cellular and extracellular components; 840 nm using 420 nm bandpass filter for SHG. The ECTI surface was identified as the interface at which SHG signal began following the epithelium and was modeled as a 3D surface using Matlab. ECTI surface area and cell features at sites of epithelial expansion where ECTI was altered were measured; Imaged sites were biopsied and processed for histology. ROC analysis using ECTI image metrics indicated the ability to delineate normal from neoplasia with high sensitivity and specificity and it is noteworthy that inflammation did not significantly alter diagnostic potential of MPAM-SHGM .

Transcriptome Sequencing Revealed Significant Alteration of Cortical Promoter Usage and Splicing in Schizophrenia

PubMed Central

Wu, Jing Qin; Wang, Xi; Beveridge, Natalie J.; Tooney, Paul A.; Scott, Rodney J.; Carr, Vaughan J.; Cairns, Murray J.

2012-01-01

Background While hybridization based analysis of the cortical transcriptome has provided important insight into the neuropathology of schizophrenia, it represents a restricted view of disease-associated gene activity based on predetermined probes. By contrast, sequencing technology can provide un-biased analysis of transcription at nucleotide resolution. Here we use this approach to investigate schizophrenia-associated cortical gene expression. Methodology/Principal Findings The data was generated from 76 bp reads of RNA-Seq, aligned to the reference genome and assembled into transcripts for quantification of exons, splice variants and alternative promoters in postmortem superior temporal gyrus (STG/BA22) from 9 male subjects with schizophrenia and 9 matched non-psychiatric controls. Differentially expressed genes were then subjected to further sequence and functional group analysis. The output, amounting to more than 38 Gb of sequence, revealed significant alteration of gene expression including many previously shown to be associated with schizophrenia. Gene ontology enrichment analysis followed by functional map construction identified three functional clusters highly relevant to schizophrenia including neurotransmission related functions, synaptic vesicle trafficking, and neural development. Significantly, more than 2000 genes displayed schizophrenia-associated alternative promoter usage and more than 1000 genes showed differential splicing (FDR<0.05). Both types of transcriptional isoforms were exemplified by reads aligned to the neurodevelopmentally significant doublecortin-like kinase 1 (DCLK1) gene. Conclusions This study provided the first deep and un-biased analysis of schizophrenia-associated transcriptional diversity within the STG, and revealed variants with important implications for the complex pathophysiology of schizophrenia. PMID:22558445

Overexpression of Human-Derived DNMT3A Induced Intergenerational Inheritance of Active DNA Methylation Changes in Rat Sperm

PubMed Central

Zheng, Xiaoguo; Li, Zhenhua; Wang, Guishuan; Li, Zhengzheng; Liang, Ajuan; Wang, Hanshu; Dai, Yubing; Huang, Xingxu; Chen, Xuejin; Ma, Yuanwu; Sun, Fei

2017-01-01

DNA methylation is the major focus of studies on paternal epigenetic inheritance in mammals, but most previous studies about inheritable DNA methylation changes are passively induced by environmental factors. However, it is unclear whether the active changes mediated by variations in DNA methyltransferase activity are heritable. Here, we established human-derived DNMT3A (hDNMT3A) transgenic rats to study the effect of hDNMT3A overexpression on the DNA methylation pattern of rat sperm and to investigate whether this actively altered DNA methylation status is inheritable. Our results revealed that hDNMT3A was overexpressed in the testis of transgenic rats and induced genome-wide alterations in the DNA methylation pattern of rat sperm. Among 5438 reliable loci identified with 64 primer-pair combinations using a methylation-sensitive amplification polymorphism method, 28.01% showed altered amplified band types. Among these amplicons altered loci, 68.42% showed an altered DNA methylation status in the offspring of transgenic rats compared with wild-type rats. Further analysis based on loci which had identical DNA methylation status in all three biological replicates revealed that overexpression of hDNMT3A in paternal testis induced hypermethylation in sperm of both genotype-negative and genotype-positive offspring. Among the differentially methylated loci, 34.26% occurred in both positive and negative offspring of transgenic rats, indicating intergenerational inheritance of active DNA methylation changes in the absence of hDNM3A transmission. Furthermore, 75.07% of the inheritable loci were hyper-methylated while the remaining were hypomethylated. Distribution analysis revealed that the DNA methylation variations mainly occurred in introns and intergenic regions. Functional analysis revealed that genes related to differentially methylated loci were involved in a wide range of functions. Finally, this study demonstrated that active DNA methylation changes induced by hDNMT3A expression were intergenerationally inherited by offspring without transmission of the transgene, which provided evidence for the transmission of active endogenous-factors-induced epigenetic variations. PMID:29312436

Integrative genomics identifies molecular alterations that challenge the linear model of melanoma progression.

PubMed

Rose, Amy E; Poliseno, Laura; Wang, Jinhua; Clark, Michael; Pearlman, Alexander; Wang, Guimin; Vega Y Saenz de Miera, Eleazar C; Medicherla, Ratna; Christos, Paul J; Shapiro, Richard; Pavlick, Anna; Darvishian, Farbod; Zavadil, Jiri; Polsky, David; Hernando, Eva; Ostrer, Harry; Osman, Iman

2011-04-01

Superficial spreading melanoma (SSM) and nodular melanoma (NM) are believed to represent sequential phases of linear progression from radial to vertical growth. Several lines of clinical, pathologic, and epidemiologic evidence suggest, however, that SSM and NM might be the result of independent pathways of tumor development. We utilized an integrative genomic approach that combines single nucleotide polymorphism array (6.0; Affymetrix) with gene expression array (U133A 2.0; Affymetrix) to examine molecular differences between SSM and NM. Pathway analysis of the most differentially expressed genes between SSM and NM (N = 114) revealed significant differences related to metabolic processes. We identified 8 genes (DIS3, FGFR1OP, G3BP2, GALNT7, MTAP, SEC23IP, USO1, and ZNF668) in which NM/SSM-specific copy number alterations correlated with differential gene expression (P < 0.05; Spearman's rank). SSM-specific genomic deletions in G3BP2, MTAP, and SEC23IP were independently verified in two external data sets. Forced overexpression of metabolism-related gene MTAP (methylthioadenosine phosphorylase) in SSM resulted in reduced cell growth. The differential expression of another metabolic-related gene, aldehyde dehydrogenase 7A1 (ALDH7A1), was validated at the protein level by using tissue microarrays of human melanoma. In addition, we show that the decreased ALDH7A1 expression in SSM may be the result of epigenetic modifications. Our data reveal recurrent genomic deletions in SSM not present in NM, which challenge the linear model of melanoma progression. Furthermore, our data suggest a role for altered regulation of metabolism-related genes as a possible cause of the different clinical behavior of SSM and NM.

Integrative genomics identifies molecular alterations that challenge the linear model of melanoma progression

PubMed Central

Rose, Amy E.; Poliseno, Laura; Wang, Jinhua; Clark, Michael; Pearlman, Alexander; Wang, Guimin; Vega y Saenz de Miera, Eleazar C.; Medicherla, Ratna; Christos, Paul J.; Shapiro, Richard; Pavlick, Anna; Darvishian, Farbod; Zavadil, Jiri; Polsky, David; Hernando, Eva; Ostrer, Harry; Osman, Iman

2011-01-01

Superficial spreading melanoma (SSM) and nodular melanoma (NM) are believed to represent sequential phases of linear progression from radial to vertical growth. Several lines of clinical, pathological and epidemiologic evidence suggest, however, that SSM and NM might be the result of independent pathways of tumor development. We utilized an integrative genomic approach that combines single nucleotide polymorphism array (SNP 6.0, Affymetrix) with gene expression array (U133A 2.0, Affymetrix) to examine molecular differences between SSM and NM. Pathway analysis of the most differentially expressed genes between SSM and NM (N=114) revealed significant differences related to metabolic processes. We identified 8 genes (DIS3, FGFR1OP, G3BP2, GALNT7, MTAP, SEC23IP, USO1, ZNF668) in which NM/SSM-specific copy number alterations correlated with differential gene expression (P<0.05, Spearman’s rank). SSM-specific genomic deletions in G3BP2, MTAP, and SEC23IP were independently verified in two external data sets. Forced overexpression of metabolism-related gene methylthioadenosine phosphorylase (MTAP) in SSM resulted in reduced cell growth. The differential expression of another metabolic related gene, aldehyde dehydrogenase 7A1 (ALDH7A1), was validated at the protein level using tissue microarrays of human melanoma. In addition, we show that the decreased ALDH7A1 expression in SSM may be the result of epigenetic modifications. Our data reveal recurrent genomic deletions in SSM not present in NM, which challenge the linear model of melanoma progression. Furthermore, our data suggest a role for altered regulation of metabolism-related genes as a possible cause of the different clinical behavior of SSM and NM. PMID:21343389

Mice lacking sialyltransferase ST3Gal-II develop late-onset obesity and insulin resistance

PubMed Central

Lopez, Pablo HH; Aja, Susan; Aoki, Kazuhiro; Seldin, Marcus M; Lei, Xia; Ronnett, Gabriele V; Wong, G William; Schnaar, Ronald L

2017-01-01

Sialyltransferases are a family of 20 gene products in mice and humans that transfer sialic acid from its activated precursor, CMP-sialic acid, to the terminus of glycoprotein and glycolipid acceptors. ST3Gal-II (coded by the St3gal2 gene) transfers sialic acid preferentially to the three positions of galactose on the Galβ1-3GalNAc terminus of gangliosides GM1 and GD1b to synthesize GD1a and GT1b, respectively. Mice with a targeted disruption of St3gal2 unexpectedly displayed late-onset obesity and insulin resistance. At 3 months of age, St3gal2-null mice were the same weight as their wild type (WT) counterparts, but by 13 months on standard chow they were visibly obese, 22% heavier and with 37% greater fat/lean ratio than WT mice. St3gal2-null mice became hyperglycemic and displayed impaired glucose tolerance by 9 months of age. They had sharply reduced insulin responsiveness despite equivalent pancreatic islet morphology. Analyses of insulin receptor (IR) tyrosine kinase substrate IRS-1 and downstream target Akt revealed decreased insulin-induced phosphorylation in adipose tissue but not liver or skeletal muscle of St3gal2-null mice. Thin-layer chromatography and mass spectrometry revealed altered ganglioside profiles in the adipose tissue of St3gal2-null mice compared to WT littermates. Metabolically, St3gal2-null mice display a reduced respiratory exchange ratio compared to WT mice, indicating a preference for lipid oxidation as an energy source. Despite their altered metabolism, St3gal2-null mice were hyperactive. We conclude that altered ganglioside expression in adipose tissue results in diminished IR sensitivity and late-onset obesity. PMID:27683310

Biomechanical properties of bone in a mouse model of Rett syndrome.

PubMed

Kamal, Bushra; Russell, David; Payne, Anthony; Constante, Diogo; Tanner, K Elizabeth; Isaksson, Hanna; Mathavan, Neashan; Cobb, Stuart R

2015-02-01

Rett syndrome (RTT) is an X-linked genetic disorder and a major cause of intellectual disability in girls. Mutations in the methyl-CpG binding protein 2 (MECP2) gene are the primary cause of the disorder. Despite the dominant neurological phenotypes, MECP2 is expressed ubiquitously throughout the body and a number of peripheral phenotypes such as scoliosis, reduced bone mineral density and skeletal fractures are also common and important clinical features of the disorder. In order to explore whether MeCP2 protein deficiency results in altered structural and functional properties of bone and to test the potential reversibility of any defects, we have conducted a series of histological, imaging and biomechanical tests of bone in a functional knockout mouse model of RTT. Both hemizygous Mecp2(stop/y) male mice in which Mecp2 is silenced in all cells and female Mecp2(stop/+) mice in which Mecp2 is silenced in ~50% of cells as a consequence of random X-chromosome inactivation, revealed significant reductions in cortical bone stiffness, microhardness and tensile modulus. Microstructural analysis also revealed alterations in both cortical and cancellous femoral bone between wild-type and MeCP2-deficient mice. Furthermore, unsilencing of Mecp2 in adult mice cre-mediated stop cassette deletion resulted in a restoration of biomechanical properties (stiffness, microhardness) towards wild-type levels. These results show that MeCP2-deficiency results in overt, but potentially reversible, alterations in the biomechanical integrity of bone and highlights the importance of targeting skeletal phenotypes in considering the development of pharmacological and gene-based therapies. Copyright © 2014. Published by Elsevier Inc.

Next-Generation Sequencing-based genomic profiling of brain metastases of primary ovarian cancer identifies high number of BRCA-mutations.

PubMed

Balendran, S; Liebmann-Reindl, S; Berghoff, A S; Reischer, T; Popitsch, N; Geier, C B; Kenner, L; Birner, P; Streubel, B; Preusser, M

2017-07-01

Ovarian cancer represents the most common gynaecological malignancy and has the highest mortality of all female reproductive cancers. It has a rare predilection to develop brain metastases (BM). In this study, we evaluated the mutational profile of ovarian cancer metastases through Next-Generation Sequencing (NGS) with the aim of identifying potential clinically actionable genetic alterations with options for small molecule targeted therapy. Library preparation was conducted using Illumina TruSight Rapid Capture Kit in combination with a cancer specific enrichment kit covering 94 genes. BRCA-mutations were confirmed by using TruSeq Custom Amplicon Low Input Kit in combination with a custom-designed BRCA gene panel. In our cohort all eight sequenced BM samples exhibited a multitude of variant alterations, each with unique molecular profiles. The 37 identified variants were distributed over 22 cancer-related genes (23.4%). The number of mutated genes per sample ranged from 3 to 7 with a median of 4.5. The most commonly altered genes were BRCA1/2, TP53, and ATM. In total, 7 out of 8 samples revealed either a BRCA1 or a BRCA2 pathogenic mutation. Furthermore, all eight BM samples showed mutations in at least one DNA repair gene. Our NGS study of BM of ovarian carcinoma revealed a significant number of BRCA-mutations beside TP53, ATM and CHEK2 mutations. These findings strongly suggest the implication of BRCA and DNA repair malfunction in ovarian cancer metastasizing to the brain. Based on these findings, pharmacological PARP inhibition could be one potential targeted therapeutic for brain metastatic ovarian cancer patients.

Targeted next generation sequencing of endoscopic ultrasound acquired cytology from ampullary and pancreatic adenocarcinoma has the potential to aid patient stratification for optimal therapy selection

PubMed Central

Gleeson, Ferga C.; Kerr, Sarah E.; Kipp, Benjamin R.; Voss, Jesse S.; Minot, Douglas M.; Tu, Zheng Jin; Henry, Michael R.; Graham, Rondell P.; Vasmatzis, George; Cheville, John C.; Lazaridis, Konstantinos N.; Levy, Michael J.

2016-01-01

Background & Aims Less than 10% of registered drug intervention trials for pancreatic ductal adenocarcinoma (PDAC) include a biomarker stratification strategy. The ability to identify distinct mutation subsets via endoscopic ultrasound fine needle aspiration (EUS FNA) molecular cytology could greatly aid clinical trial patient stratification and offer predictive markers. We identified chemotherapy treatment naïve ampullary adenocarcinoma and PDAC patients who underwent EUS FNA to assess multigene mutational frequency and diversity with a surgical resection concordance assessment, where available. Methods Following strict cytology smear screening criteria, targeted next generation sequencing (NGS) using a 160 cancer gene panel was performed. Results Complete sequencing was achieved in 29 patients, whereby 83 pathogenic alterations were identified in 21 genes. Cytology genotyping revealed that the majority of mutations were identified in KRAS (93%), TP53 (72%), SMAD4 (31%), and GNAS (10%). There was 100% concordance for the following pathogenic alterations: KRAS, TP53, SMAD4, KMT2D, NOTCH2, MSH2, RB1, SMARCA4, PPP2R1A, PIK3R1, SCL7A8, ATM, and FANCD2. Absolute multigene mutational concordance was 83%. Incremental cytology smear mutations in GRIN2A, GATA3 and KDM6A were identified despite re-examination of raw sequence reads in the corresponding resection specimens. Conclusions EUS FNA cytology genotyping using a 160 cancer gene NGS panel revealed a broad spectrum of pathogenic alterations. The fidelity of cytology genotyping to that of paired surgical resection specimens suggests that EUS FNA represents a suitable surrogate and may complement the conventional stratification criteria in decision making for therapies and may guide future biomarker driven therapeutic development. PMID:27203738

The molecular basis for development of proinflammatory autoantibodies to progranulin.

PubMed

Thurner, Lorenz; Fadle, Natalie; Regitz, Evi; Kemele, Maria; Klemm, Philipp; Zaks, Marina; Stöger, Elisabeth; Bette, Birgit; Carbon, Gabi; Zimmer, Vincent; Assmann, Gunter; Murawski, Niels; Kubuschok, Boris; Held, Gerhard; Preuss, Klaus-Dieter; Pfreundschuh, Michael

2015-07-01

Recently we identified in a wide spectrum of autoimmune diseases frequently occurring proinflammatory autoantibodies directed against progranulin, a direct inhibitor of TNFR1 & 2 and of DR3. In the present study we investigated the mechanisms for the breakdown of self-tolerance against progranulin. Isoelectric focusing identified a second, differentially electrically charged progranulin isoform exclusively present in progranulin-antibody-positive patients. Alkaline phosphatase treatment revealed this additional progranulin isoform to be hyperphosphorylated. Subsequently Ser81, which is located within the epitope region of progranulin-antibodies, was identified as hyperphosphorylated serine residue by site directed mutagenesis of candidate phosphorylation sites. Hyperphosphorylated progranulin was detected exclusively in progranulin-antibody-positive patients during the courses of their diseases. The occurrence of hyperphosphorylated progranulin preceded seroconversions of progranulin-antibodies, indicating adaptive immune response. Utilizing panels of kinase and phosphatase inhibitors, PKCβ1 was identified as the relevant kinase and PP1 as the relevant phosphatase for phosphorylation and dephosphorylation of Ser81. In contrast to normal progranulin, hyperphosphorylated progranulin interacted exclusively with inactivated (pThr320) PP1, suggesting inactivated PP1 to cause the detectable occurrence of phosphorylated Ser81 PGRN. Investigation of possible functional alterations of PGRN due to Ser81 phosphorylation revealed, that hyperphosphorylation prevents the interaction and thus direct inhibition of TNFR1, TNFR2 and DR3, representing an additional direct proinflammatory effect. Finally phosphorylation of Ser81 PGRN alters the conversion pattern of PGRN. In conclusion, inactivated PP1 induces hyperphosphorylation of progranulin in a wide spectrum of autoimmune diseases. This hyperphosphorylation prevents direct inhibition of TNFR1, TNFR2 and DR3 by PGRN, alters the conversion of PGRN, and is strongly associated with the occurrence of neutralizing, proinflammatory PGRN-antibodies, indicating immunogenicity of this alternative secondary modification. Copyright © 2015 Elsevier Ltd. All rights reserved.

Maternal high fructose diet and neonatal immune challenge alter offspring anxiety-like behavior and inflammation across the lifespan.

PubMed

Bukhari, Syed Hussain F; Clark, Olivia E; Williamson, Lauren L

2018-03-15

This study examined the interaction between maternal high fructose diet and neonatal inflammation in neonates (P7), juveniles (P26-34) and adults on measures of anxiety-like behavior and cognition. The study aimed to assess the potential synergistic effects of these two forms of early-life inflammation. We fed Sprague-Dawley dams with high fructose (60%) diet or normal chow. Each litter was treated with either saline or lipopolysaccharide (LPS) on postnatal day (P)3 and P5 and two pups were tested for USVs after maternal separation on P7. Post-weaning, juveniles were tested on the elevated zero maze (EZM) and in a context-object discrimination (COD) task prior to tissue harvest. Adults were tested on the EZM and the COD task as well. Immunohistochemistry and ELISA were used to assess molecular and cellular changes in the offspring. This study demonstrates that maternal diet and neonatal inflammation altered peripheral inflammation in neonates, altered anxiety-like behavior in juveniles, and altered anxiety-like behavior in adulthood. Maternal diet and sex increased juvenile peripheral inflammation and altered memory on the context-discrimination task. Maternal diet has a profound impact on fetal and neonatal development, especially as obesity rates are on the rise worldwide. Together, these findings reveal enduring effects of maternal diet on offspring, support the findings on the effects of neonatal inflammation on anxiety-like behaviors in later-life periods, and add to the complex relationship between gestational and neonatal inflammation and anxiety. Copyright © 2018 Elsevier Inc. All rights reserved.

Altered structure-function relations of semantic processing in youths with high-functioning autism: a combined diffusion and functional MRI study.

PubMed

Lo, Yu-Chun; Chou, Tai-Li; Fan, Li-Ying; Gau, Susan Shur-Fen; Chiu, Yen-Nan; Tseng, Wen-Yih Isaac

2013-12-01

Deficits in language and communication are among the core symptoms of autism, a common neurodevelopmental disorder with long-term impairment. Despite the striking nature of the autistic language impairment, knowledge about its corresponding alterations in the brain is still evolving. We hypothesized that the dual stream language network is altered in autism, and that this alteration could be revealed by changes in the relationships between microstructural integrity and functional activation. The study recruited 20 right-handed male youths with autism and 20 carefully matched individually, typically developing (TD) youths. Microstructural integrity of the left dorsal and left ventral pathways responsible for language processing and the functional activation of the connected brain regions were investigated by using diffusion spectrum imaging and functional magnetic resonance imaging of a semantic task, respectively. Youths with autism had significantly poorer language function, and lower functional activation in left dorsal and left ventral regions of the language network, compared with TD youths. The TD group showed a significant correlation of the functional activation of the left dorsal region with microstructural integrity of the left ventral pathway, whereas the autism group showed a significant correlation of the functional activation of the left ventral region with microstructural integrity of the left dorsal pathway, and moreover verbal comprehension index was correlated with microstructural integrity of the left ventral pathway. These altered structure-function relationships in autism suggest possible involvement of the dual pathways in supporting deficient semantic processing. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.

Maternal Phthalate and Personal Care Products Exposure Alters Extracellular Placental miRNA Profile in Twin Pregnancies.

PubMed

Zhong, Jia; Baccarelli, Andrea A; Mansur, Abdallah; Adir, Michal; Nahum, Ravit; Hauser, Russ; Bollati, Valentina; Racowsky, Catherine; Machtinger, Ronit

2018-01-01

Prenatal exposure to endocrine-disrupting chemicals (EDCs) exerts both short- and long-term adverse effects on the developing fetus. However, the mechanisms underlying these effects have yet to be uncovered. Maternal-fetal signaling is mediated in part by signaling molecules (eg, microRNAs [miRNAs]) contained in extracellular vesicles (EVs) that are released by the placenta into the maternal circulation. We investigated whether maternal exposure to the EDCs phthalates and personal care products alters the miRNA profile of placental-derived EVs circulating in maternal blood. Blood and urine samples from pregnant women with uncomplicated term dichorionic, diamniotic twin pregnancies were analyzed as part of a larger study investigating correlations between exposure of phthalate and personal care products and epigenetic alterations in twin pregnancies. We explored correlations between maternal urinary levels of 13 phthalate and 12 personal care products metabolites and the miRNA profile of placental EVs (EV-miRNAs) circulating in maternal blood. The expression of miR-518e was highest among women with high urinary levels of monobenzyl phthalate and methyl paraben. miR-373-3p was the least expressed in women exposed to high levels of methyl paraben, and miR-543 was significantly downregulated in women exposed to high levels of paraben metabolites, dichlorophenol metabolites, and triclosan. In conclusion, this pilot study reveals that prenatal exposure to EDCs is associated with altered profile of circulating placenta-derived EV-miRNAs. Further studies are needed to generalize these results to singleton pregnancies and to assess whether these alterations are associated with pregnancy complications.

Network Analysis: Applications for the Developing Brain

PubMed Central

Chu-Shore, Catherine J.; Kramer, Mark A.; Bianchi, Matt T.; Caviness, Verne S.; Cash, Sydney S.

2011-01-01

Development of the human brain follows a complex trajectory of age-specific anatomical and physiological changes. The application of network analysis provides an illuminating perspective on the dynamic interregional and global properties of this intricate and complex system. Here, we provide a critical synopsis of methods of network analysis with a focus on developing brain networks. After discussing basic concepts and approaches to network analysis, we explore the primary events of anatomical cortical development from gestation through adolescence. Upon this framework, we describe early work revealing the evolution of age-specific functional brain networks in normal neurodevelopment. Finally, we review how these relationships can be altered in disease and perhaps even rectified with treatment. While this method of description and inquiry remains in early form, there is already substantial evidence that the application of network models and analysis to understanding normal and abnormal human neural development holds tremendous promise for future discovery. PMID:21303762

14 CFR 26.45 - Holders of type certificates-Alterations and repairs to alterations.

Code of Federal Regulations, 2010 CFR

2010-01-01

... AIRPLANES Aging Airplane Safety-Damage Tolerance Data for Repairs and Alterations § 26.45 Holders of type... alteration data developed by the holder of a type certificate, the holder must— (1) Review existing... Repairs Made to Alterations. For existing and future repair data developed by a holder of a type...

Investigating Genetic Alterations in Bladder Cancer | Center for Cancer Research

Cancer.gov

Bladder cancer (BC) is the fifth most common cancer worldwide and the sixth most common cancer in the U.S. Mutations in a number of oncogenes and tumor suppressor genes were previously associated with invasive or noninvasive forms of the disease. More recently, next generation sequencing (NGS) of bladder tumors from over 100 Chinese patients revealed alterations in additional

The Adverse Effects of Triptolide on the Reproductive System of Caenorhabditis elegans: Oogenesis Impairment and Decreased Oocyte Quality

PubMed Central

Ruan, Qinli; Xu, Yun; Xu, Rui; Wang, Jiaying; Hua, Yongqing; Wang, Meng; Duan, Jinao

2017-01-01

Previous studies have revealed that Triptolide damages female reproductive capacity, but the mechanism is unclear. In this study, we used Caenorhabditis elegans to investigate the effects of Triptolide on the germline and explore its possible mechanisms. Our data show that exposure for 4 h to 50 and 100 mg/L Triptolide reduced C. elegans fertility, led to depletion and inactivation of spermatids with the changes in the expression levels of related genes, and increased the number of unfertilized oocytes through damaging chromosomes and DNA damage repair mechanisms. After 24 and 48 h of the 4 h exposure to 50 and 100 mg/L Triptolide, we observed shrink in distal tip cells, an increase in the number of apoptotic cells, a decrease in the number of mitotic germ cells and oocytes in diakinesis stage, and chromatin aggregates in −1 oocytes. Moreover, expression patterns of the genes associated with mitotic germ cell proliferation, apoptosis, and oocyte quality were altered after Triptolide exposure. Therefore, Triptolide may damage fertility of nematodes by hampering the development of oocytes at different developmental stages. Alterations in the expression patterns of genes involved in oocyte development may explain the corresponding changes in oocyte development in nematodes exposed to Triptolide. PMID:28230788

Early-life stress links 5-hydroxymethylcytosine to anxiety-related behaviors

PubMed Central

Papale, Ligia A.; Madrid, Andy; Li, Sisi; Alisch, Reid S.

2017-01-01

ABSTRACT Environmental stress contributes to the development of psychiatric disorders, including posttraumatic stress disorder and anxiety. While even acute stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in the brain and is associated with active transcription of neuronal genes. Here we examined behavioral and molecular alterations in adult mice that experienced an early-life stress before weaning (postnatal day 12 to 18) and found anxiety-like behaviors in adult female mice that were accompanied by correlated disruptions of hypothalamic 5hmC and gene expression in 118 genes, revealing potentially functional 5hmC (i.e., gene regulation). These genes are known and potentially novel stress-related targets, including Nr3c2, Nrxn1, Nfia, and Clip1, that have a significant enrichment for neuronal ontological functions, such as neuronal development and differentiation. Sequence motif predictions indicated that 5hmC may regulate gene expression by mediating transcription factor binding and alternative splicing of many of these transcripts. Together, these findings represent a critical step toward understanding the effects of early environment on the neuromolecular mechanisms that underlie the risk to develop anxiety disorders. PMID:28128679

Automated segmentation reveals silent radiographic progression in adult-onset vanishing white-matter disease.

PubMed

Huber, Thomas; Herwerth, Marina; Alberts, Esther; Kirschke, Jan S; Zimmer, Claus; Ilg, Ruediger

2017-02-01

Adult-onset vanishing white-matter disease (VWM) is a rare autosomal recessive disease with neurological symptoms such as ataxia and paraparesis, showing extensive white-matter hyperintensities (WMH) on magnetic resonance (MR) imaging. Besides symptom-specific scores like the International Cooperative Ataxia Rating Scale (ICARS), there is no established tool to monitor disease progression. Because of extensive WMH, visual comparison of MR images is challenging. Here, we report the results of an automated method of segmentation to detect alterations in T2-weighted fluid-attenuated-inversion-recovery (FLAIR) sequences in a one-year follow-up study of a clinically stable patient with genetically diagnosed VWM. Signal alterations in MR imaging were quantified with a recently published WMH segmentation method by means of extreme value distribution (EVD). Our analysis revealed progressive FLAIR alterations of 5.84% in the course of one year, whereas no significant WMH change could be detected in a stable multiple sclerosis (MS) control group. This result demonstrates that automated EVD-based segmentation allows a precise and rapid quantification of extensive FLAIR alterations like in VWM and might be a powerful tool for the clinical and scientific monitoring of degenerative white-matter diseases and potential therapeutic interventions.

Identification of 15 novel partial SHOX deletions and 13 partial duplications, and a review of the literature reveals intron 3 to be a hotspot region.

PubMed

Benito-Sanz, Sara; Belinchon-Martínez, Alberta; Aza-Carmona, Miriam; de la Torre, Carolina; Huber, Celine; González-Casado, Isabel; Ross, Judith L; Thomas, N Simon; Zinn, Andrew R; Cormier-Daire, Valerie; Heath, Karen E

2017-02-01

Short stature homeobox gene (SHOX) is located in the pseudoautosomal region 1 of the sex chromosomes. It encodes a transcription factor implicated in the skeletal growth. Point mutations, deletions or duplications of SHOX or its transcriptional regulatory elements are associated with two skeletal dysplasias, Léri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD), as well as in a small proportion of idiopathic short stature (ISS) individuals. We have identified a total of 15 partial SHOX deletions and 13 partial SHOX duplications in LWD, LMD and ISS patients referred for routine SHOX diagnostics during a 10 year period (2004-2014). Subsequently, we characterized these alterations using MLPA (multiplex ligation-dependent probe amplification assay), fine-tiling array CGH (comparative genomic hybridation) and breakpoint PCR. Nearly half of the alterations have a distal or proximal breakpoint in intron 3. Evaluation of our data and that in the literature reveals that although partial deletions and duplications only account for a small fraction of SHOX alterations, intron 3 appears to be a breakpoint hotspot, with alterations arising by non-allelic homologous recombination, non-homologous end joining or other complex mechanisms.

Connectivity dynamics in typical development and its relationship to autistic traits and autism spectrum disorder.

PubMed

Rashid, Barnaly; Blanken, Laura M E; Muetzel, Ryan L; Miller, Robyn; Damaraju, Eswar; Arbabshirani, Mohammad R; Erhardt, Erik B; Verhulst, Frank C; van der Lugt, Aad; Jaddoe, Vincent W V; Tiemeier, Henning; White, Tonya; Calhoun, Vince

2018-03-30

Recent advances in neuroimaging techniques have provided significant insights into developmental trajectories of human brain function. Characterizations of typical neurodevelopment provide a framework for understanding altered neurodevelopment, including differences in brain function related to developmental disorders and psychopathology. Historically, most functional connectivity studies of typical and atypical development operate under the assumption that connectivity remains static over time. We hypothesized that relaxing stationarity assumptions would reveal novel features of both typical brain development related to children on the autism spectrum. We employed a "chronnectomic" (recurring, time-varying patterns of connectivity) approach to evaluate transient states of connectivity using resting-state functional MRI in a population-based sample of 774 6- to 10-year-old children. Dynamic connectivity was evaluated using a sliding-window approach, and revealed four transient states. Internetwork connectivity increased with age in modularized dynamic states, illustrating an important pattern of connectivity in the developing brain. Furthermore, we demonstrated that higher levels of autistic traits and ASD diagnosis were associated with longer dwell times in a globally disconnected state. These results provide a roadmap to the chronnectomic organization of the developing brain and suggest that characteristics of functional brain connectivity are related to children on the autism spectrum. © 2018 Wiley Periodicals, Inc.

Biological assessment of environmental flows for Oklahoma

USGS Publications Warehouse

Fisher, William L.; Seilheimer, Titus S.; Taylor, Jason M.

2012-01-01

Large-scale patterns in fish assemblage structure and functional groups are influenced by alterations in streamflow regime. In this study, we defined an objective threshold for alteration for Oklahoma streams using a combination of the expected range of 27 flow indices and a discriminant analysis to predict flow regime group. We found that fish functional groups in reference flow conditions had species that were more intolerant to flow alterations and preferences for stream habitat and faster flowing water. In contrast, altered sites had more tolerant species that preferred lentic habitat and slower water velocity. Ordination graphs of the presence and functional groups of species revealed an underlying geographical pattern roughly conforming to ecoregions, although there was separation between reference and altered sites within the larger geographical framework. Additionally, we found that reservoir construction and operation significantly altered fish assemblages in two different systems, Bird Creek in central Oklahoma and the Kiamichi River in southeastern Oklahoma. The Bird Creek flow regime shifted from a historically intermittent stream to one with stable perennial flows, and changes in fish assemblage structure covaried with changes in all five components of the flow regime. In contrast, the Kiamichi River flow regime did not change significantly for most flow components despite shifts in fish assemblage structure; however, most of the species associated with shifts in assemblage structure in the Kiamichi River system were characteristic of lentic environments and were likely related more to proximity of reservoirs in the drainage system than changes in flow. The spatial patterns in fish assemblage response to flow alteration, combined with different temporal responses of hydrology and fish assemblage structure at sites downstream of reservoirs, indicate that interactions between flow regime and aquatic biota vary depending on ecological setting. This supports the notion that regional variation in natural flow regimes could affect the development of flow recommendations.

Impact-Facilitated Hydrothermal Alteration in the Rim of Endeavour Crater, Mars

NASA Technical Reports Server (NTRS)

Mittlefehldt, D. W.; Schroeder, C.; Farrand, W. H.; Crumpler, L. S.; Yen, A. S.

2017-01-01

Endeavour crater, a Noachian-aged, 22 km diameter impact structure on Meridiani Planum, Mars, has been investigated by the Mars Exploration Rover Opportunuity for over 2000 sols (Mars days). The rocks of the western rim region (oldest to youngest) are: (i) the pre-impact Matijevic fm.; (ii) rim-forming Shoemaker fm. polymict impact breccias; (iii) Grasberg fm., fine-grained sediments draping the lower slopes; and (iv) Burns fm., sulfate-rich sandstones that onlap the Grasberg fm. The rim is segmented and transected by radial fracture zones. Evidence for fluid-mediated alteration includes m-scale detections of phyllosilicates from orbit, and cm-scale variations in rock/soil composition/mineralogy documented by the Opportunity instrument suite. The m-scale phyllosilicate detections include Fe(3+)-Mg and aluminous smectites that occur in patches in the Matijevic and Shoemaker fms. Rock compositions do not reveal substantial differences for smectite-bearing compared to smectite-free rocks. Interpretation: large-scale hydrothermal alteration powered by impact-deposited heat acting on limited water supplies engendered mineralogic transfomations under low water/rock, near-isochemical conditions. The cm-scale alterations, localized in fracture zones, occurred at higher water/rock as evidenced by enhanced Si and Al contents through leaching of more soluble elements, and deposition of Mg, Ni and Mn sulphates and halogen salts in soils. Visible/near infrared reflectance of narrow curvilinear red zones indicate higher nanophase ferric oxide contents and possibly hydration compared to surrounding outcrops. Broad fracture zones on the rim have reflectance features consistent with development of ferric oxide minerals. Interpretation: water fluxing through the fractures in a hydrothermal system resulting from the impact engendered alteration and leaching under high water/rock conditions. Late, localized alteration is documented by Ca-sulfate-rich veins that are not confined to fracture zones; some cross-cut the Grasberg fm. Interpretation: late fluid mobilization of soluble elements, likely in a later alteration event.

Involvement of HTLV-I Tax and CREB in aneuploidy: a bioinformatics approach.

PubMed

de la Fuente, Cynthia; Gupta, Madhur V; Klase, Zachary; Strouss, Katharine; Cahan, Patrick; McCaffery, Timothy; Galante, Anthony; Soteropoulos, Patricia; Pumfery, Anne; Fujii, Masahiro; Kashanchi, Fatah

2006-07-05

Adult T-cell leukemia (ATL) is a complex and multifaceted disease associated with human T-cell leukemia virus type 1 (HTLV-I) infection. Tax, the viral oncoprotein, is considered a major contributor to cell cycle deregulation in HTLV-I transformed cells by either directly disrupting cellular factors (protein-protein interactions) or altering their transcription profile. Tax transactivates these cellular promoters by interacting with transcription factors such as CREB/ATF, NF-kappaB, and SRF. Therefore by examining which factors upregulate a particular set of promoters we may begin to understand how Tax orchestrates leukemia development. We observed that CTLL cells stably expressing wild-type Tax (CTLL/WT) exhibited aneuploidy as compared to a Tax clone deficient for CREB transactivation (CTLL/703). To better understand the contribution of Tax transactivation through the CREB/ATF pathway to the aneuploid phenotype, we performed microarray analysis comparing CTLL/WT to CTLL/703 cells. Promoter analysis of altered genes revealed that a subset of these genes contain CREB/ATF consensus sequences. While these genes had diverse functions, smaller subsets of genes were found to be involved in G2/M phase regulation, in particular kinetochore assembly. Furthermore, we confirmed the presence of CREB, Tax and RNA Polymerase II at the p97Vcp and Sgt1 promoters in vivo through chromatin immunoprecipitation in CTLL/WT cells. These results indicate that the development of aneuploidy in Tax-expressing cells may occur in response to an alteration in the transcription profile, in addition to direct protein interactions.

Rice putative methyltransferase gene OsTSD2 is required for root development involving pectin modification.

PubMed

Qu, Lianghuan; Wu, Chunyan; Zhang, Fei; Wu, Yangyang; Fang, Chuanying; Jin, Cheng; Liu, Xianqing; Luo, Jie

2016-10-01

Pectin synthesis and modification are vital for plant development, although the underlying mechanisms are still not well understood. Here, we report the functional characterization of the OsTSD2 gene, which encodes a putative methyltransferase in rice. All three independent T-DNA insertion lines of OsTSD2 displayed dwarf phenotypes and serial alterations in different zones of the root. These alterations included abnormal cellular adhesion and schizogenous aerenchyma formation in the meristematic zone, inhibited root elongation in the elongation zone, and higher lateral root density in the mature zone. Immunofluorescence (with LM19) and Ruthenium Red staining of the roots showed that unesterified homogalacturonan (HG) was increased in Ostsd2 mutants. Biochemical analysis of cell wall pectin polysaccharides revealed that both the monosaccharide composition and the uronic acid content were decreased in Ostsd2 mutants. Increased endogenous ABA content and opposite roles performed by ABA and IAA in regulating cellular adhesion in the Ostsd2 mutants suggested that OsTSD2 is required for root development in rice through a pathway involving pectin synthesis/modification. A hypothesis to explain the relationship among OsTSD2, pectin methylesterification, and root development is proposed, based on pectin's function in regional cell extension/division in a zone-dependent manner. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.

UNUSUAL FLORAL ORGANS Controls Meristem Identity and Organ Primordia Fate in Arabidopsis.

PubMed

Wilkinson, M. D.; Haughn, G. W.

1995-09-01

A novel gene that is involved in regulating flower initiation and development has been identified in Arabidopsis. This gene has been designated UNUSUAL FLORAL ORGANS (UFO), with five corresponding nuclear recessive alleles designated ufo[middot]1 to ufo[middot]5. Under short day-length conditions, ufo homozygotes generate more coflorescences than do the wild type, and coflorescences often appear apical to the first floral shoot, resulting in a period of inflorescence development in which regions of floral and coflorescence shoots are produced alternately. ufo enhances the phenotype of weak leafy alleles, and the double mutant Ufo-1 Apetala1-1 produces only coflorescence-like shoots, suggesting that these two genes control different aspects of floral initiation. Floral development was also altered in Ufo plants. Ufo flowers have an altered organ number in all whorls, and organs in the first, second, and third whorls exhibit variable homeotic transformations. Ufo single and double mutant phenotypes suggest that the floral changes result from reduction in class B floral homeotic gene expression and fluctuations in the expression boundaries of class C function and FLO10. Surprisingly, in situ hybridization analysis revealed no obvious differences in expression pattern or level in developing Ufo flowers compared with that of the wild type for any class B or C gene studied. We propose that UFO acts in concert with known floral initiation genes and regulates the domains of floral homeotic gene function.

Control of Maize Vegetative and Reproductive Development, Fertility, and rRNAs Silencing by HISTONE DEACETYLASE 108

PubMed Central

Forestan, Cristian; Farinati, Silvia; Rouster, Jacques; Lassagne, Hervé; Lauria, Massimiliano; Dal Ferro, Nicola; Varotto, Serena

2018-01-01

Histone deacetylases (HDACs) catalyze the removal of acetyl groups from acetylated histone tails that consequently interact more closely with DNA, leading to chromatin state refractory to transcription. Zea mays HDA108 belongs to the Rpd3/HDA1 HDAC family and is ubiquitously expressed during development. The newly isolated hda108/hda108 insertional mutant exhibited many developmental defects: significant reduction in plant height, alterations of shoot and leaf development, and alterations of inflorescence patterning and fertility. Western blot analyses and immunolocalization experiments revealed an evident increase in histone acetylation, accompanied by a marked reduction in H3K9 dimethylation, in mutant nuclei. The DNA methylation status, in the CHG sequence context, and the transcript level of ribosomal sequences were also affected in hda108 mutants, while enrichment in H3 and H4 acetylation characterizes both repetitive and nonrepetitive transcriptional up-regulated loci. RNA-Seq of both young leaf and anthers indicated that transcription factor expression is highly affected and that the pollen developmental program is disrupted in hda108 mutants. Crosses between hda108/hda108 and epiregulator mutants did not produce any double mutant progeny indicating possible genetic interactions of HDA108 with distinct epigenetic pathways. Our findings indicate that HDA108 is directly involved in regulation of maize development, fertility, and epigenetic regulation of genome activity. PMID:29382649

Larval Population Density Alters Adult Sleep in Wild-Type Drosophila melanogaster but Not in Amnesiac Mutant Flies

PubMed Central

Chi, Michael W.; Griffith, Leslie C.; Vecsey, Christopher G.

2014-01-01

Sleep has many important biological functions, but how sleep is regulated remains poorly understood. In humans, social isolation and other stressors early in life can disrupt adult sleep. In fruit flies housed at different population densities during early adulthood, social enrichment was shown to increase subsequent sleep, but it is unknown if population density during early development can also influence adult sleep. To answer this question, we maintained Drosophila larvae at a range of population densities throughout larval development, kept them isolated during early adulthood, and then tested their sleep patterns. Our findings reveal that flies that had been isolated as larvae had more fragmented sleep than those that had been raised at higher population densities. This effect was more prominent in females than in males. Larval population density did not affect sleep in female flies that were mutant for amnesiac, which has been shown to be required for normal memory consolidation, adult sleep regulation, and brain development. In contrast, larval population density effects on sleep persisted in female flies lacking the olfactory receptor or83b, suggesting that olfactory signals are not required for the effects of larval population density on adult sleep. These findings show that population density during early development can alter sleep behavior in adulthood, suggesting that genetic and/or structural changes are induced by this developmental manipulation that persist through metamorphosis. PMID:25116571

Altered sucrose synthase and invertase expression affects the local and systemic sugar metabolism of nematode-infected Arabidopsis thaliana plants

PubMed Central

Hofmann, Julia

2014-01-01

Sedentary endoparasitic nematodes of plants induce highly specific feeding cells in the root central cylinder. From these, the obligate parasites withdraw all required nutrients. The feeding cells were described as sink tissues in the plant’s circulation system that are supplied with phloem-derived solutes such as sugars. Currently, there are several publications describing mechanisms of sugar import into the feeding cells. However, sugar processing has not been studied so far. Thus, in the present work, the roles of the sucrose-cleaving enzymes sucrose synthases (SUS) and invertases (INV) in the development of Heterodera schachtii were studied. Gene expression analyses indicate that both enzymes are regulated transcriptionally. Nematode development was enhanced on multiple INV and SUS mutants. Syncytia of these mutants were characterized by altered enzyme activity and changing sugar pool sizes. Further, the analyses revealed systemically affected sugar levels and enzyme activities in the shoots of the tested mutants, suggesting changes in the source–sink relationship. Finally, the development of the root-knot nematode Meloidogyne javanica was studied in different INV and SUS mutants and wild-type Arabidopsis plants. Similar effects on the development of both sedentary endoparasitic nematode species (root-knot and cyst nematode) were observed, suggesting a more general role of sucrose-degrading enzymes during plant–nematode interactions. PMID:24187419

Larval Population Density Alters Adult Sleep in Wild-Type Drosophila melanogaster but Not in Amnesiac Mutant Flies.

PubMed

Chi, Michael W; Griffith, Leslie C; Vecsey, Christopher G

2014-08-11

Sleep has many important biological functions, but how sleep is regulated remains poorly understood. In humans, social isolation and other stressors early in life can disrupt adult sleep. In fruit flies housed at different population densities during early adulthood, social enrichment was shown to increase subsequent sleep, but it is unknown if population density during early development can also influence adult sleep. To answer this question, we maintained Drosophila larvae at a range of population densities throughout larval development, kept them isolated during early adulthood, and then tested their sleep patterns. Our findings reveal that flies that had been isolated as larvae had more fragmented sleep than those that had been raised at higher population densities. This effect was more prominent in females than in males. Larval population density did not affect sleep in female flies that were mutant for amnesiac, which has been shown to be required for normal memory consolidation, adult sleep regulation, and brain development. In contrast, larval population density effects on sleep persisted in female flies lacking the olfactory receptor or83b, suggesting that olfactory signals are not required for the effects of larval population density on adult sleep. These findings show that population density during early development can alter sleep behavior in adulthood, suggesting that genetic and/or structural changes are induced by this developmental manipulation that persist through metamorphosis.

The extended curse: being a woman every day.

PubMed

Berg, D H; Coutts, L B

1994-01-01

Inductive analysis of the portrayal of menstruating women in contemporary menstrual product advertisements revealed a profound shift in the meaning of feminine hygiene over the last few decades. The phrase sanitary protection has been replaced by a more euphemistic phrase, feminine hygiene, to refer to menstrual management products. What first appeared to be mere euphemistic substitution, on further analysis, was revealed to involve considerably more than semantics. In the case of panty liners, it was found that the marketing of these specialized products involves the invocation of negative definitions of femaleness and a concomitant subscription to altered definitions of femininity. These altered meanings, conveyed in recent menstrual product advertisements, have serious implications for contemporary women's self-images.

Genomic profiling of pediatric acute myeloid leukemia reveals a changing mutational landscape from disease diagnosis to relapse | Office of Cancer Genomics

Cancer.gov

The genomic and clinical information used to develop and implement therapeutic approaches for AML originated primarily from adult patients and has been generalized to patients with pediatric AML. However, age-specific molecular alterations are becoming more evident and may signify the need to age-stratify treatment regimens. The NCI/COG TARGET-AML initiative employed whole exome capture sequencing (WXS) to interrogate the genomic landscape of matched trios representing specimens collected upon diagnosis, remission, and relapse from 20 cases of de novo childhood AML.

Lycopene loaded gelatin nanoparticles induces internucleosmal DNA fragmentation and apoptosis in human breast adenocarcinoma cells

NASA Astrophysics Data System (ADS)

Preetha, K. Mary Anne; Devasena, T.

2018-06-01

The complex disease, cancer is caused by genetic uncertainty and various molecular alterations. Due to the present ineffective diagnostic and prognostic classifications, the complete heterogeneity of a tumor is not revealed which in turn affects the selection of suitable treatment and patient outcome. Cancer nanotechnology is an emerging interdisciplinary research field that covers important aspects of chemistry, engineering, biology and medicine, leading to the advancement of cancer diagnosis and treatment. Hence the main aim of this study is to develop lycopene loaded gelatin nanoparticles and evaluate its in vitro anticancer activity using breast adenocarcinoma cells.

Analysis of microdissected neurons by 18O mass spectrometry reveals altered protein expression in Alzheimer's disease

PubMed Central

Hashimoto, Masakazu; Bogdanovic, Nenad; Nakagawa, Hiroyuki; Volkmann, Inga; Aoki, Mikio; Winblad, Bengt; Sakai, Jun; Tjernberg, Lars O

2012-01-01

Abstract It is evident that the symptoms of Alzheimer's disease (AD) are derived from severe neuronal damage, and especially pyramidal neurons in the hippocampus are affected pathologically. Here, we analysed the proteome of hippocampal neurons, isolated from post-mortem brains by laser capture microdissection. By using 18O labelling and mass spectrometry, the relative expression levels of 150 proteins in AD and controls were estimated. Many of the identified proteins are involved in transcription and nucleotide binding, glycolysis, heat-shock response, microtubule stabilization, axonal transport or inflammation. The proteins showing the most altered expression in AD were selected for immunohistochemical analysis. These analyses confirmed the altered expression levels, and showed in many AD cases a pathological pattern. For comparison, we also analysed hippocampal sections by Western blot. The expression levels found by this method showed poor correlation with the neuron-specific analysis. Hence, we conclude that cell-specific proteome analysis reveals differences in the proteome that cannot be detected by bulk analysis. PMID:21883897

Quantitative proteomic analysis reveals posttranslational responses to aneuploidy in yeast

PubMed Central

Dephoure, Noah; Hwang, Sunyoung; O'Sullivan, Ciara; Dodgson, Stacie E; Gygi, Steven P; Amon, Angelika; Torres, Eduardo M

2014-01-01

Aneuploidy causes severe developmental defects and is a near universal feature of tumor cells. Despite its profound effects, the cellular processes affected by aneuploidy are not well characterized. Here, we examined the consequences of aneuploidy on the proteome of aneuploid budding yeast strains. We show that although protein levels largely scale with gene copy number, subunits of multi-protein complexes are notable exceptions. Posttranslational mechanisms attenuate their expression when their encoding genes are in excess. Our proteomic analyses further revealed a novel aneuploidy-associated protein expression signature characteristic of altered metabolism and redox homeostasis. Indeed aneuploid cells harbor increased levels of reactive oxygen species (ROS). Interestingly, increased protein turnover attenuates ROS levels and this novel aneuploidy-associated signature and improves the fitness of most aneuploid strains. Our results show that aneuploidy causes alterations in metabolism and redox homeostasis. Cells respond to these alterations through both transcriptional and posttranscriptional mechanisms. DOI: http://dx.doi.org/10.7554/eLife.03023.001 PMID:25073701

The Origin of Dark Inclusions in Allende: New Evidence from Lithium Isotopes

NASA Technical Reports Server (NTRS)

Sephton, Mark A.; James, Rachael H.; Zolensky, Michael E.

2006-01-01

Aqueous and thermal processing of primordial material occurred prior to and during planet formation in the early solar system. A record of how solid materials were altered at this time is present in the carbonaceous chondrites, which are naturally delivered fragments of primitive asteroids. It has been proposed that some materials, such as the clasts termed dark inclusions found in type III chondrites, suggest a sequence of aqueous and thermal events. Lithium isotopes (Li-6 and Li-7) can reveal the role of liquid water in dark inclusion history. During aqueous alteration, Li-7 passes preferentially into solution leaving Li-6 behind in the solid phase and, consequently, any relatively extended periods of interaction with Li-7-rich fluids would have left the dark inclusions enriched in the heavier isotope when compared to the meteorite as a whole. Our analyses of lithium isotopes in Allende and its dark inclusions reveal marked isotopic homogeneity and no evidence of greater levels of aqueous alteration in dark inclusion history.

Identification of significantly mutated regions across cancer types highlights a rich landscape of functional molecular alterations

PubMed Central

Araya, Carlos L.; Cenik, Can; Reuter, Jason A.; Kiss, Gert; Pande, Vijay S.; Snyder, Michael P.; Greenleaf, William J.

2015-01-01

Cancer sequencing studies have primarily identified cancer-driver genes by the accumulation of protein-altering mutations. An improved method would be annotation-independent, sensitive to unknown distributions of functions within proteins, and inclusive of non-coding drivers. We employed density-based clustering methods in 21 tumor types to detect variably-sized significantly mutated regions (SMRs). SMRs reveal recurrent alterations across a spectrum of coding and non-coding elements, including transcription factor binding sites and untranslated regions mutated in up to ∼15% of specific tumor types. SMRs reveal spatial clustering of mutations at molecular domains and interfaces, often with associated changes in signaling. Mutation frequencies in SMRs demonstrate that distinct protein regions are differentially mutated among tumor types, as exemplified by a linker region of PIK3CA in which biophysical simulations suggest mutations affect regulatory interactions. The functional diversity of SMRs underscores both the varied mechanisms of oncogenic misregulation and the advantage of functionally-agnostic driver identification. PMID:26691984

Alterations in the gut microbiota associated with HIV-1 infection.

PubMed

Lozupone, Catherine A; Li, Marcella; Campbell, Thomas B; Flores, Sonia C; Linderman, Derek; Gebert, Matthew J; Knight, Rob; Fontenot, Andrew P; Palmer, Brent E

2013-09-11

Understanding gut microbiota alterations associated with HIV infection and factors that drive these alterations may help explain gut-linked diseases prevalent with HIV. 16S rRNA sequencing of feces from HIV-infected individuals revealed that HIV infection is associated with highly characteristic gut community changes, and antiretroviral therapy does not consistently restore the microbiota to an HIV-negative state. Despite the chronic gut inflammation characteristic of HIV infection, the associated microbiota showed limited similarity with other inflammatory states and instead showed increased, rather than decreased, diversity. Meta-analysis revealed that the microbiota of HIV-infected individuals in the U.S. was most similar to a Prevotella-rich community composition typically observed in healthy individuals in agrarian cultures of Malawi and Venezuela and related to that of U.S. individuals with carbohydrate-rich, protein- and fat-poor diets. By evaluating innate and adaptive immune responses to lysates from bacteria that differ with HIV, we explore the functional drivers of these compositional differences. Copyright © 2013 Elsevier Inc. All rights reserved.

Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity.

PubMed

Jones, Michelle R; Brower, Meredith A; Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii-Der I; Taylor, Kent D; Azziz, Ricardo; Goodarzi, Mark O

2015-08-01

Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.

[Sequence of venous blood flow alterations in patients after recently endured acute thrombosis of lower-limb deep veins based on the findings of ultrasonographic duplex scanning].

PubMed

Tarkovskiĭ, A A; Zudin, A M; Aleksandrova, E S

2009-01-01

This study was undertaken to investigate the sequence of alterations in the venous blood flow to have occurred within the time frame of one year after sustained acute thrombosis of the lower-limb deep veins, which was carried out using the standard technique of ultrasonographic duplex scanning. A total of thirty-two 24-to-62-year-old patients presenting with newly onset acute phlebothrombosis were followed up. All the patients were sequentially examined at 2 days, 3 weeks, 3 months, 6 months and 12 months after the manifestation of the initial clinical signs of the disease. Amongst the parameters to determine were the patency of the deep veins and the condition of the valvular apparatus of the deep, superficial and communicant veins. According to the obtained findings, it was as early as at the first stage of the phlebohaemodynamic alterations after the endured thrombosis, i. e., during the acute period of the disease, that seven (21.9%) patients were found to have developed valvular insufficiency of the communicant veins of the cms, manifesting itself in the formation of a horizontal veno-venous reflux, and 6 months later, these events were observed to have occurred in all the patients examined (100%). Afterwards, the second stage of the phlebohaemodynamic alterations was, simultaneously with the process of recanalization of the thrombotic masses in the deep veins, specifically characterized by the formation of valvular insufficiency of the latter, manifesting itself in the form of the development of a deep vertical veno-venous reflux, which was revealed at month six after the onset of the disease in 56.3% of the examined subjects, to be then observed after 12 months in 93.8% of the patients involved. Recanalization of thrombotic masses was noted to commence 3 months after the onset of thrombosis in twelve (37.5%) patients, and after 12 months it was seen to ensue in all the patients (100%), eventually ending in complete restoration of the patency of the affected veins (to have occurred in 25% of the cases). Of special interest was the finding that insufficiency of the ostial valve of the great saphenous vein, manifesting itself by a superficial vertical veno-venous reflux, was revealed only in two (6.25%) patients examined 12 months after the onset of the disease, which may be regarded as the third stage of the phlebohaemodynamic alterations. That low prevalence and no evidence of varicose transformation of superficial veins appear to suggest an important part they play in compensation of the venous outflow from the extremity affected.

Histological and Transcriptomic Changes in Male Zebrafish Testes Due to Early Life Exposure to Low Level 2,3,7,8-Tetrachlorodibenzo-p-Dioxin.

PubMed

Baker, Bridget B; Yee, Jeremiah S; Meyer, Danielle N; Yang, Doris; Baker, Tracie R

2016-10-01

We have shown that zebrafish (Danio rerio) are an excellent model for evaluating the link between early life stage exposure to environmental chemicals and disease in adulthood and subsequent unexposed generations. Previously, we used this model to identify transgenerational effects of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]) on skeletal development, sex ratio, and reproductive capacity. Transgenerational inheritance of TCDD toxicity, notably decreased reproductive capacity, appears to be mediated through the male germ line. Thus, we examine testicular tissue for structural and gene expression changes using histology, microarray, and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Histological analysis revealed decreased spermatozoa with concurrent increase in spermatogonia, and decreased germinal epithelium thickness in TCDD-exposed males compared with controls. We also identified altered expression of genes associated with testis development, steroidogenesis, spermatogenesis, hormone metabolism, and xenobiotic response. Altered genes are in pathways involving lipid metabolism, molecular transport, small molecule biochemistry, cell morphology, and metabolism of vitamins and minerals. These data will inform future investigations to elucidate the mechanism of adult-onset and transgenerational infertility due to TCDD exposure in zebrafish.

The role of Arabidopsis 5PTase13 in root gravitropism through modulation of vesicle trafficking.

PubMed

Wang, Yuan; Lin, Wen-Hui; Chen, Xu; Xue, Hong-Wei

2009-10-01

Inositol polyphosphate 5-phosphatases (5PTases) are enzymes of phosphatidylinositol metabolism that affect various aspects of plant growth and development. Arabidopsis 5PTase13 regulates auxin homeostasis and hormone-related cotyledon vein development, and here we demonstrate that its knockout mutant 5pt13 has elevated sensitivity to gravistimulation in root gravitropic responses. The altered responses of 5pt13 mutants to 1-N-naphthylphthalamic acid (an auxin transport inhibitor) indicate that 5PTase13 might be involved in the regulation of auxin transport. Indeed, the auxin efflux carrier PIN2 is expressed more broadly under 5PTase13 deficiency, and observations of the internalization of the membrane-selective dye FM4-64 reveal altered vesicle trafficking in 5pt13 mutants. Compared with wild-type, 5pt13 mutant seedlings are less sensitive to the inhibition by brefeldin A of vesicle cycling, seedling growth, and the intracellular cycling of the PIN1 and PIN2 proteins. Further, auxin redistribution upon gravitropic stimulation is stimulated under 5PTase13 deficiency. These results suggest that 5PTase13 may modulate auxin transport by regulating vesicle trafficking and thereby play a role in root gravitropism.

Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations

PubMed Central

Apollo, Alessandro; Pescucci, Chiara; Licastro, Danilo; Urso, Carmelo; Gerlini, Gianni; Borgognoni, Lorenzo; Luzzatto, Lucio; Stecca, Barbara

2016-01-01

Cutaneous melanoma is one of the most aggressive type of skin tumor. Early stage melanoma can be often cured by surgery; therefore current management guidelines dictate a different approach for thin (<1mm) versus thick (>4mm) melanomas. We have carried out whole-exome sequencing in 5 thin and 5 thick fresh-frozen primary cutaneous melanomas. Unsupervised hierarchical clustering analysis of somatic copy number alterations (SCNAs) identified two groups corresponding to thin and thick melanomas. The most striking difference between them was the much greater abundance of SCNAs in thick melanomas, whereas mutation frequency did not significantly change between the two groups. We found novel mutations and focal SCNAs in genes that are embryonic regulators of axon guidance, predominantly in thick melanomas. Analysis of publicly available microarray datasets provided further support for a potential role of Ephrin receptors in melanoma progression. In addition, we have identified a set of SCNAs, including amplification of BRAF and ofthe epigenetic modifier EZH2, that are specific for the group of thick melanomas that developed metastasis during the follow-up. Our data suggest that mutations occur early during melanoma development, whereas SCNAs might be involved in melanoma progression. PMID:27095580

Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations.

PubMed

Montagnani, Valentina; Benelli, Matteo; Apollo, Alessandro; Pescucci, Chiara; Licastro, Danilo; Urso, Carmelo; Gerlini, Gianni; Borgognoni, Lorenzo; Luzzatto, Lucio; Stecca, Barbara

2016-05-24

Cutaneous melanoma is one of the most aggressive type of skin tumor. Early stage melanoma can be often cured by surgery; therefore current management guidelines dictate a different approach for thin (<1mm) versus thick (>4mm) melanomas. We have carried out whole-exome sequencing in 5 thin and 5 thick fresh-frozen primary cutaneous melanomas. Unsupervised hierarchical clustering analysis of somatic copy number alterations (SCNAs) identified two groups corresponding to thin and thick melanomas. The most striking difference between them was the much greater abundance of SCNAs in thick melanomas, whereas mutation frequency did not significantly change between the two groups. We found novel mutations and focal SCNAs in genes that are embryonic regulators of axon guidance, predominantly in thick melanomas. Analysis of publicly available microarray datasets provided further support for a potential role of Ephrin receptors in melanoma progression. In addition, we have identified a set of SCNAs, including amplification of BRAF and ofthe epigenetic modifier EZH2, that are specific for the group of thick melanomas that developed metastasis during the follow-up. Our data suggest that mutations occur early during melanoma development, whereas SCNAs might be involved in melanoma progression.

Epileptogenesis: can the science of epigenetics give us answers?

PubMed

Lubin, Farah D

2012-05-01

Epigenetic mechanisms are regulatory processes that control gene expression changes involved in multiple aspects of neuronal function, including central nervous system development, synaptic plasticity, and memory. Recent evidence indicates that dysregulation of epigenetic mechanisms occurs in several human epilepsy syndromes. Despite this discovery of a potential role for epigenetic mechanisms in epilepsy, few studies have fully explored their contribution to the process of epilepsy development known as epileptogenesis. The purpose of this article is to discuss recent findings suggesting that the process of epileptogenesis may alter the epigenetic landscape, affecting the gene expression patterns observed in epilepsy. Future studies focused on a better characterization of these aberrant epigenetic mechanisms hold the promise of revealing novel treatment options for the prevention and even the reversal of epilepsy.

Malignant hypertension-associated thrombotic microangiopathy following cocaine use.

PubMed

Lamia, Rais; El Ati, Zohra; Ben Fatma, Lilia; Zouaghi, Karim; Smaoui, Wided; Rania, Khedher; Krid, Madiha; Ben Hmida, Fathi; Béji, Soumaya; Ben Moussa, Fatma

2016-01-01

Cocaine is one of the most commonly used illicit drugs with distribution and consumption throughout the world. Acute renal failure associated with rhabdomyolysis, direct vasoconstriction and hemodynamic alteration is well described in patients with cocaine intoxication. Cocaine use is associated with high blood pressure and may rarely induce malignant hypertension associated with thrombotic microangiopathy. We report the case of a patient who developed malignant hypertension associated with thrombotic microangiopathy after chronic consumption of cocaine. A kidney biopsy revealed thrombotic microangiopathy with fibrinoid necrosis of arterioles and glomerular tufts. He required dialysis sessions. Cocaine-mediated endothelial injury and platelet activation may play important pathogenetic roles in cocaine abusers who develop malignant hypertension associated with thrombotic microangiopathy. Clinicians need to be aware of this rare feature of cocaine intoxication.

Responses to Interpersonal Stress: Normative Changes Across Childhood and the Impact of Peer Victimization

PubMed Central

Troop-Gordon, Wendy; Sugimura, Niwako; Rudolph, Karen D.

2016-01-01

This research examined the development of stress responses across 2nd to 6th grades and whether exposure to peer victimization alters stress response trajectories. Youth (338 girls; 298 boys; M age = 7.97 years, SD = .37) reported on stress responses; teachers and youth reported on peer victimization. Latent growth curve modeling revealed an increase in effortful engagement responses and a decrease in disengagement and involuntary engagement responses during this period. Peer victimization disrupted these normative trajectories, resulting in less effortful engagement and more effortful disengagement and involuntary stress responses in early adolescence. These findings suggest that early peer victimization sensitizes youth to stress by interfering with the development of effective coping and fostering maladaptive stress responses. PMID:27709602

Metabolic and miRNA Profiling of TMV Infected Plants Reveals Biphasic Temporal Changes

PubMed Central

Bazzini, Ariel A.; Manacorda, Carlos A.; Tohge, Takayuki; Conti, Gabriela; Rodriguez, Maria C.; Nunes-Nesi, Adriano; Villanueva, Sofía; Fernie, Alisdair R.; Carrari, Fernando; Asurmendi, Sebastian

2011-01-01

Plant viral infections induce changes including gene expression and metabolic components. Identification of metabolites and microRNAs (miRNAs) differing in abundance along infection may provide a broad view of the pathways involved in signaling and defense that orchestrate and execute the response in plant-pathogen interactions. We used a systemic approach by applying both liquid and gas chromatography coupled to mass spectrometry to determine the relative level of metabolites across the viral infection, together with a miRs profiling using a micro-array based procedure. Systemic changes in metabolites were characterized by a biphasic response after infection. The first phase, detected at one dpi, evidenced the action of a systemic signal since no virus was detected systemically. Several of the metabolites increased at this stage were hormone-related. miRs profiling after infection also revealed a biphasic alteration, showing miRs alteration at 5 dpi where no virus was detected systemically and a late phase correlating with virus accumulation. Correlation analyses revealed a massive increase in the density of correlation networks after infection indicating a complex reprogramming of the regulatory pathways, either in response to the plant defense mechanism or to the virus infection itself. Our data propose the involvement of a systemic signaling on early miRs alteration. PMID:22174812

Electrical stimulation reduces smokers' craving by modulating the coupling between dorsal lateral prefrontal cortex and parahippocampal gyrus.

PubMed

Yang, Li-Zhuang; Shi, Bin; Li, Hai; Zhang, Wei; Liu, Ying; Wang, Hongzhi; Zhou, Yanfei; Wang, Ying; Lv, Wanwan; Ji, Xuebing; Hudak, Justin; Zhou, Yifeng; Fallgatter, Andreas J; Zhang, Xiaochu

2017-08-01

Applying electrical stimulation over the prefrontal cortex can help nicotine dependents reduce cigarette craving. However, the underlying mechanism remains ambiguous. This study investigates this issue with functional magnetic resonance imaging. Thirty-two male chronic smokers received real and sham stimulation over dorsal lateral prefrontal cortex (DLPFC) separated by 1 week. The neuroimaging data of the resting state, the smoking cue-reactivity task and the emotion task after stimulation were collected. The craving across the cue-reactivity task was diminished during real stimulation as compared with sham stimulation. The whole-brain analysis on the cue-reactivity task revealed a significant interaction between the stimulation condition (real vs sham) and the cue type (smoking vs neutral) in the left superior frontal gyrus and the left middle frontal gyrus. The functional connectivity between the left DLPFC and the right parahippocampal gyrus, as revealed by both psychophysical interaction analysis and the resting state functional connectivity, is altered by electrical stimulation. Moreover, the craving change across the real and sham condition is predicted by alteration of functional connectivity revealed by psychophysical interaction analysis. The local and long-distance coupling, altered by the electrical stimulation, might be the underlying neural mechanism of craving regulation. © The Author (2017). Published by Oxford University Press.

Mass change calculations of hydrothermal alterations within the volcanogenic metasediments hosted Cu-Pb (-Zn) mineralization at Halilar area, NW Turkey

NASA Astrophysics Data System (ADS)

Kiran Yildirim, Demet; Abdelnasser, Amr; Doner, Zeynep; Kumral, Mustafa

2016-04-01

The Halilar Cu-Pb (-Zn) mineralization that is formed in the volcanogenic metasediments of Bagcagiz Formation at Balikesir province, NW Turkey, represents locally vein-type deposit as well as restricted to fault gouge zone directed NE-SW along with the lower boundary of Bagcagiz Formation and Duztarla granitic intrusion in the study area. Furthermore, This granite is traversed by numerous mineralized sheeted vein systems, which locally transgress into the surrounding metasediments. Therefore, this mineralization closely associated with intense hydrothermal alteration within brecciation, and quartz stockwork veining. The ore mineral assemblage includes chalcopyrite, galena, and some sphalerite with covellite and goethite formed during three phases of mineralization (pre-ore, main ore, and supergene) within an abundant gangue of quartz and calcite. The geologic and field relationships, petrographic and mineralogical studies reveal two alteration zones occurred with the Cu-Pb (-Zn) mineralization along the contact between the Bagcagiz Formation and Duztarla granite; pervasive phyllic alteration (quartz, sericite, and pyrite), and selective propylitic alteration (albite, calcite, epidote, sericite and/or chlorite). This work, by using the mass balance calculations, reports the mass/volume changes (gain and loss) of the chemical components of the hydrothermal alteration zones associated with Halilar Cu-Pb (-Zn) mineralization at Balikesir area (Turkey). It revealed that the phyllic alteration has enrichments of Si, Fe, K, Ba, and LOI with depletion of Mg, Ca, and Na reflect sericitization of alkali feldspar and destruction of ferromagnesian minerals. This zone has high Cu and Pb with Zn contents represents the main mineralized zone. On the other hand, the propylitic zone is characterized by addition of Ca, Na, K, Ti, P, and Ba with LOI and Cu (lower content) referring to the replacement of plagioclase and ferromagnesian minerals by albite, calcite, epidote, and sericite with chlorite. Keywords: Mass balance calculations; hydrothermal alterations; Cu-Pb (-Zn) mineralization; Halilar area; NW Turkey

An expanding universe of the non-coding genome in cancer biology.

PubMed

Xue, Bin; He, Lin

2014-06-01

Neoplastic transformation is caused by accumulation of genetic and epigenetic alterations that ultimately convert normal cells into tumor cells with uncontrolled proliferation and survival, unlimited replicative potential and invasive growth [Hanahan,D. et al. (2011) Hallmarks of cancer: the next generation. Cell, 144, 646-674]. Although the majority of the cancer studies have focused on the functions of protein-coding genes, emerging evidence has started to reveal the importance of the vast non-coding genome, which constitutes more than 98% of the human genome. A number of non-coding RNAs (ncRNAs) derived from the 'dark matter' of the human genome exhibit cancer-specific differential expression and/or genomic alterations, and it is increasingly clear that ncRNAs, including small ncRNAs and long ncRNAs (lncRNAs), play an important role in cancer development by regulating protein-coding gene expression through diverse mechanisms. In addition to ncRNAs, nearly half of the mammalian genomes consist of transposable elements, particularly retrotransposons. Once depicted as selfish genomic parasites that propagate at the expense of host fitness, retrotransposon elements could also confer regulatory complexity to the host genomes during development and disease. Reactivation of retrotransposons in cancer, while capable of causing insertional mutagenesis and genome rearrangements to promote oncogenesis, could also alter host gene expression networks to favor tumor development. Taken together, the functional significance of non-coding genome in tumorigenesis has been previously underestimated, and diverse transcripts derived from the non-coding genome could act as integral functional components of the oncogene and tumor suppressor network. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Network analysis of genomic alteration profiles reveals co-altered functional modules and driver genes for glioblastoma.

PubMed

Gu, Yunyan; Wang, Hongwei; Qin, Yao; Zhang, Yujing; Zhao, Wenyuan; Qi, Lishuang; Zhang, Yuannv; Wang, Chenguang; Guo, Zheng

2013-03-01

The heterogeneity of genetic alterations in human cancer genomes presents a major challenge to advancing our understanding of cancer mechanisms and identifying cancer driver genes. To tackle this heterogeneity problem, many approaches have been proposed to investigate genetic alterations and predict driver genes at the individual pathway level. However, most of these approaches ignore the correlation of alteration events between pathways and miss many genes with rare alterations collectively contributing to carcinogenesis. Here, we devise a network-based approach to capture the cooperative functional modules hidden in genome-wide somatic mutation and copy number alteration profiles of glioblastoma (GBM) from The Cancer Genome Atlas (TCGA), where a module is a set of altered genes with dense interactions in the protein interaction network. We identify 7 pairs of significantly co-altered modules that involve the main pathways known to be altered in GBM (TP53, RB and RTK signaling pathways) and highlight the striking co-occurring alterations among these GBM pathways. By taking into account the non-random correlation of gene alterations, the property of co-alteration could distinguish oncogenic modules that contain driver genes involved in the progression of GBM. The collaboration among cancer pathways suggests that the redundant models and aggravating models could shed new light on the potential mechanisms during carcinogenesis and provide new indications for the design of cancer therapeutic strategies.

Subtracting the sequence bias from partially digested MNase-seq data reveals a general contribution of TFIIS to nucleosome positioning.

PubMed

Gutiérrez, Gabriel; Millán-Zambrano, Gonzalo; Medina, Daniel A; Jordán-Pla, Antonio; Pérez-Ortín, José E; Peñate, Xenia; Chávez, Sebastián

2017-12-07

TFIIS stimulates RNA cleavage by RNA polymerase II and promotes the resolution of backtracking events. TFIIS acts in the chromatin context, but its contribution to the chromatin landscape has not yet been investigated. Co-transcriptional chromatin alterations include subtle changes in nucleosome positioning, like those expected to be elicited by TFIIS, which are elusive to detect. The most popular method to map nucleosomes involves intensive chromatin digestion by micrococcal nuclease (MNase). Maps based on these exhaustively digested samples miss any MNase-sensitive nucleosomes caused by transcription. In contrast, partial digestion approaches preserve such nucleosomes, but introduce noise due to MNase sequence preferences. A systematic way of correcting this bias for massively parallel sequencing experiments is still missing. To investigate the contribution of TFIIS to the chromatin landscape, we developed a refined nucleosome-mapping method in Saccharomyces cerevisiae. Based on partial MNase digestion and a sequence-bias correction derived from naked DNA cleavage, the refined method efficiently mapped nucleosomes in promoter regions rich in MNase-sensitive structures. The naked DNA correction was also important for mapping gene body nucleosomes, particularly in those genes whose core promoters contain a canonical TATA element. With this improved method, we analyzed the global nucleosomal changes caused by lack of TFIIS. We detected a general increase in nucleosomal fuzziness and more restricted changes in nucleosome occupancy, which concentrated in some gene categories. The TATA-containing genes were preferentially associated with decreased occupancy in gene bodies, whereas the TATA-like genes did so with increased fuzziness. The detected chromatin alterations correlated with functional defects in nascent transcription, as revealed by genomic run-on experiments. The combination of partial MNase digestion and naked DNA correction of the sequence bias is a precise nucleosomal mapping method that does not exclude MNase-sensitive nucleosomes. This method is useful for detecting subtle alterations in nucleosome positioning produced by lack of TFIIS. Their analysis revealed that TFIIS generally contributed to nucleosome positioning in both gene promoters and bodies. The independent effect of lack of TFIIS on nucleosome occupancy and fuzziness supports the existence of alternative chromatin dynamics during transcription elongation.

Muscle biopsies from human muscle diseases with myopathic pathology reveal common alterations in mitochondrial function.

PubMed

Sunitha, Balaraju; Gayathri, Narayanappa; Kumar, Manish; Keshava Prasad, Thottethodi Subrahmanya; Nalini, Atchayaram; Padmanabhan, Balasundaram; Srinivas Bharath, Muchukunte Mukunda

2016-07-01

Muscle diseases are clinically and genetically heterogeneous and manifest as dystrophic, inflammatory and myopathic pathologies, among others. Our previous study on the cardiotoxin mouse model of myodegeneration and inflammation linked muscle pathology with mitochondrial damage and oxidative stress. In this study, we investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies from muscle disease patients, represented by dysferlinopathy (dysfy) (dystrophic pathology; n = 43), polymyositis (PM) (inflammatory pathology; n = 24), and distal myopathy with rimmed vacuoles (DMRV) (distal myopathy; n = 31) were analyzed. Mitochondrial damage (ragged blue and COX-deficient fibers) was revealed in dysfy, PM, and DMRV cases by enzyme histochemistry (SDH and COX-SDH), electron microscopy (vacuolation and altered cristae) and biochemical assays (significantly increased ADP/ATP ratio). Proteomic analysis of muscle mitochondria from all three muscle diseases by isobaric tag for relative and absolute quantitation labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis demonstrated down-regulation of electron transport chain (ETC) complex subunits, assembly factors and Krebs cycle enzymes. Interestingly, 80 of the under-expressed proteins were common among the three pathologies. Assay of ETC and Krebs cycle enzyme activities validated the MS data. Mitochondrial proteins from muscle pathologies also displayed higher tryptophan (Trp) oxidation and the same was corroborated in the cardiotoxin model. Molecular modeling predicted Trp oxidation to alter the local structure of mitochondrial proteins. Our data highlight mitochondrial alterations in muscle pathologies, represented by morphological changes, altered mitochondrial proteome and protein oxidation, thereby establishing the role of mitochondrial damage in human muscle diseases. We investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies from dysferlinopathy (Dysfy), polymyositis (PM), and distal myopathy with rimmed vacuoles (DMRV) displayed morphological and biochemical evidences of mitochondrial dysfunction. Proteomic analysis revealed down-regulation of electron transport chain (ETC) subunits, assembly factors, and tricarboxylic acid (TCA) cycle enzymes, with 80 proteins common among the three pathologies. Mitochondrial proteins from muscle pathologies also displayed higher Trp oxidation that could alter the local structure. Cover image for this issue: doi: 10.1111/jnc.13324. © 2016 International Society for Neurochemistry.

Comprehensive Genomic Profiling of Esthesioneuroblastoma Reveals Additional Treatment Options.

PubMed

Gay, Laurie M; Kim, Sungeun; Fedorchak, Kyle; Kundranda, Madappa; Odia, Yazmin; Nangia, Chaitali; Battiste, James; Colon-Otero, Gerardo; Powell, Steven; Russell, Jeffery; Elvin, Julia A; Vergilio, Jo-Anne; Suh, James; Ali, Siraj M; Stephens, Philip J; Miller, Vincent A; Ross, Jeffrey S

2017-07-01

Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant neoplasm of the olfactory mucosa. Despite surgical resection combined with radiotherapy and adjuvant chemotherapy, ENB often relapses with rapid progression. Current multimodality, nontargeted therapy for relapsed ENB is of limited clinical benefit. We queried whether comprehensive genomic profiling (CGP) of relapsed or refractory ENB can uncover genomic alterations (GA) that could identify potential targeted therapies for these patients. CGP was performed on formalin-fixed, paraffin-embedded sections from 41 consecutive clinical cases of ENBs using a hybrid-capture, adaptor ligation based next-generation sequencing assay to a mean coverage depth of 593X. The results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes (amplifications and homozygous deletions). Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in clinical trials. A total of 28 ENBs harbored GA, with a mean of 1.5 GA per sample. Approximately half of the ENBs (21, 51%) featured at least one CRGA, with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), with GA in PIK3CA , NF1 , CDKN2A , and CDKN2C occurring in 7% of samples. We report comprehensive genomic profiles for 41 ENB tumors. CGP revealed potential new therapeutic targets, including targetable GA in the mTOR, CDK and growth factor signaling pathways, highlighting the clinical value of genomic profiling in ENB. Comprehensive genomic profiling of 41 relapsed or refractory ENBs reveals recurrent alterations or classes of mutation, including amplification of tyrosine kinases encoded on chromosome 5q and mutations affecting genes in the mTOR/PI3K pathway. Approximately half of the ENBs (21, 51%) featured at least one clinically relevant genomic alteration (CRGA), with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), and alterations in PIK3CA , NF1 , CDKN2A , or CDKN2C were identified in 7% of samples. Responses to treatment with the kinase inhibitors sunitinib, everolimus, and pazopanib are presented in conjunction with tumor genomics. © AlphaMed Press 2017.

Commensal microbiota stimulate systemic neutrophil migration through induction of Serum amyloid A

PubMed Central

Kanther, Michelle; Tomkovich, Sarah; Sun, Xiaolun; Grosser, Melinda R.; Koo, Jaseol; Flynn, Edward J.; Jobin, Christian; Rawls, John F.

2015-01-01

Summary Neutrophils serve critical roles in inflammatory responses to infection and injury, and mechanisms governing their activity represent attractive targets for controlling inflammation. The commensal microbiota is known to regulate the activity of neutrophils and other leucocytes in the intestine, but the systemic impact of the microbiota on neutrophils remains unknown. Here we utilized in vivo imaging in gnotobiotic zebrafish to reveal diverse effects of microbiota colonization on systemic neutrophil development and function. The presence of a microbiota resulted in increased neutrophil number and myeloperoxidase expression, and altered neutrophil localization and migratory behaviours. These effects of the microbiota on neutrophil homeostasis were accompanied by an increased recruitment of neutrophils to injury. Genetic analysis identified the microbiota-induced acute phase protein serum amyloid A (Saa) as a host factor mediating microbial stimulation of tissue-specific neutrophil migratory behaviours. In vitro studies revealed that zebrafish cells respond to Saa exposure by activating NF-κB, and that Saa-dependent neutrophil migration requires NF-κB-dependent gene expression. These results implicate the commensal microbiota as an important environmental factor regulating diverse aspects of systemic neutrophil development and function, and reveal a critical role for a Saa-NF-κB signalling axis in mediating neutrophil migratory responses. PMID:24373309

Tropomyosin 1: Multiple roles in the developing heart and in the formation of congenital heart defects.

PubMed

England, Jennifer; Granados-Riveron, Javier; Polo-Parada, Luis; Kuriakose, Diji; Moore, Christopher; Brook, J David; Rutland, Catrin S; Setchfield, Kerry; Gell, Christopher; Ghosh, Tushar K; Bu'Lock, Frances; Thornborough, Christopher; Ehler, Elisabeth; Loughna, Siobhan

2017-05-01

Tropomyosin 1 (TPM1) is an essential sarcomeric component, stabilising the thin filament and facilitating actin's interaction with myosin. A number of sarcomeric proteins, such as alpha myosin heavy chain, play crucial roles in cardiac development. Mutations in these genes have been linked to congenital heart defects (CHDs), occurring in approximately 1 in 145 live births. To date, TPM1 has not been associated with isolated CHDs. Analysis of 380 CHD cases revealed three novel mutations in the TPM1 gene; IVS1+2T>C, I130V, S229F and a polyadenylation signal site variant GATAAA/AATAAA. Analysis of IVS1+2T>C revealed aberrant pre-mRNA splicing. In addition, abnormal structural properties were found in hearts transfected with TPM1 carrying I130V and S229F mutations. Phenotypic analysis of TPM1 morpholino-treated embryos revealed roles for TPM1 in cardiac looping, atrial septation and ventricular trabeculae formation and increased apoptosis was seen within the heart. In addition, sarcomere assembly was affected and altered action potentials were exhibited. This study demonstrated that sarcomeric TPM1 plays vital roles in cardiogenesis and is a suitable candidate gene for screening individuals with isolated CHDs. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Embryonic critical windows: changes in incubation temperature alter survival, hatchling phenotype, and cost of development in lake whitefish (Coregonus clupeaformis).

PubMed

Mueller, Casey A; Eme, John; Manzon, Richard G; Somers, Christopher M; Boreham, Douglas R; Wilson, Joanna Y

2015-04-01

The timing, success and energetics of fish embryonic development are strongly influenced by temperature. However, it is unclear if there are developmental periods, or critical windows, when oxygen use, survival and hatchling phenotypic characteristics are particularly influenced by changes in the thermal environment. Therefore, we examined the effects of constant incubation temperature and thermal shifts on survival, hatchling phenotype, and cost of development in lake whitefish (Coregonus clupeaformis) embryos. We incubated whitefish embryos at control temperatures of 2, 5, or 8 °C, and shifted embryos across these three temperatures at the end of gastrulation or organogenesis. We assessed hatch timing, mass at hatch, and yolk conversion efficiency (YCE). We determined cost of development, the amount of oxygen required to build a unit of mass, for the periods from fertilization-organogenesis, organogenesis-fin flutter, fin flutter-hatch, and for total development. An increase in incubation temperature decreased time to 50 % hatch (164 days at 2 °C, 104 days at 5 °C, and 63 days at 8 °C), survival decreased from 55 % at 2 °C, to 38 % at 5 °C, and 17 % at 8 °C, and hatchling yolk-free dry mass decreased from 1.27 mg at 2 °C to 0.61 mg at 8 °C. Thermal shifts altered time to 50 % hatch and hatchling yolk-free dry mass and revealed a critical window during gastrulation in which a temperature change reduced survival. YCE decreased and cost of development increased with increased incubation temperature, but embryos that hatched at 8 °C and were incubated at colder temperatures during fertilization-organogenesis had reduced cost. The relationship between cost of development and temperature was altered during fin flutter-hatch, indicating it may be a critical window during which temperature has the greatest impact on energetic processes. The increase in cost of development with an increase in temperature has not been documented in other fishes and suggests whitefish embryos are more energy efficient at colder temperatures.

Non-ionic surfactant based vesicular drug delivery system for topical delivery of caffeine for treatment of cellulite: design, formulation, characterization, histological anti-cellulite activity, and pharmacokinetic evaluation.

PubMed

Teaima, Mahmoud H; Abdelhalim, Sally A; El-Nabarawi, Mohamed A; Attia, Dalia A; Helal, Doaa A

2018-01-01

Cellulite is a common topographical alteration where skin acquires an orange peel or mattress appearance with alterations in adipose tissue and microcirculation. This work aims to develop and evaluate a topical niosomal gel formulae with good permeation to reach the subcutaneous fat layer. Several caffeine niosomal dispersions were prepared and incorporated into gel formulae using Carbopol 940 polymer, chemical penetration enhancers, and iontophoresis, then the prepared gels were applied onto the skin of rats and anticellulite activity of caffeine from the prepared gels compared to that of the commercial product Cellu Destock ® was evaluated by histological study of the skin and measurement of plasma level of caffeine passing through the skin using liquid chromatography (LC/MS-MS). Results of histology revealed reduction of size and thickness of fatty layer of rat skin in the following order: FVII > FXIV > Cellu Destock ®  > FVII + Iontophoresis > FXIV + Iontophoresis. Pharmacokinetic results of caffeine in plasma revealed that C max , T max , and AUC 0-12h decreased in the following order: FXIV > FVII > Cellu Destock ® . These results conclude that incorporation of caffeine niosomal dispersion into gel matrix with penetration enhancers and iontophoresis resulted in improvement in penetration of caffeine through the skin into the underlying fatty layer in treatment of cellulite.

Microstructural Abnormalities Were Found in Brain Gray Matter from Patients with Chronic Myofascial Pain

PubMed Central

Xie, Peng; Qin, Bangyong; Song, Ganjun; Zhang, Yi; Cao, Song; Yu, Jin; Wu, Jianjiang; Wang, Jiang; Zhang, Tijiang; Zhang, Xiaoming; Yu, Tian; Zheng, Hong

2016-01-01

Myofascial pain, presented as myofascial trigger points (MTrPs)-related pain, is a common, chronic disease involving skeletal muscle, but its underlying mechanisms have been poorly understood. Previous studies have revealed that chronic pain can induce microstructural abnormalities in the cerebral gray matter. However, it remains unclear whether the brain gray matters of patients with chronic MTrPs-related pain undergo alteration. In this study, we employed the Diffusion Kurtosis Imaging (DKI) technique, which is particularly sensitive to brain microstructural perturbation, to monitor the MTrPs-related microstructural alterations in brain gray matter of patients with chronic pain. Our results revealed that, in comparison with the healthy controls, patients with chronic myofascial pain exhibited microstructural abnormalities in the cerebral gray matter and these lesions were mainly distributed in the limbic system and the brain areas involved in the pain matrix. In addition, we showed that microstructural abnormalities in the right anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) had a significant negative correlation with the course of disease and pain intensity. The results of this study demonstrated for the first time that there are microstructural abnormalities in the brain gray matter of patients with MTrPs-related chronic pain. Our findings may provide new insights into the future development of appropriate therapeutic strategies to this disease. PMID:28066193

Label-free Raman spectroscopy provides early determination and precise localization of breast cancer-colonized bone alterations† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc02905e

PubMed Central

Zhang, Chi; Winnard Jr, Paul T.; Dasari, Sidarth; Kominsky, Scott L.; Doucet, Michele; Jayaraman, Swaathi

2017-01-01

Breast neoplasms frequently colonize bone and induce development of osteolytic bone lesions by disrupting the homeostasis of the bone microenvironment. This degenerative process can lead to bone pain and pathological bone fracture, a major cause of cancer morbidity and diminished quality of life, which is exacerbated by our limited ability to monitor early metastatic disease in bone and assess fracture risk. Spurred by its label-free, real-time nature and its exquisite molecular specificity, we employed spontaneous Raman spectroscopy to assess and quantify early metastasis driven biochemical alterations to bone composition. As early as two weeks after intracardiac inoculations of MDA-MB-435 breast cancer cells in NOD-SCID mice, Raman spectroscopic measurements in the femur and spine revealed consistent changes in carbonate substitution, overall mineralization as well as crystallinity increase in tumor-bearing bones when compared with their normal counterparts. Our observations reveal the possibility of early stage detection of biochemical changes in the tumor-bearing bones – significantly before morphological variations are captured through radiographic diagnosis. This study paves the way for a better molecular understanding of altered bone remodeling in such metastatic niches, and for further clinical studies with the goal of establishing a non-invasive tool for early metastasis detection and prediction of pathological fracture risk in breast cancer. PMID:29629144

Feedback Microtubule Control and Microtubule-Actin Cross-talk in Arabidopsis Revealed by Integrative Proteomic and Cell Biology Analysis of KATANIN 1 Mutants.

PubMed

Takáč, Tomáš; Šamajová, Olga; Pechan, Tibor; Luptovčiak, Ivan; Šamaj, Jozef

2017-09-01

Microtubule organization and dynamics are critical for key developmental processes such as cell division, elongation, and morphogenesis. Microtubule severing is an essential regulator of microtubules and is exclusively executed by KATANIN 1 in Arabidopsis In this study, we comparatively studied the proteome-wide effects in two KATANIN 1 mutants. Thus, shotgun proteomic analysis of roots and aerial parts of single nucleotide mutant fra2 and T-DNA insertion mutant ktn1-2 was carried out. We have detected 42 proteins differentially abundant in both fra2 and ktn1-2 KATANIN 1 dysfunction altered the abundance of proteins involved in development, metabolism, and stress responses. The differential regulation of tubulins and microtubule-destabilizing protein MDP25 implied a feedback microtubule control in KATANIN 1 mutants. Furthermore, deregulation of profilin 1, actin-depolymerizing factor 3, and actin 7 was observed. These findings were confirmed by immunoblotting analysis of actin and by microscopic observation of actin filaments using fluorescently labeled phalloidin. Results obtained by quantitative RT-PCR analysis revealed that changed protein abundances were not a consequence of altered expression levels of corresponding genes in the mutants. In conclusion, we show that abundances of several cytoskeletal proteins as well as organization of microtubules and the actin cytoskeleton are amended in accordance with defective microtubule severing. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Altered intestinal epithelium-associated lymphocyte repertoires and function in ApcMin/+ mice.

PubMed

Marsh, Lorraine; Coletta, P Louise; Hull, Mark A; Selby, Peter J; Carding, Simon R

2012-01-01

ApcMin/+ mice spontaneously develop multiple intestinal adenomas along the length of the small intestine and colon. Currently little is known about the role of the immune system in regulating intestinal tumorigenesis in these animals. This study characterised small intestinal intraepithelial lympho-- cyte (IEL) populations in C56BL/6J ApcMin/+ mice and wild-type (Apc+/+) mice. We also determined the effect that T cells expressing either γδ or αβ encoded T cell receptors (TcR) exert on intestinal tumorigenesis. ApcMin/+ mice had significantly lower numbers of CD3+ IELs compared with Apc+/+ littermates and displayed reduced cytotoxicity against tumour target cells. Further analysis of IEL cytotoxicity revealed differences in the cytotoxic pathways utilised by IELs in ApcMin/+ and Apc+/+ mice with ApcMin/+ IELs displaying an absence of perforin/granzyme-mediated killing and increased levels of Fas-FasL-mediated cytotoxicity compared with wild-type IELs. Analysis of ApcMin/+ mice crossed with αβ T-cell deficient (TcRβ-/-) or γδ T-cell deficient (TcRδ-/-) mice on the same genetic background revealed decreased tumour multiplicity in the absence of both αβ and γδ T-cells. This study demonstrates that altered T-cell subsets play important roles in promoting tumorigenesis in ApcMin/+ mice and forms the basis for future mechanistic studies.

Isolation, electron microscopic imaging, and 3-D visualization of native cardiac thin myofilaments.

PubMed

Spiess, M; Steinmetz, M O; Mandinova, A; Wolpensinger, B; Aebi, U; Atar, D

1999-06-15

An increasing number of cardiac diseases are currently pinpointed to reside at the level of the thin myofilaments (e.g., cardiomyopathies, reperfusion injury). Hence the aim of our study was to develop a new method for the isolation of mammalian thin myofilaments suitable for subsequent high-resolution electron microscopic imaging. Native cardiac thin myofilaments were extracted from glycerinated porcine myocardial tissue in the presence of protease inhibitors. Separation of thick and thin myofilaments was achieved by addition of ATP and several centrifugation steps. Negative staining and subsequent conventional and scanning transmission electron microscopy (STEM) of thin myofilaments permitted visualization of molecular details; unlike conventional preparations of thin myofilaments, our method reveals the F-actin moiety and allows direct recognition of thin myofilament-associated porcine cardiac troponin complexes. They appear as "bulges" at regular intervals of approximately 36 nm along the actin filaments. Protein analysis using SDS-polyacrylamide gel electrophoresis revealed that only approximately 20% troponin I was lost during the isolation procedure. In a further step, 3-D helical reconstructions were calculated using STEM dark-field images. These 3-D reconstructions will allow further characterization of molecular details, and they will be useful for directly visualizing molecular alterations related to diseased cardiac thin myofilaments (e.g., reperfusion injury, alterations of Ca2+-mediated tropomyosin switch). Copyright 1999 Academic Press.

Alterations in Seed Development Gene Expression Affect Size and Oil Content of Arabidopsis Seeds1[C][W][OPEN

PubMed Central

Fatihi, Abdelhak; Zbierzak, Anna Maria; Dörmann, Peter

2013-01-01

Seed endosperm development in Arabidopsis (Arabidopsis thaliana) is under control of the polycomb group complex, which includes Fertilization Independent Endosperm (FIE). The polycomb group complex regulates downstream factors, e.g. Pheres1 (PHE1), by genomic imprinting. In heterozygous fie mutants, an endosperm develops in ovules carrying a maternal fie allele without fertilization, finally leading to abortion. Another endosperm development pathway depends on MINISEED3 (a WRKY10 transcription factor) and HAIKU2 (a leucine-rich repeat kinase). While the role of seed development genes in the embryo and endosperm establishment has been studied in detail, their impact on metabolism and oil accumulation remained unclear. Analysis of oil, protein, and sucrose accumulation in mutants and overexpression plants of the four seed development genes revealed that (1) seeds carrying a maternal fie allele accumulate low oil with an altered composition of triacylglycerol molecular species; (2) homozygous mutant seeds of phe1, mini3, and iku2, which are smaller, accumulate less oil and slightly less protein, and starch, which accumulates early during seed development, remains elevated in mutant seeds; (3) embryo-specific overexpression of FIE, PHE1, and MINI3 has no influence on seed size and weight, nor on oil, protein, or sucrose content; and (4) overexpression of IKU2 results in seeds with increased size and weight, and oil content of overexpressed IKU2 seeds is increased by 35%. Thus, IKU2 overexpression represents a novel strategy for the genetic manipulation of the oil content in seeds. PMID:24014578

Human development of the ability to learn from bad news.

PubMed

Moutsiana, Christina; Garrett, Neil; Clarke, Richard C; Lotto, R Beau; Blakemore, Sarah-Jayne; Sharot, Tali

2013-10-08

Humans show a natural tendency to discount bad news while incorporating good news into beliefs (the "good news-bad news effect"), an effect that may help explain seemingly irrational risk taking. Understanding how this bias develops with age is important because adolescents are prone to engage in risky behavior; thus, educating them about danger is crucial. We reveal a striking valence-dependent asymmetry in how belief updating develops with age. In the ages tested (9-26 y), younger age was associated with inaccurate updating of beliefs in response to undesirable information regarding vulnerability. In contrast, the ability to update beliefs accurately in response to desirable information remained relatively stable with age. This asymmetry was mediated by adequate computational use of positive but not negative estimation errors to alter beliefs. The results are important for understanding how belief formation develops and might help explain why adolescents do not respond adequately to warnings.

Human development of the ability to learn from bad news

PubMed Central

Moutsiana, Christina; Garrett, Neil; Clarke, Richard C.; Lotto, R. Beau; Blakemore, Sarah-Jayne; Sharot, Tali

2013-01-01

Humans show a natural tendency to discount bad news while incorporating good news into beliefs (the “good news–bad news effect”), an effect that may help explain seemingly irrational risk taking. Understanding how this bias develops with age is important because adolescents are prone to engage in risky behavior; thus, educating them about danger is crucial. We reveal a striking valence-dependent asymmetry in how belief updating develops with age. In the ages tested (9–26 y), younger age was associated with inaccurate updating of beliefs in response to undesirable information regarding vulnerability. In contrast, the ability to update beliefs accurately in response to desirable information remained relatively stable with age. This asymmetry was mediated by adequate computational use of positive but not negative estimation errors to alter beliefs. The results are important for understanding how belief formation develops and might help explain why adolescents do not respond adequately to warnings. PMID:24019466

Fluid/rock Interaction History of a Faulted Rhyolite-Granite Contact Determined by Sr- Pb-Isotopes, Th/U-Disequilibria and Elemental Distributions (Eastern Rhine Graben Shoulder, SW-Germany)

NASA Astrophysics Data System (ADS)

Marbach, T.; Mangini, A.; Kober, B.; Schleicher, A.; Warr, L. N.

2003-04-01

Major and trace element analyses allow to obtain information concerning the chemical changes induced by alteration. Differences are partly petrographic because the profile crosses the granite-rhyolite contact, but they are also due to different alteration levels induced by fluid circulation along the fault system which has drained the alteration processes. The granite-rhyolite contact constitutes the primary structure. Only the most incompatible elements (Si, Al, Zr, Hf) retain their original signatures and reflect a mixing between typical granite and rhyolite lithologies across the altered zones (cataclasite). The more mobile elements show a different composition within the altered zones (cataclasite) notably a high leaching of cations. The geochemical tracers also suggest at least one strong hydrothermal event with reducing conditions in the altered zones. The isotopic analyses delivered qualitative and temporal information. The use of several isotopic systems, Rb/Sr-, U/Pb-isotopes and Th/U disequilibria, reveals a complex history of polyphase fluid/rock interaction following the Permian volcanic extrusion, showing notable disturbances during the late Jurassic hydrothermal activities, the Tertiary rifting of the Rhine Graben and more recent Quaternary alteration. The granite zone of the sampling profile has underwent an event which set up a new Rb-Sr isotopic composition and reset the Rb/Sr system which originatly corresponded to the Carboniferous intrusion ages. The Rb-Sr data of the granite samples produce a whole rock isochron of 152 ± 5,7 Ma (2σ error) in good agreement with the well-known late Jurassic hydrothermal event (135--160 Ma). The rocks evolution lines for Pb support a Tertiary hydrothermal event (54 Ma ± 16; 1σ error), potentially connected with the development of the Rhine Graben. The profile samples have undergone uranium and thorium redistribution processes which have occurred within the last ˜10^6 years. The samples of the altered zones record a more complex history of uranium exchange with the aqueous phase. This uranium exchange is proportional to the porosity. The best approximation is reached for an exchange coefficient (λ_E) for uranium ranging from 2,5 E-06 [a-1] in the middle of the altered zones to 2,5 E-05 [a-1] on the sides of the altered zones.

Metabonomic Analysis Reveals Efficient Ameliorating Effects of Acupoint Stimulations on the Menopause-caused Alterations in Mammalian Metabolism

PubMed Central

Zhang, Limin; Wang, Yulan; Xu, Yunxiang; Lei, Hehua; Zhao, Ying; Li, Huihui; Lin, Xiaosheng; Chen, Guizhen; Tang, Huiru

2014-01-01

Acupoint stimulations are effective in ameliorating symptoms of menopause which is an unavoidable ageing consequence for women. To understand the mechanistic aspects of such treatments, we systematically analyzed the effects of acupoint laser-irradiation and catgut-embedding on the ovariectomy-induced rat metabolic changes using NMR and GC-FID/MS methods. Results showed that ovariectomization (OVX) caused comprehensive metabolic changes in lipid peroxidation, glycolysis, TCA cycle, choline and amino acid metabolisms. Both acupoint laser-irradiation and catgut-embedding ameliorated the OVX-caused metabonomic changes more effectively than hormone replacement therapy (HRT) with nilestriol. Such effects of acupoint stimulations were highlighted in alleviating lipid peroxidation, restoring glucose homeostasis and partial reversion of the OVX-altered amino acid metabolism. These findings provided new insights into the menopause effects on mammalian biochemistry and beneficial effects of acupoint stimulations in comparison with HRT, demonstrating metabonomics as a powerful approach for potential applications in disease prognosis and developments of effective therapies. PMID:24407431

The Homeobox Protein CEH-23 Mediates Prolonged Longevity in Response to Impaired Mitochondrial Electron Transport Chain in C. elegans

PubMed Central

Walter, Ludivine; Baruah, Aiswarya; Chang, Hsin-Wen; Pace, Heather Mae; Lee, Siu Sylvia

2011-01-01

Recent findings indicate that perturbations of the mitochondrial electron transport chain (METC) can cause extended longevity in evolutionarily diverse organisms. To uncover the molecular basis of how altered METC increases lifespan in C. elegans, we performed an RNAi screen and revealed that three predicted transcription factors are specifically required for the extended longevity of mitochondrial mutants. In particular, we demonstrated that the nuclear homeobox protein CEH-23 uniquely mediates the longevity but not the slow development, reduced brood size, or resistance to oxidative stress associated with mitochondrial mutations. Furthermore, we showed that ceh-23 expression levels are responsive to altered METC, and enforced overexpression of ceh-23 is sufficient to extend lifespan in wild-type background. Our data point to mitochondria-to-nucleus communications to be key for longevity determination and highlight CEH-23 as a novel longevity factor capable of responding to mitochondrial perturbations. These findings provide a new paradigm for how mitochondria impact aging and age-dependent diseases. PMID:21713031

Primers of glycosaminoglycan biosynthesis from Peruvian rain forest plants.

PubMed

Taylor, W H; Sinha, A; Khan, I A; McDaniel, S T; Esko, J D

1998-08-28

We have developed a rapid, high throughput screening assay for compounds that alter the assembly of glycosaminoglycan chains in Chinese hamster ovary cells. The assay uses autoradiography to measure the binding of newly synthesized [35S]proteoglycans and [35S]glycosaminoglycans to a positively charged membrane. Screening over 1000 extracts from a random plant collection obtained from the Amazon rain forest yielded five plants that stimulated glycosaminoglycan assembly in both wild-type cells and a mutant cell line defective in xylosyltransferase (the first committed enzyme involved in glycosaminoglycan biosynthesis). Fractionation of an extract of Maieta guianensis by silica gel and reverse-phase chromatography yielded two pure compounds with stimulatory activity. Spectroscopic analysis by NMR and mass spectrometry revealed that the active principles were xylosides of dimethylated ellagic acid. One of the compounds also contained a galloyl group at C-3 of the xylose moiety. These findings suggest that plants and other natural products may be a source of agents that can potentially alter glycosaminoglycan and proteoglycan formation in animal cells.

Network-Based Analysis of Nutraceuticals in Human Hepatocellular Carcinomas Reveals Mechanisms of Chemopreventive Action

PubMed Central

Michailidou, M; Melas, IN; Messinis, DE; Klamt, S; Alexopoulos, LG; Kolisis, FN; Loutrari, H

2015-01-01

Chronic inflammation is associated with the development of human hepatocellular carcinoma (HCC), an essentially incurable cancer. Anti-inflammatory nutraceuticals have emerged as promising candidates against HCC, yet the mechanisms through which they influence the cell signaling machinery to impose phenotypic changes remain unresolved. Herein we implemented a systems biology approach in HCC cells, based on the integration of cytokine release and phospoproteomic data from high-throughput xMAP Luminex assays to elucidate the action mode of prominent nutraceuticals in terms of topology alterations of HCC-specific signaling networks. An optimization algorithm based on SigNetTrainer, an Integer Linear Programming formulation, was applied to construct networks linking signal transduction to cytokine secretion by combining prior knowledge of protein connectivity with proteomic data. Our analysis identified the most probable target phosphoproteins of interrogated compounds and predicted translational control as a new mechanism underlying their anticytokine action. Induced alterations corroborated with inhibition of HCC-driven angiogenesis and metastasis. PMID:26225263

Metabonomic Analysis Reveals Efficient Ameliorating Effects of Acupoint Stimulations on the Menopause-caused Alterations in Mammalian Metabolism

NASA Astrophysics Data System (ADS)

Zhang, Limin; Wang, Yulan; Xu, Yunxiang; Lei, Hehua; Zhao, Ying; Li, Huihui; Lin, Xiaosheng; Chen, Guizhen; Tang, Huiru

2014-01-01

Acupoint stimulations are effective in ameliorating symptoms of menopause which is an unavoidable ageing consequence for women. To understand the mechanistic aspects of such treatments, we systematically analyzed the effects of acupoint laser-irradiation and catgut-embedding on the ovariectomy-induced rat metabolic changes using NMR and GC-FID/MS methods. Results showed that ovariectomization (OVX) caused comprehensive metabolic changes in lipid peroxidation, glycolysis, TCA cycle, choline and amino acid metabolisms. Both acupoint laser-irradiation and catgut-embedding ameliorated the OVX-caused metabonomic changes more effectively than hormone replacement therapy (HRT) with nilestriol. Such effects of acupoint stimulations were highlighted in alleviating lipid peroxidation, restoring glucose homeostasis and partial reversion of the OVX-altered amino acid metabolism. These findings provided new insights into the menopause effects on mammalian biochemistry and beneficial effects of acupoint stimulations in comparison with HRT, demonstrating metabonomics as a powerful approach for potential applications in disease prognosis and developments of effective therapies.

The Role of Medical Imaging in the Recharacterization of Mild Traumatic Brain Injury Using Youth Sports as a Laboratory.

PubMed

Talavage, Thomas M; Nauman, Eric A; Leverenz, Larry J

2015-01-01

The short- and long-term impact of mild traumatic brain injury (TBI) is an increasingly vital concern for both military and civilian personnel. Such injuries produce significant social and financial burdens and necessitate improved diagnostic and treatment methods. Recent integration of neuroimaging and biomechanical studies in youth collision-sport athletes has revealed that significant alterations in brain structure and function occur even in the absence of traditional clinical markers of "concussion." While task performance is maintained, athletes exposed to repetitive head accelerations exhibit structural changes to the underlying white matter, altered glial cell metabolism, aberrant vascular response, and marked changes in functional network behavior. Moreover, these changes accumulate with accrued years of exposure, suggesting a cumulative trauma mechanism that may culminate in categorization as "concussion" and long-term neurological deficits. The goal of this review is to elucidate the role of medical imaging in recharacterizing TBI, as a whole, to better identify at-risk individuals and improve the development of preventative and interventional approaches.

Marine ecological habitat: a case study on projected thermal power plant around Dharamtar Creek, India.

PubMed

Kulkarni, Vikrant A; Naidu, Velamala S; Jagtap, Tanaji G

2011-03-01

Estuaries and tidal creeks, harboring mangroves particularly, face tremendous anthropogenic pressures. Expansion of mega cities and the thermal power plants are generally proposed in the vicinity of estuaries and creek, due to the feasibility of intake and discharge of water for cooling. Discharges from such developments remain constant threat of increasing thermal pollution and affecting the quality of environment. The baseline information on prevailing quality of aquatic environment comes handy for understanding alterations due to such activities. Principle component analysis (PCA) revealed that temperature, pH, salinity, suspended solids, DO, BOD and phaeophytins are major parameters influencing the creek system. Heated effluents may have direct and adverse impacts on these parameters, altering biotic constituents. Hence, periodic and detailed observations are necessary to estimate exact response of biotic communities to changing environment. The present paper is based on case study, projecting a power plant in the vicinity of major mangrove habitats of Dharamtar creek.

Modification of the Smeloff mitral prosthesis.

PubMed

Smeloff, E A; Davey, T B; Riemenschneider, T A; Epstein, M L; Janos, G; Marshall, R

1982-07-01

The simplicity of the ball valve with its random seating capabilities coupled with its durability, reliability, and predictability has made it the attractive choice of many surgeons. A low incidence of embolic phenomena with the Smeloff full-orifice, double-caged, bare-strutted ball valve has made us reluctant to alter the design over 17 years. Recent evaluation of the reasons for reoperation on the Smeloff mitral valve implantation in 376 cases revealed 16 cases in which development of fibrous subvalvular pannus with signs and symptoms of mitral stenosis occurred. The mean occurrence time was 7.5 years for adults and 4.6 years for children under age 8 years. No such problem has been encountered with the valve in the aortic position. Many of these patients are maintained on aspirin and Persantine alone. Valve design was explored as a possible cause of mitral subvalvular stenosis. Alterations of the design were examined in the engineering laboratory and in dog implantations by catheterization, electrophysiologic evaluation, and echocardiography. The results were encouraging.

Cardiac Metabolism in Heart Failure - Implications beyond ATP production

PubMed Central

Doenst, Torsten; Nguyen, T. Dung; Abel, E. Dale

2013-01-01

The heart has a high rate of ATP production and turnover which is required to maintain its continuous mechanical work. Perturbations in ATP generating processes may therefore affect contractile function directly. Characterizing cardiac metabolism in heart failure revealed several metabolic alterations termed metabolic remodeling, ranging from changes in substrate utilization to mitochondrial dysfunction, ultimately resulting in ATP deficiency and impaired contractility. However, ATP depletion is not the only relevant consequence of metabolic remodeling during heart failure. By providing cellular building blocks and signaling molecules, metabolic pathways control essential processes such as cell growth and regeneration. Thus, alterations in cardiac metabolism may also affect the progression to heart failure by mechanisms beyond ATP supply. Our aim is therefore to highlight that metabolic remodeling in heart failure not only results in impaired cardiac energetics, but also induces other processes implicated in the development of heart failure such as structural remodeling and oxidative stress. Accordingly, modulating cardiac metabolism in heart failure may have significant therapeutic relevance that goes beyond the energetic aspect. PMID:23989714

[New methods of patient selection for improved anticholinergic therapy].

PubMed

Neuhaus, J; Schwalenberg, T; Schlichting, N; Schulze, M; Horn, L-C; Stolzenburg, J-U

2007-09-01

M3-specific inhibitors are currently preferred for anticholinergic therapy of OAB. However, not all of the patients profit from this regimen. This might reflect a heterogeneity of the patient group. The aim of this work is to define subgroups of patients with specific alterations of receptor expression and to profile the receptor expression individually. These receptor profiles might be used for the development of evidence-based "tailored" therapies. Detrusor probes from bladder carcinoma patients (BCa, n=9 F, n=7 male) and interstitial cystitis patients (IC, n=9 female) were examined using confocal immunofluorescence and PCR. M2, M3, P2X1-3, and H1-3 mRNAs were demonstrated in detrusor tissue. As revealed by immunofluorescence, the M2 receptor expression was significantly higher in female compared to male BCa tissues. In addition, the M2 receptor was further upregulated in IC vs BCa in female detrusor. IC patients showed specific alterations of their receptor profile. Individual receptor profiles might be used to optimize medicinal therapies.

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

Powell, Joshua D.; Chen, Qiang; Mason, Hugh S.

Abstract Key message nta-miR-398 is significantly up-regulated while nta-miR-428d is significantly down-regulated in tobacco after agroinfiltration AbstractMicroRNAs are a class of non-coding regulatory RNAs that can modulate development as well as alter innate antiviral defenses in plants. In this study we explored host changes at the microRNA level within tobacco (Nicotiana benthamiana) after expression of a recombinant anti-Ebola GP1 antibody through Agrobacterium tumefaciens agroinfiltration delivery. A multiplex nanoparticle-based cytometry assay tracked the host expression changes of 53 tobacco microRNAs. Our results revealed that the most abundant microRNAs in actively growing leaves corresponded to nanoparticle probes specific to nta-mir-6149 and nta-miR-168b.more » After agroinfiltration, probes targeting nta-mir-398 and nta-mir-482d were significantly altered in their respective expression levels and were further verified through RT-qPCR analysis. To our knowledge this study is the first to profile microRNA expression in tobacco after agroinfiltration using a multiplex nanoparticle approach.« less

An atypical case of neuroleptic malignant syndrome precipitated by valproate

PubMed Central

Verma, Rajesh; Junewar, Vivek; Rathaur, Bhanu Pratap Singh

2014-01-01

Neuroleptic malignant syndrome (NMS) can be caused by various drugs. We report a case of a 60-year-old woman who presented with high-grade fever, muscular rigidity, tachycardia, tachypnoea and altered sensorium along with seizures. She had been taking olanzapine for the past 2 years for psychosis. For the last month valproate was added to her treatment. Her blood investigations revealed hyponatraemia and raised serum ammonia and creatinine phosphokinase (CPK) levels. In view of hyperthermia, muscular rigidity, autonomic disturbances, altered mental status and raised CPK, a diagnosis of NMS was made. Valproate could have probably precipitated NMS; although the patient was taking antipsychotics for a long time, it was only with the addition of valproate that she developed these symptoms. Raised serum ammonia levels also indicated the presence of valproate toxicity. Seizures were probably due to electrolyte disturbances. Offending drugs were withdrawn. The patient improved with treatment by dopamine agonist and other supportive treatments. PMID:24604797

Chronobiology of ethanol: animal models.

PubMed

Rosenwasser, Alan M

2015-06-01

Clinical and epidemiological observations have revealed that alcohol abuse and alcoholism are associated with widespread disruptions in sleep and other circadian biological rhythms. As with other psychiatric disorders, animal models have been very useful in efforts to better understand the cause and effect relationships underlying the largely correlative human data. This review summarizes the experimental findings indicating bidirectional interactions between alcohol (ethanol) consumption and the circadian timing system, emphasizing behavioral studies conducted in the author's laboratory. Together with convergent evidence from multiple laboratories, the work summarized here establishes that ethanol intake (or administration) alters fundamental properties of the underlying circadian pacemaker. In turn, circadian disruption induced by either environmental or genetic manipulations can alter voluntary ethanol intake. These reciprocal interactions may create a vicious cycle that contributes to the downward spiral of alcohol and drug addiction. In the future, such studies may lead to the development of chronobiologically based interventions to prevent relapse and effectively mitigate some of the societal burden associated with such disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

Keratin 17 null mice exhibit age- and strain-dependent alopecia

PubMed Central

McGowan, Kevin M.; Tong, Xuemei; Colucci-Guyon, Emma; Langa, Francina; Babinet, Charles; Coulombe, Pierre A.

2002-01-01

Onset of type I keratin 17 (K17) synthesis marks the adoption of an appendageal fate within embryonic ectoderm, and its expression persists in specific cell types within mature hair, glands, and nail. We report that K17 null mice develop severe alopecia during the first week postbirth, correlating with hair fragility, alterations in follicular histology, and apoptosis in matrix cells. These alterations are incompletely penetrant and normalize starting with the first postnatal cycle. Absence of a hair phenotype correlates with a genetic strain-dependent compensation by related keratins, including K16. These findings reveal a crucial role for K17 in the structural integrity of the first hair produced and the survival of hair-producing cells. Given that identical inherited mutations in this gene can cause either pachyonychia congenita or steatocystoma multiplex, the features of this mouse model suggest that this clinical heterogeneity arises from a cell type-specific, genetically determined compensation by related keratins. PMID:12050118

Brain development, environment and sex: what can we learn from studying graviperception, gravitransduction and the gravireaction of the developing CNS to altered gravity?

PubMed

Sajdel-Sulkowska, Elizabeth M

2008-01-01

As man embarks on space exploration and contemplates space habitation, there is a critical need for basic understanding of the impact of the environmental factors of space, and in particular gravity, on human survival, health, reproduction and development. This review summarizes our present knowledge on the effect of altered gravity on the developing CNS with respect to the response of the developing CNS to altered gravity (gravireaction), the physiological changes associated with altered gravity that could contribute to this effect (gravitransduction), and the possible mechanisms involved in the detection of altered gravity (graviperception). Some of these findings transcend gravitational research and are relevant to our understanding of the impact of environmental factors on CNS development on Earth.

The neural markers of MRI to differentiate depression and panic disorder.

PubMed

Lai, Chien-Han

2018-04-27

Depression and panic disorder (PD) share the common pathophysiology from the perspectives of neurotransmitters. The relatively high comorbidity between depression and PD contributes to the substantial obstacles to differentiate from depression and PD, especially for the brain pathophysiology. There are significant differences in the diagnostic criteria between depression and PD. However, the paradox of similar pathophysiology and different diagnostic criteria in these two disorders were still the issues needing to be addressed. Therefore the clarification of potential difference in the field of neuroscience and pathophysiology between depression and PD can help the clinicians and scientists to understand more comprehensively about significant differences between depression and PD. The researchers should be curious about the underlying difference of pathophysiology beneath the significant distinction of clinical symptoms. In this review article, I tried to find some evidences for the differences between depression and PD, especially for neural markers revealed by magnetic resonance imaging (MRI). The distinctions of structural and functional alterations in depression and PD are reviewed. From the structural perspectives, PD seems to have less severe gray matter alterations in frontal and temporal lobes than depression. The study of white matter microintegrity reveals more widespread alterations in fronto-limbic circuit of depression patients than PD patients, such as the uncinate fasciculus and anterior thalamic radiation. PD might have a more restrictive pattern of structural alterations when compared to depression. For the functional perspectives, the core site of depression pathophysiology is the anterior subnetwork of resting-state network, such as anterior cingulate cortex, which is not significantly altered in PD. A possibly emerging pattern of fronto-limbic distinction between depression and PD has been revealed by these explorative reports. The future trend for machine learning and pattern recognition might confirm the differentiation pattern between depression and PD based on the explorative results. Copyright © 2018 Elsevier Inc. All rights reserved.

Micro-RNA Profiling in Human Serum Reveals Compartment-Specific Roles of miR-571 and miR-652 in Liver Cirrhosis

PubMed Central

Roderburg, Christoph; Mollnow, Tobias; Bongaerts, Brenda; Elfimova, Natalia; Vargas Cardenas, David; Berger, Katharina; Zimmermann, Henning; Koch, Alexander; Vucur, Mihael; Luedde, Mark; Hellerbrand, Claus; Odenthal, Margarete; Trautwein, Christian; Tacke, Frank; Luedde, Tom

2012-01-01

Background and Aims Micro-RNAs (miRNAs) have recently emerged as crucial modulators of molecular processes involved in chronic liver diseases. The few miRNAs with previously proposed roles in liver cirrhosis were identified in screening approaches on liver parenchyma, mostly in rodent models. Therefore, in the present study we performed a systematic screening approach in order to identify miRNAs with altered levels in the serum of patients with chronic liver disease and liver cirrhosis. Methods We performed a systematic, array-based miRNA expression analysis on serum samples from patients with liver cirrhosis. In functional experiments we evaluated the relationship between alterations of miRNA serum levels and their role in distinct cellular compartments involved in hepatic cirrhosis. Results The array analysis and the subsequent confirmation by qPCR in a larger patient cohort identified significant alterations in serum levels of miR-513-3p, miR-571 and miR-652, three previously uncharacterized miRNAs, in patients with alcoholic or hepatitis C induced liver cirrhosis. Of these, miR-571 serum levels closely correlated with disease stages, thus revealing potential as a novel biomarker for hepatic cirrhosis. Further analysis revealed that up-regulation of miR-571 in serum reflected a concordant regulation in cirrhotic liver tissue. In isolated primary human liver cells, miR-571 was up-regulated in human hepatocytes and hepatic stellate cells in response to the pro-fibrogenic cytokine TGF-β. In contrast, alterations in serum levels of miR-652 were stage-independent, reflecting a concordant down-regulation of this miRNA in circulating monocytes of patients with liver cirrhosis, which was inducible by proinflammatory stimuli like bacterial lipopolysaccharide. Conclusion Alterations of miR571 and miR-652 serum levels in patients with chronic liver disease reflect their putative roles in the mediation of fibrogenic and inflammatory processes in distinct cellular compartments involved in the pathogenesis of liver cirrhosis. PMID:22412969

Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability. | Office of Cancer Genomics

Cancer.gov

Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent.

Clues on Acid-Sulfate Alteration and Hematite Formation on Earth and Mars From Iron Isotopic Analyses of Terrestrial Analogues From Hawaii

NASA Technical Reports Server (NTRS)

Nie, N. X.; Dauphas, N.; Morris, R. V

2017-01-01

The Mars Exploration Rover mission revealed the presence of rocks and minerals indicative of water-rock interactions on Mars. A range of mineralogies have been identified, including hematite spherules (i.e., blueberries), jarosite, Mg-, Ca-sulfates, silica-rich materials and silicate relics from basaltic rocks. The mineral assemblages have been interpreted to be derived from acid-sulfate alteration of basaltic materials. Indeed, the chemical compositions of rocks and soils at Home Plate in Gusev Crater follow the trends expected for acid-sulfate alteration.

Production of cross-kingdom oxylipins by pathogenic fungi: An update on their role in development and pathogenicity

PubMed Central

Fischer, Gregory J.; Keller, Nancy P.

2016-01-01

Oxylipins are a class of molecules derived from the incorporation of oxygen into polyunsaturated fatty acid substrates through the action of oxygenases. While extensively investigated in the context of mammalian immune responses, over the last decade it has become apparent that oxylipins are a common means of communication among and between plants, animals, and fungi to control development and alter host-microbe interactions. In fungi, some oxylipins are derived non-enzymatically while others are produced by lipoxygenases, cyclooxygenases, and monooxygenases with homology to plant and human enzymes. Recent investigations of numerous plant and human fungal pathogens have revealed oxylipins to be involved in the establishment and progression of disease This review highlights oxylipin production by pathogenic fungi and their role in fungal development and pathogen/host interactions. PMID:26920885

Iranian undergraduate nursing student perceptions of informal learning: A qualitative research.

PubMed

Seylani, Khatereh; Negarandeh, Reza; Mohammadi, Easa

2012-11-01

Nursing education is both formal and informal. Formal education represents only a small part of all the learning involved; and many students learn more effectively through informal processes. There is little information about nursing student informal education and how it affects their character and practice. This qualitative study explores undergraduate nursing student perceptions of informal learning during nursing studies. Data were gathered through semi-structured interviews with a sample of undergraduate nursing students (n = 14). Strauss and Corbin's constant comparison analysis approach was used for data analysis. The categories that emerged included personal maturity and emotional development, social development, closeness to God, alterations in value systems, and ethical and professional commitment. Findings reveal that nursing education could take advantage of informal learning opportunities to develop students' nontechnical skills and produce more competent students. Implications for nursing education are discussed.

Revealing Risks in Adaptation Planning: expanding Uncertainty Treatment and dealing with Large Projection Ensembles during Planning Scenario development

NASA Astrophysics Data System (ADS)

Brekke, L. D.; Clark, M. P.; Gutmann, E. D.; Wood, A.; Mizukami, N.; Mendoza, P. A.; Rasmussen, R.; Ikeda, K.; Pruitt, T.; Arnold, J. R.; Rajagopalan, B.

2015-12-01

Adaptation planning assessments often rely on single methods for climate projection downscaling and hydrologic analysis, do not reveal uncertainties from associated method choices, and thus likely produce overly confident decision-support information. Recent work by the authors has highlighted this issue by identifying strengths and weaknesses of widely applied methods for downscaling climate projections and assessing hydrologic impacts. This work has shown that many of the methodological choices made can alter the magnitude, and even the sign of the climate change signal. Such results motivate consideration of both sources of method uncertainty within an impacts assessment. Consequently, the authors have pursued development of improved downscaling techniques spanning a range of method classes (quasi-dynamical and circulation-based statistical methods) and developed approaches to better account for hydrologic analysis uncertainty (multi-model; regional parameter estimation under forcing uncertainty). This presentation summarizes progress in the development of these methods, as well as implications of pursuing these developments. First, having access to these methods creates an opportunity to better reveal impacts uncertainty through multi-method ensembles, expanding on present-practice ensembles which are often based only on emissions scenarios and GCM choices. Second, such expansion of uncertainty treatment combined with an ever-expanding wealth of global climate projection information creates a challenge of how to use such a large ensemble for local adaptation planning. To address this challenge, the authors are evaluating methods for ensemble selection (considering the principles of fidelity, diversity and sensitivity) that is compatible with present-practice approaches for abstracting change scenarios from any "ensemble of opportunity". Early examples from this development will also be presented.

Reactive oxygen species in the presence of high glucose alter ureteric bud morphogenesis.

PubMed

Zhang, Shao-Ling; Chen, Yun-Wen; Tran, Stella; Chenier, Isabelle; Hébert, Marie-Josée; Ingelfinger, Julie R

2007-07-01

Renal malformations are a major cause of childhood renal failure. During the development of the kidney, ureteric bud (UB) branching morphogenesis is critical for normal nephrogenesis. These studies investigated whether renal UB branching morphogenesis is altered by a high ambient glucose environment and studied underlying mechanism(s). Kidney explants that were isolated from different periods of gestation (embryonic days 12 to 18) from Hoxb7-green fluorescence protein mice were cultured for 24 h in either normal d-glucose (5 mM) or high d-glucose (25 mM) medium with or without various inhibitors. Alterations in renal morphogenesis were assessed by fluorescence microscopy. Paired-homeobox 2 (Pax-2) gene expression was determined by real-time quantitative PCR, Western blotting, and immunohistology. The results revealed that high d-glucose (25 mM) specifically stimulates UB branching morphogenesis via Pax-2 gene expression, whereas other glucose analogs, such as d-mannitol, l-glucose, and 2-deoxy-d-glucose, had no effect. The stimulatory effect of high glucose on UB branching was blocked in the presence of catalase and inhibitors of NADPH oxidase, mitochondrial electron transport chain complex I, and Akt signaling. Moreover, in in vivo studies, it seems that high glucose induces, via Pax-2 (mainly localized in UB), acceleration of UB branching but not nephron formation. Taken together, these data demonstrate that high glucose alters UB branching morphogenesis. This occurs, at least in part, via reactive oxygen species generation, activation of Akt signaling, and upregulation of Pax-2 gene expression.

THE PRESSURE OF AGING

PubMed Central

AlGhatrif, Majd; Wang, Mingyi; Fedorova, Olga V.; Bagrov, Alexei Y.; Lakatta, Edward G.

2016-01-01

Significant hemodynamic changes ensue with aging, leading to an ever-growing epidemic of hypertension. Alterations in central arterial properties play a major role in these hemodynamic changes. These alterations are characterized by an initial decline in aortic distensibility and a rise of diastolic blood pressure, followed by a sharp increase in pulse wave velocity (PWV), and a rise in pulse pressure (PP) beyond the sixth decade. However, the trajectories of PWV and PP diverge with advancing age, more profoundly in men than women, likely reflecting the more pronounced aortic dilatation in men. There is an increased prevalence of salt-sensitive hypertension with advancing age, that is, in part, mediated by marinobufagenin, an endogenous sodium pump ligand, which is also linked to central arterial stiffness. Within the arterial wall, biomechanical and humoral changes are accompanied by significant biomolecular alterations producing a proinflammatory state, in which activation of angiotensin II signaling plays a pivotal role. This proinflammatory state is in origin a reparatory response to a damaged arterial wall under a pulsatile injury. However the same reparatory process results in fibrosis, which in turn worsens arterial stiffness and produce more pulsatile hemodynamics; this relationship between the pulsatile damage and proinflammatory state is best described as a feed-forward loop. Effective efforts to counter the surging epidemic of hypertension with the aging of our population should be aimed at revealing early, pre-clinical hemodynamic and arterial wall alterations, and develop interventions that halt these processes before they reach the stage the medical community defined as “disease”. PMID:27884238

Subregional Shape Alterations in the Amygdala in Patients with Panic Disorder.

PubMed

Yoon, Sujung; Kim, Jieun E; Kim, Geon Ha; Kang, Hee Jin; Kim, Bori R; Jeon, Saerom; Im, Jooyeon Jamie; Hyun, Heejung; Moon, Sohyeon; Lim, Soo Mee; Lyoo, In Kyoon

2016-01-01

The amygdala has been known to play a pivotal role in mediating fear-related responses including panic attacks. Given the functionally distinct role of the amygdalar subregions, morphometric measurements of the amygdala may point to the pathophysiological mechanisms underlying panic disorder. The current study aimed to determine the global and local morphometric alterations of the amygdala related to panic disorder. Volumetric and surface-based morphometric approach to high-resolution three-dimensional T1-weighted images was used to examine the structural variations of the amygdala, with respect to extent and location, in 23 patients with panic disorder and 31 matched healthy individuals. There were no significant differences in bilateral amygdalar volumes between patients with panic disorder and healthy individuals despite a trend-level right amygdalar volume reduction related to panic disorder (right, β = -0.23, p = 0.09, Cohen's d = 0.51; left, β = -0.18, p = 0.19, Cohen's d = 0.45). Amygdalar subregions were localized into three groups including the superficial, centromedial, and laterobasal groups based on the cytoarchitectonically defined probability map. Surface-based morphometric analysis revealed shape alterations in the laterobasal and centromedial groups of the right amygdala in patients with panic disorder (false discovery rate corrected p < 0.05). The current findings suggest that subregion-specific shape alterations in the right amygdala may be involved in the development and maintenance of panic disorder, which may be attributed to the cause or effects of amygdalar hyperactivation.

Subregional Shape Alterations in the Amygdala in Patients with Panic Disorder

PubMed Central

Kim, Geon Ha; Kang, Hee Jin; Kim, Bori R.; Jeon, Saerom; Im, Jooyeon Jamie; Hyun, Heejung; Moon, Sohyeon; Lim, Soo Mee; Lyoo, In Kyoon

2016-01-01

Background The amygdala has been known to play a pivotal role in mediating fear-related responses including panic attacks. Given the functionally distinct role of the amygdalar subregions, morphometric measurements of the amygdala may point to the pathophysiological mechanisms underlying panic disorder. The current study aimed to determine the global and local morphometric alterations of the amygdala related to panic disorder. Methods Volumetric and surface-based morphometric approach to high-resolution three-dimensional T1-weighted images was used to examine the structural variations of the amygdala, with respect to extent and location, in 23 patients with panic disorder and 31 matched healthy individuals. Results There were no significant differences in bilateral amygdalar volumes between patients with panic disorder and healthy individuals despite a trend-level right amygdalar volume reduction related to panic disorder (right, β = -0.23, p = 0.09, Cohen's d = 0.51; left, β = -0.18, p = 0.19, Cohen's d = 0.45). Amygdalar subregions were localized into three groups including the superficial, centromedial, and laterobasal groups based on the cytoarchitectonically defined probability map. Surface-based morphometric analysis revealed shape alterations in the laterobasal and centromedial groups of the right amygdala in patients with panic disorder (false discovery rate corrected p < 0.05). Conclusions The current findings suggest that subregion-specific shape alterations in the right amygdala may be involved in the development and maintenance of panic disorder, which may be attributed to the cause or effects of amygdalar hyperactivation. PMID:27336300

5-Hydroxymethylcytosine-mediated alteration of transposon activity associated with the exposure to adverse in utero environments in human

PubMed Central

Sun, Miao; Song, Mingxi M.; Wei, Bin; Gao, Qinqin; Li, Lingjun; Yao, Bing; Chen, Li; Lin, Li; Dai, Qing; Zhou, Xiuwen; Tao, Jianying; Chen, Jie; He, Chuan; Jin, Peng; Xu, Zhice

2016-01-01

Preeclampsia and gestational diabetes mellitus (GDM) are the most common clinical conditions in pregnancy that could result in adverse in utero environments. Fetal exposure to poor environments may raise the long-term risk of postnatal disorders, while epigenetic modifications could be involved. Recent research has implicated involvement of 5-hydroxymethylcytosine (5hmC), a DNA base derived from 5-methylcytosine, via oxidation by ten–eleven translocation (TET) enzymes, in DNA methylation-related plasticity. Here, we show that the TET2 expression and 5hmC abundance are significantly altered in the umbilical veins of GDM and preeclampsia. Genome-wide profiling of 5hmC revealed its specific reduction on intragenic regions from both GDM and preeclampsia compared to healthy controls. Gene Ontology analysis using loci bearing unique GDM- and preeclampsia-specific loss-of-5hmC indicated its impact on several critical biological pathways. Interestingly, the substantial alteration of 5hmC on several transposons and repetitive elements led to their differential expression. The alteration of TET expression, 5hmC levels and 5hmC-mediated transposon activity was further confirmed using established hypoxia cell culture model, which could be rescued by vitamin C, a known activator of TET proteins. Together, these results suggest that adverse pregnancy environments could influence 5hmC-mediated epigenetic profile and contribute to abnormal development of fetal vascular systems that may lead to postnatal diseases. PMID:27005421

Cranial diameter pulsations measured by non-invasive ultrasound decrease with tilt

NASA Technical Reports Server (NTRS)

Ueno, Toshiaki; Ballard, Richard E.; Macias, Brandon R.; Yost, William T.; Hargens, Alan R.

2003-01-01

INTRODUCTION: Intracranial pressure (ICP) may play a significant role in physiological responses to microgravity by contributing to the nausea associated with microgravity exposure. However, effects of altered gravity on ICP in astronauts have not been investigated, primarily due to the invasiveness of currently available techniques. We have developed an ultrasonic device that monitors changes in cranial diameter pulsation non-invasively so that we can evaluate ICP dynamics in astronauts during spaceflight. This study was designed to demonstrate the feasibility of our ultrasound technique under the physiological condition in which ICP dynamics are changed due to altered gravitational force. METHODS: Six healthy volunteers were placed at 60 degrees head-up, 30 degrees headup, supine, and 15 degrees head-down positions for 3 min at each angle. We measured arterial blood pressure (ABP) with a finger pressure cuff, and cranial diameter pulsation with a pulsed phase lock loop device (PPLL). RESULTS: Analysis of covariance demonstrated that amplitudes of cranial diameter pulsations were significantly altered with the angle of tilt (p < 0.001). The 95% confidence interval for linear regression coefficients of the cranial diameter pulsation amplitudes with tilt angle was 0.862 to 0.968. However, ABP amplitudes did not show this relationship. DISCUSSION: Our noninvasive ultrasonic technique reveals that the amplitude of cranial diameter pulsation decreases as a function of tilt angle, suggesting that ICP pulsation follows the same relationship. It is demonstrated that the PPLL device has a sufficient sensitivity to detect changes non-invasively in ICP pulsation caused by altered gravity.

Alterations in the Colonic Microbiota of Pigs Associated with Feeding Distillers Dried Grains with Solubles.

PubMed

Burrough, Eric R; Arruda, Bailey L; Patience, John F; Plummer, Paul J

2015-01-01

In an effort to reduce feed costs, many pork producers have increased their use of coproducts of biofuel production in commercial pig diets, including increased feeding of distiller's dried grains with solubles (DDGS). The inclusion of DDGS increases the insoluble fiber content in the ration, which has the potential to impact the colonic microbiota considerably as the large intestine contains a dynamic microenvironment with tremendous interplay between microorganisms. Any alteration to the physical or chemical properties of the colonic contents has the potential to impact the resident bacterial population and potentially favor or inhibit the establishment of pathogenic species. In the present study, colonic contents collected at necropsy from pigs fed either 30% or no DDGS were analyzed to examine the relative abundance of bacterial taxa associated with feeding this ingredient. No difference in alpha diversity (richness) was detected between diet groups. However, the beta diversity was significantly different between groups with feeding of DDGS being associated with a decreased Firmicutes:Bacteriodetes ratio (P = .004) and a significantly lower abundance of Lactobacillus spp. (P = .016). Predictive functional profiling of the microbiota revealed more predicted genes associated with carbohydrate metabolism, protein digestion, and degradation of glycans in the microbiota of pigs fed DDGS. Taken together, these findings confirm that alterations in dietary insoluble fiber significantly alter the colonic microbial profile of pigs and suggest the resultant microbiome may predispose to the development of colitis.

DNA methylation regulates neurophysiological spatial representation in memory formation

PubMed Central

Roth, Eric D.; Roth, Tania L.; Money, Kelli M.; SenGupta, Sonda; Eason, Dawn E.; Sweatt, J. David

2015-01-01

Epigenetic mechanisms including altered DNA methylation are critical for altered gene transcription subserving synaptic plasticity and the retention of learned behavior. Here we tested the idea that one role for activity-dependent altered DNA methylation is stabilization of cognition-associated hippocampal place cell firing in response to novel place learning. We observed that a behavioral protocol (spatial exploration of a novel environment) known to induce hippocampal place cell remapping resulted in alterations of hippocampal Bdnf DNA methylation. Further studies using neurophysiological in vivo single unit recordings revealed that pharmacological manipulations of DNA methylation decreased long-term but not short-term place field stability. Together our data highlight a role for DNA methylation in regulating neurophysiological spatial representation and memory formation. PMID:25960947

Modulators of Stomatal Lineage Signal Transduction Alter Membrane Contact Sites and Reveal Specialization among ERECTA Kinases.

PubMed

Ho, Chin-Min Kimmy; Paciorek, Tomasz; Abrash, Emily; Bergmann, Dominique C

2016-08-22

Signal transduction from a cell's surface to its interior requires dedicated signaling elements and a cellular environment conducive to signal propagation. Plant development, defense, and homeostasis rely on plasma membrane receptor-like kinases to perceive endogenous and environmental signals, but little is known about their immediate downstream targets and signaling modifiers. Using genetics, biochemistry, and live-cell imaging, we show that the VAP-RELATED SUPPRESSOR OF TMM (VST) family is required for ERECTA-mediated signaling in growth and cell-fate determination and reveal a role for ERECTA-LIKE2 in modulating signaling by its sister kinases. We show that VSTs are peripheral plasma membrane proteins that can form complexes with integral ER-membrane proteins, thereby potentially influencing the organization of the membrane milieu to promote efficient and differential signaling from the ERECTA-family members to their downstream intracellular targets. Copyright © 2016 Elsevier Inc. All rights reserved.

Metabolite profiling of antidepressant drug action reveals novel drug targets beyond monoamine elevation.

PubMed

Webhofer, C; Gormanns, P; Tolstikov, V; Zieglgänsberger, W; Sillaber, I; Holsboer, F; Turck, C W

2011-12-13

Currently used antidepressants elevate monoamine levels in the synaptic cleft. There is good reason to assume that this is not the only source for antidepressant therapeutic activities and that secondary downstream effects may be relevant for alleviating symptoms of depression. We attempted to elucidate affected biochemical pathways downstream of monoamine reuptake inhibition by interrogating metabolomic profiles in DBA/2Ola mice after chronic paroxetine treatment. Metabolomic changes were investigated using gas chromatography-mass spectrometry profiling and group differences were analyzed by univariate and multivariate statistics. Pathways affected by antidepressant treatment were related to energy metabolism, amino acid metabolism and hormone signaling. The identified pathways reveal further antidepressant therapeutic action and represent targets for drug development efforts. A comparison of the central nervous system with blood plasma metabolite alterations identified GABA, galactose-6-phosphate and leucine as biomarker candidates for assessment of antidepressant treatment effects in the periphery.

Altered expression of the caffeine synthase gene in a naturally caffeine-free mutant of Coffea arabica.

PubMed

Maluf, Mirian Perez; da Silva, Carla Cristina; de Oliveira, Michelle de Paula Abreu; Tavares, Aline Gomes; Silvarolla, Maria Bernadete; Guerreiro, Oliveiro

2009-10-01

In this work, we studied the biosynthesis of caffeine by examining the expression of genes involved in this biosynthetic pathway in coffee fruits containing normal or low levels of this substance. The amplification of gene-specific transcripts during fruit development revealed that low-caffeine fruits had a lower expression of the theobromine synthase and caffeine synthase genes and also contained an extra transcript of the caffeine synthase gene. This extra transcript contained only part of exon 1 and all of exon 3. The sequence of the mutant caffeine synthase gene revealed the substitution of isoleucine for valine in the enzyme active site that probably interfered with enzymatic activity. These findings indicate that the absence of caffeine in these mutants probably resulted from a combination of transcriptional regulation and the presence of mutations in the caffeine synthase amino acid sequence.

Altered expression of the caffeine synthase gene in a naturally caffeine-free mutant of Coffea arabica

PubMed Central

2009-01-01

In this work, we studied the biosynthesis of caffeine by examining the expression of genes involved in this biosynthetic pathway in coffee fruits containing normal or low levels of this substance. The amplification of gene-specific transcripts during fruit development revealed that low-caffeine fruits had a lower expression of the theobromine synthase and caffeine synthase genes and also contained an extra transcript of the caffeine synthase gene. This extra transcript contained only part of exon 1 and all of exon 3. The sequence of the mutant caffeine synthase gene revealed the substitution of isoleucine for valine in the enzyme active site that probably interfered with enzymatic activity. These findings indicate that the absence of caffeine in these mutants probably resulted from a combination of transcriptional regulation and the presence of mutations in the caffeine synthase amino acid sequence. PMID:21637458

Naturally occurring tumours in the basal metazoan Hydra.

PubMed

Domazet-Lošo, Tomislav; Klimovich, Alexander; Anokhin, Boris; Anton-Erxleben, Friederike; Hamm, Mailin J; Lange, Christina; Bosch, Thomas C G

2014-06-24

The molecular nature of tumours is well studied in vertebrates, although their evolutionary origin remains unknown. In particular, there is no evidence for naturally occurring tumours in pre-bilaterian animals, such as sponges and cnidarians. This is somewhat surprising given that recent computational studies have predicted that most metazoans might be prone to develop tumours. Here we provide first evidence for naturally occurring tumours in two species of Hydra. Histological, cellular and molecular data reveal that these tumours are transplantable and might originate by differentiation arrest of female gametes. Growth of tumour cells is independent from the cellular environment. Tumour-bearing polyps have significantly reduced fitness. In addition, Hydra tumours show a greatly altered transcriptome that mimics expression shifts in vertebrate cancers. Therefore, this study shows that spontaneous tumours have deep evolutionary roots and that early branching animals may be informative in revealing the fundamental mechanisms of tumorigenesis.

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

PubMed

Marín-Padilla, Miguel

2013-09-06

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

A Paleomagnetic and Diagenetic Study of the Woodford Shale, Oklahoma, U.S.A.: The Timing of Hydrothermal Alteration

NASA Astrophysics Data System (ADS)

Roberts, J.; Elmore, R. D.

2017-12-01

An oriented Woodford Shale core from the Ardmore Basin near the Ouachita thrust zone (Core B) was sampled to identify diagenetic events and interpret their origin, and to test if a magnetization was present that can be used to date the altering event(s). The shale is extensively altered, exhibiting a complex paragenesis with multiple fractures and brecciated intervals. Multiple hydrothermal minerals, including biotite, magnesite, norsethite, witherite, gorceixite, potassium feldspar, sphalerite, chalcopyrite, and saddle dolomite, are present in and around fractures and in the matrix. Vitrinite and bitumen reflectance measurements indicate VRo values of 1.82% ( 230°C). Two other Woodford Shale cores (A and C) from the Anadarko Basin also contain hydrothermal minerals. Vitrinite and bitumen reflectance data reveal trends between thermal maturity and the level of hydrothermal alteration, with Core A (0.80% VRo ( 125°C) displaying the lowest alteration, and Core C ( 1.5% VRo ( 210°C) displaying intermediate alteration compared to core B. Paleomagnetic analysis of Core B reveals the presence of a characteristic remanent magnetization (ChRM) with south-southeasterly declinations and shallow inclinations that is unblocked by 450°C and is interpreted to reside in magnetite. This ChRM is interpreted to be either a chemical remanent magnetization (CRM) or a thermochemical remanent magnetization (TCRM) acquired during the Late Permian based on the pole position. The presence of specimens with the CRM/TCRM in altered rock and high thermal maturities suggests that this CRM/TCRM originated from alteration by hydrothermal fluids. These results suggest that the Woodford Shale evolved into an open diagenetic system. In addition to causing heightened thermal maturities, these hydrothermal fluids both increased porosity through dissolution and decreased porosity through precipitation of minerals. The Late Permian timing agrees with the dating of hydrothermal alteration found within the Ouachita and Arbuckle Mountains in other studies. The timing for these events is postcollisional, and the most consistent model for the origin of the hydrothermal minerals is fluid flow as a result of faulting that accessed reservoir(s) of warm fluids.

Oxygen isotope constraints on the alteration temperatures of CM chondrites

NASA Astrophysics Data System (ADS)

Verdier-Paoletti, Maximilien J.; Marrocchi, Yves; Avice, Guillaume; Roskosz, Mathieu; Gurenko, Andrey; Gounelle, Matthieu

2017-01-01

We report a systematic oxygen isotopic survey of Ca-carbonates in nine different CM chondrites characterized by different degrees of alteration, from the least altered known to date (Paris, 2.7-2.8) to the most altered (ALH 88045, CM1). Our data define a continuous trend that crosses the Terrestrial Fractionation Line (TFL), with a general relationship that is indistinguishable within errors from the trend defined by both matrix phyllosilicates and bulk O-isotopic compositions of CM chondrites. This bulk-matrix-carbonate (BMC) trend does not correspond to a mass-dependent fractionation (i.e., slope 0.52) as it would be expected during fluid circulation along a temperature gradient. It is instead a direct proxy of the degree of O-isotopic equilibration between 17,18O-rich fluids and 16O-rich anhydrous minerals. Our O-isotopic survey revealed that, for a given CM, no carbonate is in O-isotopic equilibrium with its respective surrounding matrix. This precludes direct calculation of the temperature of carbonate precipitation. However, the O-isotopic compositions of alteration water in different CMs (inferred from isotopic mass-balance calculation and direct measurements) define another trend (CMW for CM Water), parallel to BMC but with a different intercept. The distance between the BMC and CMW trends is directly related to the temperature of CM alteration and corresponds to average carbonates and serpentine formation temperatures of 110 °C and 75 °C, respectively. However, carbonate O-isotopic variations around the BMC trend indicate that they formed at various temperatures ranging between 50 and 300 °C, with 50% of the carbonates studied here showing precipitation temperature higher than 100 °C. The average Δ17O and the average carbonate precipitation temperature per chondrite are correlated, revealing that all CMs underwent similar maximum temperature peaks, but that altered CMs experienced protracted carbonate precipitation event(s) at lower temperatures than the least altered CMs. Our data suggest that the Δ17O value of Ca-carbonates could be a reliable proxy of the degree of alteration experienced by CM chondrites.

Identification of the Schistosoma mansoni TNF-Alpha Receptor Gene and the Effect of Human TNF-Alpha on the Parasite Gene Expression Profile

PubMed Central

Oliveira, Katia C.; Carvalho, Mariana L. P.; Venancio, Thiago M.; Miyasato, Patricia A.; Kawano, Toshie; DeMarco, Ricardo; Verjovski-Almeida, Sergio

2009-01-01

Background Schistosoma mansoni is the major causative agent of schistosomiasis. The parasite takes advantage of host signals to complete its development in the human body. Tumor necrosis factor-alpha (TNF-α) is a human cytokine involved in skin inflammatory responses, and although its effect on the adult parasite's metabolism and egg-laying process has been previously described, a comprehensive assessment of the TNF-α pathway and its downstream molecular effects is lacking. Methodology/Principal Findings In the present work we describe a possible TNF-α receptor (TNFR) homolog gene in S. mansoni (SmTNFR). SmTNFR encodes a complete receptor sequence composed of 599 amino acids, and contains four cysteine-rich domains as described for TNFR members. Real-time RT-PCR experiments revealed that SmTNFR highest expression level is in cercariae, 3.5 (±0.7) times higher than in adult worms. Downstream members of the known human TNF-α pathway were identified by an in silico analysis, revealing a possible TNF-α signaling pathway in the parasite. In order to simulate parasite's exposure to human cytokine during penetration of the skin, schistosomula were exposed to human TNF-α just 3 h after cercariae-to-schistosomula in vitro transformation, and large-scale gene expression measurements were performed with microarrays. A total of 548 genes with significantly altered expression were detected, when compared to control parasites. In addition, treatment of adult worms with TNF-α caused a significantly altered expression of 1857 genes. Interestingly, the set of genes altered in adults is different from that of schistosomula, with 58 genes in common, representing 3% of altered genes in adults and 11% in 3 h-old early schistosomula. Conclusions/Significance We describe the possible molecular elements and targets involved in human TNF-α effect on S. mansoni, highlighting the mechanism by which recently transformed schistosomula may sense and respond to this host mediator at the site of cercarial penetration into the skin. PMID:19956564

Proteomic profiling reveals crucial retinal protein alterations in the early phase of an experimental glaucoma model.

PubMed

Anders, Fabian; Teister, Julia; Funke, Sebstian; Pfeiffer, Norbert; Grus, Franz; Solon, Thanos; Prokosch, Verena

2017-07-01

Clinical glaucoma is difficult to assess in terms of molecular pathophysiology, prompting studies in experimental models of glaucoma. The purpose of this study was to investigate quantitative changes in retinal protein expression at the onset of experimental glaucoma in rats. Analyzing the proteome provides a suitable tool to decipher the pathophysiological processes in glaucomatous degeneration. Thermic cauterization of episcleral veins was utilized to elevate the intraocular pressure in Sprague Dawley rats. Morphological changes were surveyed on a cellular level with a staining of Brn3a-positive cells. The retinal nerve fiber layer was investigated using optical coherence tomography (OCT, Heidelberg Engineering) and the optic nerve was analyzed by an axonal grading system. Mass spectrometry-featured quantitative proteomics and immunohistochemical staining was used to identify specifically altered proteins in the course of intraocular pressure elevation and initial neurodegeneration. Proteomic data were further analyzed with Ingenuity Pathway Analysis and Cytoscape to analyze further molecular associations. The intraocular pressure rose significantly (p < 0.001) for the follow-up period of 3 weeks after which animals were sacrificed. Eyes exposed to an elevated intraocular pressure showed an initial decrease of retinal ganglion cells, retinal nerve fiber layer (p < 0.05) and an impairment of the optic nerve (p < 0.01). Mass spectrometry led to the identification and quantification of 931 retinal proteins, whereas 32 were considerably altered. Bioinformatics-assisted clustering revealed that a majority of these proteins are functionally associated with cell differentiation, apoptosis and stress response. The creation of an interactive protein network showed that numerous altered proteins are connected regarding their cellular function. Protein kinase b, mitogen-activated protein kinase 1 and the NF-κB complex seem to be essential molecules in this context. In conclusion, these results provide further lines of evidence that substantial molecular changes occur at the onset of the disease, identifying potential key players, which might be useful as biomarkers for diagnostics and development of medical treatment in the future.

Redox Indicator Mice Stably Expressing Genetically Encoded Neuronal roGFP: Versatile Tools to Decipher Subcellular Redox Dynamics in Neuropathophysiology.

PubMed

Wagener, Kerstin C; Kolbrink, Benedikt; Dietrich, Katharina; Kizina, Kathrin M; Terwitte, Lukas S; Kempkes, Belinda; Bao, Guobin; Müller, Michael

2016-07-01

Reactive oxygen species (ROS) and downstream redox alterations not only mediate physiological signaling but also neuropathology. For long, ROS/redox imaging was hampered by a lack of reliable probes. Genetically encoded redox sensors overcame this gap and revolutionized (sub)cellular redox imaging. Yet, the successful delivery of sensor-coding DNA, which demands transfection/transduction of cultured preparations or stereotaxic microinjections of each subject, remains challenging. By generating transgenic mice, we aimed to overcome limiting cultured preparations, circumvent surgical interventions, and to extend effectively redox imaging to complex and adult preparations. Our redox indicator mice widely express Thy1-driven roGFP1 (reduction-oxidation-sensitive green fluorescent protein 1) in neuronal cytosol or mitochondria. Negative phenotypic effects of roGFP1 were excluded and its proper targeting and functionality confirmed. Redox mapping by ratiometric wide-field imaging reveals most oxidizing conditions in CA3 neurons. Furthermore, mitochondria are more oxidized than cytosol. Cytosolic and mitochondrial roGFP1s reliably report cell endogenous redox dynamics upon metabolic challenge or stimulation. Fluorescence lifetime imaging yields stable, but marginal, response ranges. We therefore developed automated excitation ratiometric 2-photon imaging. It offers superior sensitivity, spatial resolution, and response dynamics. Redox indicator mice enable quantitative analyses of subcellular redox dynamics in a multitude of preparations and at all postnatal stages. This will uncover cell- and compartment-specific cerebral redox signals and their defined alterations during development, maturation, and aging. Cross-breeding with other disease models will reveal molecular details on compartmental redox homeostasis in neuropathology. Combined with ratiometric 2-photon imaging, this will foster our mechanistic understanding of cellular redox signals in their full complexity. Antioxid. Redox Signal. 25, 41-58.

Smad3 Deficiency in Mice Protects Against Insulin Resistance and Obesity Induced by a High-Fat Diet

PubMed Central

Tan, Chek Kun; Leuenberger, Nicolas; Tan, Ming Jie; Yan, Yew Wai; Chen, Yinghui; Kambadur, Ravi; Wahli, Walter; Tan, Nguan Soon

2011-01-01

OBJECTIVE Obesity and associated pathologies are major global health problems. Transforming growth factor-β/Smad3 signaling has been implicated in various metabolic processes, including adipogenesis, insulin expression, and pancreatic β-cell function. However, the systemic effects of Smad3 deficiency on adiposity and insulin resistance in vivo remain elusive. This study investigated the effects of Smad3 deficiency on whole-body glucose and lipid homeostasis and its contribution to the development of obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS We compared various metabolic profiles of Smad3-knockout and wild-type mice. We also determined the mechanism by which Smad3 deficiency affects the expression of genes involved in adipogenesis and metabolism. Mice were then challenged with a high-fat diet to study the impact of Smad3 deficiency on the development of obesity and insulin resistance. RESULTS Smad3-knockout mice exhibited diminished adiposity with improved glucose tolerance and insulin sensitivity. Chromatin immunoprecipitation assay revealed that Smad3 deficiency increased CCAAT/enhancer-binding protein β-C/EBP homologous protein 10 interaction and exerted a differential regulation on proliferator-activated receptor β/δ and proliferator-activated receptor γ expression in adipocytes. Focused gene expression profiling revealed an altered expression of genes involved in adipogenesis, lipid accumulation, and fatty acid β-oxidation, indicative of altered adipose physiology. Despite reduced physical activity with no modification in food intake, these mutant mice were resistant to obesity and insulin resistance induced by a high-fat diet. CONCLUSIONS Smad3 is a multifaceted regulator in adipose physiology and the pathogenesis of obesity and type 2 diabetes, suggesting that Smad3 may be a potential target for the treatment of obesity and its associated disorders. PMID:21270259

Comprehensive analyses of imprinted differentially methylated regions reveal epigenetic and genetic characteristics in hepatoblastoma

PubMed Central

2013-01-01

Background Aberrant methylation at imprinted differentially methylated regions (DMRs) in human 11p15.5 has been reported in many tumors including hepatoblastoma. However, the methylation status of imprinted DMRs in imprinted loci scattered through the human genome has not been analyzed yet in any tumors. Methods The methylation statuses of 33 imprinted DMRs were analyzed in 12 hepatoblastomas and adjacent normal liver tissue by MALDI-TOF MS and pyrosequencing. Uniparental disomy (UPD) and copy number abnormalities were investigated with DNA polymorphisms. Results Among 33 DMRs analyzed, 18 showed aberrant methylation in at least 1 tumor. There was large deviation in the incidence of aberrant methylation among the DMRs. KvDMR1 and IGF2-DMR0 were the most frequently hypomethylated DMRs. INPP5Fv2-DMR and RB1-DMR were hypermethylated with high frequencies. Hypomethylation was observed at certain DMRs not only in tumors but also in a small number of adjacent histologically normal liver tissue, whereas hypermethylation was observed only in tumor samples. The methylation levels of long interspersed nuclear element-1 (LINE-1) did not show large differences between tumor tissue and normal liver controls. Chromosomal abnormalities were also found in some tumors. 11p15.5 and 20q13.3 loci showed the frequent occurrence of both genetic and epigenetic alterations. Conclusions Our analyses revealed tumor-specific aberrant hypermethylation at some imprinted DMRs in 12 hepatoblastomas with additional suggestion for the possibility of hypomethylation prior to tumor development. Some loci showed both genetic and epigenetic alterations with high frequencies. These findings will aid in understanding the development of hepatoblastoma. PMID:24373183

Nicotinic Receptor Alpha7 Expression during Tooth Morphogenesis Reveals Functional Pleiotropy

PubMed Central

Rogers, Scott W.; Gahring, Lorise C.

2012-01-01

The expression of nicotinic acetylcholine receptor (nAChR) subtype, alpha7, was investigated in the developing teeth of mice that were modified through homologous recombination to express a bi-cistronic IRES-driven tau-enhanced green fluorescent protein (GFP); alpha7GFP) or IRES-Cre (alpha7Cre). The expression of alpha7GFP was detected first in cells of the condensing mesenchyme at embryonic (E) day E13.5 where it intensifies through E14.5. This expression ends abruptly at E15.5, but was again observed in ameloblasts of incisors at E16.5 or molar ameloblasts by E17.5–E18.5. This expression remains detectable until molar enamel deposition is completed or throughout life as in the constantly erupting mouse incisors. The expression of alpha7GFP also identifies all stages of innervation of the tooth organ. Ablation of the alpha7-cell lineage using a conditional alpha7Cre×ROSA26-LoxP(diphtheria toxin A) strategy substantially reduced the mesenchyme and this corresponded with excessive epithelium overgrowth consistent with an instructive role by these cells during ectoderm patterning. However, alpha7knock-out (KO) mice exhibited normal tooth size and shape indicating that under normal conditions alpha7 expression is dispensable to this process. The function of ameloblasts in alpha7KO mice is altered relative to controls. High resolution micro-computed tomography analysis of adult mandibular incisors revealed enamel volume of the alpha7KO was significantly reduced and the organization of enamel rods was altered relative to controls. These results demonstrate distinct and varied spatiotemporal expression of alpha7 during tooth development, and they suggest that dysfunction of this receptor would have diverse impacts upon the adult organ. PMID:22666322

Cardio-chemical exchange saturation transfer magnetic resonance imaging reveals molecular signatures of endogenous fibrosis and exogenous contrast media.

PubMed

Vandsburger, Moriel; Vandoorne, Katrien; Oren, Roni; Leftin, Avigdor; Mpofu, Senzeni; Delli Castelli, Daniela; Aime, Silvio; Neeman, Michal

2015-01-01

Application of emerging molecular MRI techniques, including chemical exchange saturation transfer (CEST)-MRI, to cardiac imaging is desirable; however, conventional methods are poorly suited for cardiac imaging, particularly in small animals with rapid heart rates. We developed a CEST-encoded steady state and retrospectively gated cardiac cine imaging sequence in which the presence of fibrosis or paraCEST contrast agents was directly encoded into the steady-state myocardial signal intensity (cardioCEST). Development of cardioCEST: A CEST-encoded cardiac cine MRI sequence was implemented on a 9.4T small animal scanner. CardioCEST of fibrosis was serially performed by acquisition of a series of CEST-encoded cine images at multiple offset frequencies in mice (n=7) after surgically induced myocardial infarction. Scar formation was quantified using a spectral modeling approach and confirmed with histological staining. Separately, circulatory redistribution kinetics of the paramagnetic CEST agent Eu-HPDO3A were probed in mice using cardioCEST imaging, revealing rapid myocardial redistribution, and washout within 30 minutes (n=6). Manipulation of vascular tone resulted in heightened peak CEST contrast in the heart, but did not alter redistribution kinetics (n=6). At 28 days after myocardial infarction (n=3), CEST contrast kinetics in infarct zone tissue were altered, demonstrating gradual accumulation of Eu-HPDO3A in the increased extracellular space. cardioCEST MRI enables in vivo imaging of myocardial fibrosis using endogenous contrast mechanisms, and of exogenously delivered paraCEST agents, and can enable multiplexed imaging of multiple molecular targets at high-resolution coupled with conventional cardiac MRI scans. © 2013 American Heart Association, Inc.

The SK3 channel promotes placental vascularization by enhancing secretion of angiogenic factors.

PubMed

Rada, Cara C; Murray, Grace; England, Sarah K

2014-11-15

Proper placental perfusion is essential for fetal exchange of oxygen, nutrients, and waste with the maternal circulation. Impairment of uteroplacental vascular function can lead to pregnancy complications, including preeclampsia and intrauterine growth restriction (IUGR). Potassium channels have been recognized as regulators of vascular proliferation, angiogenesis, and secretion of vasoactive factors, and their dysfunction may underlie pregnancy-related vascular diseases. Overexpression of one channel in particular, the small-conductance calcium-activated potassium channel 3 (SK3), is known to increase vascularization in mice, and mice overexpressing the SK3 channel (SK3(T/T) mice) have a high rate of fetal demise and IUGR. Here, we show that overexpression of SK3 causes fetal loss through abnormal placental vascularization. We previously reported that, at pregnancy day 14, placentas isolated from SK3(T/T) mice are smaller than those obtained from wild-type mice. In this study, histological analysis reveals that SK3(T/-) placentas at this stage have abnormal placental morphology, and microcomputed tomography shows that these placentas have significantly larger and more blood vessels than those from wild-type mice. To identify the mechanism by which these vascularization defects occur, we measured levels of vascular endothelial growth factor (VEGF), placental growth factor, and the soluble form of VEGF receptor 1 (sFlt-1), which must be tightly regulated to ensure proper placental development. Our data reveal that overexpression of SK3 alters systemic and placental ratios of the angiogenic factor VEGF to antiangiogenic factor sFlt-1 throughout pregnancy. Additionally, we observe increased expression of hypoxia-inducing factor 2α in SK3(T/-) placentas. We conclude that the SK3 channel modulates placental vascular development and fetal health by altering VEGF signaling. Copyright © 2014 the American Physiological Society.

Redox Indicator Mice Stably Expressing Genetically Encoded Neuronal roGFP: Versatile Tools to Decipher Subcellular Redox Dynamics in Neuropathophysiology

PubMed Central

Wagener, Kerstin C.; Kolbrink, Benedikt; Dietrich, Katharina; Kizina, Kathrin M.; Terwitte, Lukas S.; Kempkes, Belinda; Bao, Guobin

2016-01-01

Abstract Aims: Reactive oxygen species (ROS) and downstream redox alterations not only mediate physiological signaling but also neuropathology. For long, ROS/redox imaging was hampered by a lack of reliable probes. Genetically encoded redox sensors overcame this gap and revolutionized (sub)cellular redox imaging. Yet, the successful delivery of sensor-coding DNA, which demands transfection/transduction of cultured preparations or stereotaxic microinjections of each subject, remains challenging. By generating transgenic mice, we aimed to overcome limiting cultured preparations, circumvent surgical interventions, and to extend effectively redox imaging to complex and adult preparations. Results: Our redox indicator mice widely express Thy1-driven roGFP1 (reduction–oxidation-sensitive green fluorescent protein 1) in neuronal cytosol or mitochondria. Negative phenotypic effects of roGFP1 were excluded and its proper targeting and functionality confirmed. Redox mapping by ratiometric wide-field imaging reveals most oxidizing conditions in CA3 neurons. Furthermore, mitochondria are more oxidized than cytosol. Cytosolic and mitochondrial roGFP1s reliably report cell endogenous redox dynamics upon metabolic challenge or stimulation. Fluorescence lifetime imaging yields stable, but marginal, response ranges. We therefore developed automated excitation ratiometric 2-photon imaging. It offers superior sensitivity, spatial resolution, and response dynamics. Innovation and Conclusion: Redox indicator mice enable quantitative analyses of subcellular redox dynamics in a multitude of preparations and at all postnatal stages. This will uncover cell- and compartment-specific cerebral redox signals and their defined alterations during development, maturation, and aging. Cross-breeding with other disease models will reveal molecular details on compartmental redox homeostasis in neuropathology. Combined with ratiometric 2-photon imaging, this will foster our mechanistic understanding of cellular redox signals in their full complexity. Antioxid. Redox Signal. 25, 41–58. PMID:27059697

Morphine Regulated Synaptic Networks Revealed by Integrated Proteomics and Network Analysis*

PubMed Central

Stockton, Steven D.; Gomes, Ivone; Liu, Tong; Moraje, Chandrakala; Hipólito, Lucia; Jones, Matthew R.; Ma'ayan, Avi; Morón, Jose A.; Li, Hong; Devi, Lakshmi A.

2015-01-01

Despite its efficacy, the use of morphine for the treatment of chronic pain remains limited because of the rapid development of tolerance, dependence and ultimately addiction. These undesired effects are thought to be because of alterations in synaptic transmission and neuroplasticity within the reward circuitry including the striatum. In this study we used subcellular fractionation and quantitative proteomics combined with computational approaches to investigate the morphine-induced protein profile changes at the striatal postsynaptic density. Over 2,600 proteins were identified by mass spectrometry analysis of subcellular fractions enriched in postsynaptic density associated proteins from saline or morphine-treated striata. Among these, the levels of 34 proteins were differentially altered in response to morphine. These include proteins involved in G-protein coupled receptor signaling, regulation of transcription and translation, chaperones, and protein degradation pathways. The altered expression levels of several of these proteins was validated by Western blotting analysis. Using Genes2Fans software suite we connected the differentially expressed proteins with proteins identified within the known background protein-protein interaction network. This led to the generation of a network consisting of 116 proteins with 40 significant intermediates. To validate this, we confirmed the presence of three proteins predicted to be significant intermediates: caspase-3, receptor-interacting serine/threonine protein kinase 3 and NEDD4 (an E3-ubiquitin ligase identified as a neural precursor cell expressed developmentally down-regulated protein 4). Because this morphine-regulated network predicted alterations in proteasomal degradation, we examined the global ubiquitination state of postsynaptic density proteins and found it to be substantially altered. Together, these findings suggest a role for protein degradation and for the ubiquitin/proteasomal system in the etiology of opiate dependence and addiction. PMID:26149443

Neonatal finasteride administration decreases dopamine release in nucleus accumbens after alcohol and food presentation in adult male rats.

PubMed

Llidó, Anna; Bartolomé, Iris; Darbra, Sònia; Pallarès, Marc

2016-08-01

Endogenous levels of the neurosteroid (NS) allopregnanolone (AlloP) during neonatal stages are crucial for the correct development of the central nervous system (CNS). In a recent work we reported that the neonatal administration of AlloP or finasteride (Finas), an inhibitor of the enzyme 5α-reductase needed for AlloP synthesis, altered the voluntary consumption of ethanol and the ventrostriatal dopamine (DA) levels in adulthood, suggesting that neonatal NS manipulations can increase alcohol abuse vulnerability in adulthood. Moreover, other authors have associated neonatal NS alterations with diverse dopaminergic (DAergic) alterations. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP alter the DAergic response in the nucleus accumbens (NAcc) during alcohol intake in rats. We administered AlloP or Finas from postnatal day (PND) 5 to PND9. At PND98, we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v)+glucose 3% (w/v), and glucose 3% (w/v)) for 12 days. On the last day of consumption, we measured the DA and 3,4-dihydroxyphenylacetic acid (DOPAC) release in NAcc in response to ethanol intake. The samples were obtained by means of in vivo microdialysis in freely moving rats, and DA and DOPAC levels were determined by means of high-performance liquid chromatography analysis (HPLC). The results revealed that neonatal Finas increased ethanol consumption in some days of the consumption phase, and decreased the DA release in the NAcc in response to solutions (ethanol+glucose) and food presentation. Taken together, these results suggest that neonatal NS alterations can affect alcohol rewarding properties. Copyright © 2016 Elsevier B.V. All rights reserved.

Microstructural White Matter Alterations in the Corpus Callosum of Girls With Conduct Disorder.

PubMed

Menks, Willeke Martine; Furger, Reto; Lenz, Claudia; Fehlbaum, Lynn Valérie; Stadler, Christina; Raschle, Nora Maria

2017-03-01

Diffusion tensor imaging (DTI) studies in adolescent conduct disorder (CD) have demonstrated white matter alterations of tracts connecting functionally distinct fronto-limbic regions, but only in boys or mixed-gender samples. So far, no study has investigated white matter integrity in girls with CD on a whole-brain level. Therefore, our aim was to investigate white matter alterations in adolescent girls with CD. We collected high-resolution DTI data from 24 girls with CD and 20 typically developing control girls using a 3T magnetic resonance imaging system. Fractional anisotropy (FA) and mean diffusivity (MD) were analyzed for whole-brain as well as a priori-defined regions of interest, while controlling for age and intelligence, using a voxel-based analysis and an age-appropriate customized template. Whole-brain findings revealed white matter alterations (i.e., increased FA) in girls with CD bilaterally within the body of the corpus callosum, expanding toward the right cingulum and left corona radiata. The FA and MD results in a priori-defined regions of interest were more widespread and included changes in the cingulum, corona radiata, fornix, and uncinate fasciculus. These results were not driven by age, intelligence, or attention-deficit/hyperactivity disorder comorbidity. This report provides the first evidence of white matter alterations in female adolescents with CD as indicated through white matter reductions in callosal tracts. This finding enhances current knowledge about the neuropathological basis of female CD. An increased understanding of gender-specific neuronal characteristics in CD may influence diagnosis, early detection, and successful intervention strategies. Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Alterations in the lenticular protein profile in experimental selenite-induced cataractogenesis and prevention by ellagic acid.

PubMed

Sakthivel, Muniyan; Geraldine, Pitchairaj; Thomas, Philip A

2011-08-01

Accumulating evidence suggests that oxidative stress underlies age-related formation of cataract, and that antioxidants retard cataractogenesis. This study aimed to evaluate whether ellagic acid, a natural polyphenol with antioxidant properties, prevents alterations in the lenticular protein profile in an experimental model of selenite cataract. Alterations in lenticular protein were determined by two-dimensional electrophoresis (2DE) and image analysis. Eluted αA-crystallin spots were analyzed by mass spectrometry. Western blot analysis was also performed to confirm the differential expression of certain crystallins and cytoskeletal proteins. In cataractous lenses, 2DE and image analysis revealed approximately 45 and 60 prominent spots in soluble and insoluble protein fractions respectively. Analysis of the pI and molecular weight of protein spots revealed differences in the expression of crystallin proteins in soluble and insoluble fractions. Western blot analysis confirmed changes in the expression of αA- and βB1- crystallins in both soluble and insoluble protein fractions, while mass spectrometry confirmed the degradation of αA-crystallin in selenite cataractous lenses. Western blot analysis also confirmed the occurrence of altered expression of certain cytoskeletal proteins in insoluble fractions. However, the lenticular protein profile in lenses from selenite-challenged, ellagic acid-treated rats was essentially similar to that noted in lenses from normal rats. The present study confirms the importance of structural and cytoskeletal proteins in the maintenance of lenticular transparency; the results also suggest that ellagic acid prevents lenticular protein alterations induced by selenite in an experimental setting.

Systematic Analysis of Two-Component Systems in Citrobacter rodentium Reveals Positive and Negative Roles in Virulence.

PubMed

Thomassin, Jenny-Lee; Leclerc, Jean-Mathieu; Giannakopoulou, Natalia; Zhu, Lei; Salmon, Kristiana; Portt, Andrea; Daigle, France; Le Moual, Hervé; Gruenheid, Samantha

2017-02-01

Citrobacter rodentium is a murine pathogen used to model intestinal infections caused by the human diarrheal pathogens enterohemorrhagic and enteropathogenic Escherichia coli During infection, bacteria use two-component systems (TCSs) to detect changing environmental cues within the host, allowing for rapid adaptation by altering the expression of specific genes. In this study, 26 TCSs were identified in C. rodentium, and quantitative PCR (qPCR) analysis showed that they are all expressed during murine infection. These TCSs were individually deleted, and the in vitro and in vivo effects were analyzed to determine the functional consequences. In vitro analyses only revealed minor differences, and surprisingly, type III secretion (T3S) was only affected in the ΔarcA strain. Murine infections identified 7 mutants with either attenuated or increased virulence. In agreement with the in vitro T3S assay, the ΔarcA strain was attenuated and defective in colonization and cell adherence. The ΔrcsB strain was among the most highly attenuated strains. The decrease in virulence of this strain may be associated with changes to the cell surface, as Congo red binding was altered, and qPCR revealed that expression of the wcaA gene, which has been implicated in colanic acid production in other bacteria, was drastically downregulated. The ΔuvrY strain exhibited increased virulence compared to the wild type, which was associated with a significant increase in bacterial burden within the mesenteric lymph nodes. The systematic analysis of virulence-associated TCSs and investigation of their functions during infection may open new avenues for drug development. Copyright © 2017 American Society for Microbiology.

Fatty acid-binding protein 5 (FABP5) promotes lipolysis of lipid droplets, de novo fatty acid (FA) synthesis and activation of nuclear factor-kappa B (NF-κB) signaling in cancer cells.

PubMed

Senga, Shogo; Kobayashi, Narumi; Kawaguchi, Koichiro; Ando, Akira; Fujii, Hiroshi

2018-06-12

Fatty acid-binding proteins (FABPs) are involved in binding and storing hydrophobic ligands such as long-chain fatty acids, as well as transporting them to the appropriate compartments in the cell. Epidermal fatty acid-binding protein (FABP5) is an intracellular lipid-binding protein that is abundantly expressed in adipocytes and macrophages. Previous studies have revealed that the FABP5 expression level is closely related to malignancy in various types of cancer. However, its precise functions in the metabolisms of cancer cells remain unclear. Here, we revealed that FABP5 knockdown significantly induced downregulation of the genes expression, such as hormone-sensitive lipase (HSL), monoacylglycerol lipase (MAGL), elongation of long-chain fatty acid member 6 (Elovl6), and acyl-CoA synthetase long-chain family member 1 (ACSL1), which are involved in altered lipid metabolism, lipolysis, and de novo FA synthesis in highly aggressive prostate and breast cancer cells. Moreover, we demonstrated that FABP5 induced inflammation and cytokine production through the nuclear factor-kappa B signaling pathway activated by reactive oxygen species and protein kinase C in PC-3 and MDA-MB-231 cells. Thus, FABP5 might regulate lipid quality and/or quantity to promote aggressiveness such as cell growth, invasiveness, survival, and inflammation in prostate and breast cancer cells. In the present study, we have revealed for the first time that high expression of FABP5 plays a critical role in alterations of lipid metabolism, leading to cancer development and metastasis in highly aggressive prostate and breast cancer cells. Copyright © 2018. Published by Elsevier B.V.

Functional Connectivity Estimated from Resting-State fMRI Reveals Selective Alterations in Male Adolescents with Pure Conduct Disorder

PubMed Central

Lu, Feng-Mei; Zhou, Jian-Song; Zhang, Jiang; Xiang, Yu-Tao; Zhang, Jian; Liu, Qi; Wang, Xiao-Ping; Yuan, Zhen

2015-01-01

Conduct disorder (CD) is characterized by a persistent pattern of antisocial behavior and aggression in childhood and adolescence. Previous task-based and resting-state functional magnetic resonance imaging (fMRI) studies have revealed widespread brain regional abnormalities in adolescents with CD. However, whether the resting-state networks (RSNs) are altered in adolescents with CD remains unknown. In this study, resting-state fMRI data were first acquired from eighteen male adolescents with pure CD and eighteen age- and gender-matched typically developing (TD) individuals. Independent component analysis (ICA) was implemented to extract nine representative RSNs, and the generated RSNs were then compared to show the differences between the CD and TD groups. Interestingly, it was observed from the brain mapping results that compared with the TD group, the CD group manifested decreased functional connectivity in four representative RSNs: the anterior default mode network (left middle frontal gyrus), which is considered to be correlated with impaired social cognition, the somatosensory network (bilateral supplementary motor area and right postcentral gyrus), the lateral visual network (left superior occipital gyrus), and the medial visual network (right fusiform, left lingual gyrus and right calcarine), which are expected to be relevant to the perceptual systems responsible for perceptual dysfunction in male adolescents with CD. Importantly, the novel findings suggested that male adolescents with pure CD were identified to have dysfunctions in both low-level perceptual networks (the somatosensory network and visual network) and a high-order cognitive network (the default mode network). Revealing the changes in the functional connectivity of these RSNs enhances our understanding of the neural mechanisms underlying the modulation of emotion and social cognition and the regulation of perception in adolescents with CD. PMID:26713867

Molecular characterization of colorectal adenomas with and without malignancy reveals distinguishing genome, transcriptome and methylome alterations.

PubMed

Druliner, Brooke R; Wang, Panwen; Bae, Taejeong; Baheti, Saurabh; Slettedahl, Seth; Mahoney, Douglas; Vasmatzis, Nikolaos; Xu, Hang; Kim, Minsoo; Bockol, Matthew; O'Brien, Daniel; Grill, Diane; Warner, Nathaniel; Munoz-Gomez, Miguel; Kossick, Kimberlee; Johnson, Ruth; Mouchli, Mohamad; Felmlee-Devine, Donna; Washechek-Aletto, Jill; Smyrk, Thomas; Oberg, Ann; Wang, Junwen; Chia, Nicholas; Abyzov, Alexej; Ahlquist, David; Boardman, Lisa A

2018-02-16

The majority of colorectal cancer (CRC) arises from precursor lesions known as polyps. The molecular determinants that distinguish benign from malignant polyps remain unclear. To molecularly characterize polyps, we utilized Cancer Adjacent Polyp (CAP) and Cancer Free Polyp (CFP) patients. CAPs had tissues from the residual polyp of origin and contiguous cancer; CFPs had polyp tissues matched to CAPs based on polyp size, histology and dysplasia. To determine whether molecular features distinguish CAPs and CFPs, we conducted Whole Genome Sequencing, RNA-seq, and RRBS on over 90 tissues from 31 patients. CAPs had significantly more mutations, altered expression and hypermethylation compared to CFPs. APC was significantly mutated in both polyp groups, but mutations in TP53, FBXW7, PIK3CA, KIAA1804 and SMAD2 were exclusive to CAPs. We found significant expression changes between CAPs and CFPs in GREM1, IGF2, CTGF, and PLAU, and both expression and methylation alterations in FES and HES1. Integrative analyses revealed 124 genes with alterations in at least two platforms, and ERBB3 and E2F8 showed aberrations specific to CAPs across all platforms. These findings provide a resource of molecular distinctions between polyps with and without cancer, which have the potential to enhance the diagnosis, risk assessment and management of polyps.

Geology and hydrothermal alteration at the Madh adh Dhahab epithermal precious-metal deposit, Kingdom of Saudi Arabia

USGS Publications Warehouse

Doebrich, J.L.; LeAnderson, J.P.

1984-01-01

Vein-related alteration consisting of quartz-sericite-pyrite, chloritic, argillic, and silicic halos was superimposed on broad zones of pervasive silicic, potassic, and argillic alteration that surrounds the rhyolite intrusive body. Quartz-sericite-pyrite alteration associated with the earliest stage of mineralization was followed by broad, pervasive, stratigraphically controlled potassic alteration. Subsequent mineralization was accompanied by quartz-sericitepyrite alteration and was followed by the main stage of mineralization that formed strong chloritic alteration halos. Development of broad zones and halos of argillic alteration also may have been related to the main stage of mineralization. Development of silicic halos was characteristic of the late stages of mineralization. Broad, pervasive propylitic alteration was then superimposed on all alteration types and represents cooling and inward encroachment of the hydrothermal system. All alteration, except the early silicic alteration is interpreted to have been related to circulating meteoric fluids heated by the rhyolite.

Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution.

PubMed

Kim, Hoon; Zheng, Siyuan; Amini, Seyed S; Virk, Selene M; Mikkelsen, Tom; Brat, Daniel J; Grimsby, Jonna; Sougnez, Carrie; Muller, Florian; Hu, Jian; Sloan, Andrew E; Cohen, Mark L; Van Meir, Erwin G; Scarpace, Lisa; Laird, Peter W; Weinstein, John N; Lander, Eric S; Gabriel, Stacey; Getz, Gad; Meyerson, Matthew; Chin, Lynda; Barnholtz-Sloan, Jill S; Verhaak, Roel G W

2015-03-01

Glioblastoma (GBM) is a prototypical heterogeneous brain tumor refractory to conventional therapy. A small residual population of cells escapes surgery and chemoradiation, resulting in a typically fatal tumor recurrence ∼ 7 mo after diagnosis. Understanding the molecular architecture of this residual population is critical for the development of successful therapies. We used whole-genome sequencing and whole-exome sequencing of multiple sectors from primary and paired recurrent GBM tumors to reconstruct the genomic profile of residual, therapy resistant tumor initiating cells. We found that genetic alteration of the p53 pathway is a primary molecular event predictive of a high number of subclonal mutations in glioblastoma. The genomic road leading to recurrence is highly idiosyncratic but can be broadly classified into linear recurrences that share extensive genetic similarity with the primary tumor and can be directly traced to one of its specific sectors, and divergent recurrences that share few genetic alterations with the primary tumor and originate from cells that branched off early during tumorigenesis. Our study provides mechanistic insights into how genetic alterations in primary tumors impact the ensuing evolution of tumor cells and the emergence of subclonal heterogeneity. © 2015 Kim et al.; Published by Cold Spring Harbor Laboratory Press.

Altered muscular activation during prone hip extension in women with and without low back pain.

PubMed

Arab, Amir M; Ghamkhar, Leila; Emami, Mahnaz; Nourbakhsh, Mohammad R

2011-08-14

Altered movement pattern has been associated with the development of low back pain (LBP). The purpose of this study was to investigate the activity pattern of the ipsilateral erector spinae (IES) and contralateral erectorspinae (CES), gluteus maximus (GM) and hamstring (HAM) muscles during prone hip extension (PHE) test in women with and without LBP. A cross-sectional non-experimental design was used. Convenience sample of 20 female participated in the study. Subjects were categorized into two groups: with LBP (n = 10) and without LBP (n = 10). The electromyography (EMG) signal amplitude of the tested muscles during PHE (normalized to maximum voluntary electrical activity (MVE)) was measured in the dominant lower extremity in all subjects. Statistical analysis revealed greater normalized EMG signal amplitude in women with LBP compared to non-LBP women. There was significant difference in EMG activity of the IES (P = 0.03) and CES (P = 0.03) between two groups. However, no significant difference was found in EMG signals of the GM (P = 0.11) and HAM (P = 0.14) among two groups. The findings of this study demonstrated altered activation pattern of the lumbo-pelvic muscles during PHE in the women with chronic LBP. This information is important for investigators using PHE as either an evaluation tool or a rehabilitation exercise.

Influence of hesperidin on renal cell surface glycoprotein content, nucleic acids, lysosomal enzymes and macromolecules against 7, 12-dimethylbenz [a] anthracene induced experimental breast carcinoma.

PubMed

Nandakumar, Natarajan; Jayaprakash, Ramachandran; Balasubramanian, Maruthaiveeran Periyasamy

2012-01-01

Therapeutic substances may reduce the risk of developing cancer by modulating the factors responsible for carcinogenesis. To evaluate these hypotheses, the present study was designed to investigate the modulatory effect of bioflavonoid "Hesperidin" against DMBA induced experimental breast cancer with reference to renal cell surface glycoproteins, nucleic acids, protein content, lipid profile and lysosomal enzymes. The female sprague-dawley rats were orally administered with single dose of 7, 12-DMBA to induce breast cancer and were treated with hesperidin [30 mg/kg/body weight] for a consecutive 45 days. The results revealed that there was a significant elevation in the levels of glycoproteins, nucleic acids, lysosomal enzymes and also significant alterations in macromolecules in renal tissues of cancer bearing animals. Interestingly, the altered levels of these parameters were remarkably reverted back to near normal in hesperidin treatment. The histopathological analysis of liver and kidney tissues were well supported the biochemical alterations and inevitably proves the protective role of hesperidin. It is proposed that, the effect of hesperidin during DMBA induced breast cancer could be due to the intervention strategies of hesperidin in the protein, nucleic acid biosynthesis, membrane stabilizing potentials on lysosomal compartment and inhibitory effect on cell surface glycoproteins and bio-fuel such as lipids.

Overexpression of AtLOV1 in Switchgrass alters plant architecture, lignin content, and flowering time.

PubMed

Xu, Bin; Sathitsuksanoh, Noppadon; Tang, Yuhong; Udvardi, Michael K; Zhang, Ji-Yi; Shen, Zhengxing; Balota, Maria; Harich, Kim; Zhang, Percival Y-H; Zhao, Bingyu

2012-01-01

Switchgrass (Panicum virgatum L.) is a prime candidate crop for biofuel feedstock production in the United States. As it is a self-incompatible polyploid perennial species, breeding elite and stable switchgrass cultivars with traditional breeding methods is very challenging. Translational genomics may contribute significantly to the genetic improvement of switchgrass, especially for the incorporation of elite traits that are absent in natural switchgrass populations. In this study, we constitutively expressed an Arabidopsis NAC transcriptional factor gene, LONG VEGETATIVE PHASE ONE (AtLOV1), in switchgrass. Overexpression of AtLOV1 in switchgrass caused the plants to have a smaller leaf angle by changing the morphology and organization of epidermal cells in the leaf collar region. Also, overexpression of AtLOV1 altered the lignin content and the monolignol composition of cell walls, and caused delayed flowering time. Global gene-expression analysis of the transgenic plants revealed an array of responding genes with predicted functions in plant development, cell wall biosynthesis, and flowering. To our knowledge, this is the first report of a single ectopically expressed transcription factor altering the leaf angle, cell wall composition, and flowering time of switchgrass, therefore demonstrating the potential advantage of translational genomics for the genetic improvement of this crop.

Recent advances in genomic profiling of adenosquamous carcinoma of the pancreas.

PubMed

Marcus, Rebecca; Maitra, Anirban; Roszik, Jason

2017-11-01

Adenosquamous carcinoma of the pancreas (ASCP) is a mixed tumor type which contains squamous cell carcinoma and also ductal adenocarcinoma components. Due to the rarity of this malignancy, only very limited genomic profiling has been performed. A recent paper by Fang et al. published in The Journal of Pathology contributed to our knowledge of genomic alterations by performing whole-genome and -exome sequencing of 17 ASCP tumors. They found major genomic similarities to pancreatic ductal adenocarcinoma; however, the p53 pathway was altered in a greater proportion of cases, while a high frequency of 3p loss was a distinct copy number alteration pattern observed in ASCP. Laser capture microdissection revealed that adenocarcinoma and squamous carcinoma components of ASCP harbor similar genomic variations, indicating that the origin of tumor components is the same or similar. Although the study published by Fang et al. increases our knowledge of this rare mixed tumor type, further investigation, including RNA sequencing, will be needed to fully characterize this malignancy and to aid the development of novel treatment approaches. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Effects of hydrogen peroxide on the light reflectance and morphology of bovine enamel.

PubMed

Kwon, Y H; Huo, M S; Kim, K H; Kim, S K; Kim, Y J

2002-05-01

The purpose of this study was to examine the effects of a bleaching agent (30% hydrogen peroxide) on the surface of bovine enamel using a scanning electron microscope and a UV-VIS-NIR spectrophotometer. Five non-carious bovine incisors were bleached for 0, 1, 2 and 3 days using 30% hydrogen peroxide. The light reflectance spectrum was measured using a spectrophotometer with diffuse reflectance mode. Colour values and colour differences in the teeth were evaluated from the reflectance measurements with the CIE L*a*b* colour coordinate system. Surface alterations in the bleached and unbleached teeth were studied using a scanning electron microscope. The change of reflectance in the teeth was related to the change of colour. Most reflectance change occurred within a 1-day bleaching, and this result was confirmed by a CIE L*a*b* colour coordinate system. The colour differences in the bleached teeth were significant enough to be perceived by the observer's eye. The comparison of bleached to unbleached bovine enamel revealed that the bleached surface showed non-uniform slight morphological alterations, and it developed varying degrees of surface porosity. This study indicates that the bleached bovine teeth showed apparent colour differences as well as slight morphological alterations after bleaching.

Altered chromosome 6 in immortal human fibroblasts

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

Hubbard-Smith, K.; Pardinas, J.R.; Jha, K.K.

1992-05-01

Human diploid fibroblasts have a limited life span in vitro, and spontaneous immortalization is an extremely rare event. We have used transformation of human diploid fibroblasts by an origin-defective simian virus 40 genome to develop series of genetically matched immortal cell lines to analyze immortalization. Comparison of a preimmortal transformant (SVtsA/HF-A) with its uncloned and cloned immortalized derivatives (AR5 and HAL) has failed to reveal any major alteration involving the simian virus 40 genome. Karyotypic analysis, however, demonstrated that all of the immortal cell lines in this series have alterations of chromosome 6 involving loss of the portion distal tomore » 6q21. The karyotypic analysis was corroborated by DNA analyses. Southern analysis demonstrated that only one copy of three proto-oncogene loci (ros1, c-myb, and mas1) on 6q was retained in immortal cells. Polymerase chain reaction analysis of the microsatellite polymorphism at 6q22 (D6S87) showed loss of heterozygosity. In addition, elevated expression of c-myb (6q22-23) was observed. We hypothesize that the region at and/or distal to 6q21 plays a role in immortalization, consistent with the presence of a growth suppressor gene. 66 refs., 6 figs., 2 tabs.« less

Testicular lactate content is compromised in men with Klinefelter Syndrome.

PubMed

Alves, Marco G; Martins, Ana D; Jarak, Ivana; Barros, Alberto; Silva, Joaquina; Sousa, Mário; Oliveira, Pedro F

2016-03-01

Klinefelter syndrome (KS) is the most common genetic cause of human infertility, but the mechanism(s) responsible for its phenotype remain largely unknown. KS is associated with alterations in body composition and with a higher risk of developing metabolic diseases. We therefore hypothesized that KS men seeking fertility treatment possess an altered testicular metabolism profile that may hamper the nutritional support of spermatogenesis. Testicular biopsies from control (46, XY) (n = 6) and KS (47, XXY) (n = 6) individuals were collected and analyzed by proton high-resolution magic-angle spinning nuclear magnetic resonance spectroscopy. The mRNA and protein expression of crucial glycolysis-associated enzymes and transporters were evaluated in parallel by quantitative PCR and Western blot, respectively. Our data revealed altered regulation of glucose transporters (GLUT1 and GLUT3); phosphofructokinase 1, liver isoform (PFKL); and lactate dehydrogenase A (LDHA) expression in the testis of KS patients. Moreover, we detected a severe reduction in lactate and creatine accumulation within testicular tissue from KS men. The aberrant levels of the biomarkers detected in testicular biopsies of KS men may therefore be associated with the infertility phenotypes presented by these men. Mol. Reprod. Dev. 83: 208-216, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

X-ray micro-computed tomography in willow reveals tissue patterning of reaction wood and delay in programmed cell death.

PubMed

Brereton, Nicholas James Beresford; Ahmed, Farah; Sykes, Daniel; Ray, Michael Jason; Shield, Ian; Karp, Angela; Murphy, Richard James

2015-03-11

Variation in the reaction wood (RW) response has been shown to be a principle component driving differences in lignocellulosic sugar yield from the bioenergy crop willow. The phenotypic cause(s) behind these differences in sugar yield, beyond their common elicitor, however, remain unclear. Here we use X-ray micro-computed tomography (μCT) to investigate RW-associated alterations in secondary xylem tissue patterning in three dimensions (3D). Major architectural alterations were successfully quantified in 3D and attributed to RW induction. Whilst the frequency of vessels was reduced in tension wood tissue (TW), the total vessel volume was significantly increased. Interestingly, a delay in programmed-cell-death (PCD) associated with TW was also clearly observed and readily quantified by μCT. The surprising degree to which the volume of vessels was increased illustrates the substantial xylem tissue remodelling involved in reaction wood formation. The remodelling suggests an important physiological compromise between structural and hydraulic architecture necessary for extensive alteration of biomass and helps to demonstrate the power of improving our perspective of cell and tissue architecture. The precise observation of xylem tissue development and quantification of the extent of delay in PCD provides a valuable and exciting insight into this bioenergy crop trait.

Development of a Vaccine for Bacterial Kidney Disease in Salmon, 1984 Annual Report.

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

Kaattari, Stephen L.

1985-06-01

The data presented here demonstrate that there is some variability to the antigenic structure of KDB. Although gel filtration of all antigenic preparations revealed a wide range of sizes for antigens, resolution on a denaturing gel revealed relatively few protein bands and immunological assays revealed the same (3) low number of antigens. It is of particular interest that there seems to be a protein of 60 kd in all preparations, but that there are not larger individual molecular species. This, in turn indicates that the larger molecular weight species detected in gel filtration are most likely aggregates or membrane fragmentsmore » composed of a lower molecular weight subunit. Use of ultrafiltration of KDM-2 medium appears to be successful in eliminating contamination of high molecular weight material found in KDM-2. There appears to be no alteration in the number of soluble antigens produced by growth in either medium, nor in the number of proteins, as detected by SDS-PAGE. However, soluble antigens isolated from UF-KDM-2 does appear to have greater heterogeneity in their isoelectric focusing (IEF) patterns than those from UF-KDM-2. Also, although there does appear to be an extended lag period in KDB growth on UF-KDM-2, there is no alteration in final O.D. or wet weight of cells. Thus, it appears that UF-KDM-2 may be an alternate medium for those wishing to isolate purified bacterial proteins or antigens. ELISA assays have been developed for the detection of soluble KDB antigens. This system is currently being developed as a sensitive measure of the presence of soluble antigen in serum and tissues of fish. Such a sensitive assay may also allow for the detection of KD+ spawners by the testing of ovarian fluid or serum. ELISA assays have also been developed to detect antibodies to soluble and cellular antigens of KDB. These systems have been proven successful in the detection of rabbit and murine monoclonal antibodies against KDB antigens. Future work will develop the use of anti-fish immunoglobulin (Ig) reagents to detect the presence of fish antibodies to KDB. This would be an extremely useful tool to be used in monitoring the immune response of salmon to the various test vaccines. The various antigens characterized in this study, along with whole KDB cells are currently being conjugated to various immunopotentiating agents. Testing of these prototype vaccines is currently under study.« less

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

NASA Technical Reports Server (NTRS)

Brearley, Adrian J.; Prinz, Martin

1992-01-01

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

Responses of grapevine rootstocks to drought through altered root system architecture and root transcriptomic regulations.

PubMed

Yıldırım, Kubilay; Yağcı, Adem; Sucu, Seda; Tunç, Sümeyye

2018-06-01

Roots are the major interface between the plant and various stress factors in the soil environment. Alteration of root system architecture (RSA) (root length, spread, number and length of lateral roots) in response to environmental changes is known to be an important strategy for plant adaptation and productivity. In light of ongoing climate changes and global warming predictions, the breeding of drought-tolerant grapevine cultivars is becoming a crucial factor for developing a sustainable viticulture. Root-trait modeling of grapevine rootstock for drought stress scenarios, together with high-throughput phenotyping and genotyping techniques, may provide a valuable background for breeding studies in viticulture. Here, tree grafted grapevine rootstocks (110R, 5BB and 41B) having differential RSA regulations and drought tolerance were investigated to define their drought dependent root characteristics. Root area, root length, ramification and number of root tips reduced less in 110R grafted grapevines compared to 5BB and 41B grafted ones during drought treatment. Root relative water content as well as total carbohydrate and nitrogen content were found to be much higher in the roots of 110R than it was in the roots of other rootstocks under drought. Microarray-based root transcriptome profiling was also conducted on the roots of these rootstocks to identify their gene regulation network behind drought-dependent RSA alterations. Transcriptome analysis revealed totally 2795, 1196 and 1612 differentially expressed transcripts at the severe drought for the roots of 110R, 5BB and 41B, respectively. According to this transcriptomic data, effective root elongation and enlargement performance of 110R were suggested to depend on three transcriptomic regulations. First one is the drought-dependent induction in sugar and protein transporters genes (SWEET and NRT1/PTR) in the roots of 110R to facilitate carbohydrate and nitrogen accumulation. In the roots of the same rootstock, expression increase in osmolyte producer genes revealed another transcriptomic regulation enabling effective root osmotic adjustment under drought stress. The third mechanism was linked to root suberization with upregulation of transcripts functional in wax producing enzymes (Caffeic acid 3-O-methyltransferase, Eceriferum3, 3-ketoacyl-CoAsynthase). These three transcriptomic regulations were suggested to provide essential energy and water preservation to the roots of 110R for its effective RSA regulation under drought. This phenotypic and genotypic knowledge could be used to develop root-dependent drought tolerant grapevines in breeding programs and could facilitate elucidation of genetic regulations behind RSA alteration in other plants. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Determination of aluminium induced metabolic changes in mice liver: a Fourier transform infrared spectroscopy study.

PubMed

Sivakumar, S; Sivasubramanian, J; Khatiwada, Chandra Prasad; Manivannan, J; Raja, B

2013-06-01

In this study, we made a new approach to evaluate aluminium induced metabolic changes in liver tissue of mice using Fourier transform infrared spectroscopy analysis taking one step further in correlation with strong biochemical evidence. This finding reveals the alterations on the major biochemical constituents, such as lipids, proteins, nucleic acids and glycogen of the liver tissues of mice. The peak area value of amide A significantly decrease from 288.278±3.121 to 189.872±2.012 between control and aluminium treated liver tissue respectively. Amide I and amide II peak area value also decrease from 40.749±2.052 to 21.170±1.311 and 13.167±1.441 to 8.953±0.548 in aluminium treated liver tissue respectively. This result suggests an alteration in the protein profile. The absence of olefinicCH stretching band and CO stretching of triglycerides in aluminium treated liver suggests an altered lipid levels due to aluminium exposure. Significant shift in the peak position of glycogen may be the interruption of aluminium in the calcium metabolism and the reduced level of calcium. The overall findings exhibit that the liver metabolic program is altered through increasing the structural modification in proteins, triglycerides and quantitative alteration in proteins, lipids, and glycogen. All the above mentioned modifications were protected in desferrioxamine treated mice. Histopathological results also revealed impairment of aluminium induced alterations in liver tissue. The results of the FTIR study were found to be in agreement with biochemical studies and which demonstrate FTIR can be used successfully to indicate the molecular level changes. Copyright © 2013 Elsevier B.V. All rights reserved.

Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity

PubMed Central

Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii-Der I.; Taylor, Kent D.; Azziz, Ricardo; Goodarzi, Mark O.

2015-01-01

Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS. PMID:26305227

Comprehensive genomic profiling reveals inactivating SMARCA4 mutations and low tumor mutational burden in small cell carcinoma of the ovary, hypercalcemic-type.

PubMed

Lin, Douglas I; Chudnovsky, Yakov; Duggan, Bridget; Zajchowski, Deborah; Greenbowe, Joel; Ross, Jeffrey S; Gay, Laurie M; Ali, Siraj M; Elvin, Julia A

2017-12-01

Small cell carcinoma of the ovary, hypercalcemic-type (SCCOHT) is a rare, extremely aggressive neoplasm that usually occurs in young women and is characterized by deleterious germline or somatic SMARCA4 mutations. We performed comprehensive genomic profiling (CGP) to potentially identify additional clinically and pathophysiologically relevant genomic alterations in SCCOHT. CGP assessment of all classes of coding alterations in up to 406 genes commonly altered in cancer and intronic regions for up to 31 genes commonly rearranged in cancer was performed on 18 SCCOHT cases (16 exhibiting classic morphology and 2 cases exhibiting exclusive a large cell variant morphology). In addition, a retrospective database search for clinically advanced ovarian tumors with genomic profiles similar to SCCOHT yielded 3 additional cases originally diagnosed as non-SCCOHT. CGP revealed inactivating SMARCA4 alterations and low tumor mutational burden (TMB) (<6mutations/Mb) in 94% (15/16) of SCCOHT with classic morphology. In contrast, both (2/2) cases exhibiting only large cell variant morphology were hypermutated (TMB scores of 90 and 360mut/Mb) and were wildtype for SMARCA4. In our retrospective search, an index ovarian cancer patient harboring inactivating SMARCA4 alterations, initially diagnosed as endometrioid carcinoma, was re-classified as SCCOHT and responded to an SCCOHT chemotherapy regimen. The vast majority of SCCOHT demonstrate genomic SMARCA4 loss with only rare co-occurring alterations. Our data support a role for CGP in the diagnosis and management of SCCOHT and of other lesions with overlapping histological and clinical features, since identifying the former by genomic profile suggests benefit from an appropriate regimen and treatment decisions, as illustrated by an index patient. Copyright © 2017 Elsevier Inc. All rights reserved.

Determination of aluminium induced metabolic changes in mice liver: A Fourier transform infrared spectroscopy study

NASA Astrophysics Data System (ADS)

Sivakumar, S.; Sivasubramanian, J.; Khatiwada, Chandra Prasad; Manivannan, J.; Raja, B.

2013-06-01

In this study, we made a new approach to evaluate aluminium induced metabolic changes in liver tissue of mice using Fourier transform infrared spectroscopy analysis taking one step further in correlation with strong biochemical evidence. This finding reveals the alterations on the major biochemical constituents, such as lipids, proteins, nucleic acids and glycogen of the liver tissues of mice. The peak area value of amide A significantly decrease from 288.278 ± 3.121 to 189.872 ± 2.012 between control and aluminium treated liver tissue respectively. Amide I and amide II peak area value also decrease from 40.749 ± 2.052 to 21.170 ± 1.311 and 13.167 ± 1.441 to 8.953 ± 0.548 in aluminium treated liver tissue respectively. This result suggests an alteration in the protein profile. The absence of olefinicdbnd CH stretching band and Cdbnd O stretching of triglycerides in aluminium treated liver suggests an altered lipid levels due to aluminium exposure. Significant shift in the peak position of glycogen may be the interruption of aluminium in the calcium metabolism and the reduced level of calcium. The overall findings exhibit that the liver metabolic program is altered through increasing the structural modification in proteins, triglycerides and quantitative alteration in proteins, lipids, and glycogen. All the above mentioned modifications were protected in desferrioxamine treated mice. Histopathological results also revealed impairment of aluminium induced alterations in liver tissue. The results of the FTIR study were found to be in agreement with biochemical studies and which demonstrate FTIR can be used successfully to indicate the molecular level changes.

Comparative transcript profiling of alloplasmic male-sterile lines revealed altered gene expression related to pollen development in rice (Oryza sativa L.).

PubMed

Hu, Jihong; Chen, Guanglong; Zhang, Hongyuan; Qian, Qian; Ding, Yi

2016-08-05

Cytoplasmic male sterility (CMS) is an ideal model for investigating the mitochondrial-nuclear interaction and down-regulated genes in CMS lines which might be the candidate genes for pollen development in rice. In this study, a set of rice alloplasmic sporophytic CMS lines was obtained by successive backcrossing of Meixiang B, with three different cytoplasmic types: D62A (D type), ZS97A (WA type) and XQZ-A (DA type). Using microarray, the anther transcript profiles of the three indica rice CMS lines revealed 622 differentially expressed genes (DEGs) in each of the three CMS lines compared with the maintainer line Meixiang B. GO and MapMan analysis indicated that these DEGs were mainly involved in lipid metabolism and cell wall organization. Compared with the gene expression of sporophytic and gametophytic CMS lines, 303 DEGs were identified and 56 of them were down-regulated in all the CMS lines of rice. These down-regulated DEGs in the CMS lines were found to be involved in tapetum or cell wall formation and their suppressed expression might be related to male sterility. Weighted gene co-expression network analysis (WGCNA) revealed that two modules were significantly associated with male sterility and many hub genes that were differentially expressed in the CMS lines. A large set of putative genes involved in anther development was identified in the present study. The results will give some information for the nuclear gene regulation by different cytoplasmic genotypes and provide a rich resource for further functional research on the pollen development in rice.

Aberrant striatal functional connectivity in children with autism.

PubMed

Di Martino, Adriana; Kelly, Clare; Grzadzinski, Rebecca; Zuo, Xi-Nian; Mennes, Maarten; Mairena, Maria Angeles; Lord, Catherine; Castellanos, F Xavier; Milham, Michael P

2011-05-01

Models of autism spectrum disorders (ASD) as neural disconnection syndromes have been predominantly supported by examinations of abnormalities in corticocortical networks in adults with autism. A broader body of research implicates subcortical structures, particularly the striatum, in the physiopathology of autism. Resting state functional magnetic resonance imaging has revealed detailed maps of striatal circuitry in healthy and psychiatric populations and vividly captured maturational changes in striatal circuitry during typical development. Using resting state functional magnetic resonance imaging, we examined striatal functional connectivity (FC) in 20 children with ASD and 20 typically developing children between the ages of 7.6 and 13.5 years. Whole-brain voxelwise statistical maps quantified within-group striatal FC and between-group differences for three caudate and three putamen seeds for each hemisphere. Children with ASD mostly exhibited prominent patterns of ectopic striatal FC (i.e., functional connectivity present in ASD but not in typically developing children), with increased functional connectivity between nearly all striatal subregions and heteromodal associative and limbic cortex previously implicated in the physiopathology of ASD (e.g., insular and right superior temporal gyrus). Additionally, we found striatal functional hyperconnectivity with the pons, thus expanding the scope of functional alterations implicated in ASD. Secondary analyses revealed ASD-related hyperconnectivity between the pons and insula cortex. Examination of FC of striatal networks in children with ASD revealed abnormalities in circuits involving early developing areas, such as the brainstem and insula, with a pattern of increased FC in ectopic circuits that likely reflects developmental derangement rather than immaturity of functional circuits. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Convergent synaptic and circuit substrates underlying autism genetic risks.

PubMed

McGee, Aaron; Li, Guohui; Lu, Zhongming; Qiu, Shenfeng

2014-02-01

There has been a surge of diagnosis of autism spectrum disorders (ASD) over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development.

Development of a complex amino acid supplement, Fatigue Reviva™, for oral ingestion: initial evaluations of product concept and impact on symptoms of sub-health in a group of males.

PubMed

Dunstan, R Hugh; Sparkes, Diane L; Roberts, Tim K; Crompton, Marcus J; Gottfries, Johan; Dascombe, Benjamin J

2013-08-08

A new dietary supplement, Fatigue Reviva™, has been recently developed to address issues related to amino acid depletion following illness or in conditions of sub-health where altered amino acid homeostasis has been associated with fatigue. Complex formulations of amino acids present significant challenges due to solubility and taste constraints. This initial study sets out to provide an initial appraisal of product palatability and to gather pilot evidence for efficacy. Males reporting symptoms of sub-health were recruited on the basis of being free from any significant medical or psychological condition. Each participant took an amino acid based dietary supplement (Fatigue Reviva™) daily for 30 days. Comparisons were then made between pre- and post-supplement general health symptoms and urinary amino acid profiles. Seventeen men took part in the study. Following amino acid supplementation the total Chalder fatigue score improved significantly (mean ± SEM, 12.5 ± 0.9 versus 10.0 ± 1.0, P<0.03). When asked whether they thought that the supplement had improved their health, 65% of participants responded positively. A subgroup of participants reported gastrointestinal symptoms which were attributed to the supplement and which were believed to result from the component fructooligosaccharide. Analysis of urinary amino acids revealed significant alterations in the relative abundances of a number of amino acids after supplementation including an increase in valine, isoleucine and glutamic acid and reduced levels of glutamine and ornithine. Discriminant function analysis of the urinary amino acid data revealed significant differences between the pre- and post-supplement urine excretion profiles. The results indicated that Fatigue Reviva™ was palatable and that 65% of the study group reported that they felt the product had improved their health. The product could provide an effective tool for the management of unexplained fatigue and symptoms of sub-health. Further product development may yield additional options for those patients susceptible to fructooligosaccharide.

Gold Nanoparticles for the Detection of DNA Adducts as Biomarkers of Exposure to Acrylamide

NASA Astrophysics Data System (ADS)

Larguinho, Miguel Angelo Rodrigues

The main objective of this thesis was the development of a gold nanoparticle-based methodology for detection of DNA adducts as biomarkers, to try and overcome existing drawbacks in currently employed techniques. For this objective to be achieved, the experimental work was divided in three components: sample preparation, method of detection and development of a model for exposure to acrylamide. Different techniques were employed and combined for de-complexation and purification of DNA samples (including ultrasonic energy, nuclease digestion and chromatography), resulting in a complete protocol for sample treatment, prior to detection. The detection of alkylated nucleotides using gold nanoparticles was performed by two distinct methodologies: mass spectrometry and colorimetric detection. In mass spectrometry, gold nanoparticles were employed for laser desorption/ionisation instead of the organic matrix. Identification of nucleotides was possible by fingerprint, however no specific mass signals were denoted when using gold nanoparticles to analyse biological samples. An alternate method using the colorimetric properties of gold nanoparticles was employed for detection. This method inspired in the non-cross-linking assay allowed the identification of glycidamide-guanine adducts and DNA adducts generated in vitro. For the development of a model of exposure, two different aquatic organisms were studies: a goldfish and a mussel. Organisms were exposed to waterborne acrylamide, after which mortality was recorded and effect concentrations were estimated. In goldfish, both genotoxicity and metabolic alterations were assessed and revealed dose-effect relationships of acrylamide. Histopathological alterations were verified primarily in pancreatic cells, but also in hepatocytes. Mussels showed higher effect concentrations than goldfish. Biomarkers of oxidative stress, biotransformation and neurotoxicity were analysed after prolonged exposure, showing mild oxidative stress in mussel cells, and induction of enzymes involved in detoxification of oxygen radicals. A qualitative histopathological screening revealed gonadotoxicity in female mussels, which may present some risk to population equilibrium.

Microperimetric assessment of the two optical coherence tomography subtypes of acute macular neuroretinopathy.

PubMed

Battaglia Parodi, Maurizio; Iacono, Pierluigi; Panico, Daniele; Cascavilla, Marialucia; Bandello, Francesco

2015-01-01

This study evaluates the morpho-functional alterations associated with acute macular neuroretinopathy (AMNR). Prospective observational case series study carried out at the University Vita-Salute, Scientific Institute San Raffaele. Five out of six eyes (three patients) showed the typical features of AMNR. The patients underwent an ophthalmological examination, including best-corrected visual acuity (BCVA) measurement, electroretinogram and electroculogram (ERG/EOG), multifocal electroretinogram (mfERG), infrared reflectance, short wavelength and near-infrared-fundus autofluorescence (SW-FAF/NIR-FAF), spectral-domain optical coherence tomography (SD-OCT) and microperimetry. Microperimetric alterations in the two SD-OCT subtypes of AMNR. The BCVA was 20/20 in all patients. ERG and EOG were normal; mfERG revealed a generally reduced response with a more reduced signal in the areas corresponding to the macular lesions. SD-OCT demonstrated two different patterns of retinal alterations. In case 1, SD-OCT revealed a hyperreflective, plaque-like band at the junction of the outer plexiform layer (OPL) and the inner nuclear layer (INL), extending into the INL (type 1 lesion). In cases 2 and 3, SD-OCT disclosed a hyperreflectivity of the OPL associated with outer nuclear layer thinning and disruption of the outer segment/retinal pigment epithelium junction (type 2 lesion). Microperimetry revealed a wide scotoma involving the entire macular area in all eyes, including the unaffected eye of case 1. The reduction in retinal sensitivity was greatest in type 1. SD-OCT confirms that AMNR may occur in different patterns. Microperimetry demonstrated that functional alterations are also discernible in apparently uninvolved areas. Both examinations are extremely valuable in characterizing the changes associated with AMNR. © 2015 Royal Australian and New Zealand College of Ophthalmologists.

Assessment of the structural brain network reveals altered connectivity in children with unilateral cerebral palsy due to periventricular white matter lesions

PubMed Central

Pannek, Kerstin; Boyd, Roslyn N.; Fiori, Simona; Guzzetta, Andrea; Rose, Stephen E.

2014-01-01

Background Cerebral palsy (CP) is a term to describe the spectrum of disorders of impaired motor and sensory function caused by a brain lesion occurring early during development. Diffusion MRI and tractography have been shown to be useful in the study of white matter (WM) microstructure in tracts likely to be impacted by the static brain lesion. Aim The purpose of this study was to identify WM pathways with altered connectivity in children with unilateral CP caused by periventricular white matter lesions using a whole-brain connectivity approach. Methods Data of 50 children with unilateral CP caused by periventricular white matter lesions (5–17 years; manual ability classification system [MACS] I = 25/II = 25) and 17 children with typical development (CTD; 7–16 years) were analysed. Structural and High Angular Resolution Diffusion weighted Images (HARDI; 64 directions, b = 3000 s/mm2) were acquired at 3 T. Connectomes were calculated using whole-brain probabilistic tractography in combination with structural parcellation of the cortex and subcortical structures. Connections with altered fractional anisotropy (FA) in children with unilateral CP compared to CTD were identified using network-based statistics (NBS). The relationship between FA and performance of the impaired hand in bimanual tasks (Assisting Hand Assessment—AHA) was assessed in connections that showed significant differences in FA compared to CTD. Results FA was reduced in children with unilateral CP compared to CTD. Seven pathways, including the corticospinal, thalamocortical, and fronto-parietal association pathways were identified simultaneously in children with left and right unilateral CP. There was a positive relationship between performance of the impaired hand in bimanual tasks and FA within the cortico-spinal and thalamo-cortical pathways (r2 = 0.16–0.44; p < 0.05). Conclusion This study shows that network-based analysis of structural connectivity can identify alterations in FA in unilateral CP, and that these alterations in FA are related to clinical function. Application of this connectome-based analysis to investigate alterations in connectivity following treatment may elucidate the neurological correlates of improved functioning due to intervention. PMID:25003031

Using structural equation modeling to link human activities to wetland ecological integrity

USGS Publications Warehouse

Schweiger, E. William; Grace, James B.; Cooper, David; Bobowski, Ben; Britten, Mike

2016-01-01

The integrity of wetlands is of global concern. A common approach to evaluating ecological integrity involves bioassessment procedures that quantify the degree to which communities deviate from historical norms. While helpful, bioassessment provides little information about how altered conditions connect to community response. More detailed information is needed for conservation and restoration. We have illustrated an approach to addressing this challenge using structural equation modeling (SEM) and long-term monitoring data from Rocky Mountain National Park (RMNP). Wetlands in RMNP are threatened by a complex history of anthropogenic disturbance including direct alteration of hydrologic regimes; elimination of elk, wolves, and grizzly bears; reintroduction of elk (absent their primary predators); and the extirpation of beaver. More recently, nonnative moose were introduced to the region and have expanded into the park. Bioassessment suggests that up to half of the park's wetlands are not in reference condition. We developed and evaluated a general hypothesis about how human alterations influence wetland integrity and then develop a specific model using RMNP wetlands. Bioassessment revealed three bioindicators that appear to be highly sensitive to human disturbance (HD): (1) conservatism, (2) degree of invasion, and (3) cover of native forbs. SEM analyses suggest several ways human activities have impacted wetland integrity and the landscape of RMNP. First, degradation is highest where the combined effects of all types of direct HD have been the greatest (i.e., there is a general, overall effect). Second, specific HDs appear to create a “mixed-bag” of complex indirect effects, including reduced invasion and increased conservatism, but also reduced native forb cover. Some of these effects are associated with alterations to hydrologic regimes, while others are associated with altered shrub production. Third, landscape features created by historical beaver activity continue to influence wetland integrity years after beavers have abandoned sites via persistent landforms and reduced biomass of tall shrubs. Our model provides a system-level perspective on wetland integrity and provides a context for future evaluations and investigations. It also suggests scientifically supported natural resource management strategies that can assist in the National Park Service mission of maintaining or, when indicated, restoring ecological integrity “unimpaired for future generations.”

Dietary Alpha-Lipoic Acid Alters Piglet Neurodevelopment.

PubMed

Mudd, Austin T; Waworuntu, Rosaline V; Berg, Brian M; Dilger, Ryan N

2016-01-01

Alpha-lipoic acid (a-LA) is an antioxidant shown to ameliorate age-associated impairments of brain and cardiovascular function. Human milk is known to have high antioxidant capacity; however, the role of antioxidants in the developing brain is largely uncharacterized. This exploratory study aimed to examine the dose-response effects of a-LA on piglet growth and neurodevelopment. Beginning at 2 days of age, 31 male pigs received 1 of 3 diets: control (CONT) (0 mg a-LA/100 g), low a-LA (LOW) (120 mg a-LA/100 g), or high a-LA (HIGH) (240 mg a-LA/100 g). From 14 to 28 days of age, pigs were subjected to spatial T-maze assessment, and macrostructural and microstructural neuroimaging procedures were performed at 31 days of age. No differences due to diet were observed for bodyweight gain or intestinal weight and length. Spatial T-maze assessment did not reveal learning differences due to diet in proportion of correct choices or latency to choice measures. Diffusion tensor imaging revealed decreased (P = 0.01) fractional anisotropy (FA) in the internal capsule of HIGH-fed pigs compared with both the CONT (P < 0.01)- and LOW (P = 0.03)-fed pigs, which were not different from one another. Analysis of axial diffusivity (AD) within the internal capsule revealed a main effect of diet (P < 0.01) in which HIGH-fed piglets exhibited smaller (P < 0.01) rates of diffusion compared with CONT piglets, but HIGH-fed piglets were not different (P = 0.12) than LOW-fed piglets. Tract-based spatial statistics, a comparison of FA values along white matter tracts, revealed 1,650 voxels where CONT piglets exhibited higher (P < 0.05) values compared with HIGH-fed piglets. The lack of differences in intestinal and bodyweight measures among piglets indicate a-LA supplementation does not impact overall growth, regardless of concentration. Additionally, no observed differences between CONT- and LOW-fed piglets in behavior and neuroimaging measures indicate a low concentration of a-LA does not affect normal brain development. Supplementation of a-LA at a high concentration appeared to alter white matter maturation in the internal capsule, which may indicate delayed neurodevelopment in these piglets.

Genetic alteration of UDP-rhamnose metabolism in Botrytis cinerea leads to the accumulation of UDP-KDG that adversely affects development and pathogenicity.

PubMed

Ma, Liang; Salas, Omar; Bowler, Kyle; Oren-Young, Liat; Bar-Peled, Maor; Sharon, Amir

2017-02-01

Botrytis cinerea is a model plant-pathogenic fungus that causes grey mould and rot diseases in a wide range of agriculturally important crops. A previous study has identified two enzymes and corresponding genes (bcdh, bcer) that are involved in the biochemical transformation of uridine diphosphate (UDP)-glucose, the major fungal wall nucleotide sugar precursor, to UDP-rhamnose. We report here that deletion of bcdh, the first biosynthetic gene in the metabolic pathway, or of bcer, the second gene in the pathway, abolishes the production of rhamnose-containing glycans in these mutant strains. Deletion of bcdh or double deletion of both bcdh and bcer has no apparent effect on fungal development or pathogenicity. Interestingly, deletion of the bcer gene alone adversely affects fungal development, giving rise to altered hyphal growth and morphology, as well as reduced sporulation, sclerotia production and virulence. Treatments with wall stressors suggest the alteration of cell wall integrity. Analysis of nucleotide sugars reveals the accumulation of the UDP-rhamnose pathway intermediate UDP-4-keto-6-deoxy-glucose (UDP-KDG) in hyphae of the Δbcer strain. UDP-KDG could not be detected in hyphae of the wild-type strain, indicating fast conversion to UDP-rhamnose by the BcEr enzyme. The correlation between high UDP-KDG and modified cell wall and developmental defects raises the possibility that high levels of UDP-KDG result in deleterious effects on cell wall composition, and hence on virulence. This is the first report demonstrating that the accumulation of a minor nucleotide sugar intermediate has such a profound and adverse effect on a fungus. The ability to identify molecules that inhibit Er (also known as NRS/ER) enzymes or mimic UDP-KDG may lead to the development of new antifungal drugs. © 2016 BSPP AND JOHN WILEY & SONS LTD.

Nutrition-induced ketosis alters metabolic and signaling gene networks in liver of periparturient dairy cows.

PubMed

Loor, Juan J; Everts, Robin E; Bionaz, Massimo; Dann, Heather M; Morin, Dawn E; Oliveira, Rosane; Rodriguez-Zas, Sandra L; Drackley, James K; Lewin, Harris A

2007-12-19

Dairy cows are highly susceptible after parturition to developing liver lipidosis and ketosis, which are costly diseases to farmers. A bovine microarray platform consisting of 13,257-annotated oligonucleotides was used to study hepatic gene networks underlying nutrition-induced ketosis. On day 5 postpartum, 14 Holstein cows were randomly assigned to ketosis-induction (n = 7) or control (n = 7) groups. Cows in the ketosis-induction group were fed at 50% of day 4 intake until they developed signs of clinical ketosis, and cows in the control group were fed ad libitum throughout the treatment period. Liver was biopsied at 10-14 (ketosis) or 14 days postpartum (controls). Feed restriction increased blood concentrations of nonesterified fatty acids and beta-hydroxybutyrate, but decreased glucose. Liver triacylglycerol concentration also increased. A total of 2,415 genes were altered by ketosis (false discovery rate = 0.05). Ingenuity Pathway Analysis revealed downregulation of genes associated with oxidative phosphorylation, protein ubiquitination, and ubiquinone biosynthesis with ketosis. Other molecular adaptations included upregulation of genes and nuclear receptors associated with cytokine signaling, fatty acid uptake/transport, and fatty acid oxidation. Genes downregulated during ketosis included several associated with cholesterol metabolism, growth hormone signaling, proton transport, and fatty acid desaturation. Feed restriction and ketosis resulted in previously unrecognized alterations in gene network expression underlying key cellular functions and discrete metabolic events. These responses might help explain well-documented physiological adaptations to reduced feed intake in early postpartum cows and, thus, provide molecular targets that might be useful in prevention and treatment of liver lipidosis and ketosis.

The central tower of the cathedral of Schleswig - New investigations to understand the alcali-silica reaction of historical mortars

NASA Astrophysics Data System (ADS)

Wedekind, Wanja; Protz, Andreas

2016-04-01

The damaging alcali-silica reaction leads to crack-formation and structural destruction at noumerous, constructed with cement mortar, buildings worldwide. The ASR-reaction causes the expansion of altered aggregates by the formation of a swelling gel. This gel consists of calcium silicate hydrate (C-S-H) that increases in volume with water, which exerts an expansive pressure inside the material. The cathedral of Schleswig is one of the oldest in northern Germany. The first church was built in 985-965. The Romanesque building part was erected around 1180 and the Gothic nave at the end of the 13th century. The central tower was constructed between 1888 and 1894 with brick and cement mortar. With 112 meters, the tower is the second-largest church spire of the country of Schleswig-Holstein in northern Germany. Due to the formation of cracks and damages from 1953 to 1956 first restoration works took place. Further developments of cracks are making restoration necessary again today. For developing a suitable conservation strategy, different investigations were done. The investigation included the determination of the pore space properties, the hygric and thermal dilatation and mercury porosimetry measurements. Furthermore, the application of cathodoluminescence microscopy may give information about the alteration process and microstructures present and reveal the differences between unaltered and altered mortars. An obvious relation between the porosity and the swelling intensity could be detected. Furthermore it becomes apparent, that a clear zonation of the mortar took place. The mortar near the surface is denser with a lower porosity and has a significantly lower swelling or dilatation.

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

PubMed

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

2016-06-01

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

Phenotypic Characterization of Mice Carrying Homozygous Deletion of KLF11, a Gene in Which Mutations Cause Human Neonatal and MODY VII Diabetes

PubMed Central

Mathison, Angela; Escande, Carlos; Calvo, Ezequiel; Seo, Seungmae; White, Thomas; Salmonson, Ann; Faubion, William A.; Buttar, Navtej; Iovanna, Juan; Lomberk, Gwen; Chini, Eduardo N.

2015-01-01

We have previously shown that amino acid changes in the human Kruppel-Like Factor (KLF) 11 protein is associated with the development of maturity onset diabetes of the young VII, whereas complete inactivation of this pathway by the −331 human insulin mutation causes neonatal diabetes mellitus. Here, we report that Klf11−/− mice have decreased circulating insulin levels, alterations in the control of blood glucose and body weight, as well as serum dyslipidemia, but do not develop diabetes. Functional assays using ex vivo liver tissue sections demonstrate that Klf11−/− mice display increased insulin sensitivity. Genome-wide experiments validated by pathway-specific quantitative PCR arrays reveal that the Klf11−/− phenotype associates to alterations in the regulation of gene networks involved in lipid metabolism, in particular those regulated by peroxisome proliferator-activated receptor-γ. Combined, these results demonstrate that the major phenotype given by the whole-body deletion of Klf11 in mouse is not diabetes but increased insulin sensitivity, likely due to altered transcriptional regulation in target tissues. The absence of diabetes in the Klf11−/− mouse either indicates an interspecies difference for the role of this transcription factor in metabolic homeostasis between mouse and humans, or potentially highlights the fact that other molecular factors can compensate for its absence. Nevertheless, the data of this study, gathered at the whole-organism level, further support a role for KLF11 in metabolic processes like insulin sensitivity, which regulation is critical in several forms of diabetes. PMID:26248217

Acute systemic rapamycin induces neurobehavioral alterations in rats.

PubMed

Hadamitzky, Martin; Herring, Arne; Keyvani, Kathy; Doenlen, Raphael; Krügel, Ute; Bösche, Katharina; Orlowski, Kathrin; Engler, Harald; Schedlowski, Manfred

2014-10-15

Rapamycin is a drug with antiproliferative and immunosuppressive properties, widely used for prevention of acute graft rejection and cancer therapy. It specifically inhibits the activity of the mammalian target of rapamycin (mTOR), a protein kinase known to play an important role in cell growth, proliferation and antibody production. Clinical observations show that patients undergoing therapy with immunosuppressive drugs frequently suffer from affective disorders such as anxiety or depression. However, whether these symptoms are attributed to the action of the distinct compounds remains rather elusive. The present study investigated in rats neurobehavioral consequences of acute rapamycin treatment. Systemic administration of a single low dose rapamycin (3mg/kg) led to enhanced neuronal activity in the amygdala analyzed by intracerebral electroencephalography and FOS protein expression 90min after drug injection. Moreover, behavioral investigations revealed a rapamycin-induced increase in anxiety-related behaviors in the elevated plus-maze and in the open-field. The behavioral alterations correlated to enhanced amygdaloid expression of KLK8 and FKBP51, proteins that have been implicated in the development of anxiety and depression. Together, these results demonstrate that acute blockade of mTOR signaling by acute rapamycin administration not only causes changes in neuronal activity, but also leads to elevated protein expression in protein kinase pathways others than mTOR, contributing to the development of anxiety-like behavior. Given the pivotal role of the amygdala in mood regulation, associative learning, and modulation of cognitive functions, our findings raise the question whether therapy with rapamycin may induce alterations in patients neuropsychological functioning. Copyright © 2014 Elsevier B.V. All rights reserved.

Brain Growth Rate Abnormalities Visualized in Adolescents with Autism

PubMed Central

Hua, Xue; Thompson, Paul M.; Leow, Alex D.; Madsen, Sarah K.; Caplan, Rochelle; Alger, Jeffry R.; O’Neill, Joseph; Joshi, Kishori; Smalley, Susan L.; Toga, Arthur W.; Levitt, Jennifer G.

2014-01-01

Autism spectrum disorder (ASD) is a heterogeneous disorder of brain development with wide-ranging cognitive deficits. Typically diagnosed before age 3, ASD is behaviorally defined but patients are thought to have protracted alterations in brain maturation. With longitudinal magnetic resonance imaging (MRI), we mapped an anomalous developmental trajectory of the brains of autistic compared to those of typically developing children and adolescents. Using tensor-based morphometry (TBM), we created 3D maps visualizing regional tissue growth rates based on longitudinal brain MRI scans of 13 autistic and 7 typically developing boys (mean age/inter-scan interval: autism 12.0 ± 2.3 years/2.9 ± 0.9 years; control 12.3 ± 2.4/2.8 ± 0.8). The typically developing boys demonstrated strong whole-brain white matter growth during this period, but the autistic boys showed abnormally slowed white matter development (p = 0.03, corrected), especially in the parietal (p = 0.008), temporal (p = 0.03) and occipital lobes (p =0.02). We also visualized abnormal overgrowth in autism in some gray matter structures, such as the putamen and anterior cingulate cortex. Our findings reveal aberrant growth rates in brain regions implicated in social impairment, communication deficits and repetitive behaviors in autism, suggesting that growth rate abnormalities persist into adolescence. TBM revealed persisting growth rate anomalies long after diagnosis, which has implications for evaluation of therapeutic effects. PMID:22021093

The Cysteine Protease CEP1, a Key Executor Involved in Tapetal Programmed Cell Death, Regulates Pollen Development in Arabidopsis[W][OPEN

PubMed Central

Zhang, Dandan; Liu, Di; Lv, Xiaomeng; Wang, Ying; Xun, Zhili; Liu, Zhixiong; Li, Fenglan; Lu, Hai

2014-01-01

Tapetal programmed cell death (PCD) is a prerequisite for pollen grain development in angiosperms, and cysteine proteases are the most ubiquitous hydrolases involved in plant PCD. We identified a papain-like cysteine protease, CEP1, which is involved in tapetal PCD and pollen development in Arabidopsis thaliana. CEP1 is expressed specifically in the tapetum from stages 5 to 11 of anther development. The CEP1 protein first appears as a proenzyme in precursor protease vesicles and is then transported to the vacuole and transformed into the mature enzyme before rupture of the vacuole. cep1 mutants exhibited aborted tapetal PCD and decreased pollen fertility with abnormal pollen exine. A transcriptomic analysis revealed that 872 genes showed significantly altered expression in the cep1 mutants, and most of them are important for tapetal cell wall organization, tapetal secretory structure formation, and pollen development. CEP1 overexpression caused premature tapetal PCD and pollen infertility. ELISA and quantitative RT-PCR analyses confirmed that the CEP1 expression level showed a strong relationship to the degree of tapetal PCD and pollen fertility. Our results reveal that CEP1 is a crucial executor during tapetal PCD and that proper CEP1 expression is necessary for timely degeneration of tapetal cells and functional pollen formation. PMID:25035401

The cysteine protease CEP1, a key executor involved in tapetal programmed cell death, regulates pollen development in Arabidopsis.

PubMed

Zhang, Dandan; Liu, Di; Lv, Xiaomeng; Wang, Ying; Xun, Zhili; Liu, Zhixiong; Li, Fenglan; Lu, Hai

2014-07-01

Tapetal programmed cell death (PCD) is a prerequisite for pollen grain development in angiosperms, and cysteine proteases are the most ubiquitous hydrolases involved in plant PCD. We identified a papain-like cysteine protease, CEP1, which is involved in tapetal PCD and pollen development in Arabidopsis thaliana. CEP1 is expressed specifically in the tapetum from stages 5 to 11 of anther development. The CEP1 protein first appears as a proenzyme in precursor protease vesicles and is then transported to the vacuole and transformed into the mature enzyme before rupture of the vacuole. cep1 mutants exhibited aborted tapetal PCD and decreased pollen fertility with abnormal pollen exine. A transcriptomic analysis revealed that 872 genes showed significantly altered expression in the cep1 mutants, and most of them are important for tapetal cell wall organization, tapetal secretory structure formation, and pollen development. CEP1 overexpression caused premature tapetal PCD and pollen infertility. ELISA and quantitative RT-PCR analyses confirmed that the CEP1 expression level showed a strong relationship to the degree of tapetal PCD and pollen fertility. Our results reveal that CEP1 is a crucial executor during tapetal PCD and that proper CEP1 expression is necessary for timely degeneration of tapetal cells and functional pollen formation. © 2014 American Society of Plant Biologists. All rights reserved.

Brain growth rate abnormalities visualized in adolescents with autism.

PubMed

Hua, Xue; Thompson, Paul M; Leow, Alex D; Madsen, Sarah K; Caplan, Rochelle; Alger, Jeffry R; O'Neill, Joseph; Joshi, Kishori; Smalley, Susan L; Toga, Arthur W; Levitt, Jennifer G

2013-02-01

Autism spectrum disorder is a heterogeneous disorder of brain development with wide ranging cognitive deficits. Typically diagnosed before age 3, autism spectrum disorder is behaviorally defined but patients are thought to have protracted alterations in brain maturation. With longitudinal magnetic resonance imaging (MRI), we mapped an anomalous developmental trajectory of the brains of autistic compared with those of typically developing children and adolescents. Using tensor-based morphometry, we created 3D maps visualizing regional tissue growth rates based on longitudinal brain MRI scans of 13 autistic and seven typically developing boys (mean age/interscan interval: autism 12.0 ± 2.3 years/2.9 ± 0.9 years; control 12.3 ± 2.4/2.8 ± 0.8). The typically developing boys demonstrated strong whole brain white matter growth during this period, but the autistic boys showed abnormally slowed white matter development (P = 0.03, corrected), especially in the parietal (P = 0.008), temporal (P = 0.03), and occipital lobes (P = 0.02). We also visualized abnormal overgrowth in autism in gray matter structures such as the putamen and anterior cingulate cortex. Our findings reveal aberrant growth rates in brain regions implicated in social impairment, communication deficits and repetitive behaviors in autism, suggesting that growth rate abnormalities persist into adolescence. Tensor-based morphometry revealed persisting growth rate anomalies long after diagnosis, which has implications for evaluation of therapeutic effects. Copyright © 2011 Wiley Periodicals, Inc.

Identification of a peroxisomal-targeted aldolase involved in chlorophyll biosynthesis and sugar metabolism in rice.

PubMed

Zhang, Fei; Zhang, Pan; Zhang, Yu; Wang, Shouchuang; Qu, Lianghuan; Liu, Xianqing; Luo, Jie

2016-09-01

Chlorophyll plays remarkable and critical roles in photosynthetic light-harvesting, energy transduction and plant development. In this study, we identified a rice Chl-deficient mutant, ygdl-1 (yellow green and droopy leaf-1), which showed yellow-green leaves throughout plant development with decreased content of Chls and carotene and an increased Chl a/b ratio. The ygdl-1 mutant also exhibited severe defects in chloroplast development, including disorganized grana stacks. Sequence analysis revealed that the mutant contained a T-DNA insertion within the promoter of a fructose-1,6-bisphosphate aldolase (OsAld-Y), which dramatically reduced the OsAld-Y mRNA level, and its identity was verified by transgenic complementation. Real-time PCR analysis showed that the expression levels of genes associated with chlorophyll biosynthesis and chloroplast development were concurrently altered in the ygdl-1 mutant. The expression of OsAld-Y-GFP fusion protein in tobacco epidermal cells showed that OsAld-Y was localized to the peroxisome. In addition, the analysis of primary carbon metabolites revealed the significantly reduced levels of sucrose and fructose in the mutant leaves, while the glucose content was similar to wild-type plants. Our results suggest that the OsAld-Y participates in Chl accumulation, chloroplast development and plant growth by influencing the photosynthetic rate of leaves and the sugar metabolism of rice. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Direct analysis in real time high resolution mass spectrometry as a tool for rapid characterization of mind-altering plant materials and revelation of supplement adulteration--The case of Kanna.

PubMed

Lesiak, Ashton D; Cody, Robert B; Ubukata, Masaaki; Musah, Rabi A

2016-03-01

We demonstrate the utility of direct analysis in real time ionization coupled with high resolution time-of-flight mass spectrometry (DART-HRTOFMS) in revealing the adulteration of commercially available Sceletium tortuosum, a mind-altering plant-based drug commonly known as Kanna. Accurate masses consistent with alkaloids previously isolated from S. tortuosum plant material enabled identification of the products as Kanna, and in-source collision-induced dissociation (CID) confirmed the presence of one of these alkaloids, hordenine, while simultaneously revealing the presence of an adulterant. The stimulant ephedrine, which has been banned in herbal products and supplements, was confirmed to be present in a sample through the use of in-source CID. High-throughput DART-HRTOFMS was shown to be a powerful tool to not only screen plant-based drugs of abuse for psychotropic alkaloids, but also to reveal the presence of scheduled substances and adulterants. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The cancer glycocalyx mechanically primes integrin-mediated growth and survival

PubMed Central

Paszek, Matthew J.; DuFort, Christopher C.; Rossier, Olivier; Bainer, Russell; Mouw, Janna K.; Godula, Kamil; Hudak, Jason E.; Lakins, Jonathon N.; Wijekoon, Amanda C.; Cassereau, Luke; Rubashkin, Matthew G.; Magbanua, Mark J.; Thorn, Kurt S.; Davidson, Michael W.; Rugo, Hope S.; Park, John W.; Hammer, Daniel A.; Giannone, Grégory; Bertozzi, Carolyn R.; Weaver, Valerie M.

2015-01-01

Malignancy is associated with altered expression of glycans and glycoproteins that contribute to the cellular glycocalyx. We constructed a glycoprotein expression signature, which revealed that metastatic tumours upregulate expression of bulky glycoproteins. A computational model predicted that these glycoproteins would influence transmembrane receptor spatial organization and function. We tested this prediction by investigating whether bulky glycoproteins in the glycocalyx promote a tumour phenotype in human cells by increasing integrin adhesion and signalling. Our data revealed that a bulky glycocalyx facilitates integrin clustering by funnelling active integrins into adhesions and altering integrin state by applying tension to matrix-bound integrins, independent of actomyosin contractility. Expression of large tumour-associated glycoproteins in non-transformed mammary cells promoted focal adhesion assembly and facilitated integrin-dependent growth factor signalling to support cell growth and survival. Clinical studies revealed that large glycoproteins are abundantly expressed on circulating tumour cells from patients with advanced disease. Thus, a bulky glycocalyx is a feature of tumour cells that could foster metastasis by mechanically enhancing cell-surface receptor function. PMID:25030168

Neonicotinoid Insecticides Alter the Gene Expression Profile of Neuron-Enriched Cultures from Neonatal Rat Cerebellum

PubMed Central

Kimura-Kuroda, Junko; Nishito, Yasumasa; Yanagisawa, Hiroko; Kuroda, Yoichiro; Komuta, Yukari; Kawano, Hitoshi; Hayashi, Masaharu

2016-01-01

Neonicotinoids are considered safe because of their low affinities to mammalian nicotinic acetylcholine receptors (nAChRs) relative to insect nAChRs. However, because of importance of nAChRs in mammalian brain development, there remains a need to establish the safety of chronic neonicotinoid exposures with regards to children’s health. Here we examined the effects of long-term (14 days) and low dose (1 μM) exposure of neuron-enriched cultures from neonatal rat cerebellum to nicotine and two neonicotinoids: acetamiprid and imidacloprid. Immunocytochemistry revealed no differences in the number or morphology of immature neurons or glial cells in any group versus untreated control cultures. However, a slight disturbance in Purkinje cell dendritic arborization was observed in the exposed cultures. Next we performed transcriptome analysis on total RNAs using microarrays, and identified significant differential expression (p < 0.05, q < 0.05, ≥1.5 fold) between control cultures versus nicotine-, acetamiprid-, or imidacloprid-exposed cultures in 34, 48, and 67 genes, respectively. Common to all exposed groups were nine genes essential for neurodevelopment, suggesting that chronic neonicotinoid exposure alters the transcriptome of the developing mammalian brain in a similar way to nicotine exposure. Our results highlight the need for further careful investigations into the effects of neonicotinoids in the developing mammalian brain. PMID:27782041