bluuebunny/crossref_metadata_2025_split huggingface dataset:
CardioPy: An open-source heart rate variability toolkit for single-lead EKG
Authors: Gottshall Jackie L. , Recoder Natasha , Schiff Nicholas D. 
Published: October 2020

ABSTRACTBackground and ObjectiveHeart rate variability (HRV) is a promising clinical marker of health and disease. Although HRV methodology is relatively straightforward, accurate detection of R-peaks remains a significant methodological challenge; this is especially true for single-lead EKG signals, which are routinely collected alongside EEG monitoring and for which few software options exist. Most developed algorithms with favorable R-peak detection profiles require significant mathematical and computational proficiency for implementation, providing a significant barrier for clinical research. Our objective was to address these challenges by developing a simple, free, and open-source software package for HRV analysis of single-lead EKG signals.MethodsCardioPy was developed in python and optimized for short-term (5-minute) single-lead EKG recordings. CardioPy’s R-peak detection trades full automation and algorithmic complexity for an adaptive thresholding mechanism, manual artifact removal and parameter adjustment. Standard time and frequency domain analyses are included, such that CardioPy may be used as a stand-alone HRV analysis package. An example use-case of HRV across wakefulness and sleep is presented and results validated against the widely used Kubios HRV software.ResultsHRV analyses were conducted in 66 EKG segments collected from five healthy individuals. Parameter optimization was conducted or each segment, requiring ~1-3 minutes of manual inspection time. With optimization, CardioPy’s R-peak detection algorithm achieved a mean sensitivity of 100.0% (SD 0.05%) and positive predictive value of 99.8% (SD 0.20%). HRV results closely matched those produced by Kubios HRV, both by eye and by quantitative comparison; CardioPy power spectra explained an average of 99.7% (SD 0.50%) of the variance present in Kubios spectra. HRV analyses showed significant group differences between brain states; SDNN, low frequency power, and low frequency-to-high frequency ratio were reduced in slow wave sleep compared to wakefulness.ConclusionsCardioPy provides an accessible and transparent tool for HRV analyses. Manual parameter optimization and artifact removal allow granular control over data quality and a highly reproducible analytic pipeline, despite additional time requirements. Future versions are slated to include automatic parameter optimization and a graphical user interface, further reducing analysis time and improving accessibility.
Systemic benefits of Gc inhibition to preserve insulin sensitivity
Authors: Kuo Taiyi , Accili Domenico 
Published: October 2020

ABSTRACTType 2 diabetes is caused by an imbalanced supply and demand of insulin. Insulin resistance and impaired β-cell function contribute to the onset of hyperglycemia. No single treatment modality can affect both aspects of diabetes pathophysiology. Thus, current treatments focus either on increasing insulin secretion (incretin mimetics, sulfonylureas) or insulin sensitivity (metformin and TZD), or reducing hyperglycemia (insulin, sglt2i). Previously, we reported that ablation ofGc, encoding a secreted protein with a primary role in vitamin D transport, improves pancreatic β-cell function in models of diet-induced insulin resistance. Here, we show thatGcablation has systemic insulin-sensitizing effects to prevent weight gain, hyperglycemia, glucose intolerance, and lower NEFA and triglyceride in mice fed a high-fat diet. Hyperinsulinemic-euglycemic clamps show that Gc ablation protects insulin’s ability to reduce hepatic glucose production, and increases glucose uptake in skeletal muscle and adipose tissue. Moreover, acute Gc inhibition by way of adeno-associated virus encoding a short hairpin RNA to promote Gc mRNA degradation, prevents glucose intolerance caused by high fat feeding. The data suggest that Gc inhibition can provide an approach to increase insulin production in β-cells, and insulin action in peripheral tissues.RESEARCH IN CONTEXT▪ The goal was to find a therapeutic target that can improve insulin sensitivity and β-cell function simultaneously.▪ Gc ablation preserves β-cell insulin secretionex vivoandin vivo.▪ Deletion of Gc prevents weight gain, reduces fat mass, lowers fasting glycemia, improves glucose tolerance, reduces hepatic glucose production after feeding, and increased glucose uptake in muscle and adipose.▪ Acute Gc inhibition improves glucose tolerance, which suggests that targeting Gc could provide an alternative way to treat type 2 diabetes.
De novostructural mutation rates and gamete-of-origin biases revealed through genome sequencing of 2,396 families
Authors: Belyeu Jonathan R. , Brand Harrison , Wang Harold , Zhao Xuefang , Pedersen Brent S. , Feusier Julie , Gupta Meenal , Nicholas Thomas J. , Baird Lisa , Devlin Bernie , Sanders Stephan J. , Jorde Lynn B. , Talkowski Michael E. , Quinlan Aaron R. 
Published: October 2020

AbstractEach human genome includesde novomutations that arose during gametogenesis. While these germline mutations represent a fundamental source of new genetic diversity, they can also create deleterious alleles that impact fitness. The germline mutation rate for single nucleotide variants and factors that significantly influence this rate, such as parental age, are now well established. However, far less is known about the frequency, distribution, and features that impactde novostructural mutations. We report a large, family-based study of germline mutations, excluding aneuploidy, that affect genome structure among 572 genomes from 33 families in a multigenerational CEPH-Utah cohort and 2,363 cases of non-familial autism spectrum disorder (ASD), 1,938 unaffected siblings, and both parents (9,599 genomes in total). We find thatde novostructural mutations detected by alignment-based, short-read WGS occurred at an overall rate of at least 0.160 events per genome in unaffected individuals and was significantly higher (0.206 per genome) in ASD cases. In both probands and unaffected samples, nearly 73% ofde novostructural mutations arose in paternal gametes, and predict mostde novostructural mutations to be caused by mutational mechanisms that do not require sequence homology. After multiple testing correction we did not observe a statistically significant correlation between parental age and the rate ofde novostructural variation in offspring. These results highlight that a spectrum of mutational mechanisms contribute to germline structural mutations, and that these mechanisms likely have markedly different rates and selective pressures than those leading to point mutations.
A critical role of stable grain filling rate in maximizing rice yield revealed by whole plant carbon nitrogen interaction modeling
Authors: Chang Tian-Gen , Wei Zhong-Wei , Shi Zai , Xiao Yi , Zhao Honglong , Chang Shuo-Qi , Qu Mingnan , Song Qingfeng , Chen Faming , Miao Fenfen , Zhu Xin-Guang 
Published: October 2020

ABSTRACTCrop yield is co-determined by potential size of the harvest organ, photosynthetic potential of source organs, and pattern of partitioning and use of photosynthates among sink organs. Given a sufficient potential size of the harvest organ at flowering, how to fully fill them remains a central challenge in crop breeding for high yields. Here, we develop a kinetic model of rice grain filling, scaling primary biochemical and biophysical processes to whole-plant carbon and nitrogen dynamics. Predicted post-anthesis physiological and agronomic behaviors validate experimental observations under six endogenous and external perturbations. By large scale in silico screening, we show here that a stable grain filling rate from flowering to harvest is required to maximize grain yield, which is validated here in two independent super-high yielding rice cultivars (~21 t ha-1 rough rice yield at 14% moisture). On the other hand, we show grain yields in an elite rice cultivar may increase by about 30-40% by stabilizing its grain filling rate. Intriguingly, we have found that the sum of grain filling rates around 15 and 38 days after flowering largely determines grain yield, and have further developed a novel in situ approach quantifying grain filling rates and grain yield precisely with the measurements of ear respiratory rates (r>0.93). Potential post-anthesis molecular targets to maximize rice yield include delaying leaf senescence, enhancing leaf sucrose synthesis and export, limiting root growth, strengthening stem starch synthesis, accelerating endosperm starch synthesis, and moderating endosperm cell division. Our study provides an effective computational framework for post-anthesis crop physiology research and ideotype design.
Blocking of EGFR Signaling is a Latent Strategy for the Improvement of Prognosis of HPV Induced Cancer
Authors: Qiu Jianfa , Hu Feifei , Shao Tingting , Guo Yuqiang , Dai Zongmao , Nie Huanhuan , Olasunkanmi Oluwatayo Israel , Chen Yang , Lin Lexun , Zhao Wenran , Zhong Zhaohua , Wang Yan 
Published: October 2020

AbstractHuman papillomavirus (HPV) is a dsDNA virus and its high-risk subtypes increase cancer risks. Yet, the mechanism of HPV infection and pathogenesis still remain unclear. Therefore, understanding the molecular mechanisms, and the pathogenesis of HPV are crucial in the prevention of HPV related cancers. In this study, we analyzed cervix squamous cell carcinoma (CESC) and head and neck carcinoma (HNSC) combined data to investigate various HPV induced cancer common feature. We showed that epidermal growth factor receptor (EGFR) was downregulated in HPV positive (HPV+) cancer, and that HPV+ cancer patients exhibited better prognosis than HPV negative (HPV−) cancer patients. Our study also showed that TP53 mutation rate is lower in HPV+ cancer than in HPV− cancer and that TP53 can be modulated by HPV E7 protein. However, there was no significant difference in the expression of wildtype TP53 in both groups. Subsequently, we constructed HPV-human interaction network and found that EGFR is a critical factor. From the network, we also noticed that EGFR is regulated by HPV E7 protein and hsa-miR-944. Moreover, while phosphorylated EGFR is associated with a worse prognosis, EGFR total express level is not significantly correlated with prognosis. This indicates that EGFR activation will induce a worse outcome in HPV+ cancer patients. Further enrichment analysis showed that EGFR downstream pathway and cancer relative pathway are diversely activated in HPV+ cancer and HPV− cancer. In summary, HPV E7 protein downregulates EGFR that downregulates phosphorylated EGFR and inhibit EGFR related pathways which in turn and consequently induce better prognosis.ImportanceAlthough HPV infection has been studied in various cancer types, there are only limited studies that have focused on the common effect of HPV related cancer. Consequently, this study focused on CESC and HNSC, two cancer types with high HPV infection proportion in cohort, thereby, intending to dig out the common effects and mechanisms of HPV+ cancers.Unlike some virus-human interaction prediction studies, the P-HIPSter database provides virus-human protein interaction based on protein structure prediction. Through this data, our interaction network was able to uncover previously unnoticed protein interactions. Our finding revealed that HPV infection caused various gene expression differences, and a great amount of which interact with EGFR, a cancer related gene. Therefore, since EGFR is associated with HPV+ cancer patients’ survival, some FDA proved EGFR inhibitors would be potential anti-HPV drugs.
Landscape of allele-specific transcription factor binding in the human genome
Authors: Abramov Sergey , Boytsov Alexandr , Bykova Dariia , Penzar Dmitry D. , Yevshin Ivan , Kolmykov Semyon K. , Fridman Marina V. , Favorov Alexander V. , Vorontsov Ilya E. , Baulin Eugene , Kolpakov Fedor , Makeev Vsevolod J. , Kulakovskiy Ivan V. 
Published: October 2020

AbstractSequence variants in gene regulatory regions alter gene expression and contribute to phenotypes of individual cells and the whole organism, including disease susceptibility and progression. Single-nucleotide variants in enhancers or promoters may affect gene transcription by altering transcription factor binding sites. Differential transcription factor binding in heterozygous genomic loci provides a natural source of information on such regulatory variants. We present a novel approach to call the allele-specific transcription factor binding events at single-nucleotide variants in ChIP-Seq data, taking into account the joint contribution of aneuploidy and local copy number variation, that is estimated directly from variant calls. We have conducted a meta-analysis of more than 7 thousand ChIP-Seq experiments and assembled the database of allele-specific binding events listing more than half a million entries at nearly 270 thousand single-nucleotide polymorphisms for several hundred human transcription factors and cell types. These polymorphisms are enriched for associations with phenotypes of medical relevance and often overlap eQTLs, making candidates for causality by linking variants with molecular mechanisms. Specifically, there is a special class of switching sites, where different transcription factors preferably bind alternative alleles, thus revealing allele-specific rewiring of molecular circuitry.
Extremely potent human monoclonal antibodies from convalescent Covid-19 patients
Authors: Andreano Emanuele , Nicastri Emanuele , Paciello Ida , Pileri Piero , Manganaro Noemi , Piccini Giulia , Manenti Alessandro , Pantano Elisa , Kabanova Anna , Troisi Marco , Vacca Fabiola , Cardamone Dario , De Santi Concetta , Benincasa Linda , Agrati Chiara , Capobianchi Maria Rosaria , Castilletti Concetta , Emiliozzi Arianna , Fabbiani Massimiliano , Montagnani Francesca , Depau Lorenzo , Brunetti Jlenia , Bracci Luisa , Montomoli Emanuele , Sala Claudia , Ippolito Giuseppe , Rappuoli Rino 
Published: October 2020

SUMMARYHuman monoclonal antibodies are safe, preventive and therapeutic tools, that can be rapidly developed to help restore the massive health and economic disruption caused by the Covid-19 pandemic. By single cell sorting 4277 SARS-CoV-2 spike protein specific memory B cells from 14 Covid-19 survivors, 453 neutralizing antibodies were identified and 220 of them were expressed as IgG. Up to 65,9% of monoclonals neutralized the wild type virus at a concentration of >500 ng/mL, 23,6% neutralized the virus in the range of 100 - 500 ng/mL and 9,1% had a neutralization potency in the range of 10 - 100 ng/mL. Only 1,4% neutralized the authentic virus with a potency of 1-10 ng/mL. We found that the most potent neutralizing antibodies are extremely rare and recognize the RBD, followed in potency by antibodies that recognize the S1 domain, the S-protein trimeric structure and the S2 subunit. The three most potent monoclonal antibodies identified were able to neutralize the wild type and D614G mutant viruses with less than 10 ng/mL and are good candidates for the development of prophylactic and therapeutic tools against SARS-CoV-2.One Sentence SummaryExtremely potent neutralizing human monoclonal antibodies isolated from Covid-19 convalescent patients for prophylactic and therapeutic interventions.
Single-Cell Transcriptomic Analysis Reveals Molecular Diversity of Human Oligodendrocyte Progenitor Cells
Authors: Chamling Xitiz , Kallman Alyssa , Berlinicke Cindy , Devkota Prajwal , Mertz Joseph L. , Chang Calvin , Kaushik Aniruddha , Chen Liben , Calabresi Peter A. , Mao Hai-Quan , Wang Tza-Huei , Zack Donald J. 
Published: October 2020

ABSTRACTInjury and loss of oligodendrocytes can cause demyelinating diseases such as multiple sclerosis. To improve our understanding of oligodendrocyte development, which could facilitate development of remyelination-based treatment strategies, we performed single-cell-transcriptomic-analysis of developing human oligodendrocyte-precursor-cells (hOPCs). We engineered knock-in hESC-reporter lines in which an Identification-and-Purification tag is expressed under control of the endogenous, OPC-specific,PDGFRαpromoter, and performed time-course single-cell-RNA-sequencing of purified hOPCs. Our analysis uncovered marked transcriptional heterogeneity of PDGFRα+ hOPCs and identified regulatory genes and networks that control their differentiation and myelination competence. Pseudotime trajectory analysis revealed two distinct trajectories for the development of oligodendrocytes vs astrocytes from hOPCs. We also identified novel transcription factors and other genes that developing hOPCs potentially use to choose between oligodendrocyte vs astrocyte lineages. In addition, pathway enrichment analysis followed by pharmacological intervention of those pathways confirm that mTOR and cholesterol biosynthesis signaling pathways are involved in maturation of oligodendrocytes from hOPCs.
Algorithmic and data modeling: Will algorithmic modeling improve predictions of traits evaluated on ordinal scales?
Authors: Xu Zhanyou , Kurek Andreomar , Cannon Steven B. , Beavis Williams D. 
Published: October 2020

AbstractSelection of markers linked to alleles at quantitative trait loci (QTL) for tolerance to Iron Deficiency Chlorosis (IDC) has not been successful. Genomic selection has been advocated for continuous numeric traits such as yield and plant height. For ordinal data types such as IDC, genomic prediction models have not been systematically compared. The objectives of research reported in this manuscript were to evaluate the most commonly used genomic prediction method, ridge regression and it’s equivalent logistic ridge regression method, with algorithmic modeling methods including random forest, gradient boosting, support vector machine, K-nearest neighbors, Naïve Bayes, and artificial neural network using the usual comparator metric of prediction accuracy. In addition we compared the methods using metrics of greater importance for decisions about selecting and culling lines for use in variety development and genetic improvement projects. These metrics include specificity, sensitivity, precision, decision accuracy, and area under the receiver operating characteristic curve. We found that Support Vector Machine provided the best specificity for culling IDC susceptible lines, while Random Forest GP models provided the best combined set of decision metrics for retaining IDC tolerant and culling IDC susceptible lines.
The gut virome of healthy children during the first year of life is diverse and dynamic
Authors: Taboada Blanca , Morán Patricia , Serrano-Vázquez Angélica , Iša Pavel , Rojas-Velázquez Liliana , Pérez-Juárez Horacio , López Susana , Torres Javier , Ximenez Cecilia , Arias Carlos F. 
Published: October 2020

AbstractIn this work, we determined the diversity and dynamics of the gut virome of infants during the first year of life. Fecal samples were collected monthly, from birth to one year of age, from three healthy children living in a semi-rural village in Mexico. Most of the viral reads were classified into six families of bacteriophages including five dsDNA virus families of the orderCaudovirales, withSiphoviridaeandPodoviridaebeing the most abundant. Eukaryotic viruses were detected as early as two weeks after birth and remained present all along the first year of life. Thirty-four different eukaryotic virus families were found, where eight of these families accounted for 98% of all eukaryotic viral reads:Anelloviridae,Astroviridae,Caliciviridae,Genomoviridae,Parvoviridae, Picornaviridae,Reoviridaeand the plant-infecting viruses of theVirgaviridaefamily. Some viruses in these families are known human pathogens, and it is surprising that they were found during the first year of life in infants without gastrointestinal symptoms. The eukaryotic virus species richness found in this work was higher than that observed in previous studies; on average between 7 and 24 virus species were identified per sample. The richness and abundance of the eukaryotic virome significantly increased during the second semester of life, probably because of an increased environmental exposure of infants with age. Our findings suggest an early and permanent contact of infants with a diverse array of bacteriophages and eukaryotic viruses, whose composition changes over time. The bacteriophages and eukaryotic viruses found in these children could represent a metastable virome, whose potential influence on the development of the infant’s immune system or on the health of the infants later in life, remains to be investigated.
Depletion of voltage-dependent anion channel (VDAC) ofToxoplasma gondiiaffects multiple mitochondrial functions, but not calcium signalling
Authors: Mallo Natalia , Martins Duarte Erica S. , Baehr Stephan C. , Biddau Marco , Ovciarikova Jana , Wilde Mary-Louise , Uboldi Alessandro D , Lemgruber Leandro , Tonkin Christopher J , Wideman Jeremy G. , Harding Clare R. , Sheiner Lilach 
Published: October 2020

AbstractThe Voltage Dependent Anion channel (VDAC) is a ubiquitous channel in the outer membrane of the mitochondrion with multiple roles in protein, metabolite and small molecule transport. In mammalian cells, VDAC, as part of a larger complex including the inositol triphosphate receptor, has been shown to have a role in mediating contact between the mitochondria and ER. We identify VDAC of the pathogenic apicomplexanToxoplasma gondiiand demonstrate its importance for parasite growth. We show that VDAC is involved in protein import and metabolite transfer to the mitochondria, but does not appear to modulate calcium (Ca2+) signalling. Further, depletion of VDAC resulted in significant morphological changes of the mitochondrion and ER, suggesting a role in mediating contacts between these organelles inT. gondii.
Developmental effects of oxytocin neurons on social affiliation and processing of social information
Authors: Nunes Ana Rita , Gliksberg Michael , Varela Susana A.M. , Teles Magda , Wircer Einav , Blechman Janna , Petri Giovanni , Levkowitz Gil , Oliveira Rui F. 
Published: October 2020

AbstractHormones regulate behavior either through activational effects that facilitate the acute expression of specific behaviors or through organizational effects that shape the development of the nervous system thereby altering adult behavior. Much research has implicated the neuropeptide oxytocin (OXT) in acute modulation of various aspects of social behaviors across vertebrate species, and OXT signaling is associated with the developmental social deficits observed in autism spectrum disorders, however, little is known about the role of OXT in the neurodevelopment of the social brain. We show that perturbation of OXT neurons during early zebrafish development led to a loss of dopaminergic neurons, associated with visual processing and reward, and blunted the neuronal response to social stimuli in the adult brain. Ultimately, adult fish whose OXT neurons were ablated in early life, displayed altered functional connectivity within social decision-making brain nuclei both in naïve state and in response to social stimulus and became less social. We propose that OXT neurons have an organizational role, namely to shape forebrain neuroarchitecture during development and to acquire an affiliative response towards conspecifics.Significance StatementSocial behavior is developed over the lifetime of an organism and the neuropeptide oxytocin modulates social behaviors across vertebrate species, and is associated with neuro-developmental social deficits such as autism. However, whether oxytocin plays a role in the developmental maturation of neural systems that are necessary for social behavior remains poorly explored. We show that proper behavioral and neural response to social stimuli depends on a developmental process orchestrated by oxytocin neurons. Animals whose oxytocin system is ablated in early life show blunted neuronal and behavioral responses to social stimuli as well as wide ranging disruptions in the functional connectivity of the Social Brain. We provide a window into the mechanisms underlying oxytocin-dependent developmental processes that implement adult sociality.