bluuebunny/crossref_metadata_2025_split huggingface dataset:
The flower pot method of REM sleep deprivation causes apoptotic cell death in the hepatocytes of rat
Authors: Pandey Atul , Kumar Devesh , Ray Gopesh , Kar Santosh 
Published: July 2018

AbstractIntroductionThe rapid eye movement sleep deprivation (REMSD) of rats relates with increased inflammations, acute phase response, oxidative damage, neuronal cell loss, and neurodegenerative diseases. Whereas, its role outside brain are not well studied. This study tried to explore the causal effect of REM sleep loss on hepatocytes.MethodsWe deprived the rats of REM sleep using standard flower pot method. We focused on liver to see the REMSD affects which controls most of the metabolic processes of the body.ResultsWe report here that flower pot induced REMSD causes apoptotic cell death of hepatocytes (~10% by Annexin Assay & ~20% by TUNEL assay). This were further got alleviated up to extent after sleep recovery of 5 days (recovered approximately 8.0% by Annexin Assay & 14% by TUNEL assay). The gene expression and protein level profiling revealed the up-regulation of p53, Bax, Cytochrome c, Caspase 3, and Caspase 9. While, Bcl2 which is an anti-apoptotic protein were down-regulated in response to REMSD. Relentless recovery of 5 days affected the expression pattern of these genes/proteins.ConclusionsOur study offer great pathological and physiological significance for sleep loss, by inferring the apoptotic cell-death in the hepatocytes of rat. This further signifies the functional and preventive role of REM sleep which is unique to mammals and avians with certain exceptions, as its loss can affect the natural well-being and survival of the individuals.Highlights of the studyWe observed significant apoptosis in the hepatocytes of REMSD group of rats.Our expression analysis confirmed altered expression for genes p53, Bcl2, Bax, and Caspase-3 after REMSD.Protein level analysis supported our gene expression results for p53, Bcl2, Bax, Caspase 3 and Caspase 9 after REMSD.Sleep recovery improved the respective genes and protein expression levels towards normalcy, signifying the functional role of REM sleep.
Inhibition of proteasomal degradation rescues a pathogenic variant of mitochondrial Respiratory chain assembly 1 factor
Authors: Mohanraj Karthik , Wasilewski Michal , Benincá Cristiane , Cysewski Dominik , Poznanski Jarosław , Sakowska Paulina , Deckers Markus , Dennerlein Sven , Fernandez-Vizarra Erika , Rehling Peter , Dadlez Michal , Zeviani Massimo , Chacinska Agnieszka 
Published: July 2018

AbstractNuclear and mitochondrial genome mutations lead to various mitochondrial diseases, many of which affect the mitochondrial respiratory chain. The proteome of the intermembrane space (IMS) of mitochondria consists of several important assembly factors that participate in the biogenesis of mitochondrial respiratory chain complexes. The present study comprehensively analyzed a recently identified IMS protein, RESpiratory chain Assembly 1 (RESA1) factor, or cytochrome c oxidase assembly factor 7 (COA7) that is associated with a rare form of mitochondrial leukoencephalopathy and complex IV deficiency. We found that RESA1 requires the mitochondrial IMS import and assembly (MIA) pathway for efficient accumulation in the IMS. We also found that pathogenic mutant versions of RESA1 are imported slower than the wild type protein, and mislocalized mutant proteins are degraded in the cytosol by proteasome machinery. Interestingly, proteasome inhibition rescued both the mitochondrial localization of mutant RESA1 and complex IV activity in patient-derived fibroblasts. We propose that proteasome inhibition is a novel therapeutic approach for a broad range of mitochondrial pathologies that are associated with the excessive degradation of mitochondrial proteins that is caused by genetic mutations or biogenesis defects.
Guanabenz treatment improves Oculopharyngeal muscular dystrophy phenotype
Authors: Malerba Alberto , Roth Fanny , Harish Pradeep , Dhiab Jamila , Lu-Nguyen Ngoc , Cappellari Ornella , Jarmin Susan , Mahoudeau Alexandrine , Ythier Victor , Lainé Jeanne , Negroni Elisa , Abgueguen Emmanuelle , Simonelig Martine , Guedat Philippe , Mouly Vincent , Butler-Browne Gillian , Voisset Cécile , Dickson George , Trollet Capucine 
Published: July 2018

AbstractOculopharyngeal muscular dystrophy (OPMD) is a rare late onset genetic disease affecting most profoundly eyelid and pharyngeal muscles, leading respectively to ptosis and dysphagia, and proximal limb muscles at later stages. A short abnormal (GCG) triplet expansion in the polyA– binding protein nuclear 1 (PABPN1) gene leads to PABPN1-containing aggregates in the muscles of OPMD patients. It is commonly accepted that aggregates themselves, the aggregation process and/or the early oligomeric species of PABPN1 are toxic in OPMD. Decreasing PABPN1 aggregate load in animal models of OPMD ameliorates the muscle phenotype. In order to identify a potential therapeutic molecule that would prevent and reduce aggregates, we tested guanabenz acetate (GA), an FDA-approved antihypertensive drug, in OPMD cells as well as in the A17 OPMD mouse model. We demonstrate that treating mice with GA reduces the size and number of nuclear aggregates, improves muscle force, protects myofibres from the pathology-derived turnover and decreases fibrosis. GA is known to target various cell processes, including the unfolded protein response (UPR), which acts to attenuate endoplasmic reticulum (ER) stress. Here we used a cellular model of OPMD to demonstrate that GA increases both the phosphorylation of the eukaryotic translation initiator factor 2α subunit (eIF2α) and the splicing of Xbp1, key components of the UPR. Altogether these data suggest that modulation of protein folding regulation can be beneficial for OPMD and support the further development of guanabenz or its derivatives for treatment of OPMD in humans.Significance StatementOculopharyngeal muscular dystrophy (OPMD) is a rare late onset incurable genetic disease characterized by the formation of insoluble aggregates in skeletal muscles. It has been shown that the reduction of aggregates correlates with an improvement of the disease. Here we used a mouse model of OPMD to show that Guanabenz acetate, the active constituent of a marketed but recently discontinued drug for hypertension, decreases the number and the size of aggregates after systemic delivery and improves many aspects of the disease. We also describe experimental evidences explaining the mechanism behind the efficacy of such compound for OPMD.
Improving the diagnostic yield of exome-sequencing, by predicting gene-phenotype associations using large-scale gene expression analysis
Authors: Deelen Patrick , Dam Sipko van , Herkert Johanna C. , Karjalainen Juha M. , Brugge Harm , Abbott Kristin M. , van Diemen Cleo C. , der Zwaag Paul A. van , Gerkes Erica H. , Folkertsma Pytrik , Gillett Tessa , der Velde K. Joeri van , Kanninga Roan , den Akker Peter C. van , Jan Sabrina Z. , Hoorntje Edgar T. , te Rijdt Wouter P. , Vos Yvonne J. , Jongbloed Jan D.H. , van Ravenswaaij-Arts Conny M.A. , Sinke Richard , Sikkema-Raddatz Birgit , Kerstjens-Frederikse Wilhelmina S. , Swertz Morris A. , Franke Lude 
Published: July 2018

AbstractClinical interpretation of exome and genome sequencing data remains challenging and time consuming, with many variants with unknown effects found in genes with unknown functions. Automated prioritization of these variants can improve the speed of current diagnostics and identify previously unknown disease genes. Here, we used 31,499 RNA-seq samples to predict the phenotypic consequences of variants in genes. We developed GeneNetwork Assisted Diagnostic Optimization (GADO), a tool that uses these predictions in combination with a patient’s phenotype, denoted using HPO terms, to prioritize identified variants and ease interpretation. GADO is unique because it does not rely on existing knowledge of a gene and can therefore prioritize variants missed by tools that rely on existing annotations or pathway membership. In a validation trial on patients with a known genetic diagnosis, GADO prioritized the causative gene within the top 3 for 41% of the cases. Applying GADO to a cohort of 38 patients without genetic diagnosis, yielded new candidate genes for seven cases. Our results highlight the added value of GADO (www.genenetwork.nl) for increasing diagnostic yield and for implicating previously unknown disease-causing genes.
The Site Frequency Spectrum under Finite and Time-Varying Mutation Rates
Authors: Melfi Andrew , Viswanath Divakar 
Published: July 2018

AbstractThe diversity in genomes is due to the accumulation of mutations and the site frequency spectrum (SFS) is a popular statistic for summarizing genomic data. The current coalescent algorithm for calculating the SFS for a given demography assumes theμ→ 0 limit, whereμis the mutation probability (or rate) per base pair per generation. The algorithm is applicable whenμN,Nbeing the haploid population size, is negligible. We derive a coalescent based algorithm for calculating the SFS that allows the mutation rateμ(t) as well as the population sizeN(t) to vary arbitrarily as a function of time. That algorithm shows that the probability of two mutations in the genealogy becomes noticeable already forμ= 10-8for samples ofn= 105haploid human genomes and increases rapidly withμ. Our algorithm calculates the SFS under the assumption of a single mutation in the genealogy, and the part of the SFS due to a single mutation depends only mildly on the finiteness ofμ. However, the dependence of the SFS on variation inμcan be substantial for evenn= 100 samples. In addition, increasing and decreasing mutation rates alter the SFS in different ways and to different extents.
Multiscale analysis of 3D nuclear morphology reveals new insights into growth plate organization in mice
Authors: Rubin Sarah , Stern Tomer , Villoutreix Paul , Stegmaier Johannes , Addadi Yoseph , Zelzer Elazar 
Published: July 2018

AbstractThe shape of the nucleus is tightly associated with cell morphology, the mechanical environment, and differentiation and transcriptional states. Yet, imaging of nuclei in three dimensions while preserving the spatial context of the tissue has been highly challenging. Here, using the embryonic tibial growth plate as a model for cell differentiation, we study nuclear morphology by imaging cleared samples by light-sheet fluorescence microscopy. Next, we quickly segmented tens of thousands of nuclei using several open-source tools including machine learning. Finally, segmented nuclei underwent morphometric analysis and 3D spatial reconstruction using newly designed algorithms. Our method revealed differences in nuclear morphology between chondrocytes at different differentiation stages. Additionally, we identified different morphological patterns in opposing growth plates, such as gradients of volume and surface area, as well as features characteristic of specific growth plate zones, such as sphericity and orientation. Altogether, this work supports a link between nuclear morphology and cell differentiation. Moreover, it demonstrates the suitability of our approach for studying the relationships between nuclear morphology and organ development.Author summaryThere has been a growing interest in the relationship between nuclear morphology and its regulation of gene expression. However, to study global patterns of nuclear morphology within a tissue we must address the problem of acquiring and analyzing multiscale data, ranging from the tissue level through to subcellular resolution. We have established a new pipeline that enables acquisition and segmentation of hundreds of thousands of nuclei at a resolution that allows quantitative analysis. Moreover we have developed new algorithms that allow superimposing morphological aspects of hundreds of thousands of nuclei onto a visual representation of the entire tissue, allowing us to study nuclear morphology at an organ level. Using mouse growth plates as a model for the relationship between nuclear morphology and tissue differentiation, we show that nuclei change different aspects of their morphology during chondrocyte differentiation. Growth plates are usually described generically in the literature, suggesting they lack unique characteristics. We challenge this dogma by showing that morphological features such as volume distribute differently in opposing growth plates. Altogether, this work highlights the possible role of nuclear shape in the regulation of cell differentiation and demonstrates that our approach enables the study of nuclear morphology patterns within a tissue.
Vertical transmission of Zika virus in orally-infected Aedes aegypti produces infectious adult progeny
Authors: Comeau Genevieve , Zinna Robert A. , Scott Taylor , Ernst Kacey , Walker Kathleen , Carrière Yves , Riehle Michael A. 
Published: July 2018

AbstractVertical transmission, or pathogen transfer from mother to offspring, can facilitate persistence of emerging arboviruses, such as Zika virus (ZIKV), in mosquito populations. Understanding vertical transmission and the different environmental and temporal conditions that affect it is important to assess whether new outbreaks could occur without reintroduction of the virus. To determine the rate of vertical transmission for ZIKV, Aedes aegypti females were fed on ZIKV infected blood, maintained under three temperature conditions (27°C, 30°C, and 33°C), and allowed to oviposit three times. Progeny were tested for virus presence at 3, 7, and 14 days after adult emergence. The overall vertical transmission rate was 6.5% (3.9 - 9.9). Vertical transmission was observed across all maternal temperature conditions and was detected in adult progeny as young as 3 days and as late as 14 days post-emergence. In total, 3.4% (1.6 - 6.2) of adult progeny produced saliva with detectable ZIKV, indicating their capacity to transmit ZIKV to humans. To our knowledge, this is the first evidence that vertical transmission occurs from orally-infected female Aedes aegypti to their adult progeny at a range of temperatures, and proof that Zika virus can persist in the saliva of those progeny throughout their lifetimes. These results suggest that the virus may be maintained in Ae. aegypti populations without a vertebrate host, allowing for human infections to occur without consistent re-introductions of ZIKV.Author SummaryIn 2015, Zika virus spread to over 50 countries. However, it is not known whether the virus persisted in the outbreak areas or became locally extinct. One way mosquito-borne viruses, like Zika, could become established is by transferring directly between mosquito generations rather than circulating between mosquitoes and humans. This is known as vertical transmission, and happens when the virus infects the developing eggs of infected maternal mosquitoes. As with other mosquito-borne diseases, like dengue, in order to infect humans the virus must be present in the saliva of infected mosquito progeny during blood feeding. We found vertical transmission occurred throughout the infected mother’s reproductive lifetime and across a range of temperature conditions. Vertically infected progeny had Zika virus in their saliva as early as three days after adult emergence, implying that they could infect a person even during their first bloodmeal. Importantly, this work indicates that Zika virus could establish itself in the mosquito population even when human to mosquito transmission is not actively occurring.
High-density linkage map and QTLs for growth in snapper (Chrysophrys auratus)
Authors: Ashton David T. , Ritchie Peter A. , Wellenreuther Maren 
Published: July 2018

ABSTRACTCharacterizing the genetic variation underlying phenotypic traits is a central objective in biological research. This research has been hampered in the past by the limited genomic resources available for most non-model species. However, recent advances in sequencing technology and related genotyping methods are rapidly changing this. Here we report the use of genome-wide SNP data from the ecologically and commercially important marine fish species Chrysophrys auratus (snapper) to 1) construct the first linkage map for this species, 2) scan for growth QTLs, and 3) search for candidate genes in the surrounding QTL regions. The newly constructed linkage map contained ~11K SNP markers and is the densest map to date in the fish family Sparidae. Comparisons with available genome scaffolds indicated that overall marker placement was strongly correlated between the scaffolds and linkage map (R = 0.7), but at fine scales (< 5 cM) there were some precision limitations. Of the 24 linkage groups, which reflect the 24 chromosomes of this species, three were found to contain QTLs with genome-wide significance for growth-related traits. A scan for 13 known candidate growth genes located the genes for growth hormone, parvalbumin, and myogenin within 13.2, 2.6, and 5.0 cM of these genome-wide significant QTLs, respectively. The linkage map and QTLs found in this study will advance the investigation of genome structure and selective breeding in snapper.
Transcription promotes the interaction of the FAcilitates Chromatin Transactions (FACT) complex with nucleosomes inS. cerevisiae
Authors: Martin Benjamin J.E. , Chruscicki Adam T. , Howe LeAnn J. 
Published: July 2018

ABSTRACTThe FACT (FAcilitates Chromatin Transactions) complex is enriched on highly expressed genes, where it facilitates transcription while maintaining chromatin structure. How it is targeted to these regions is unknown. In vitro, FACT binds destabilized nucleosomes, supporting the hypothesis that FACT is targeted to transcribed chromatin through recognition of RNA polymerase-disrupted nucleosomes. In this study, we used high resolution analysis of FACT occupancy inS. cerevisiaeto test this hypothesis. We demonstrate that FACT interacts with unstable nucleosomesin vivoand its interaction with chromatin is dependent on transcription by any of the three RNA polymerases. Deep sequencing of micrococcal nuclease-resistant fragments shows that FACT-bound nucleosomes exhibit differences in micrococcal nuclease sensitivity compared to bulk chromatin, consistent with a modified nucleosome structure being the preferred ligand for this complex. While the presence of altered nucleosomes associated with FACT can also be explained by the known ability of this complex to modulate nucleosome structure, transcription inhibition alleviates this effect indicating that it is not due to FACT interaction alone. Collectively these results suggest that FACT is targeted to transcribed genes through preferential interaction with RNA polymerase disrupted nucleosomes.
Glucose intake hampers PKA-regulated HSP90 chaperone activity
Authors: Chen Yu-Chen , Jiang Pei-Heng , Chen Hsuan-Ming , Chen Chang-Han , Wang Yi-Ting , Chen Yu-Ju , Yu Chia-Jung , Teng Shu-Chun 
Published: July 2018

AbstractAging is an intricate phenomenon associated with the gradual loss of physiological functions, and both nutrient sensing and proteostasis control lifespan. Although multiple approaches have facilitated the identification of candidate genes that govern longevity, the molecular mechanisms that link aging pathways are still elusive. Here, we conducted a quantitative mass spectrometry screen and identified all phosphorylation/dephosphorylation sites on yeast proteins that significantly responded to calorie restriction, a well-established approach to extend lifespan. Functional screening of 135 potential regulators uncovered that Ids2 is activated by PP2C under CR and inactivated by PKA under glucose intake.ids2Δorids2phosphomimetic cells displayed heat sensitivity and lifespan shortening. Ids2 serves as a co-chaperone to form a complex with Hsc82 or the redundant Hsp82, and phosphorylation of Ids2 impedes its association with chaperone HSP90. Thus, PP2C and PKA orchestrate glucose sensing and protein folding to enable cells to maintain protein quality for sustained longevity.
Bed nucleus of the stria terminalis regulates fear to unpredictable threat signals
Authors: Goode Travis D. , Ressler Reed L. , Acca Gillian M. , Miles Olivia W. , Maren Stephen 
Published: July 2018

ABSTRACTThe bed nucleus of the stria terminalis (BNST) has been implicated in conditioned fear and anxiety, but the specific factors that engage the BNST in defensive behaviors are unclear. Here we examined whether the BNST mediates freezing to conditioned stimuli (CSs) that poorly predict the onset of aversive unconditioned stimuli (USs) in rats. Reversible inactivation of the BNST selectively reduced freezing to CSs that poorly signaled US onset (e.g., a backward CS that followed the US), but did not eliminate freezing to forward CSs even when they predicted USs of variable intensity. Additionally, backward (but not forward) CSs selectively increased Fos in the ventral BNST and in BNST-projecting neurons in the infralimbic region of the medial prefrontal cortex (mPFC), but not in the hippocampus or amygdala. These data reveal that BNST circuits regulate fear to unpredictable threats, which may be critical to the etiology and expression of anxiety.IMPACT STATEMENTThe bed nucleus of the stria terminalis (BNST) is required for the expression of defensive behavior to unpredictable threats, a function that may be central to pathological anxiety.
RNA polymerase mapping in plants identifies enhancers enriched in causal variants
Authors: Lozano Roberto , Booth Gregory T. , Omar Bilan Yonis , Li Bo , Buckler Edward S. , Lis John T. , Jannink Jean-Luc , del Carpio Dunia Pino 
Published: July 2018

AbstractPromoter-proximal pausing and divergent transcription at promoters and enhancers, which are prominent features in animals, have been reported to be absent in plants based on a study of Arabidopsis thaliana. Here, our PRO-Seq analysis in cassava (Manihot esculenta) identified peaks of transcriptionally-engaged RNA polymerase II (Pol2) at both 5’ and 3’ ends of genes, consistent with paused or slowly-moving Pol2, and divergent transcription at potential intragenic enhancers. A full genome search for bi-directional transcription using an algorithm for enhancer detection developed in mammals (dREG) identified many enhancer candidates. These sites show distinct patterns of methylation and nucleotide variation based on genomic evolutionary rate profiling characteristic of active enhancers. Maize GRO-Seq data showed RNA polymerase occupancy at promoters and enhancers consistent with cassava but not Arabidopsis. Furthermore, putative enhancers in maize identified by dREG significantly overlapped with sites previously identified on the basis of open chromatin, histone marks, and methylation. We show that SNPs within these divergently transcribed intergenic regions predict significantly more variation in fitness and root composition than SNPs in chromosomal segments randomly ascertained from the same intergenic distribution, suggesting a functional importance of these sites on cassava. The findings shed new light on plant transcription regulation and its impact on development and plasticity.