bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polygenic risk score from a multi-ancestry GWAS uncovers susceptibility of heart failure
Authors: Wu Kuan-Han H. , Douville Nicholas J. , Konerman Matthew C. , Mathis Michael R. , Hummel Scott L. , Wolford Brooke N. , Surakka Ida , Graham Sarah E. , Joo Hyeon , Hirbo Jibril , Cox Nancy J. , Lee Simon , Preuss Michael , Loos Ruth J.F. , Daly Mark J. , Neale Benjamin M. , Zhou Wei , Hornsby Whitney E. , Willer Cristen. J. 
Published: December 2021

SUMMARYIdentifying individuals at high risk of heart failure during precursor stages could allow for earlier initiation of treatments to modify disease progression. We performed a GWAS meta- analysis to generate a heart failure (HF) polygenic risk score (PRS) then tested the association with phenotypic subtypes (reduced ejection fraction [HFrEF] and preserved ejection fraction [HFpEF]) to evaluate the value of polygenic risk prediction. Results from the European-ancestry analysis showed that an ancestry-matched PRS, calculated from GBMI meta-analysis outperformed the previous HF GWAS (HERMES), yielding an adjusted odds ratio (aOR) of 2.27 (95% CI: 2.05-2.51; p: 1.76×10−56) from GBMI compared to 1.30 (95% CI: 1.18-1.44; p: 1.42×10− 7) from HERMES, and 1.49 (95% CI: 1.33-1.66; p: 8.38×10−13) compared to 1.17 (95% CI: 1.05- 1.31; p: 0.004) for HFrEF and HFpEF, respectively. Next, we evaluated the performance differences between ancestry-matched and multi-ancestry PRS in the African American cohort. The GBMI multi-ancestry GWAS-based PRS had a significant aOR of 1.49 (p: 0.006). Findings suggest that a PRS for heart failure derived from the GBMI multi-ancestry study is useful in predicting HFrEF, but less powerful in predicting HFpEF in an independent cohort. The difficulty in predicting HFpEF could result from the GBMI HF phenotype, preferencing HFrEF over HFpEF, and/or greater genetic heterogeneity in the HFpEF phenotype.
Cohesin modulates DNA replication to preserve genome integrity
Authors: Wu Jinchun , Liu Yang , Zhangding Zhengrong , Liu Xuhao , Ai Chen , Gan Tingting , Liu Yiyang , Yin Jianhang , Zhang Weiwei , Hu Jiazhi 
Published: December 2021

AbstractCohesin participates in loop formation by extruding DNA fibers from its ring-shaped structure. Cohesin dysfunction eliminates chromatin loops but only causes modest transcription perturbation, which cannot fully explain the frequently observed mutations of cohesin in various cancers. Here, we found that DNA replication initiates at more than one thousand extra dormant origins after acute depletion of RAD21, a core subunit of cohesin, resulting in earlier replicating timing at approximately 30% of the human genomic regions. In contrast, CTCF is dispensable for suppressing the early firing of dormant origins that are distributed away from the loop boundaries. Furthermore, greatly elevated levels of gross DNA breaks and genome-wide chromosomal translocations arise in RAD21-depleted cells, accompanied by dysregulated replication timing at dozens of hotspot genes. Thus, we conclude that cohesin coordinates DNA replication initiation to ensure proper replication timing and safeguards genome integrity.
AP-1 transcription factor network explains diverse patterns of cellular plasticity in melanoma cells
Authors: Comandante-Lou Natacha , Baumann Douglas G. , Fallahi-Sichani Mohammad 
Published: December 2021

SummaryCellular plasticity associated with fluctuations in transcriptional programs allows individual cells in a tumor to adopt heterogeneous differentiation states and switch phenotype during their adaptive responses to therapies. Despite increasing knowledge of such transcriptional programs, the molecular basis of cellular plasticity remains poorly understood. Here, we combine multiplexed transcriptional and protein measurements at population and single-cell levels with multivariate statistical modeling to show that the state of AP-1 transcription factor network plays a unifying role in explaining diverse patterns of plasticity in melanoma. We find that a regulated balance between AP-1 factors cJUN, JUND, FRA2, FRA1 and cFOS determines the intrinsic diversity of differentiation states and adaptive responses to MAPK inhibitors in melanoma cells. Perturbing this balance through genetic depletion of specific AP-1 proteins, or by MAPK inhibitors, shifts cellular heterogeneity in a predictable fashion. Thus, AP-1 may serve as a critical node for manipulating cellular plasticity with potential therapeutic implications.
Brain–heart dynamics during emotional processing under uncertain conditions: An index of depression risk
Authors: Chan Hui-Ling , Kanayama Noriaki , Mizuochi Ryohei , Yamawaki Shigeto , Machizawa Maro G. 
Published: December 2021

AbstractRecent studies have highlighted the essential role of interoception in healthy emotional processing and the pathology of major depressive disorder. However, it is unclear how individual differences in healthy people with high depression risk (HDR; i.e., individual differences in depression risk) are related to the neurophysiological underpinnings of interoception and emotional reactions under different degrees of certainty. We examined whether an individual’s depression risk mediates the relationships of heartbeat-evoked potentials (HEPs), a neurophysiological marker of cardiac interoception, with heart rate (HR) and heart rate variability (HRV), indices for cardiac reactivity. In a concurrent electroencephalogram-electrocardiogram (EEG-ECG) experiment, 26 healthy participants completed an emotion-evoking picture-evaluation task. Each trial began with a differential auditory cue that was associated with the certainty of subsequently seeing a pleasant or unpleasant picture. The results showed the following: after participants saw a cue of uncertainty, HDR was associated with 1) reduced neural activity when anticipating upcoming pictures and 2) enhanced physiological reactions tounexpected, unpleasant pictures. These results suggest that weaker predictions and augmented prediction errors for negative emotional stimuli reflect depression risk. Moreover, depression risk significantly mediated the relationships between HEPs and HR and between HEPs and HRV for unexpected, unpleasant stimuli. This study provides evidence that interoception and autonomic cardiac regulation may be altered by depression risk. This highlights the insights provided by specific indices of brain–heart interactions, such as HEPs, into the underlying activity of the autonomic nervous system and unique interoceptive disturbances associated with depression risk.
Meet me in the middle: median temperatures impact cyanobacteria and photoautotrophy in eruptive Yellowstone hot springs
Authors: Hamilton Trinity L. , Havig Jeff 
Published: December 2021

AbstractGeographic isolation can be a main driver of microbial evolution in hot springs while temperature plays a role on local scales. For example, cyanobacteria, particularly high temperature Synechococcus spp., have undergone ecological diversification along temperature gradients in hot spring outflow channels. While water flow, and thus temperature, is largely stable in many hot springs, flow can vary in geysing/eruptive hot springs resulting in large temperature fluctuations (sometimes more than 40°C). However, the role of large temperature fluctuations in driving diversification of cyanobacteria in eruptive hot springs has not been explored. Here, we examined phototroph community composition and potential photoautotrophic activity in two alkaline eruptive hot springs with similar geochemistry in the Lower Geyser Basin in Yellowstone National Park, WY. We observed distinct cyanobacterial amplicon sequencing variants (ASVs) consistent with allopatry and levels of light-dependent inorganic carbon uptake rates similar to other hot springs, despite large temperature fluctuations. Our data suggests median temperatures may drive phototroph fitness in eruptive hot springs while future studies are necessary to determine the evolutionary consequences of thriving under continuously fluctuating temperatures. We propose that large temperature swings in eruptive hot springs offer unique environments to examine the role of allopatry vs. physical and chemical characteristics of ecosystems in driving cyanobacteria evolution and add to the debate regarding the ecology of thermal adaptation and the potential for narrowing niche breadth with increasing temperature.ImportanceHot spring cyanobacteria have long been model systems for examining ecological diversification as well as characterizing microbial adaptation and evolution to extreme environments. These studies have reported cyanobacterial diversification in hot spring outflow channels that can be defined by distinct temperature ranges. Our study builds on these previous studies by examining cyanobacteria in geysing hot springs. Geysing hot springs result in outflow channel that experience regular and large temperature fluctuations. While community composition is similar between geysing and nongeysing hot spring outflow channels, our data suggests median, rather than high temperature, drive the fitness of cyanobacteria in geysing hot springs. We propose that large temperature swings may result in patterns of ecological diversification that are distinct from more stable outflows.
Decoding the absolute stoichiometric composition and structural plasticity of α-carboxysomes
Authors: Sun Yaqi , Harman Victoria M. , Johnson James R. , Chen Taiyu , Dykes Gregory F. , Lin Yongjun , Beynon Robert J. , Liu Lu-Ning 
Published: December 2021

AbstractCarboxysomes are anabolic bacterial microcompartments that play an essential role in carbon fixation in cyanobacteria and some chemoautotrophs. This self-assembling organelle encapsulates the key CO2-fixing enzymes, Rubisco, and carbonic anhydrase using a polyhedral protein shell that is constructed by hundreds of shell protein paralogs. The α-carboxysome from the chemoautotroph Halothiobacillus neapolitanus serves as a model system in fundamental studies and synthetic engineering of carboxysomes. Here we adopt a QconCAT-based quantitative mass spectrometry to determine the absolute stoichiometric composition of native α-carboxysomes from H. neapolitanus. We further performed an in-depth comparison of the protein stoichiometry of native and recombinant α-carboxysomes heterologously generated in Escherichia coli to evaluate the structural variability and remodeling of α-carboxysomes. Our results provide insight into the molecular principles that mediate carboxysome assembly, which may aid in rational design and reprogramming of carboxysomes in new contexts for biotechnological applications.
SIR Modeling the Dual Disaster Impacts of Omicron B.1.1.529 and Natural Disaster Events on Simulated 6 Months (December 2021 – May 2022) Healthcare System Resiliences in Fragile SE Asia Ring of Fire Ecosystems
Authors: Wibowo Andri 
Published: December 2021

AbstractFor some countries that have experienced numerous natural disasters, including massive earthquakes and tsunamis, managing the COVID-19 pandemic can be very challenging. This situation arises considering that the disaster can directly and indirectly affect the healthcare system’ s capacity to serve the COVID-19 cases. With severely damaged healthcare facilities due to the disaster, there will be severely ill COVID-19 cases unmanaged. The coupling and interplay between these two phenomena can indeed be catastrophic. One of the regions where this issue becomes concerned is in Southeast Asia, where most of the Asian countries lie in the fragile ring of fire ecosystem, contributing to the high tsunami and earthquake disasters in the world. At the same time, Asia is one of the regions that have been severely impacted due to the current COVID-19 Delta Variant. Recently, a more contagious Omicron Variant has emerged and put a more massive burden on the healthcare facilities that are impacted by disasters. Then, in this situation, this paper aims to assess healthcare resilience in managing the Omicron pandemic amid disaster impacts. SIR simulation was used to determine whether severely ill Omicron cases were below or above healthcare and ICU capacity under different vaccination coverage. Our result confirms that vaccination coverage was the imminent factor in reducing the severely ill cases in every healthcare facility, whether the facilities were damaged or not. Increasing vaccination coverage from 30% to 60% will significantly reduce the number of severely ill cases that fall below the capacity of healthcare. Based on the current SIR model on the Omicron epidemic variables and Ro, it is estimated that the Omicron will reach its peak after 180 days in February 2022 and will totally disappear in May 2022 in this modeled area. When healthcare system facilities were fully operational and no disaster happened, combined with 60% vaccination rates, all Omicron case numbers were below and under the available hospital beds and even available ICU beds. While the situation is changed when a disaster occurs and causes 30% damage or reduction to healthcare facilities. In this situation, there are portions of Omicron cases that cannot be managed by the healthcare system since the cases have exceeded the available beds. The situations become more apparent where the healthcare facilities are severely damaged and lose 60% of their functionality. In this situation, all modeled Omicron cases and even the severe cases have exceeded the ICU capacity.
DALI (Diversity AnaLysis Interface): a novel tool for the integrated analysis of multimodal single cell RNAseq data and immune receptor profiling
Authors: Verstaen Kevin , Ibech Kevin , Lammens Inés , Roels Jana , Saeys Yvan , Lambrecht Bart N , Vandamme Niels , Vanhee Stijn 
Published: December 2021

AbstractSingle-cell RNA sequencing is instrumental to unravel the cellular and transcriptomic heterogeneity of T and B cells in health and disease. Recent technological advances add additional layers of information allowing researchers to simultaneously explore the transcriptomic, surface protein and immune receptor diversity during adaptive immune responses. The increasing data complexity poses a burden on the workload for bioinformaticians, who are often not familiar with the specificities and biology of immune receptor profiling. The wet-lab modalities and sequencing capabilities currently have outpaced bioinformatics solutions, which forms an ever-increasing barrier for many biologists to analyze their datasets. Here, we present DALI (Diversity AnaLysis Interface), a software package to identify and analyze T cell and B cell receptor diversity in high-throughput single-cell sequencing data. DALI aims to support bioinformaticians with a functional toolbox, allowing seamless integration of multimodal scRNAseq and immune receptor profiling data generated through 10X Genomics Cell Ranger software. The R-based package builds further on workflows using the Seurat package and other existing tools for BCR/TCR analyses. In addition, DALI is designed to engage immunologists having limited coding experience with their data, using a browser-based interactive graphical user interface. The implementation of DALI can effectively lead to a two-way communication between wet-lab scientists and bioinformaticians to advance the analysis of complex datasets.
A target capture approach for phylogenomic analyses at multiple evolutionary timescales in rosewoods (Dalbergiaspp.) and the legume family (Fabaceae)
Authors: Crameri Simon , Fior Simone , Zoller Stefan , Widmer Alex 
Published: December 2021

AbstractUnderstanding the genetic changes associated with the evolution of biological diversity is of fundamental interest to molecular ecologists. The assessment of genetic variation at hundreds or thousands of unlinked genetic loci forms a sound basis to address questions ranging from micro-to macro-evolutionary timescales, and is now possible thanks to advances in sequencing technology. Major difficulties are associated with i) the lack of genomic resources for many taxa, especially from tropical biodiversity hotspots, ii) scaling the numbers of individuals analyzed and loci sequenced, and iii) building tools for reproducible bioinformatic analyses of such datasets. To address these challenges, we developed a set of target capture probes for phylogenomic studies of the highly diverse, pantropically distributed and economically significant rosewoods (Dalbergiaspp.), explored the performance of an overlapping probe set for target capture across the legume family (Fabaceae), and built a general-purpose bioinformatics pipeline. Phylogenomic analyses ofDalbergiaspecies from Madagascar yielded highly resolved and well supported hypotheses of evolutionary relationships. Population genomic analyses identified differences between closely related species and revealed the existence of a potentially new species, suggesting that the diversity of MalagasyDalbergiaspecies has been underestimated. Analyses at the family level corroborated previous findings by the recovery of monophyletic subfamilies and many well-known clades, as well as high levels of gene tree discordance, especially near the root of the family. The new genomic and bioinformatics resources will hopefully advance systematics and ecological genetics research in legumes, and promote conservation of the highly diverse and endangeredDalbergiarosewoods.
Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes
Authors: Kitamoto Takumi , Lee Yun-Kyoung , Sultana Nishat , McKimpson Wendy M. , Watanabe Hitoshi , Du Wen , Fan Jason , Diaz Bryan , Lin Hua V. , Leibel Rudolph L. , Belvedere Sandro , Accili Domenico 
Published: December 2021

ABSTRACTLifelong insulin replacement remains the mainstay of type 1 diabetes treatment. Genetic FoxO1 ablation promotes enteroendocrine cell (EECs) conversion into glucose-responsive β-like cells. Here, we tested whether chemical FoxO1 inhibitors can generate β-like gut cells. Pan-intestinal epithelial FoxO1 ablation expanded the EEC pool, induced β-like cells, and improved glucose tolerance in Ins2Akita/+ mice. This genetic effect was phenocopied by small molecule FoxO1 inhibitor, Cpd10. Cpd10 induced β-like cells that released insulin in response to glucose in mouse gut organoids, and this effect was strengthened by the Notch inhibitor, DBZ. In Ins2Akita/+ mice, a five-day course of either Cpd10 or DBZ induced insulin-immunoreactive β-like cells in the gut, lowered glycemia, and increased plasma insulin levels without apparent adverse effects. These results provide proof of principle of gut cell conversion into β-like cells by a small molecule FoxO1 inhibitor, paving the way for clinical applications.One Sentence SummaryOrally available small molecule FoxO1 inhibitor phenocopied genetic FoxO1 ablation in generating gut β-like cells
Stem cell specific interferon stimulated gene expression is regulated by the formative pluripotency network through IRF1
Authors: Romeike Merrit , Spach Stephanie , Huber Marie , Feng Songjie , Vainorius Gintautas , Elling Ulrich , Buecker Christa 
Published: December 2021

AbstractStem cells intrinsically express a subset of genes which are normally associated with interferon stimulation, and thus the innate immunity response. Expression of these interferon stimulated genes (ISG) in stem cells is independent of external stimuli such as viral infection. Here we show that the interferon regulatory factor 1, Irf1, is directly controlled by the murine formative pluripotency gene regulatory network and therefore upregulated in the transition from naive to formative pluripotency. IRF1 in turn binds to regulatory regions of a conserved set of ISGs and is required for their faithful expression in formative pluripotent cells. IRF1 also binds to an enhancer of the formative pluripotency transcription factor Oct6 and is partially required for upregulation of Oct6. IRF1 therefore acts as a link between the formative pluripotency network and the regulation of innate immunity genes in formative pluripotency.
Collinearity of alpha-helices or beta strands in membrane proteins causes a characteristic peak centred on 4.9 Å resolution in diffraction intensity profiles, inducing higher diffraction anisotropy
Authors: Martin Juliette , Robert Xavier , Gouet Patrice , Falson Pierre , Chaptal Vincent 
Published: December 2021

AbstractDiffraction anisotropy is a phenomenon that impacts more specifically membrane proteins, compared to soluble ones, but the reasons for this discrepancy remained unclear. Often, it is referred to a difference in resolution limits between highest and lowest diffraction limits as a signature for anisotropy. We show in this article that there is no simple correlation between anisotropy and difference in resolution limits, with notably a substantial number of structures displaying various anisotropy with no difference in resolution limits. We further investigated diffraction intensity profiles, and observed a peak centred on 4.9Å resolution more predominant in membrane proteins. Since this peak is in the region corresponding to secondary structures, we investigated the influence of secondary structure ratio. We showed that secondary structure content has little influence on this profile, while secondary structure collinearity in membrane proteins correlate with a stronger peak. Finally, we could further show that the presence of this peak is linked to higher diffraction anisotropy.SynopsisMembrane protein diffraction anisotropy originates from a peak at 4.9 Å resolution in intensity profiles, due to secondary structure collinearity.
Modeling diverse genetic subtypes of lung adenocarcinoma with a next-generation alveolar type 2 organoid platform
Authors: Naranjo Santiago , Cabana Christina M. , LaFave Lindsay M. , Westcott Peter M.K. , Romero Rodrigo , Ghosh Arkopravo , Liao Laura Z. , Schenkel Jason M. , Priore Isabella Del , Bhutkar Arjun , Yang Dian , Jacks Tyler 
Published: December 2021

ABSTRACTLung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD), the most common histological subtype, accounts for 40% of all cases. While genetically engineered mouse models (GEMMs) recapitulate the histological progression and transcriptional evolution of human LUAD, they are slow and technically demanding. In contrast, cell line transplant models are fast and flexible, but are often derived from clonal idiosyncratic tumors that fail to capture the full spectrum of clinical disease. Organoid technologies provide a means to create next-generation cancer models that integrate the most relevant features of autochthonous and transplant-based systems, yet robust and faithful LUAD organoid platforms are currently lacking. Here, we describe optimized conditions to continuously expand murine alveolar type 2 cells (AT2), a prominent cell-of-origin for LUAD, in organoid culture. These organoids display canonical features of AT2 cells, including marker gene expression, the presence of lamellar bodies, and an ability to differentiate into the AT1 lineage. We used this system to develop flexible and versatile immunocompetent organoid-based models of KRAS and ALK-mutant LUAD. Notably, the resultant tumors closely resemble their autochthonous murine counterparts and human LUAD. In contrast to comparable organoid platforms, our system supports long-term maintenance of the AT2 cellular identity, providing unprecedented ease and reliability to study AT2 and LUAD biology in vitro and in vivo.