bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increasing Sample Diversity in Psychiatric Genetics – Introducing a new Cohort of Patients with Schizophrenia and Controls from Vietnam – Results from a Pilot Study
Authors: Nguyen VT , Braun A , Kraft J , Ta TMT , Panagiotaropoulou GM , Nguyen VP , Nguyen TH , Trubetskoy V , Le CT , Le TTH , Pham XT , Heuser-Collier I , Lam NH , Böge K , Hahne IM , Bajbouj M , Zierhut MM , Hahn E , Ripke S 
Published: April 2021

AbstractObjectivesGenome-Wide Association Studies (GWAS) of Schizophrenia (SCZ) have provided new biological insights; however, most cohorts are of European ancestry. As a result, derived polygenic risk scores (PRS) show decreased predictive power when applied to populations of different ancestries. We aimed to assess the feasibility of a large-scale data collection in Hanoi, Vietnam, contribute to international efforts to diversify ancestry in SCZ genetic research and examine the transferability of SCZ-PRS to individuals of Vietnamese Kinh ancestry.MethodsIn a pilot study, 368 individuals (including 190 SCZ cases) were recruited at the Hanoi Medical University’s associated psychiatric hospitals and outpatient facilities. Data collection included sociodemographic data, baseline clinical data, clinical interviews assessing symptom severity and genome-wide SNP genotyping. SCZ-PRS were generated using different training data sets: i) European, ii) East-Asian and iii) trans-ancestry GWAS summary statistics from the latest SCZ GWAS meta-analysis.ResultsSCZ-PRS significantly predicted case status in Vietnamese individuals using mixed-ancestry (R2 liability=4.9%, p=6.83*10−8), East-Asian (R2 liability=4.5%, p=2.73*10−7) and European (R2 liability=3.8%, p = 1.79*10−6) discovery samples.DiscussionOur results corroborate previous findings of reduced PRS predictive power across populations, highlighting the importance of ancestral diversity in GWA studies.
Mathematical modeling suggests pre-existing immunity to SARS-CoV-2
Authors: Carlsson Marcus , Hatem Gad , Söderberg-Nauclér Cecilia 
Published: April 2021

AbstractMathematical models have largely failed to predict the unfolding of the COVID-19 pandemic. We revisit several variants of the SEIR-model and investigate various adjustments to the model in order to achieve output consistent with measured data in Manaus, India and Stockholm. In particular, Stockholm is interesting due to the almost constant NPI’s, which substantially simplifies the mathematical modeling. Analyzing mobility data for Stockholm, we argue that neither behavioral changes, age and activity stratification nor NPI’s alone are sufficient to explain the observed pandemic progression. We find that the most plausible hypothesis is that a large portion of the population, between 40 to 60 percent, have some protection against infection with the original variant of SARS-CoV-2.
Effects of B.1.1.7 and B.1.351 on COVID-19 dynamics. A campus reopening study
Authors: Linka Kevin , Peirlinck Mathias , Schäfer Amelie , Tikenogullari Oguz Ziya , Goriely Alain , Kuhl Ellen 
Published: April 2021

AbstractThe timing and sequence of safe campus reopening has remained the most controversial topic in higher education since the outbreak of the COVID-19 pandemic. By the end of March 2020, almost all colleges and universities in the United States had transitioned to an all online education and many institutions have not yet fully reopened to date. For a residential campus like Stanford University, the major challenge of reopening is to estimate the number of incoming infectious students at the first day of class. Here we learn the number of incoming infectious students using Bayesian inference and perform a series of retrospective and projective simulations to quantify the risk of campus reopening. We create a physics-based probabilistic model to infer the local reproduction dynamics for each state and adopt a network SEIR model to simulate the return of all undergraduates, broken down by their year of enrollment and state of origin. From these returning student populations, we predict the outbreak dynamics throughout the spring, summer, fall, and winter quarters using the inferred reproduction dynamics of Santa Clara County. We compare three different scenarios: the true outbreak dynamics under the wild-type SARS-CoV-2, and the hypothetical outbreak dynamics under the new COVID-19 variants B.1.1.7 and B.1.351 with 56% and 50% increased transmissibility. Our study reveals that even small changes in transmissibility can have an enormous impact on the overall case numbers. With no additional countermeasures, during the most affected quarter, the fall of 2020, there would have been 203 cases under base-line reproduction, compared to 4727 and 4256 cases for the B.1.1.7 and B.1.351 variants. Our results suggest that population mixing presents an increased risk for local outbreaks, especially with new and more infectious variants emerging across the globe. Tight outbreak control through mandatory quarantine and test-trace-isolate strategies will be critical in successfully managing these local outbreak dynamics.
Approximate Reciprocal Relationship Between Two Cause-Specific Hazard Ratios in COVID-19 Data With Mutually Exclusive Events
Authors: Cetin Sirin , Ulgen Ayse , Sivgin Hakan , Li Wentian 
Published: April 2021

ABSTRACTCOVID-19 survival data presents a special situation where not only the time-to-event period is short, but also the two events or outcome types, death and release from hospital, are mutually exclusive, leading to two cause-specific hazard ratios (csHRd and csHRr). The eventual mortality/release outcome can also be analyzed by logistic regression to obtain odds-ratio (OR). We have the following three empirical observations concerning csHRd, csHRr and OR: (1) The magnitude of OR is an upper limit of the csHRd: | log(OR) | ≥ | log(csHRd)|. This relationship between OR and HR might be understood from the definition of the two quantities; (2) csHRd and csHRr point in opposite directions: log(csHRd)· log(csHRr) < 0; This relation is a direct consequence of the nature of the two events; and (3) there is a tendency for a reciprocal relation between csHRd and csHRr: csHRd ∼ 1/csHRr. Though an approximate reciprocal trend between the two hazard ratios is in indication that the same factor causing faster death also lead to slow recovery by a similar mechanism, and vice versa, a quantitative relation between csHRd and csHRr in this context is not obvious. These resutls may help future analyses of COVID-19 data, in particular if the deceased samples are lacking.
A Pan-Cancer Census of Dominant Tumor Immune Archetypes
Authors: Combes Alexis J. , Samad Bushra , Tsui Jessica , Chew Nayvin W. , Yan Peter , Reeder Gabriella C. , Kushnoor Divyashree , Shen Alan , Davidson Brittany , Barczac Andrea J. , Adkisson Michael , Edwards Austin , Naser Mohammad , Barry Kevin C. , Courau Tristan , Hammoudi Taymour , Arguëllo Rafael J , Rao Arjun Arkal , Olshen Adam B. ,   The Immunoprofiler consortium, Cai Cathy , Zhan Jenny , Davis Katelyn C. , Kelley Robin K. , Chapman Jocelyn S. , Attreya Chloe E. , Patel Amar , Daud Adil I. , Ha Patrick , Diaz Aaron A. , Kratz Johannes R. , Collisson Eric A. , Fragiadakis Gabriela K , Erle David J. , Boissonnas Alexandre , Asthana Saurabh , Chan Vincent , Krummel Matthew F. 
Published: April 2021

SUMMARYCancers display significant heterogeneity with respect to tissue of origin, driver mutations and other features of the surrounding tissue. It is likely that persistent tumors differentially engage inherent patterns–here ‘Archetypes’–of the immune system, to both benefit from a tumor immune microenvironment (TIME) and to disengage tumor-targeting. To discover dominant immune system archetypes, the Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub compartments uncovered archetypes that exist across indications. These Immune composition-based archetypes differentiate tumors based upon unique immune and tumor gene-expression patterns. Archetypes discovered this way also tie closely to well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune infiltration and provides a rational path forward to learn how to modulate these patterns to improve therapy.
Discovery of an unusual high number ofde novomutations in sperm of older men using duplex sequencing
Authors: Salazar Renato , Arbeithuber Barbara , Ivankovic Maja , Heinzl Monika , Moura Sofia , Hartl Ingrid , Mair Theresa , Lahnsteiner Angelika , Ebner Thomas , Shebl Omar , Pröll Johannes , Tiemann-Boege Irene 
Published: April 2021

AbstractDe novomutations (DNMs) are an important player in heritable diseases and evolution. Of particular interest are highly recurrent DNMs associated with congenital disorders that have been described as selfish mutations expanding in the male germline, thus becoming more frequent with age. Here, we have adapted duplex sequencing (DS), an ultra-deep sequencing method that renders sequence information on both DNA strands; thus, one mutation can be reliably called in millions of sequenced bases. With DS, we examined ∼4.5 kb of theFGFR3coding region in sperm DNA from older and younger donors. We identified sites with variant frequencies of 10−4to 10−5, with an overall mutation frequency of the region of ∼6×10−7. Some of the substitutions were re-current and were found at a higher variant frequency in older donors than in younger ones, or exclusively, in older donors. Also, older donors harbored more mutations associated with congenital disorders. Other mutations were present in both age groups suggesting that these might result from a different mechanism (e.g., post-zygotic mosaicism). We also observed that independent of age, the frequency and deleteriousness of the mutational spectra was more similar to COSMIC than to gnomAD variants. Our approach is an important strategy to identify mutations that could be associated with a gain-of-function of the receptor tyrosine kinase activity, with unexplored consequences in a society with delayed fatherhood.
Quantitative imaging ofCaenorhabditis elegansdauer larvae during cryptobiotic transition using optical diffraction tomography
Authors: Kim Kyoohyun , Gade Vamshidhar R. , Kurzchalia Teymuras V. , Guck Jochen 
Published: April 2021

AbstractUpon starvation or overcrowding, the nematodeCaenorhabditis elegansenters diapause by forming a dauer larva. This larva can further transit into an anhydrobiotic state and survive harsh desiccation. We previously identified the genetic and biochemical pathways essential for survival — but without an accompanying physical model, the mechanistic understanding of this amazing phenomenon will remain inadequate. Neither microscopic investigation of structural changes upon entry into anhydrobiosis nor the most basic quantitative characterization of material properties of living desiccated larvae, however, have been feasible, due to lack of appropriate techniques. Here, we employed optical diffraction tomography (ODT) to quantitatively assess the internal mass density distribution of living larvae in the reproductive and diapause stages. More importantly, ODT allowed for the first time physical analysis of desiccated dauer larvae: their mass density was significantly increased in the anhydrobiotic state. We also applied ODT on different mutants that are sensitive to desiccation. Remarkably, one of them displayed structural abnormalities in the anhydrobiotic stage that could not be observed either by conventional light or electron microscopy. Our advance opens a door to quantitatively assessing fine differences in material properties and structure necessary to fully understanding an organism on the verge of life and death.
Quantifying chromosomal instability from intratumoral karyotype diversity using agent-based modeling and Bayesian inference
Authors: Lynch A.R. , Arp N.L. , Zhou A.S. , Weaver B.A. , Burkard M.E. 
Published: April 2021

ABSTRACTChromosomal instability (CIN) — persistent chromosome gain or loss through abnormal karyokinesis — is a hallmark of cancer that drives aneuploidy. Intrinsic chromosome mis-segregation rates, a measure of CIN, can inform prognosis and are a likely biomarker for response to anti-microtubule agents. However, existing methodologies to measure this rate are labor intensive, indirect, and confounded by karyotype selection reducing observable diversity. We developed a framework to simulate and measure CIN, accounting for karyotype selection, and recapitulated karyotype-level clonality in simulated populations. We leveraged approximate Bayesian computation using phylogenetic topology and diversity to infer mis-segregation rates and karyotype selection from single-cell DNA sequencing data. Experimental validation of this approach revealed extensive chromosome mis-segregation rates caused by the chemotherapy paclitaxel (17.5±0.14/division). Extending this approach to clinical samples revealed the inferred rates fell within direct observations of cancer cell lines. This work provides the necessary framework to quantify CIN in human tumors and develop it as a predictive biomarker.
PEAR: a flexible fluorescent reporter for the identification and enrichment of successfully prime edited cells
Authors: Simon Dorottya A. , Tálas András , Kulcsár Péter I. , Welker Ervin 
Published: April 2021

ABSTRACTPrime editing is a recently developed gene engineering tool that allows the introduction of short insertions, deletions or substitutions into the genome. However, the efficiency of prime editing, generally reaching around 10-30% editing, has not resembled its versatility. Here, Prime Editor Activity Reporter (PEAR), a sensitive fluorescent tool is introduced for the identification of single cells with prime editing activity. Possessing no background fluorescence, PEAR specifically reports on prime editing events in individual cells. By design, it ensures unrestricted flexibility for sequence variations in the full length of the target sequence. The application of PEAR as an enrichment marker of prime editing can increase the edited population by up to 70% and alleviate the burden of the otherwise time and labour consuming process of cloning of the correctly edited cells, therefore considerably improving the applicability of prime editing in fundamental research and biotechnological uses.
Loss ofMafbandMafdistorts myeloid cell ratios and disrupts fetal mouse testis vascularization and organogenesis
Authors: Li Shu-Yun , Gu Xiaowei , Heinrich Anna , Hurley Emily G. , Capel Blanche , DeFalco Tony 
Published: April 2021

AbstractTestis differentiation is initiated whenSryin pre-Sertoli cells directs the gonad toward a male-specific fate. Sertoli cells are essential for testis development, but cell types within the interstitial compartment, such as immune and endothelial cells, are also critical for organ formation. Our previous work implicated macrophages in fetal testis morphogenesis, but little is known about genes underlying immune cell development during organogenesis. Here we examine the role of the immune-associated genesMafbandMafin mouse fetal gonad development, and we demonstrate that deletion of these genes leads to aberrant hematopoiesis manifested by supernumerary gonadal monocytes.Mafb;Mafdouble knockout embryos underwent initial gonadal sex determination normally, but exhibited testicular hypervascularization, testis cord formation defects, Leydig cell deficit, and a reduced number of germ cells. In general,MafbandMafalone were dispensable for gonad development; however, when both genes were deleted, we observed significant defects in testicular morphogenesis, indicating thatMafbandMafwork redundantly during testis differentiation. These results demonstrate previously unappreciated roles forMafbandMafin immune and vascular development and highlight the importance of interstitial cells in gonadal differentiation.Summary statementDeletion ofMafbandMafgenes leads to supernumerary monocytes in fetal mouse gonads, resulting in vascular, morphogenetic, and differentiation defects during testicular organogenesis.
Maintaining grass coverage increases methane uptake in Amazonian pasture soils
Authors: de Souza Leandro Fonseca , Alvarez Dasiel Obregon , Domeignoz-Horta Luiz A. , Gomes Fabio Vitorino , de Souza Almeida Cassio , Merloti Luis Fernando , Mendes Lucas William , Andreote Fernando Dini , Bohannan Brendan J. M. , Rodrigues Jorge M. , Nüsslein Klaus , Tsai Siu Mui 
Published: April 2021

AbstractCattle ranching is the largest driver of deforestation in the Brazilian Amazon. The rainforest- to-pasture conversion affects the methane cycle in upland soils, changing it from sink to source of atmospheric methane. However, it remains unknown if management practices could reduce the impact of land-use on methane cycling. In this work, we evaluated how pasture management can regulate the soil methane cycle either by maintaining continuous grass coverage on pasture soils, or by liming the soil to amend acidity. Methane fluxes from forest and pasture soils were evaluated in moisture-controlled greenhouse experiments with and without grass cover (Urochloa brizanthacv. Marandu) or liming. In parallel, we assessed changes in the soil microbial community structure of both bare pasture soil as well as rhizosphere soil through high throughput sequencing of the 16S rRNA gene, and quantified the methane cycling microbiota by their respective marker genes related to methane generation (mcrA) or oxidation (pmoA). The experiments used soils from eastern and western Amazonia, and concurrent field studies allowed us to confirm greenhouse data. The presence of a grass cover not only increased methane uptake by up to 35% in pasture soils, but also reduced the abundance of the methane-producing community. In the grass rhizosphere this reduction was up to 10-fold. Methane-producing archaea belonged to the generaMethanosarcina sp.,Methanocella sp.,Methanobacterium sp., and Rice Cluster I. Further, we showed that liming compromised the capacity of forest and pasture soils to be a sink for methane, and instead converted formerly methane-consuming forest soils to become methane sources in only 40-80 days. Our results demonstrate that pasture management that maintains grass coverage can mitigate soil methane emissions, if compared to a bare pasture soil.
The Lack of Nrf2 Causes Hepatocyte Dedifferentiation and Reduced Albumin Production in an Experimental Extrahepatic Cholestasis Model
Authors: Wang Guo-Ying , Garcia Veronica , Lee Joonyong , Yanum Jennifer , Jiang Huaizhou , Dai Guoli 
Published: April 2021

AbstractThe transcription factor Nrf2 modulates the initiation and progression of a number of diseases including liver disorders. The aim of this study was to evaluate whether Nrf2 mediates hepatic adaptive responses to cholestasis. Wild-type and Nrf2-null mice were subjected to bile duct ligation (BDL) or a sham operation. Various assessments were performed at different days after surgery. Significant genotype-dependent changes in liver size, biliary ductular reaction, hepatocyte proliferation, and fibrotic response were not observed. However, as cholestasis progressed to Day 15 post-BDL, hepatocytes in the wild-type mice exhibited a tendency to dedifferentiate, indicated by the very weak expression of hepatic progenitor markers: CD133 and fibroblast growth factor-inducible 14 (Fn14). During the same period, Nrf2 deficiency augmented this tendency, manifested by higher CD133 expression, earlier, stronger, and continuous induction of Fn14 expression, and markedly reduced albumin production. Remarkably, as cholestasis advanced to the late stage (40 days after BDL), hepatocytes in the wild-type mice exhibited a Fn14+ phenotype and strikingly upregulated the expression of deleted in malignant brain tumor 1 (DMBT1), a protein essential for epithelial differentiation during development. In contrast, at this stage, hepatocytes in the Nrf2-null mice entirely inhibited the upregulation of DMBT1 expression, displayed a strong CD133+/Fn14+ phenotype indicative of severe dedifferentiation, and persistently reduced albumin production. Collectively, our studies revealed that Nrf2 maintains hepatocytes in the differentiated state potentially via the increased activity of the Nrf2/DMBT1 pathway during cholestasis. These findings enable us to gain novel insight into how hepatocytes respond to cholestasis.New and NoteworthyWe found that, when hepatocytes are exposed to cholestasis, they exhibit a tendency of dedifferentiation. In this case, Nrf2 is highly activated to markedly up-regulate the expression of epithelial differentiation gene DMBT1, which potentially prevent hepatocytes from dedifferentiation. Our findings revealed a plastic property of hepatocytes in response to cholestasis and demonstrated a novel Nrf2/DMBT1 pathway likely controlling this property of hepatocytes.
The parallel origins of vertebrate venoms
Authors: Barua Agneesh , Koludarov Ivan , Mikheyev Alexander S. 
Published: April 2021

AbstractEvolution can occur with surprising predictability when organisms face similar ecological challenges. How and why traits arise repeatedly remains a central question in evolutionary biology, but the complexity of most traits makes it challenging to answer. Reptiles and mammals independently evolved oral venoms consisting of proteinaceous cocktails that allow mapping between genotype and phenotype. Although biochemically similar toxins can occur as major venom components across many taxa, whether these toxins evolved via convergent or parallel processes remains unknown. Most notable among them are kallikrein-like serine proteases that form the core of most vertebrate oral venoms. We used a combination of comparative genomics and phylogenetics to investigate whether serine protease recruitment into the venom occurred independently or in parallel in mammalian and reptilian lineages. Using syntenic relationships between genes flanking known toxins, we traced the origin of kallikreins to a single locus containing one or more nearby paralogous kallikrein-like clusters. Independently, phylogenetic analysis of vertebrate serine proteases revealed that kallikrein-like toxins in mammals and reptiles are homologous. Given the shared regulatory and genetic machinery, these findings suggest a unified model underlying vertebrate venom evolution. Namely, the common tetrapod ancestor possessed salivary genes that were biochemically suitable for envenomation. We term such genes ‘toxipotent’ – in the case of salivary kallikreins they already had potent vasodilatory activity that was weaponized by venomous lineages. Furthermore, the ubiquitous distribution of kallikreins across vertebrates suggests that the evolution of envenomation may be more common than previously recognized, blurring the line between venomous and non-venomous animals.