bluuebunny/crossref_metadata_2025_split huggingface dataset:
An integrative machine learning approach to discovering multi-level molecular mechanisms of obesity using data from monozygotic twin pairs
Authors: Kibble Milla , Khan Suleiman A. , Ammad-ud-din Muhammad , Bollepalli Sailalitha , Palviainen Teemu , Kaprio Jaakko , Pietiläinen Kirsi H. , Ollikainen Miina 
Published: December 2019

AbstractWe combined clinical, cytokine, genomic, methylation and dietary data from 43 young adult monozygotic twin pairs (aged 22 – 36, 53% female), where 25 of the twin pairs were substantially weight discordant (delta BMI > 3kg/ m2). These measurements were originally taken as part of the TwinFat study, a substudy of The Finnish Twin Cohort study. These five large multivariate data sets (comprising 42, 71, 1587, 1605 and 63 variables, respectively) were jointly analysed using an integrative machine learning method called Group Factor Analysis (GFA) to offer new hypotheses into the multi-molecular-level interactions associated with the development of obesity. New potential links between cytokines and weight gain are identified, as well as associations between dietary, inflammatory and epigenetic factors. This encouraging case study aims to enthuse the research community to boldly attempt new machine learning approaches which have the potential to yield novel and unintuitive hypotheses. The source code of the GFA method is publically available as the R package GFA.
Seroprevalence of the hepatitis E virus among blood donors in the Qassim Region, Saudi Arabia
Authors: Alhatlani Bader Y. , Aljabr Waleed A. , Almarzouqi Mohammed S. , Alhatlani Sami M. , Alzunaydi Rayan N. , Alsaykhan Abeer S. , Almaiman Sulaiman H. , Aleid Ahmed A. , Alsughayir Ammar H. , Bishawri Yara E. , Almusallam Abdulrahman A. 
Published: December 2019

AbstractThe aim of this study was to evaluate the seroprevalence of hepatitis E virus (HEV), a major public health issue worldwide with the potential for transmission via blood transfusion, in blood donors in the Qassim Region, Saudi Arabia. Serum samples (n = 1,078) were collected from volunteer blood donors from January to April 2019 and tested for the presence of anti-HEV IgG and IgM by indirect enzyme-linked immunosorbent assays. Overall, the seroprevalence of anti-HEV IgG and IgM among blood donors was 5.7% and 1.3%, respectively. Additionally, the seropositive rates of anti-HEV IgG and IgM were significantly higher in non-Saudi donors (22.1% and 7.8%) than in Saudi donors (3% and 0.2%). The seroprevalence of anti-HEV IgG increased with age; however, there was no correlation between gender and anti-HEV IgG and/or IgM. The seroprevalence of HEV among blood donors in the Qassim Region was lower than previous estimates for other regions of the country. Further studies covering a wider geographical area are needed to validate and expand the findings and to determine the importance of HEV screening in the region.
Massively parallel, time-resolved single-cell RNA sequencing with scNT-Seq
Authors: Qiu Qi , Hu Peng , Govek Kiya W. , Camara Pablo G. , Wu Hao 
Published: December 2019

ABSTRACTSingle-cell RNA sequencing offers snapshots of whole transcriptomes but obscures the temporal dynamics of RNA biogenesis and decay. Here we present single-cell new transcript tagging sequencing (scNT-Seq), a method for massively parallel analysis of newly-transcribed and pre-existing RNAs from the same cell. This droplet microfluidics-based method enables high-throughput chemical conversion on barcoded beads, efficiently marking metabolically labeled newly-transcribed RNAs with T-to-C substitutions. By simultaneously measuring new and old transcriptomes, scNT-Seq reveals neuronal subtype-specific gene regulatory networks and time-resolved RNA trajectories in response to brief (minutes) versus sustained (hours) neuronal activation. Integrating scNT-Seq with genetic perturbation reveals that DNA methylcytosine dioxygenases may inhibit stepwise transition from pluripotent embryonic stem cell state to intermediate and totipotent two-cell-embryo-like (2C-like) states by promoting global RNA biogenesis. Furthermore, pulse-chase scNT-Seq enables transcriptome-wide measurements of RNA stability in rare 2C-like cells. Time-resolved single-cell transcriptomic analysis thus opens new lines of inquiry regarding cell-type-specific RNA regulatory mechanisms.
Incipient resistance to an effective pesticide results from genetic adaptation and the canalization of gene expression
Authors: Yin Xiaoshen , Martinez Alexander S. , Perkins Abigail , Sparks Morgan M. , Harder Avril M. , Willoughby Janna R. , Sepúlveda Maria S. , Christie Mark R. 
Published: December 2019

AbstractThe resistance of bacteria, disease vectors, and pest species to chemical controls has vast ecological, economic, and societal costs. In most cases, resistance is only detected after spreading throughout an entire population. Detecting resistance in its incipient stages, by comparison, provides time to implement preventative strategies. Incipient resistance can be detected by coupling standard toxicology assays with large-scale gene expression experiments. We apply this approach to a system where an invasive parasite, sea lamprey (Petromyzon marinus), has been treated with the highly-effective pesticide 3-trifluoromethyl-4-nitrophenol (TFM) for 60 years. Toxicological experiments revealed that lamprey from treated populations did not have higher survival to TFM exposure than lamprey from their native range, demonstrating that full-fledged resistance has not yet evolved. In contrast, we find hundreds of genes differentially expressed in response to TFM in the population with the longest history of exposure, many of which relate to TFM’s primary mode of action, the uncoupling of oxidative phosphorylation and subsequent depletion of ATP. Three genes critical to oxidative phosphorylation,ATP5PB, PLCB1, andNDUFA9, were nearly fixed for alternative alleles in comparisons of SNPs between native and treated populations (FST> 5 SD from the mean).ATP5PBencodes subunit b of ATP synthase and an additional subunit,ATP5F1B, was canalized for high expression in treated populations, but remained plastic in response to TFM treatment in individuals from the native range. These combined genomic and transcriptomic results demonstrate that an adaptive, genetic response to TFM is driving incipient resistance in a damaging pest species.
Cell type- and stage-specific expression of Otx2 is coordinated by a cohort of transcription factors and multiplecis-regulatory modules in the retina
Authors: Chan Candace , Lonfat Nicolas , Zhao Rong , Davis Alexander , Li Liang , Wu Man-Ru , Lin Cheng-Hui , Ji Zhe , Cepko Constance L. , Wang Sui 
Published: December 2019

AbstractTranscription factors (TFs) are often used repeatedly during development and homeostasis to control distinct processes in the same and/or different cellular contexts. Considering the limited number of TFs in the genome and the tremendous number of events that need to be regulated, re-use of TFs is an advantageous strategy. However, the mechanisms that control the activation of TFs in different cell types and at different stages of development remain unclear. The neural retina serves as a model of the development of a complex tissue. We used this system to analyze how expression of the homeobox TF, Orthodenticle homeobox 2 (Otx2), is regulated in a cell type- and stage-specific manner during retinogenesis. We identified sevenOtx2 cis-regulatory modules (CRMs), among which the O5, O7 and O9 CRMs mark three distinct cellular contexts of Otx2 expression. These include mature bipolar interneurons, photoreceptors, and retinal progenitor/precursor cells. We discovered that Otx2, Crx and Sox2, which are well-known TFs regulating retinal development, bind to and activate the O5, O7 or O9 CRMs respectively. The chromatin status of these three CRMs was found to be distinct in vivo in different retinal cell types and at different stages, as revealed by ATAC-seq and DNase-seq analyses. We conclude that retinal cells utilize a cohort of TFs with different expression patterns, and multiple CRMs with different chromatin configurations, to precisely regulate the expression of Otx2 in a cell type- and stage-specific manner in the retina.
Interaction of an abiraterone with calf thymus DNA: Investigation with spectroscopic technique and modeling studies
Authors: Wani Tanveer A. , Alsaif Nawaf , Bakheit Ahmed H. , Zargar Seema , Al-Mehizia Abdurrahman A. , Khan Azmat Ali 
Published: December 2019

AbstractBinding of toxic ligands to DNA could result in undesirable biological processes, such as carcinogenesis or mutagenesis. Binding mode of Abiraterone (ABR), a steroid drug and ctDNA(calf thymus DNA was investigated in this study using fluorescence and ultraviolet–visible spectroscopy. The probable prediction of binding and the type of interaction forces involved in the arrangement between ABR and ctDNA were explored through spectroscopic and molecular docking studies. The results indicated the binding of ABR to ctDNA in the minor groove. The binding constants were in the range of 1.35 × 106– 0.36× 106L mol-1at the studied temperatures. Fluorescence and spectrophotometric data suggested static quenching between ctDNA and ABR The endothermic values of thermodynamic parameters ΔH= -82.8 kJ mol−1; ΔS= - 161 J mol−1K−1suggested that hydrogen bonding is the main force involved in binding ctDNA and ABR. In experimental studies the free binding energy at 298K was −34.9 kJ mol−1with the relative binding energy ≈ −29.65 kJ mol−1of docked structure. The Ksv obtained for ABR-KI was similar to that for ABR-ctDNA -KI demonstrating no protection by ctDNA against quenching effect of KI. Thus, suggesting involvement of groove binding between ABR and ctDNA. No change in the fluorescence intensity of ABR-ctDNA was observed in presence of NaCl. Thus, ruling out the involvement of electrostatic interaction. These studies could serve as new insights in understanding the mechanisms of toxicity, resistance and side effects of ABR.
Low costs of adaptation to dietary restriction
Authors: Moger-Reischer Roy Z. , Snider Elizabeth V. , McKenzie Kelsey L. , Lennon Jay T. 
Published: December 2019

ABSTRACTDietary restriction (DR) is the most successful and widespread means of extending organismal lifespan. However, the evolutionary basis of life extension under DR remains uncertain. The traditional evolutionary explanation is that when organisms experience DR, they allocate endogenous resources to survival and postpone reproduction until conditions improve. However, this life-extension strategy should be maladaptive if DR continues for multiple generations due to tradeoffs between longevity and reproduction. To test this prediction, we subjected the budding yeastSaccharomyces cerevisiaeto 1,800 generations of evolution on restricted (i.e., DR) vs. non-restricted diets. Adaptation to a non-restricted diet improved reproductive fitness by 57% on that diet, but provided a much smaller (14%) advantage on a restricted diet. In contrast, adaptation to DR resulted in an approximately 35% increase in reproductive fitness on both restricted and non-restricted diets. Importantly, the life-extending effect of DR did not decrease following long-term evolution on the restricted diet. Thus, contrary to theoretical expectations, we found no evidence that the life-extending DR response became maladaptive during multigenerational DR. Our results suggest the DR response may have a low cost and that this phenomenon may have evolved for reasons that extend beyond the benefits of postponing reproduction.
Distinct evolutionary trajectories of V1R clades across mouse species
Authors: Miller Caitlin H , Campbell Polly , Sheehan Michael J 
Published: December 2019

ABSTRACTBackgroundMany animals rely heavily on olfaction to navigate their environment. Among rodents, olfaction is crucial for a wide range of social behaviors. The vomeronasal olfactory system in particular plays an important role in mediating social communication, including the detection of pheromones and recognition signals. Currently, very few vomeronasal receptors have known ligands, which severely limits our understanding of chemosensory-driven social communication. In this study we examine patterns of vomeronasal type-1 receptor (V1R) evolution in the house mouse and related species within the genusMus. By exploring the evolution of these receptors, we provide insight into the functional roles of receptor subtypes as well as the dynamics of gene family evolution.ResultsWe generated transcriptomes from the vomeronasal organs of 5Musspecies, and produced high quality V1R repertoires for each species. We find that V1R clades in the house mouse and relatives exhibit distinct evolutionary trajectories. Some clades are highly conserved, while others reveal patterns of rapid evolutionary change. We identify putative species-specific gene expansions, including a dramatic clade D expansion in the house mouse. While gene gains are abundant, we detect very few gene losses. We describe a novel V1R clade and highlight candidate receptors for future de-orphanization. Based on clade-level evolutionary patterns, we identify receptor families that are strong candidates for detecting social signals and predator cues. Our results further support the view that V1Rs are important for detecting the physiological status of conspecifics, particularly female estrus cues.ConclusionAnalysis of clade-level evolution is critical for understanding species’ chemosensory adaptations. This study provides clear evidence that V1R clades are characterized by distinct evolutionary trajectories. As receptor evolution is shaped by ligand identity, these results provide a framework for examining the functional roles of different receptors.
Personalized genealogical history inferred from biobank-scale IBD segments
Authors: Naseri Ardalan , Tang Kecong , Geng Xin , Shi Junjie , Zhang Jing , Liu Xiaoming , Zhang Shaojie , Zhi Degui 
Published: December 2019

AbstractWhen modern biobanks collect genotype information for a significant fraction of a population, dense genetic connections of a person can be traced using identity by descent (IBD) segments. These connections offer opportunities to characterize individuals in the context of the underlying populations. Here, we conducted an individual-centric analysis of IBDs among the UK Biobank participants that represent 0.7% of the UK population. On average, one UK individual shares IBDs over 5 cM with 14,000 UK Biobank participants, which we refer to as “cousins”. Using these segments, approximately 80% of a person’s genome can be reconstructed. Also, using changes of cousin counts sharing IBDs at different lengths, we identified a group, potentially British Jews, who has a distinct pattern of familial expansion history. Finally, using the enrichment of cousins in one’s neighborhood, we identified regional variations of personal preference favoring living closer to one’s extended families. In summary, our analysis revealed genetic makeup, personal genealogical history, and social behaviors at population scale, opening possibilities for further studies of individual’s genetic connections in biobank data.
Single molecule studies reveal that p53 tetramers dynamically bind response elements containing one or two half sites
Authors: Ly Elina , Kugel Jennifer F. , Goodrich James A. 
Published: December 2019

AbstractThe tumor suppressor protein p53 is at the nexus of cell fate decisions, including apoptosis, senescence, and cell cycle arrest. p53 is a tetrameric transcription factor that binds to DNA response elements to regulate transcription of its target genes, a process activated by cellular stress. p53 response elements consist of two decameric half-sites, and most data suggest one p53 dimer in the tetramer binds to each half-site. Despite a broad literature describing p53 binding to DNA, unanswered questions remain, due in part to the need for more quantitative and structural studies with the full length protein. Here we describe a single molecule fluorescence system to visualize full length p53 tetramers binding to DNA in real time. The data reveal a dynamic interaction with many p53 binding and dissociation events occurring on single DNA molecules over minutes. We found that p53 tetramers bound to response elements containing only a single half site. The kinetic stability of tetramer/DNA complexes depended on the number of half sites and the helical phasing between them, with the most stable complexes forming on DNA containing two adjacent half sites. The forward rate of binding was not strongly impacted when one half site was mutated. These studies provide real time kinetic measurements of full length p53 tetramers binding to single molecules of DNA, and reveal new insight into the mechanisms by which this nucleoprotein complex forms.
Learning steers the ontogeny of an efficient hunting sequence in zebrafish larvae
Authors: Lagogiannis Konstantinos , Diana Giovanni , Meyer Martin P 
Published: December 2019

AbstractThe success of goal-directed behaviours relies on the coordinated execution of a sequence of component actions. In young animals, such sequences may be poorly coordinated, but with age and experience, behaviour progressively adapts to efficiently exploit the animal’s ecological niche. How experience impinges on the developing neural circuits of behaviour is an open question. As a model system, larval zebrafish (Danio rerio) hold enormous potential for studying both the development of behaviour and the underlying circuits, but no relevant experience-dependent learning paradigm has yet been characterized. To address this, we have conducted a detailed study of the effects of experience on the ontogeny of hunting behaviour in larval zebrafish. We report that larvae with prior prey experience consume considerably more prey than naive larvae. This is mainly due to increased capture success that is also accompanied by a modest increase in hunt rate. We identified two components of the hunting sequence that are jointly modified by experience. At the onset of the hunting sequence, the orientation strategy of the turn towards prey is modified such that experienced larvae undershoot prey azimuth. Near the end of the hunt sequence, we find that experienced larvae are more likely to employ high-speed capture swims initiated from longer distances to prey. Combined, these modified turn and capture manoeuvrers can be used to predict the probability of capture success and suggest that their development provides advantages specific to larvae feeding on live-prey. Our findings establish an ethologically relevant paradigm in zebrafish for studying how the brain is shaped by experience to drive the ontogeny of efficient behaviour.
Short-term Effects of Vagus Nerve Stimulation on Learning and Evoked Activity in Auditory Cortex
Authors: Lai Jesyin , David Stephen V. 
Published: December 2019

ABSTRACTChronic vagus nerve stimulation (VNS) can facilitate learning of sensory and motor behaviors. VNS is believed to trigger release of neuromodulators, including norepinephrine and acetylcholine, which can mediate cortical plasticity associated with learning. Most previous work has studied effects of VNS over many days, and less is known about how acute VNS influences neural coding and behavior over the shorter term. To explore this question, we measured effects of VNS on learning of an auditory discrimination over 1-2 days. Ferrets implanted with cuff electrodes on the vagus nerve were trained by classical conditioning on a tone frequency-reward association. One tone was associated with reward while another tone, was not. The frequencies and reward associations of the tones were changed every two days, requiring learning of a new relationship. When the tones (both rewarded and non-rewarded) were paired with VNS, rates of learning increased on the first day following a change in reward association. To examine VNS effects on auditory coding, we recorded single- and multi-unit neural activity in primary auditory cortex (A1) of passively listening animals following brief periods of VNS (20 trials/session) paired with tones. Because afferent VNS induces changes in pupil size associated with fluctuations in neuromodulation, we also measured pupil during recordings. After pairing VNS with a neuron’s best-frequency (BF) tone, responses in a subpopulation of neurons were reduced. Pairing with an off-BF tone or performing VNS during the inter-trial interval had no effect on responses. We separated the change in A1 activity into two components, one that could be predicted by fluctuations in pupil and one that persisted after VNS and was not accounted for by pupil. The BF-specific reduction in neural responses remained, even after regressing out changes that could be explained by pupil. In addition, the size of VNS-mediated changes in pupil predicted the magnitude of persistent changes in the neural response. This interaction suggests that changes in neuromodulation associated with arousal gate the long-term effects of VNS on neural activity. Taken together, these results support a role for VNS in auditory learning and help establish VNS as a tool to facilitate neural plasticity.
Inhibitory control of active expiration by the Bötzinger complex in rats
Authors: Flor Karine C. , Barnett William H. , Karlen-Amarante Marlusa , Molkov Yaroslav , Zoccal Daniel B. 
Published: December 2019

ABSTRACTThe expiratory neurons of the Bötzinger complex (BötC) provide inhibitory inputs to the respiratory network, which, during eupnea, are critically important for respiratory phase transition and duration control. Herein, we investigated how the BötC neurons interact with the expiratory oscillator located in the parafacial respiratory group (pFRG) and control the abdominal activity during active expiration. Using the decerebrated, arterially perfusedin siturat preparations, we recorded the neuronal activity and performed pharmacological manipulations of the BötC and pFRG during hypercapnia or after the exposure to short-term sustained hypoxia – conditions that generate active expiration. The experimental data were integrated in a mathematical model to gain new insights in the inhibitory connectome within the respiratory central pattern generator. Our results reveal a complex inhibitory circuitry within the BötC that provides inhibitory inputs to the pFRG thus restraining abdominal activity under resting conditions and contributing to abdominal expiratory pattern formation during active expiration.