bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using the drug-protein interactome to identify anti-ageing compounds for humans
Authors: Fuentealba Valenzuela Matías , Melike Dönertaş Handan , Williams Rhianna , Labbadia Johnathan , Thornton Janet , Partridge Linda 
Published: October 2018

AbstractAdvancing age is the dominant risk factor for most of the major killer diseases in developed countries. Hence, ameliorating the effects of ageing may prevent multiple diseases simultaneously. Drugs licensed for human use against specific diseases have proved to be effective in extending lifespan and healthspan in animal models, suggesting that there is scope for drug repurposing in humans. New bioinformatic methods to identify and prioritise potential anti-ageing compounds for humans are therefore of interest. In this study, we first used drug-protein interaction information, to rank 1,147 drugs by their likelihood of targeting ageing-related gene products in humans. Among 19 statistically significant drugs, 6 have already been shown to have pro-longevity properties in animal models (p < 0.001). Using the targets of each drug, we established its association with ageing at multiple levels of biological actions including pathways, functions and protein interactions. Finally, combining all the data, we calculated a comprehensive ranked list of drugs that predicted tanespimycin, an inhibitor of HSP-90, as the top-ranked novel anti-ageing candidate. We experimentally validated the pro-longevity effect of tanespimycin through its HSP-90 target in Caenorhabditis elegans.Author SummaryHuman life expectancy is continuing to increase worldwide, as a result of successive improvements in living conditions and medical care. Although this trend is to be celebrated, advancing age is the major risk factor for multiple impairments and chronic diseases. As a result, the later years of life are often spent in poor health and lowered quality of life. However, these effects of ageing are not inevitable, because very long-lived people often suffer rather little ill-health at the end of their lives. Furthermore, laboratory experiments have shown that animals fed with specific drugs can live longer and with fewer age-related diseases than their untreated companions. We therefore need to identify drugs with anti-ageing properties for humans. We have therefore used computers to search for drugs that affect components and processes known to be important in human ageing. This approach worked, because it was able to re-discover several drugs known to increase lifespan in animal models, plus some new ones, including one that we tested experimentally and validated in this study. These drugs are now a high priority for animal testing and for exploring effects on human ageing.
The neonatal Fc receptor is a pan-echovirus receptor
Authors: Morosky Stefanie , Evans Azia , Lemon Kathryn , Schmus Sandra , Bakkenist Christopher J. , Coyne Carolyn B 
Published: October 2018

AbstractEchoviruses are the main causative agents of aseptic meningitis worldwide and are particularly devastating in the neonatal population, where they are associated with severe hepatitis, neurological disease including meningitis and encephalitis, and even death. Here, we identify the neonatal Fc receptor (FcRn) as a pan-echovirus receptor. We show that loss of expression of FcRn or its binding partner beta 2 microglubulin (β2M) renders human brain microvascular cells resistant to infection by a panel of echoviruses at the stage of virus attachment and that a blocking antibody to β2M inhibit echovirus infection in cell lines and in primary human fetal intestinal epithelial cells. We also show that expression of human, but not mouse, FcRn renders non-permissive human and mouse cells sensitive to echovirus infection and that the extracellular domain of human FcRn directly binds echoviral particles and neutralizes infection. Lastly, we show that primary cells isolated from mice that express human FcRn are highly susceptible to echovirus infection. Our findings thus identify FcRn as a pan-echovirus receptor, which may explain the enhanced susceptibility of neonates to echovirus infections.SignificanceEchoviruses are associated with aseptic meningitis and induce severe disease, and even death, in neonates and young infants. Here, we identify the neonatal Fc receptor (FcRn) as a pan-echovirus receptor. FcRn is expressed on the surface of the human placenta, and throughout life in intestinal enterocytes, liver hepatocytes, and in the microvascular endothelial cells that line the blood-brain barrier. This pattern of expression is consistent with the organ sites targeted by echoviruses in humans, with the primary entry site of infection in the intestinal tract and subsequent infection of secondary tissues including the liver and brain. These findings provide important insights into echovirus pathogenesis and may explain the enhanced susceptibility of infants and neonates to echovirus-induced disease.
Analyses of Neanderthal introgression suggest that Levantine and southern Arabian populations have a shared population history
Authors: Vyas Deven N. , Mulligan Connie J. 
Published: October 2018

AbstractObjectivesModern humans are thought to have interbred with Neanderthals in the Near East soon after modern humans dispersed out of Africa. This introgression event likely took place in either the Levant or southern Arabian depending on which dispersal route out of Africa was followed. In this study, we compare Neanderthal introgression in contemporary Levantine and southern Arabian populations to investigate Neanderthal introgression and to study Near Eastern population history.Materials and MethodsWe analyzed genotyping data on >400,000 autosomal SNPs from seven Levantine and five southern Arabian populations and compared those data to populations from around the world including Neanderthal and Denisovan genomes. We used f4and D statistics to estimate and compare levels of Neanderthal introgression between Levantine, southern Arabian, and comparative global populations. We also identified 1,581 putative Neanderthal-introgressed SNPs within our dataset and analyzed their allele frequencies as a means to compare introgression patterns in Levantine and southern Arabian genomes.ResultsWe find that Levantine and southern Arabian populations have similar levels of Neanderthal introgression to each other but lower levels than other non-Africans. Furthermore, we find that introgressed SNPs have very similar allele frequencies in the Levant and southern Arabia, which indicates that Neanderthal introgression is similarly distributed in Levantine and southern Arabian genomes.DiscussionWe infer that the ancestors of contemporary Levantine and southern Arabian populations received Neanderthal introgression prior to separating from each other and that there has been extensive gene flow between these populations.
Altered chromatin localization of hybrid lethality proteins inDrosophila
Authors: Cooper J.C. , Lukacs A. , Reich S. , Schauer T. , Imhof A. , Phadnis N. 
Published: October 2018

AbstractUnderstanding hybrid incompatibilities is a fundamental pursuit in evolutionary genetics. In crosses betweenDrosophila melanogasterfemales andDrosophila simulansmales, the interaction of at least three genes is necessary for hybrid male lethality:Hmrmel,Lhrsim, andgfzfsim. All three hybrid incompatibility genes are chromatin associated factors. While HMR and LHR physically bind each other and function together in a single complex, the connection between either of these proteins andgfzfremains mysterious. Here, we investigate the allele specific chromatin binding patterns ofgfzf. First, our cytological analyses show that there is little difference in protein localization of GFZF between the two species except at telomeric sequences. In particular, GFZF binds the telomeric retrotransposon repeat arrays, and the differential binding of GFZF at telomeres reflects the rapid changes in sequence composition at telomeres betweenD. melanogasterandD. simulans. Second, we investigate the patterns of GFZF and HMR co-localization and find that the two proteins do not normally co-localize inD. melanogaster. However, in inter-species hybrids, HMR shows extensive mis-localization to GFZF sites, and this altered localization requires the presence ofgfzfsim. Third, we find by ChIP-Seq that over-expression of HMR and LHR within species is sufficient to cause HMR to mis-localize to GFZF binding sites, indicating that HMR has a natural low affinity for GFZF sites. Together, these studies provide the first insights into the different properties ofgfzfbetweenD. melanogasterandD. simulansas well as a molecular interaction betweengfzfandHmrin the form of altered protein localization.
OrgaQuant: Intestinal Organoid Localization and Quantification Using Deep Convolutional Neural Networks
Authors: Kassis Timothy , Hernandez-Gordillo Victor , Langer Ronit , Griffith Linda G. 
Published: October 2018

AbstractOrganoid cultures are proving to be powerful in vitro models that closely mimic the cellular constituents of their native tissue. The organoids are typically expanded and cultured in a 3D environment using either naturally derived or synthetic extracellular matrices. Assessing the morphology and growth characteristics of these cultures has been difficult due to the many imaging artifacts that accompany the corresponding images. Unlike single cell cultures, there are no reliable segmentation techniques that allow for the localization and quantification of organoids in their 3D culture environment. Here we describe OrgaQuant, a deep convolutional neural network implementation that can locate and quantify the size distribution of intestinal organoids in brightfield images. OrgaQuant is an end-to-end trained neural network that requires no parameter tweaking, thus it can be fully automated to analyze thousands of images with no user intervention. To develop OrgaQuant we created a unique dataset of manually annotated intestinal organoid images and trained an object detection pipeline using TensorFlow. We have made the dataset, trained model and inference scripts publically available along with detailed usage instructions.
Deep brain stimulation of the nucleus accumbens shell does not decrease cocaine self-administration in cocaine-dependent rats but increases GluR1/GluA1 in the central nucleus of the amygdala
Authors: Kononoff Jenni , Melas Philippe A. , Qvist Johanna S. , Guglielmo Giordano de , Kallupi Marsida , Kandel Eric R. , George Olivier 
Published: October 2018

AbstractBackgroundCocaine addiction is a major public health problem. Despite decades of intense research, no effective treatments are available. Both preclinical and clinical studies of drug addiction strongly suggest that the nucleus accumbens (NAcc) is a viable target for deep brain stimulation (DBS).ObjectiveAlthough previous studies have shown that DBS of the NAcc decreases cocaine seeking and reinstatement, the effects of DBS on cocaine intake in cocaine-dependent animals have not yet been investigated.MethodsRats were made cocaine-dependent by allowing them to self-administer cocaine in long-access sessions (6 h, 0.5 mg/kg/infusion). The effects of high-frequency DBS of the NAcc shell on cocaine intake was then studied. Furthermore, cocaine-induced locomotor activity, irritability-like behavior during cocaine abstinence and the levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits 1 and 2 (GluR1/GluA1 and GluR2/GluA2) after DBS were investigated.ResultsContrary to our expectations, DBS of the NAcc shell induced a slight increase in both cocaine self-administration and cocaine-induced locomotor activity. In addition, 18 h into cocaine withdrawal, we found that DBS decreased irritability-like behavior. We also found that DBS-induced a robust increase in both cytosolic and synaptosomal levels of GluR1, but not GluR2, specifically in the central nucleus of the amygdala but not in other brain regions.ConclusionsThese preclinical results with cocaine-dependent animals do not support high-frequency DBS of the NAcc shell as a therapeutic approach for the treatment of cocaine addiction in active cocaine users. However, the decrease in irritability-like behavior during cocaine abstinence, together with previous findings showing that DBS of the NAcc shell reduces the reinstatement of cocaine seeking in abstinent animals, warrants future investigations of DBS as a treatment for negative emotional states and craving during abstinence.HighlightsHigh-frequency DBS of the NAcc shell for the treatment of cocaine addiction is proposedDBS of the NAcc shell does not decrease cocaine intake in cocaine-dependent ratsDBS increases the level of GluR1 specifically in the central nucleus of the amygdala
TET enzymes augment AID expression via 5hmC modifications at the Aicda superenhancer
Authors: Lio Chan-Wang J. , Shukla Vipul , Samaniego-Castruita Daniela , González-Avalos Edahi , Chakraborty Abhijit , Yue Xiaojing , Schatz David G. , Ay Ferhat , Rao Anjana 
Published: October 2018

AbstractTET enzymes are dioxygenases that promote DNA demethylation by oxidizing the methyl group of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Here we report a close correspondence between 5hmC-marked regions, chromatin accessibility and enhancer activity in B cells, and a strong enrichment for consensus binding motifs for basic region-leucine zipper (bZIP) transcription factors at TET-responsive genomic regions. Functionally, Tet2 and Tet3 regulate class switch recombination (CSR) in murine B cells by enhancing expression of Aicda, encoding the cytidine deaminase AID essential for CSR. TET enzymes deposit 5hmC, demethylate and maintain chromatin accessibility at two TET-responsive elements, TetE1 and TetE2, located within a superenhancer in the Aicda locus. Transcriptional profiling identified BATF as the bZIP transcription factor involved in TET-dependent Aicda expression. 5hmC is not deposited at TetE1 in activated Batf-deficient B cells, indicating that BATF recruits TET proteins to the Aicda enhancer. Our data emphasize the importance of TET enzymes for bolstering AID expression, and highlight 5hmC as an epigenetic mark that captures enhancer dynamics during cell activation.
Suppressor of Fused controls the proliferation of postnatal neural stem and precursor cells via a Gli3-dependent mechanism
Authors: Gomez Hector G. , Castillo Jesse Garcia , Noguchi Hirofumi , Aguilar David , Pleasure Samuel J. , Yabut Odessa R. 
Published: October 2018

ABSTRACTThe ventricular-subventricular zone (V-SVZ) of the forebrain is the source of neurogenic stem/precursor cells for adaptive and homeostatic needs throughout the life of most mammals. Here, we report that Suppressor of Fused (SUFU) plays a critical role in the establishment of the V-SVZ at early neonatal stages by controlling the proliferation of distinct subpopulations of stem/precursor cells. Conditional deletion of Sufu in radial glial progenitor cells (RGCs) at E13.5 resulted in a dramatic increase in the proliferation of Sox2+ Type B cells, as well as Gsx2+ ventral forebrain derived transit amplifying precursor cells (TACs). In contrast, we found a significant decrease in Tbr2+ dorsal forebrain derived TACs indicating that innate differences between dorsal and ventral forebrain derived Type B cells influence Sufu function. However, most precursors failed to survive and accumulated in the dorsal V-SVZ, demonstrating that precursors are unable to transition into functional differentiated progenies. These defects were accompanied by reduced Gli3 expression, yet despite reduced Gli3 levels, activation of Sonic hedgehog (Shh) signaling did not occur implying that the Sufu-Gli3 regulatory axis may influence other signaling pathways in the neonatal dorsal V-SVZ. These data suggest that Sufu plays a critical role in controlling Gli3 function in the establishment and survival of functional stem/precursor cells in the postnatal dorsal V-SVZ.SUMMARY STATEMENTConditional deletion of Sufu cause dramatic expansion of neural stem/precursor cells in the neonatal ventricular-subventricular (SVZ) zone. This defect occurs through a Gli3-dependent mechanism that results in the downregulation of Shh signaling.
ALS mice carrying pathological mutant TDP-43, but not mutant FUS, display axonal transport defects in vivo
Authors: Sleigh James N. , Tosolini Andrew P. , Gordon David , Devoy Anny , Fratta Pietro , Fisher Elizabeth M. C. , Talbot Kevin , Schiavo Giampietro 
Published: October 2018

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease resulting from a complex interplay between genetics and environment. Impairments in the basic neuronal process of axonal transport have been identified in several ALS models. However, in vivo evidence of early/pre-symptomatic deficiencies in neuronal cargo trafficking remains limited, thus the pathogenic importance of axonal transport to the ALS disease spectrum remains to be fully resolved. We therefore analysed the in vivo dynamics of retrogradely transported, neurotrophin-containing signalling endosomes in motor neuron axons of two new mouse models of ALS that have mutations in different RNA processing genes (Tardbp and Fus). TDP-43M337V mice, which show neuromuscular pathology but no overt motor neuron loss, displayed in vivo perturbations in axonal transport that manifested between 1.5 and 3 months and preceded motor symptom onset. In contrast, signalling endosome transport remained largely unaffected in mutant FusΔ14/+ mice, despite 20% motor neuron loss. These findings indicate that deficiencies in retrograde neurotrophin signalling and axonal transport are not common to all ALS-linked genes, and that there are inherent and mechanistic distinctions in the pathogenesis of ALS caused by mutations in different RNA processing genes.
Effect of Dietary Fat on the Metabolism of Energy and Nitrogen, Serum Parameters, Rumen Fermentation, and Microbiota in twin Hu Male Lambs
Authors: Li Wenjuan , Tao Hui , Zhang Naifeng , Ma Tao , Deng Kaidong , Xie Biao , Jia Peng , Diao Qiyu 
Published: October 2018

AbstractBackgroundFat is the main substance that provides energy to animals. However, the use of fat in twin Hu lambs has not been investigated. Thirty pairs of male twin lambs were examined to investigate the effects of dietary fat on the metabolism of energy and nitrogen, ruminal fermentation, and microbial communities. The twins are randomly allotted to two groups (high fat: HF, normal fat: NF). Two diets of equal protein and different fat levels. The metabolism test was made at 50-60 days of age. Nine pairs of twin lambs are slaughtered randomly, and the rumen fluid is collected at 60 days of age.ResultsThe initial body weight (BW) in the HF group did not differ from that of NF group (P > 0.05), but the final BW was tended to higher than that of NF group (0.05 < P < 0.1). The digestive energy (DE), metabolism energy (ME), DE/ME in the HF group tend to be higher than those in the NF group (0.05 < P < 0.1). Ruminal ammonia nitrogen (NH3-N) and the proportion of total volatile fatty acids (TVFA) are higher than that in the NF group (P < 0.05). A high throughput sequencing analysis reveals that there were no differences between the two groups in terms of the richness estimates and diversity indices (P > 0.05). The Proteobacteria and Fibrobacteres phyla were higher than that in NF group (P<0.05).ConclusionsThis study demonstrated that high fat diet before weaning can affect the abundance of several groups of rumen bacteria in rumen, such as significantly increasing phyla Proteobacteria and Fibrobacteres, and genera of Succinivibrio, Alloprevotella, and Saccharofermentans, but significantly decreasing genera of Clostridium IV, Dialister, Roseburia, and Butyrivibrio. And high fat diet improved the performance of lambs at weight gain, energy utilization, and had effect on VFA composition but no effects on serum enzymes and serum hormone.
Building gene regulatory networks from scATAC-seq and scRNA-seq using Linked Self-Organizing Maps
Authors: Jansen Camden , Ramirez Ricardo N. , El-Ali Nicole C. , Gomez-Cabrero David , Tegner Jesper , Merkenschlager Matthias , Conesa Ana , Mortazavi Ali 
Published: October 2018

AbstractRapid advances in single-cell assays have outpaced methods for analysis of those data types. Different single-cell assays show extensive variation in sensitivity and signal to noise levels. In particular, scATAC-seq generates extremely sparse and noisy datasets. Existing methods developed to analyze this data require cells amenable to pseudo-time analysis or require datasets with drastically different cell-types. We describe a novel approach using self-organizing maps (SOM) to link scATAC-seq and scRNA-seq data that overcomes these challenges and can generate draft regulatory networks. Our SOMatic package generates chromatin and gene expression SOMs separately and combines them using a linking function. We applied SOMatic on a mouse pre-B cell differentiation time-course using controlled Ikaros over-expression to recover gene ontology enrichments, identify motifs in genomic regions showing similar single-cell profiles, and generate a gene regulatory network that both recovers known interactions and predicts new Ikaros targets during the differentiation process. The ability of linked SOMs to detect emergent properties from multiple types of highly-dimensional genomic data with very different signal properties opens new avenues for integrative analysis of single-cells.
Accurate characterization of expanded tandem repeat length and sequence through whole genome long-read sequencing on PromethION
Authors: De Roeck Arne , De Coster Wouter , Bossaerts Liene , Cacace Rita , De Pooter Tim , Van Dongen Jasper , D’Hert Svenn , De Rijk Peter , Strazisar Mojca , Van Broeckhoven Christine , Sleegers Kristel 
Published: October 2018

AbstractTandem repeats (TRs) can cause disease through their length, sequence motif interruptions, and nucleotide modifications. For many TRs, however, these features are very difficult - if not impossible - to assess, requiring low-throughput and labor-intensive assays. One example is a VNTR in ABCA7 for which we recently discovered that expanded alleles strongly increase risk of Alzheimer’s disease. Here, we investigated the potential of long-read whole genome sequencing to surmount these challenges, using the high-throughput PromethION platform from Oxford Nanopore Technologies. To overcome the limitations of conventional base calling and alignment, we developed an algorithm to study the TR size and sequence directly on raw PromethION current data.We report the long-read sequencing of multiple human genomes (n = 11) using only a single sequencing run and flow cell per individual. With the use of fresh DNA extractions, DNA shearing to approximately 20kb and size selection, we obtained an average output of 70 gigabases (Gb) per flow cell, corresponding to a 21x genome coverage, and a maximum yield of 98 Gb (30x genome coverage). All ABCA7 VNTR alleles, including expansions up to 10,000 bases, were spanned by long sequencing reads, validated by Southern blotting. Classical approaches of TR length estimation suffered from low accuracy, low precision, DNA strand effects and/or inability to call pathogenic repeat expansions. In contrast, our novel NanoSatellite algorithm, which circumvents base calling by using dynamic time warping on raw PromethION current data, achieved more than 90% accuracy and high precision (5.6% relative standard deviation) of TR length estimation, and detected all clinically relevant repeat expansions. In addition, we identified alternative TR sequence motifs with high consistency, allowing determination of TR sequence and distinction of VNTR alleles with homozygous length.In conclusion, we validated the robustness of single-experiment whole genome long-read sequencing on PromethION, a prerequisite for application of long-read sequencing in the clinic. In addition, we outperformed Southern blotting, enabling improved characterization of the role of expanded ABCA7 VNTR alleles in Alzheimer’s disease, and opening new opportunities for TR research.