bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maternal exposure to a mitochondrial toxicant results in life-long alterations in DNA methylation and gene expression in the offspring
Authors: Lozoya Oswaldo A. , Xu Fuhua , Grenet Dagoberto , Wang Tianyuan , Grimm Sara A. , Godfrey Veronica G. , Waidyanatha Suramya , Woychik Richard P. , Santos Janine H. 
Published: September 2019

AbstractMitochondrial-driven alterations of the epigenome have been reported but whether they are relevant at the organismal level remain unknown. The viable yellow agouti mouse (Avy) is a powerful epigenetic biosensor model that reports on the DNA methylation status of theAvylocus through the coat color of the animals. Here we show that maternal exposure to rotenone, a potent mitochondrial complex I inhibitor, changes the DNA methylation status of theAvylocus and broadly affects the liver DNA methylome of the offspring. These effects were accompanied by altered gene expression programs that persisted throughout life. Mitochondrial dysfunction was present in the mothers but not in the offspring until 12 months of age, when electron transport and antioxidant defenses were impaired. These results highlight a putative novel role for mitochondria in nuclear epigenetic remodeling during development, raising fundamental questions about the long-term impact of mitochondrial dysfunction to health and disease.
On the relative ease of speciation with periodic gene flow
Authors: Linck Ethan , Battey C.J. 
Published: September 2019

AbstractCommon models of speciation with gene flow consider constant migration or admixture on secondary contact, but earth’s recent climatic history suggests many populations have experienced cycles of isolation and contact over the last million years. How does this process impact the rate of speciation, and how much can we learn about its dynamics by analyzing the genomes of modern populations? Here we develop a simple model of speciation through Bateson-Dobzhansky-Muller incompatibilities in the face of periodic gene flow and validate our model with forward time simulations. We then use empirical atmosphericCO2concentration data from the Vostok Ice Cores to simulate cycles of isolation and secondary contact in a tropical montane landscape, and ask whether they can be distinguished from a standard isolation-with-migration model by summary statistics or joint site frequency spectrum-based demographic inference. We find speciation occurs much faster under periodic than constant gene flow with equivalent effective migration rates (Nm). These processes can be distinguished through combinations of summary statistics or demographic inference from the site frequency spectrum, but parameter estimates appear to have little resolution beyond the most recent cycle of isolation and migration. Our results suggest speciation with periodic gene flow is a common force in generating species diversity through Pleistocene climate cycles, and highlight the limits of current inference techniques for demographic models mimicking the complexity of earth’s recent climatic history.
Direct anabolic three carbon metabolism via propionate to a six carbon metabolite occurs in human heart and in vivo across mouse tissues
Authors: Doan Mary T. , Neinast Michael D. , Varner Erika L , Bedi Kenneth , Bartee David , Jiang Helen , Trefely Sophie , Xu Peining , Singh Jay P , Jang Cholsoon , Rame Eduardo , Brady Donita , Meier Jordan L. , Marguiles Kenneth , Arany Zoltan , Snyder Nathaniel W. 
Published: September 2019

AbstractAnabolic metabolism of carbon in mammals is mediated via the one and two carbon carriers S-adenosyl methionine and acetyl-coenzyme A (acetyl-CoA). In contrast, anabolic metabolism using three carbon units via propionate is not thought to occur. Mammals are primarily thought to oxidize the 3-carbon short chain fatty acid propionate by shunting propionyl-CoA to succinyl-CoA for entry into the TCA cycle. We found that this may not be absolute and that in mammals one non-oxidative fate of two units of propionyl-CoA is to condense to a six-carbon trans-2-methyl-2-pentenoyl-CoA (2M2PE-CoA). We confirmed this pathway using purified protein extracts provided limited substrates and confirmed the product with a synthetic standard. In whole-bodyin vivostable isotope tracing with infusion of13C-labeled valine achieving steady state, 2M2PE-CoA formed via propionyl-CoA in multiple murine tissues including heart, kidney, and to a lesser degree in brown adipose tissue, liver, and tibialis anterior muscle. Usingex vivoisotope tracing, we found that 2M2PE-CoA formed in human myocardial tissue incubated with propionate to a limited extent. While the complete enzymology of this pathway remains to be elucidated, these results confirm thein vivoexistence of at least one anabolic three to six carbon reaction conserved in humans and mice that utilizes three carbons via propionate.Highlights- Synthesis and confirmation of structure 2-methyl-2-pentenoyl-CoA-In vivofate of valine across organs includes formation of a 6-carbon metabolite from propionyl-CoA-Ex vivometabolism of propionate in the human heart includes direct anabolism to a 6-carbon product- In both cases, this reaction occurred at physiologically relevant concentrations of propionate and valine-In vitrothis pathway requires propionyl-CoA and NADH/NADPH as substrates
Oropouche virus detection in saliva and urine
Authors: do Nascimento Valdinete Alves , Santos João Hugo Abdalla , da Silva Monteiro Dana Cristina , Pessoa Karina Pinheiro , Cardoso Antonio José Leão , de Souza Victor Costa , Abdalla Ligia Fernandes , Naveca Felipe Gomes 
Published: September 2019

AbstractOropouche virus (OROV) is an arthropod-borne virus of the Peribunyaviridae family, transmitted to humans primarily by Culicoides paraensis. It is one of the main arboviruses that infect humans in Brazil, mainly in the Amazon region. We report the OROV detection in the saliva and urine five days after the symptom’s onset. Results were further confirmed by nucleotide sequencing and phylogenetic analysis. To our knowledge, this is the first report that OROV may be detected in the saliva and urine of infected patients. In addition, our results may contribute to the current knowledge regarding the natural history of Oropouche fever.
Polygenic Risk Scores for Cardio-renal-metabolic Diseases in the Penn Medicine Biobank
Authors: Kember R.L. , Verma A. , Verma S. , Lucas A. , Judy R. , Chen J. ,   Regeneron Genetics Center, Damrauer S. , Rader D.J. , Ritchie M.D. 
Published: September 2019

AbstractCardio-renal-metabolic (CaReMe) conditions are common and the leading cause of mortality around the world. Genome-wide association studies have shown that these diseases are polygenic and share many genetic risk factors. Identifying individuals at high genetic risk will allow us to target prevention and treatment strategies. Polygenic risk scores (PRS) are aggregate weighted counts that can demonstrate an individual’s genetic liability for disease. However, current PRS are often based on European ancestry individuals, limiting the implementation of precision medicine efforts in diverse populations. In this study, we develop PRS for six diseases and traits related to cardio-renal-metabolic disease in the Penn Medicine Biobank. We investigate their performance in both European and African ancestry individuals, and identify genetic and phenotypic overlap within these conditions. We find that genetic risk is associated with the primary phenotype in both ancestries, but this does not translate into a model of predictive value in African ancestry individuals. We conclude that future research should prioritize genetic studies in diverse ancestries in order to address this disparity.
SRPK3 regulates alternative pre-mRNA splicing required for B lymphocyte development and humoral responsiveness
Authors: Arends Tessa , Taliaferro J. Matthew , Peterman Eric , Knapp Jennifer R. , O’Connor Brian P. , Torres Raul M. , Hagman James R. 
Published: September 2019

AbstractAlternative splicing (AS) of pre-mRNA is a critical component of transcriptional regulation that diversifies the cellular proteome. The Serine-Arginine Protein Kinases (SRPK) initiate early events in AS. Using conditional knockout mice (cKO), we demonstrated the importance of the X-linked geneSrpk3in B lymphocyte development and in response to immunization in vivo. Significantly decreased numbers of immature and mature B cells were observed inSrpk3-cKOBM relative to wild-type (WT). Immunization ofSrpk3-cKOmice with a T lymphocyte-independent type-2 antigen elicited greatly reduced amounts of specific IgG3.Srpk3deletion resulted in hundreds of differentially spliced mRNAs in B cells, including mRNAs encoding proteins associated with signaling pathways and mitochondrial function. Several alternative splicing outcomes inSrpk3-cKOcells are due to altered splicing regulation of SR proteins. We conclude thatSrpk3is an immunomodulatory kinase that controls humoral immunity via its regulation of pre-mRNA splicing, antibody production, and metabolism in B cells.One Sentence SummarySRPK3 regulates alternative splicing of pre-mRNA that is crucial for B cell development, activation and antibody responses.
Approximating complex musculoskeletal biomechanics using multidimensional autogenerating polynomials
Authors: Sobinov Anton , Boots Matthew , Gritsenko Valeriya , Fisher Lee E. , Gaunt Robert A. , Yakovenko Sergiy 
Published: September 2019

AbstractComputational models of the musculoskeletal system are scientific tools used to study human movement, quantify the effects of injury and disease, and plan surgical interventions. Additionally, these models could also be used to intuitively link biological control signals and realistic high-dimensional articulated prosthetic limbs. However, implementing fast and accurate musculoskeletal computations that can be used to control a prosthetic limb in real-time is a challenging problem. As muscles typically span multiple joints, the wrapping over complex geometrical constraints changes their moment arms and length as a function of joint angle and, thus, their ability to generate joint torques. As a result of these biomechanical complexities, calculating these muscle state variables in real-time is a difficult simulation problem. Here, we report a method to accurately and efficiently calculate these variables for the forearm muscles that actuate the hand and wrist across multiple postures. The posture dependent muscle geometry, moment arms and lengths of modeled muscles, were captured using autogenerating polynomials that expanded their optimal selection of terms using information measurements. The iterative process approximated 33 musculotendon actuators, each spanning up to 6 DOFs in an 18 DOF model of the human arm and hand, defined over the full physiological range of motion. Using these polynomials, the entire forearm anatomy could be computed in <10 µs, which is far better than what is required for real-time performance, and with low errors in moment arms (below 5%) and lengths (below 0.4%). Moreover, we demonstrate that the number of elements in these autogenerating polynomials does not increase exponentially with the increase in complexity of muscles, increasing linearly instead. The similar structure and function of muscles are represented with specific invariant polynomial terms. Dimensionality reduction using the polynomial terms alone resulted in clusters comprised of muscles with similar functions, suggesting that the polynomials themselves captured biologically relevant features of muscle structure and function. We propose that this novel method of describing musculoskeletal biomechanics might further improve the applications of detailed and scalable models for the description of human movement.
PeSA: A Software Tool for Peptide Specificity Analysis
Authors: Topcu Emine , Biggar Kyle K. 
Published: September 2019

ABSTRACTThe discovery of molecular interactions is crucial towards a better understanding of complex biological functions. Particularly protein-protein interactions (i.e., PPIs), which are responsible for a variety of cellular functions from epigenetic modifications to enzyme-substrate specificity, have been studied extensively over the past decades. Position-specific scoring matrices (PSSM) in particular are used extensively to help determine interaction specificity or candidate interaction motifs. However, not all studies successfully report their results as a candidate interaction motif. In many cases, this is the result of a lack of analysis tools for simple analysis and motif generation. Peptide Specificity Analyst (PeSA) is developed with the goal of filling this gap and providing an analysis software to aid peptide array analysis and subsequent motif generation. PeSA utilizes two models of motif creation: (1) frequency-based using a peptide list, and (2) weight-based using a quantified matrix. The ability to generate motifs effortlessly will make analyzing, interpreting and sharing peptide specificity study results in a simple and straightforward process.GRAPHICAL ABSTRACTHIGHLIGHTSBiological motifs are widely used representations for peptide specificity analysis.PeSA populates a list of peptides matching a set threshold from a quantified matrix.Frequency-based motif using a peptide list to spot residue patterns.Use of quantified matrices to create weight-based motifs using residue positions.
Pre- and post-sequencing recommendations for functional annotation of human fecal metagenomes
Authors: Treiber Michelle L. , Taft Diana H. , Korf Ian , Mills David A. , Lemay Danielle G. 
Published: September 2019

AbstractBackgroundShotgun metagenomes are often assembled prior to annotation of genes which biases the functional capacity of a community towards its most abundant members. For an unbiased assessment of community function, short reads need to be mapped directly to a gene or protein database. The ability to detect genes in short read sequences is dependent on pre- and post-sequencing decisions. The objective of the current study was to determine how library size selection, read length and format, protein database, e-value threshold, and sequencing depth impact gene-centric analysis of human fecal microbiomes when using DIAMOND, an alignment tool that is up to 20,000 times faster than BLASTX.ResultsUsing metagenomes simulated from a database of experimentally verified protein sequences, we find that read length, e-value threshold, and the choice of protein database dramatically impact detection of a known target, with best performance achieved with longer reads, stricter e-value thresholds, and a custom database. Using publicly available metagenomes, we evaluated library size selection, paired end read strategy, and sequencing depth. Longer read lengths were acheivable by merging paired ends when the sequencing library was size-selected to enable overlaps. When paired ends could not be merged, a congruent strategy in which both ends are independently mapped was acceptable. Sequencing depths of 5 million merged reads minimized the error of abundance estimates of specific target genes, including an antimicrobial resistance gene.ConclusionsShotgun metagenomes of DNA extracted from human fecal samples sequenced using the Illumina platform should be size-selected to enable merging of paired end reads and should be sequenced in the PE150 format with a minimum sequencing depth of 5 million merge-able reads to enable detection of specific target genes. Expecting the merged reads to be 180-250bp in length, the appropriate e-value threshold for DIAMOND would then need to be more strict than the default. Accurate and interpretable results for specific hypotheses will be best obtained using small databases customized for the research question.
Acetylcholine modulates cerebellar granule cell spiking by regulating the balance of synaptic excitation and inhibition
Authors: Fore Taylor R. , Taylor Nathan , Brunel Nicolas , Hull Court 
Published: September 2019

AbstractSensorimotor integration in the cerebellum is essential for refining motor output, and the first stage of this processing occurs in the granule cell layer. Recent evidence suggests that granule cell layer synaptic integration can be contextually modified, though the circuit mechanisms that could mediate such modulation remain largely unknown. Here we investigate the role of Acetylcholine (ACh) in regulating granule cell layer synaptic integration. We find that Golgi cells, interneurons that provide the sole source of inhibition to the granule cell layer, express both nicotinic and muscarinic cholinergic receptors. While acute ACh application can modestly depolarize some Golgi cells, the net effect of longer, optogenetically induced ACh release is to strongly hyperpolarize Golgi cells. Golgi cell hyperpolarization by ACh leads to a significant reduction in both tonic and evoked granule cell synaptic inhibition. ACh also reduces glutamate release from mossy fibers by acting on presynaptic muscarinic receptors. Surprisingly, despite these consistent effects on Golgi cells and mossy fibers, ACh can either increase or decrease the spike probability of granule cells as measured by non-invasive cell attached recordings. By constructing an integrate and fire model of granule cell layer population activity, we find that the direction of spike rate modulation can be accounted for predominately by the initial balance of excitation and inhibition onto individual granule cells. Together, these experiments demonstrate that ACh can modulate population-level granule cell responses by altering the ratios of excitation and inhibition at the first stage of cerebellar processing.Significance StatementThe cerebellum plays a key role in motor control and motor learning. While it is known that behavioral context can modify motor learning, the circuit basis of such modulation has remained unclear. Here we find that a key neuromodulator, Acetylcholine (ACh), can alter the balance of excitation and inhibition at the first stage of cerebellar processing. These results suggest that ACh could play a key role in altering cerebellar learning by modifying how sensorimotor input is represented at the input layer of the cerebellum.
Hybridizing salamanders experience accelerated diversification
Authors: Patton Austin H. , Margres Mark J. , Epstein Brendan , Eastman Jon , Harmon Luke J. , Storfer Andrew 
Published: September 2019

ABSTRACTWhether hybridization generates or erodes species diversity has long been debated, but to date most studies have been conducted at small taxonomic scales. Salamanders (order Caudata) represent a taxonomic order in which hybridization plays a prevalent ecological and evolutionary role. We employed a recently developed model of trait-dependent diversification to test the hypothesis that hybridization impacts the diversification dynamics of species that are currently hybridizing. We find strong evidence supporting this hypothesis, showing that hybridizing salamander lineages have significantly greater net-diversification rates than non-hybridizing lineages. This pattern is driven by concurrently increased speciation rates and decreased extinction rates in hybridizing lineages. Our results support the hypothesis that hybridization can act as a generative force in macroevolutionary diversification.
Admistration of Exogenous Melatonin Improves the Diurnal Rhythms of Gut Microbiota in High Fat Diet-Fed Mice
Authors: Yin Jie , Li Yuying , Han Hui , Liu Gang , Wu Xin , Huang Xingguo , Fang Rejun , Baba Kenkichi , Bin Peng , Zhu Guoqiang , Ren Wenkai , Tan Bie , Tosini Gianluca , He Xi , Li Tiejun , Yin Yulong 
Published: September 2019

AbstractMelatonin, a circadian hormone, has been reported to improve host lipid metabolism by reprogramming gut microbiota, which also exhibits rhythmicity in a light/dark cycle. However, the effect of admistartion of exogenous melatonin on the diurnal variation in gut microbiota in high fat diet (HFD)-fed mice is obscure. Here, we further confirmed the anti-obesogenic effect of melatonin on in mice feed with HFD for two weeks. Samples were collected every 4 h within a 24-h period and diurnal rhythms of clock genes expression (Clock, Cry1, Cry2, Per1, and Per2) and serum lipid indexes varied with diurnal time. Notably, Clock and triglycerides (TG) showed a marked rhythm only in the control and melatonin treated mice, but not in the HFD-fed mice. Rhythmicity of these parameters were similar between control and melatonin treated HFD mice compared with the HFD group, indicating an improvement of melatonin in the diurnal clock of host metabolism in HFD-fed mice. 16S rDNA sequencing showed that most microbiota exhibited a daily rhythmicity and the trends differentiated at different groups and different time points. We also identified several specific microbiota correlating with the circadian clock genes and serum lipid indexes, which might contribute the potential mechanism of melatonin in HFD-fed mice. Interestingly, administration of exogenous melatonin only at daytime exhibited higher resistance to HFD-induced lipid dysmetabolism than nighttime treatment companying with altered gut microbiota (Lactobacillus, Intestinimonas, and Oscillibacter). Importantly, the responses of microbiota transplanted mice to HFD feeding also varied at different transplanting times (8:00 and 16:00) and different microbiota donors. In summary, daily oscillations in the expression of circadian clock genes, serum lipid indexes, and gut microbiota, appears to be driven by a short-time feeding of an HFD. Administration of exogenous melatonin improved the compositions and diurnal rhythmicity of gut microbiota, which might be linked to host diurnal rhythm and metabolism.ImportancePrevious studies show that a circadian hormone, melatonin, involves in host lipid metabolism by reprogramming gut microbiota, which also exhibits rhythmicity in a light/dark cycle. However, the effect of melatonin drinking on the diurnal variation in gut microbiota in high fat diet-fed mice is obscure. Here, we found that 24-h oscillations were widely occurred in circadian clock genes, serum lipid indexes, and gut microbiota. Melatonin drinking improved the compositions and circadian rhythmicity of gut microbiota, which might be linked to host circadian rhythm and metabolism.
α-synuclein in the retina leads to degeneration of dopamine amacrine cells impairing vision
Authors: Elena Marrocco , Federica Esposito , Valeria Tarallo , Anna Carboncino , Grazia Alvino Filomena , Sandro De Falco , Brunella Franco , Maria De Risi , Indrieri Alessia , Maria Surace Enrico , Elvira De Leonibus 
Published: September 2019

AbstractIntroductionα-synuclein aggregates have been identified in the retina of Parkinson’s disease patients associated to vision impairment. In this study, we sought to determine the effects of α-synuclein overexpression on the survival and function of dopaminergic (DA) amacrine cells in the retina.MethodsAdult mice were intravitreally injected with an adeno-associated viral (AAV) vector to overexpress human wild-type α-synuclein in the inner retina. Following systemic injections of levodopa (L-DOPA), retinal responses and visual acuity driven behavior were measured by electroretinography (ERG) and water maze task, respectively. Amacrine cells and ganglion cells were counted at 1, 2 and 3 months post-injection.Resultsα-synuclein led to an early loss of DA cells, which was associated with the decrease of light-adapted ERG responses and visual acuity. Systemic injections of L-DOPA rescued these retinal and visual abnormalities.ConclusionsThe data show that α-synuclein affects dopamine neurons in the retina. The approach provides a novel accessible mode of modeling the underlying mechanisms implicated in synucleinophaties pathogenesis and for testing novel treatments.