bluuebunny/crossref_metadata_2025_split huggingface dataset:
FoxP3-mediated blockage of ryanodine receptor 2 is the molecular basis for the contact-based suppression by regulatory T cells
Authors: Wang Xiaobo , Geng Shuang , Meng Junchen , Kang Ning , Liu Xinyi , Xu Yanni , Lv Huiyun , Xu Ying , Xu Xun , Song Xinrong , Zhang Bin , Wang Xin , Nuerbulati Nuerdida , Zhang Ze , Zhai Di , Mao Xin , Sun Ruya , Wang Xiaoting , Wang Ruiwu , Guo Jie , Chen S. R. Wayne , Zhou Xuyu , Xia Tie , Qi Hai , Hu Xiaoyu , Shi Yan 
Published: May 2022

AbstractThe suppression mechanism of regulatory T cells is an intensely investigated topic. As our focus has shifted towards a model centered on indirect inhibition of dendritic cells, a universally applicable effector mechanism controlled by FoxP3 expression has not been found. Here, we report that FoxP3 blocks the transcription of ER Ca2+-release channel ryanodine receptor 2. Reduced RyR2 shuts down basal Ca2+oscillation in Tregs, which reduces m-Calpain activities that is needed for T cells to disengage from DCs, suggesting a persistent blockage of DC antigen presentation. RyR2 deficiency renders the CD4+T cell pool to become immune suppressive, and behave in the same manner as FoxP3+Tregs in viral infection, asthma, hypersensitivity, colitis and tumor development. In the absence of FoxP3, RyR2-deficient CD4+T cells rescue the systemic autoimmunity associated with Scurfy mice. Therefore, FoxP3-mediated Ca2+signaling inhibition may be a central effector mechanism of Treg immune suppression.One Sentence SummaryCalcium channel RyR2 dictates Treg adhesion-based suppression
High-efficiency HDR in immortalized cell lines by crude rAAV mediated donor template delivery
Authors: Mehta Stuti , Buyanbat Altantsetseg , Zheng Ge , Liu Nan , Orkin Stuart H. 
Published: May 2022

AbstractOwing to low efficiency of homology-directed repair (HDR), precise knock-in (KI) of large DNA fragments is a challenge in genome editing. High-efficiency HDR has been reported for primary cells in preclinical gene therapy by combining CRISPR/Cas9 mediated induction of double-strand breaks (DSB) with delivery of a single-stranded DNA HDR-donor-template via highly purified recombinant adeno-associated virus (rAAV). Due in part to the labor and expense of rAAV particle purification, rAAV-mediated HDR-template delivery has been underutilized used to generate large KIs in cultured cell lines. Here, we report application of crude preparations of rAAV to deliver HDR-templates for the KI of large ∼2kb fragments at various genomic loci in several -human as well as mouse cell lines at high efficiency. Our approach should facilitate experiments necessitating KI of large DNA fragments to tag endogenous loci for visualization and/or conditional protein degradation.
KINOMO: A non-negative matrix factorization framework for recovering intra- and inter-tumoral heterogeneity from single-cell RNA-seq data
Authors: Tagore Somnath , Wang Yiping , Biermann Jana , Rabadan Raul , Azizi Elham , Izar Benjamin 
Published: May 2022

AbstractSingle-cell RNA-sequencing (scRNA-seq) is a powerful technology to uncover cellular heterogeneity in tumor ecosystems. Due to differences in underlying gene load, direct comparison between patient samples is challenging, and this is further complicated by the sparsity of data matrices in scRNA-seq. Here, we present a factorization method called KINOMO (Kernel dIfferentiability correlation-based NOn-negative Matrix factorization algorithm using Kullback-Leibler divergence loss Optimization). This tool uses quadratic approximation approach for error correction and an iterative multiplicative approach, which improves the quality assessment of NMF-identified factorization, while mitigating biases introduced by inter-patient genomic variability. We benchmarked this new approach against nine different methods across 15 scRNA-seq experiments and find that KINOMO outperforms prior methods when evaluated with an adjusted Rand index (ARI), ranging 0.82-0.91 compared to 0.68-0.77. Thus, KINOMO provides an improved approach for determining coherent transcriptional programs (and meta-programs) from scRNA-seq data of cancer tissues, enabling comparison of patients with variable genomic backgrounds.ClassificationPhysical Sciences (Applied Mathematics; Biophysics and Computational Biology), Biological Sciences (Applied Biological Sciences; Biophysics and Computational Biology; Medical Sciences; Systems Biology.).Significance StatementIdentification of shared or distinct cell programs in single-cell RNA-seq data of patient cancer cells is challenging due to underlying variability of gene load which determines transcriptional output. We developed an analytical approach to define transcriptional variability more accurately across patients and therefore enable comparison of program expression despite inherent genetic heterogeneity. Thus, this method overcomes challenges not adequately addressed by other methods broadly used for the analysis of single-cell genomics data.
Associations of antidepressants and antipsychotics with lipid parameters: Do CYP2D6/CYP2C19 genes play a role? A UK population-based study
Authors: Richards-Belle Alvin , Austin-Zimmerman Isabelle , Wang Baihan , Zartaloudi Eirini , Cotic Marius , Gracie Caitlin , Khani Noushin Saadullah , Wannasuphoprasit Yanisa , Wronska Marta , Dawda Yogita , Osborn David P.J. , Bramon Elvira 
Published: May 2022

ABSTRACTBackgroundDyslipidaemia is an important risk factor for cardiovascular morbidity in people with severe mental illness and which contributes to premature mortality in this population. The link between antipsychotics and dyslipidaemia is well-established, whilst evidence on antidepressants is mixed.AimsTo investigate (1) if antidepressant/antipsychotic use was associated with lipid parameters in UK Biobank participants, and (2) if CYP2D6 and CYP2C19 genetic variation plays a role.MethodsReview of self-reported prescription medications identified participants taking antidepressants/antipsychotics. Total, low-, and high-density lipoprotein (L/HDL-C) cholesterol and triglycerides derived from blood samples. CYP2D6 and CYP2C19 metabolic phenotypes were assigned from genetic data. Linear regression investigated study aims.ResultsOf 469,739 participants, 36,043 took antidepressants and 3,255 antipsychotics. Significant associations were found between use of amitriptyline, fluoxetine, citalopram/escitalopram, sertraline, paroxetine, and venlafaxine with worse levels of each lipid parameter (i.e., higher total cholesterol, LDL-C, and triglycerides and lower HDL-C). Venlafaxine was associated with the worst lipid profile (total cholesterol, mean difference: 0·21 mmol/L, 95% confidence interval [CI]: 0·17 to 0·26, p<0·001). Antipsychotic use was associated with lower HDL-C and higher triglycerides (0·31 mmol/L, 95% CI 0·28 to 0·35, p<0·001). In participants taking sertraline, the CYP2C19 intermediate metaboliser phenotype was associated with higher HDL-C (0·05 mmol/L 95% CI: 0·01 to 0·09, p=0·007) and lower triglycerides (-0·17 mmol/L 95% CI: -0·29 to -0·05, p=0·007).ConclusionsAntidepressants are significantly associated with adverse lipid profiles, potentially warranting baseline and regular monitoring of lipids. Further research should investigate why the CYP2C19 intermediate metaboliser phenotype may be protective for HDL-C and triglycerides in people taking sertraline.
Solid fuel use in relation to dementia risk in middle-aged and older adults: A prospective cohort study
Authors: Pu Fan , Hu Yingying , Li Chenxi , Cao Xingqi , Yang Zhenqing , Liu Yi , Zhang Jingyun , Li Xueqin , Yang Yongli , Wang Wei , Liu Xiaoting , Hu Kejia , Ma Yanan , Liu Zuyun 
Published: May 2022

AbstractObjectivesIt remains unknown whether household air pollution is associated with dementia risk. This study examined the associations between solid fuel use for cooking and heating (the main source of household air pollution) and dementia risk.MethodsThis analysis included data on 11,352 participants (aged 45+ years) from the 2011 wave of China Health and Retirement Longitudinal Study, with follow-up to 2018. Dementia risk was assessed by a risk score using the Rotterdam Study Basic Dementia Risk Model (BDRM) and then standardized for analysis. Household fuel types of cooking and heating were categorized as solid (e.g., coal, crop residue) and clean (e.g., central heating, solar). Multivariable analyses were performed using generalized estimating equations. Moreover, we examined the joint associations of solid fuel use for cooking and heating with the BDRM score.ResultsWe found an independent and significant association of solid (vs. clean) fuel use for cooking and heating with a higher BDRM score after adjusting for potential confounders (e.g., ß = 0.14 for solid fuel for cooking; 95% CI: 0.12, 0.17). Participants who used solid (vs. clean) fuel for both cooking and heating had the highest BDRM score (ß = 0.20; 95%CI: 0.16, 0.23). Subgroup analysis suggested stronger associations in participants living in rural areas.ConclusionsSolid fuel use for cooking and heating was independently associated with increased dementia risk in Chinese middle-aged and older adults, particularly among those living in rural areas. Our findings call for more efforts to facilitate universal access to clean energy for dementia prevention.
Characteristics of patients with positional OSA according to ethnicity and the identification of a novel phenotype – Lateral Positional Patients (Lateral PP): A MESA study
Authors: Sason Yuval Ben , Oksenberg Arie , Sobel Jonathan A. , Behar Joachim A. 
Published: May 2022

AbstractStudy ObjectivesTo investigate the characteristics of Obstructive Sleep Apnea (OSA) positional patients’ (PP) phenotypes among different ethnic groups in the Multi-Ethnic Study of Atherosclerosis (MESA) dataset. Moreover, we hypothesized the existence of a new OSA PP phenotype we coined “Lateral PP”, for whom the lateral apneas hypopnea index (AHI) is at least double the supine AHI.MethodsFrom 2,273 adults with sleep information, we analyzed data of 1,323 subjects that slept more than 4 hours and had at least 30 minutes of sleep in both the supine and the non-supine positions. Demographics and clinical information were compared for the different PP, and ethnic groups.Results861 (65.1%) patients had OSA and 35 (4.1%) were Lateral PP. Lateral PP patients were mainly females (62.9%), obese (31.4 median body mass index), had mild to moderate OSA (94.3%), and mostly were non-Chinese American (97.1%). Among all OSA patients, 550 (63.9%) were Supine PP, and 17.7% were supine-isolated OSA (siOSA). Supine PP and Lateral PP were present in 73.1% and 1.0% of Chinese Americans, 61.0% and 3.4% of Hispanics, 68.3% and 4.7% of White-Caucasian, and 56.2% and 5.2% of Black-African American OSA patients.ConclusionChinese-American have the highest prevalence of Supine PP, whereas Black-African American patients lean towards less Supine PP and higher Lateral PP. Lateral PP appears as a novel OSA phenotype. However, it was found for a small group of OSA patients and thus its presence should be further validated.Brief SummaryWe studied prevalence of obstructive sleep apnea (OSA) positional phenotypes among Black African-American, Caucasian, Hispanic, and Chinese American patients and described their demographic and polysomnographic characteristics. Despite similar levels of OSA severity in the four ethnic groups, Chinese American had a higher prevalence of Supine PP, whereas Black-African American patients were significantly less Supine PP, as compared to other ethnic groups.In addition, we identify a novel OSA PP phenotype we named “Lateral positional patients (Lateral-PP)”. These OSA patients had apnea and hypopnea events mainly in the lateral position. This was a small group of OSA patients (4.1%) that were mainly obese, female, with mild-moderate OSA, and more prevalent in Black-African American.
Mendelian Randomization Analysis of the Relationship Between Native American Ancestry and Gallbladder Cancer Risk
Authors: Zollner Linda , Boekstegers Felix , Ponce Carol Barahona , Scherer Dominique , Marcelain Katherine , Gárate-Calderón Valentina , Waldenberger Melanie , Morales Erik , Rojas Armando , Munoz César , Müller Bettina , Retamales Javier , de Toro Gonzalo , Kortmann Allan Vera , Barajas Olga , Teresa Rivera María , Cortés Analía , Loader Denisse , Saavedra Javiera , Gutiérrez Lorena , Ortega Alejandro , Bertrán Maria Enriqueta , Bartolotti Leonardo , Gabler Fernando , Campos Mónica , Alvarado Juan , Moisán Fabricio , Spencer Loreto , Nervi Bruno , Carvajal Daniel , Losada Héctor , Almau Mauricio , Fernández Plinio , Olloquequi Jordi , Carter Alice R. , Miquel Poblete Juan Francisco , Bustos Bernabe Ignacio , Guajardo Macarena Fuentes , Gonzalez-Jose Rolando , Cátira Bortolini Maria , Acuña-Alonzo Victor , Gallo Carla , Linares Andres Ruiz , Rothhammer Francisco , Bermejo Justo Lorenzo 
Published: May 2022

AbstractBackgroundA strong association between the proportion of Native American ancestry and the risk of gallbladder cancer (GBC) has been reported in observational studies. Chileans show the highest incidence of GBC worldwide, and the Mapuche are the largest Native American people in Chile. We set out to investigate the causal association between Native American Mapuche ancestry and GBC risk, and the possible mediating effects of gallstone disease and body mass index (BMI) on this association.MethodsMarkers of Mapuche ancestry were selected based on the informativeness for assignment measure and then used as instrumental variables in two-sample mendelian randomization (MR) analyses and complementary sensitivity analyses.ResultWe found evidence of a causal effect of Mapuche ancestry on GBC risk (inverse variance-weighted (IVW) risk increase of 0.8% for every 1% increase in Mapuche ancestry proportion, 95% CI 0.4% to 1.2%, p = 6.6×10-5). Mapuche ancestry was also causally linked to gallstone disease (IVW risk increase of 3.6% per 1% increase in Mapuche proportion, 95% CI 3.1% to 4.0%, p = 1.0×10-59), suggesting a mediating effect of gallstones in the relationship between Mapuche ancestry and GBC. In contrast, the proportion of Mapuche ancestry showed a negative causal effect on BMI (IVW estimate -0.006 kg/m2 per 1% increase in Mapuche proportion, 95% CI -0.009 to -0.003, p = 4.4×10-5).ConclusionsThe results presented here may have significant implications for GBC prevention and are important for future admixture mapping studies. Given that the association between Mapuche ancestry and GBC risk previously noted in observational studies appears to be causal, primary and secondary prevention strategies that take into account the individual proportion of Mapuche ancestry could be particularly efficient.
Hunter-gatherer oral microbiomes are shaped by contact network structure
Authors: Musciotto Federico , Dobon Begoña , Greenacre Michael , Mira Alex , Chaudhary Nikhil , Salali Gul Deniz , Gerbault Pascale , Schlaepfer Rodolph , Astete Leonora H. , Ngales Marilyn , Gomez-Gardenes Jesus , Latora Vito , Battiston Federico , Bertranpetit Jaume , Vinicius Lucio , Migliano Andrea Bamberg 
Published: May 2022

AbstractAncestral humans evolved a complex social structure still observed in extant hunter-gatherers. Here we investigate the effects of extensive sociality and mobility on the oral microbiome of 138 Agta hunter-gatherers from the Philippines. Comparisons of microbiome composition showed that the Agta are more similar to Central African Bayaka hunter-gatherers than to neighboring farmers. We also defined the Agta social microbiome as a set of 137 oral bacteria (only 7% of 1980 amplicon sequence variants) significantly influenced by social contact (quantified through wireless sensors of short-range interactions). We show that interaction networks covering large areas, and their strong links between close kin, spouses, and even unrelated friends, can significantly predict bacterial transmission networks across Agta camps. Finally, more central individuals to social networks are also bacterial supersharers. We conclude that hunter-gatherer social microbiomes, which are predominantly pathogenic, were shaped by evolutionary tradeoffs between extensive sociality and disease spread.
Organic Convolution in The Ventral Visual Pathway Can Explain the Variety of Shape Tuning in Area V4
Authors: Gold Carl 
Published: May 2022

AbstractThis modeling study proposes a novel theory for how V4 neurons embody selectivity to the varying degrees of curvature in diverse receptive field arrangements reported in previous recording studies. The model shows that a simple, unsupervised approach to curvature selectivity can explain a wide variety of past observations: V1 aggregates points into selectivity for lines and edges at a variety of rotations; V2 aggregates orientated segments into selectivity for corners at a variety of angles and rotations; V4 aggregates corners into curvature selectivity in a variety of degrees, rotations and positions. The model is implemented in 900,000 integrate and fire units in standard cortical micro-circuits obeying Dale’s law. The unit model and spike timing and transmission use realistic biophysical parameters. A novel method for simulating large numbers of integrate and fire units with tensor programming and GPU hardware is employed: By combining convolution with the time course of post-synaptic potentials, computation occurs in a feedforward cascade of loosely synchronized spikes. The model has relatively few parameters which are tuned by stochastic search with manual fine tuning. A synthesis of hierarchical and convolutional network models, this study adds novel elements to both: In comparison to previous hierarchical models there is a novel V4 mechanism and a biologically realistic computation based on single spikes using tensor convolution as the simulation engine. In comparison to previous convolution models there is a much higher degree of biological realism and a novel unsupervised approach to connection formation.
Privacy-Aware Kinship Inference in Admixed Populations using Projection on Reference Panels
Authors: Wang Su , Kim Miran , Li Wentao , Jiang Xiaoqian , Chen Han , Harmanci Arif 
Published: May 2022

AbstractEstimation of genetic relatedness, or kinship, is used occasionally for recreational purposes and in forensic applications. While numerous methods were developed to estimate kinship, they suffer from high computational requirements and often make an untenable assumption of homogeneous population ancestry of the samples. Moreover, genetic privacy is generally overlooked in the usage of kinship estimation methods. There can be ethical concerns about finding unknown familial relationships in 3rd party databases. Similar ethical concerns may arise while estimating and reporting sensitive population-level statistics such as inbreeding coefficients for the concerns around marginalization and stigmatization. Here, we make use of existing reference panels with a projection-based approach that simplifies kinship estimation in the admixed populations. We use simulated and real datasets to demonstrate the accuracy and efficiency of kinship estimation. We present a secure federated kinship estimation framework and implement a secure kinship estimator using homomorphic encryption-based primitives for computing relatedness between samples in 2 different sites while genotype data is kept confidential.
Motor and Visual Plasticity interact in Adult Humans
Authors: Sarı Izel D. , Lunghi Claudia 
Published: May 2022

AbstractNeuroplasticity is maximal during development and declines in adulthood, especially for sensory cortices. On the contrary, the motor cortex retains plasticity throughout the lifespan. This difference has led to a modular view of plasticity in which different brain regions have their own plasticity mechanisms that do not depend or translate on others. Recent evidence indicates that visual and motor plasticity share common neural mechanisms (e.g. GABAergic inhibition), indicating a possible link between these different forms of plasticity, however the interaction between visual and motor plasticity has never been tested directly. Here we show that when visual and motor plasticity are elicited at the same time in adult humans, visual plasticity is impaired, while motor plasticity is spared. This unilateral interaction between visual and motor plasticity demonstrates a clear link between these two forms of plasticity. We conclude that local neuroplasticity in separate systems might be regulated globally, to preserve overall homeostasis in the brain.
The LEPIS-HuR-TMOD4 axis regulates hepatic cholesterol homeostasis and accelerates atherosclerosis
Authors: Lv Ping , Pan Hangyu , Hu Kexin , Li Qinxian , Lin Rongzhan , Zheng Shaoyi , Guo Zhigang , Guo Kai 
Published: May 2022

Long noncoding RNAs (lncRNAs) play an important role in the entire progression of atherosclerosis. In this study, we identified an uncharacterized lncRNA, Liver Expressions by PSRC1 Induce Specifically (LEPIS). The expression of LEPIS and its potential target tropomodulin 4 (TMOD4) in the liver of ApoE-/- mice fed a high-fat diet was increased. An ApoE-/- mouse model with the overexpression of LEPIS or TMOD4 in liver was established, and we found that both LEPIS and TMOD4 increased the burden of atherosclerosis and reduced hepatic cholesterol levels. Further study revealed that LEPIS and TMOD4 affect the expression of genes related to hepatic cholesterol homeostasis, including proprotein convertase subtilisin/kexin type9 (PCSK9) and low-density lipoprotein receptor (LDLR), which are closely related to hypercholesterolemia. Mechanistically, human antigen R (HuR), an RNA-binding protein, was shown to be critical for the regulation of TMOD4 by LEPIS. Further, we found that overexpression of LEPIS promoted the shuttling of HuR from the nucleus to the cytoplasm, enhanced the stability of TMOD4 mRNA, and in turn promoted the expression of TMOD4. In addition, TMOD4 was found to affect intracellular cholesterol levels through PCSK9. These results suggest that the LEPIS-HuR-TMOD4 axis is a potential intervention target for hepatic cholesterol homeostasis and atherosclerosis.Graphical abstract
Rank concordance of polygenic indices: Implications for personalised intervention and gene-environment interplay
Authors: Muslimova Dilnoza , Pereira Rita Dias , Hinke Stephanie von , van Kippersluis Hans , Rietveld Cornelius A. , Meddens S. Fleur W. 
Published: May 2022

AbstractPolygenic indices (PGIs) are increasingly used to identify individuals at high risk of developing diseases and disorders and are advocated as a screening tool for personalised intervention in medicine and education. The performance of PGIs is typically assessed in terms of the amount of phenotypic variance they explain in independent prediction samples. However, the correct ranking of individuals in the PGI distribution is a more important performance metric when identifying individuals at high genetic risk. We empirically assess the rank concordance between PGIs that are created with different construction methods and discovery samples, focusing on cardiovascular disease (CVD) and educational attainment (EA). We find that the rank correlations between the constructed PGIs vary strongly (Spearman correlations between 0.17 and 0.94 for CVD, and between 0.40 and 0.85 for EA), indicating highly unstable rankings across different PGIs for the same trait. Simulations show that measurement error in PGIs is responsible for a substantial part of PGI rank discordance. Potential consequences for personalised medicine in CVD and research on gene-environment (G×E) interplay are illustrated using data from the UK Biobank.