bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-wide association study of 1,391 plasma metabolites in 6,136 Finnish men identifies 303 novel signals and provides biological insights into human diseases
Authors: Yin Xianyong , Chan Lap Sum , Bose Debraj , Jackson Anne U. , VandeHaar Peter , Locke Adam E. , Fuchsberger Christian , Stringham Heather M. , Yu Ketian , Silva Lilian Fernandes , Service Susan K. , Zhang Daiwei , Hector Emily C. , Young Erica , Ganel Liron , Das Indraniel , Abel Haley , Erdos Michael R. , Bonnycastle Lori L. , Kuusisto Johanna , Stitziel Nathan O. , Hall Ira , Wagner Gregory R. ,   FinnGen, Kang Jian , Morrison Jean , Burant Charles F. , Collins Francis S. , Ripatti Samuli , Palotie Aarno , Freimer Nelson B. , Mohlke Karen L. , Scott Laura J. , Wen Xiaoquan , Fauman Eric B. , Laakso Markku , Boehnke Michael 
Published: October 2021

AbstractFew studies have explored the impact of rare variants (minor allele frequency, MAF<1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1,391 plasma metabolites in 6,136 men from the late-settlement region of Finland. We identify 303 novel association signals, more than one third at variants rare or enriched in Finns. Many of these signals identify genes not previously implicated in metabolite genome-wide association studies and suggest mechanisms for diseases and disease-related traits.
Ambient heat exposure and COPD hospitalisations in England: A nationwide case-crossover study during 2007-2018
Authors: Konstantinoudis Garyfallos , Minelli Cosetta , Vicedo Cabrera Ana Maria , Ballester Joan , Gasparrini Antonio , Blangiardo Marta 
Published: October 2021

AbstractBackgroundThere is emerging evidence suggesting a link between ambient heat exposure and chronic obstructive pulmonary disease (COPD) hospitalisations. Individual and contextual characteristics can affect population vulnerabilities to COPD hospitalisation due to heat exposure. This study quantifies the effect of ambient heat on COPD hospitalisations and examines population vulnerabilities by age, sex, and contextual characteristics.MethodsIndividual data on COPD hospitalisation at high geographical resolution (postcodes) during 2007-2018 in England was retrieved from the small area health statistics unit. Maximum temperature at 1 km×1km resolution was available from the UK Met Office. We employed a case-cross over study design and fitted Bayesian conditional Poisson regression models. We adjusted for relative humidity and national holidays, and examined effect modification by age, sex, green space, average temperature, deprivation and urbanicity.ResultsAfter accounting for confounding, we found a 1.47% (95% Credible Interval 1.19% to 1.73%), increase in the hospitalisation risk for every 1°C increase in temperatures above 23.2°C (lags 0-2 days). We reported weak evidence of an effect modification by sex and age. We found a strong spatial determinant of the COPD hospitalisation risk due to heat exposure, that was alleviated when we accounted for contextual characteristics. 1 851 (95% CrI 1 576 to 2 079) COPD hospitalisations were associated with temperatures above 23.2°C annually.ConclusionOur study suggests that resources should be allocated to support the public health systems, for instance through developing or expanding heat-health alerts, to challenge the increasing future heat-related COPD hospitalisation burden.Key MessagesWhat is the key question?What is the short-term effect of heat exposure on COPD hospitalisation and which contextual/societal factors affect population vulnerability?What is the bottom line?For every 1°C increase in summer temperatures higher than 23.2°C, the risk of COPD hospitalisation increases by 1.47%, and populations in the North and in the South East are more vulnerable.Why read on?This large nationwide study in England using individual data quantifies the effect of heat exposure on COPD hospitalisations; these findings inform future policies regarding preparedness and resilience of public health systems against the increasing COPD burden due to the increasing temperatures.
SARS-CoV-2 Transmission and Impacts of Unvaccinated-Only Screening in Populations of Mixed Vaccination Status
Authors: Bubar Kate M. , Middleton Casey E. , Bjorkman Kristen K. , Parker Roy , Larremore Daniel B. 
Published: October 2021

AbstractCommunity testing programs focused on the unvaccinated population are being enacted in populations with mixed vaccination status to mitigate SARS-CoV-2 spread. Presumably, these policies assume that the unvaccinated are driving transmission, though it is not well understood how viral spread occurs in mixed-status populations. Here, we analyze a model of transmission in which a variable fraction of the population is vaccinated, with unvaccinated individuals proactively screened for infection. By exploring a range of transmission rates, vaccine effectiveness (VE) scenarios, and rates of prior infection, this analysis reveals principles of viral spread in communities of mixed vaccination status, with implications for screening policies. As vaccination rates increase, the proportion of transmission driven by the unvaccinated population decreases, such that most community spread is driven by breakthrough infections once vaccine coverage exceeds 55% (omicron) or 80% (delta), with additional variation dependent on waning or boosted VE. More broadly, the potential impacts of unvaccinated-only screening fall into three distinct parameter regions: (I) “flattening the curve” with little impact on cumulative infections, (II) effectively suppressing transmission, and (III) negligible impact because herd immunity is reached without screening. By evaluating a wide range of scenarios, this work finds broadly that effective mitigation of SARS-CoV-2 transmission by unvaccinated-only screening is highly dependent on vaccination rate, population-level immunity, screening compliance, and vaccine effectiveness against the current variant.
Neutralization of Mu and C.1.2 SARS-CoV-2 Variants by Vaccine-elicited Antibodies in Individuals With and Without Previous History of Infection
Authors: Tada Takuya , Zhou Hao , Dcosta Belinda M. , Samanovic Marie I. , Cornelius Amber , Herati Ramin S. , Mulligan Mark J. , Landau Nathaniel R. 
Published: October 2021

AbstractRecently identified SARS-CoV-2 variants Mu and C.1.2 have mutations in the receptor binding domain and N- and C-terminal domains that might confer resistance to natural and vaccine-elicited antibody. Analysis with pseudotyped lentiviruses showed that viruses with the Mu and C.1.2 spike proteins were partially resistant to neutralization by antibodies in convalescent sera and those elicited by mRNA and adenoviral vector-based vaccine-elicited antibodies. Virus with the C.1.2 variant spike, which is heavily mutated, was more neutralization-resistant than that of any of variants of concern. The resistance of the C.1.2 spike was caused by a combination of the RBD mutations N501Y, Y449H and E484K and the NTD mutations. Although Mu and C.1.2 were partially resistant to neutralizing antibody, neutralizing titers elicited by mRNA vaccination remained above what is found in convalescent sera and thus are likely to remain protective against severe disease. The neutralizing titers of sera from infection-experienced BNT162b2-vaccinated individuals, those with a history of previous SARS-CoV-2 infection, were as much as 15-fold higher than those of vaccinated individuals without previous infection and effectively neutralized all of the variants. The findings demonstrate that individuals can raise a broadly neutralizing humoral response by generating a polyclonal response to multiple spike protein epitopes that should protect against current and future variants.
Optimal Precision and Accuracy in 4Pi-STORM using Dynamic Spline PSF Models
Authors: Bates Mark , Keller-Findeisen Jan , Przybylski Adrian , Hüper Andreas , Stephan Till , Ilgen Peter , Cereceda Delgado Angel R. , D’Este Elisa , Jakobs Stefan , Sahl Steffen J. , Hell Stefan W. 
Published: October 2021

AbstractDual-objective 4Pi fluorescence detection enables single molecule localization microscopy, e.g. PALM and STORM, with sub-10 nanometer spatial resolution in 3D. Despite its outstanding sensitivity, wider application of this technique has been hindered by complex instrumentation requirements and the challenging nature of the data analysis. The point spread function (PSF) of the 4Pi optical system is difficult to model, leading to periodic image artifacts and compromised resolution. In this work we report the development of a 4Pi-STORM microscope which obtains improved resolution and accuracy by modeling the 4Pi PSF dynamically, while using a simpler optical design. We introduce dynamic spline PSF models, which incorporate fluctuations in the modulation phase of the experimentally determined PSF, capturing the temporal dynamics of the optical system. Our method reaches the theoretical limits for localization precision while largely eliminating phase-wrapping artifacts, by making full use of the information content of the data. With a 3D precision as high as 2 – 3 nanometers, 4Pi-STORM achieves new levels of image detail, and extends the range of biological questions that can be addressed by fluorescence nanoscopy, as we demonstrate by investigating protein and nucleic acid organization in primary neurons and mammalian mitochondria.
Base editors for citrus gene editing
Authors: Huang Xiaoen , Wang Yuanchun , Wang Nian 
Published: October 2021

AbstractBase editors, such as adenine base editors (ABE) and cytosine base editors (CBE), provide alternatives for precise genome editing without generating double-strand breaks (DSBs), thus avoiding the risk of genome instability and unpredictable outcomes caused by DNA repair. Precise gene editing mediated by base editors in citrus has not been reported. Here, we have successfully adapted the ABE to edit the TATA box in the promoter region of the canker susceptibility gene LOB1 from TATA to CACA in grapefruit (Citrus paradise) and sweet orange (Citrus sinensis). TATA-edited plants are resistant to the canker pathogen Xanthomonas citri subsp. citri (Xcc). In addition, CBE was successfully used to edit the acetolactate synthase (ALS) gene in citrus. ALS-edited plants were resistant to the herbicide chlorsulfuron. Two ALS-edited plants did not show green fluorescence although the starting construct for transformation contains a GFP expression cassette. The Cas9 gene was undetectable in the herbicide-resistant citrus plants. This indicates that the ALS edited plants are transgene-free, representing the first transgene-free gene-edited citrus using the CRISPR technology. In summary, we have successfully adapted the base editors for precise citrus gene editing. The CBE base editor has been used to generate transgene-free citrus via transient expression.
Expanding the pool of public controls for GWAS via a method for combining genotypes from arrays and sequencing
Authors: Mathur Ravi , Fang Fang , Gaddis Nathan , Hancock Dana B. , Cho Michael H. , Hokanson John E. , Bierut Laura J. , Lutz Sharon M. , Young Kendra , Smith Albert V. ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Silverman Edwin K. , Page Grier P. , Johnson Eric O. 
Published: October 2021

AbstractGenome-wide association studies (GWAS) have made impactful discoveries for complex diseases, often by amassing very large sample sizes. Yet, GWAS of many diseases remain underpowered, especially for non-European ancestries. One cost-effective approach to increase sample size is to combine existing case-only cohorts with public controls, but this approach is limited by the need for a large overlap in variants across genotyping arrays and the scarcity of non-European controls. We developed and validated a protocol, Genotyping Array-WGS Merge (GAWMerge), for combining genotypes from arrays and whole genome sequencing, ensuring complete variant overlap, and allowing for diverse samples like Trans-Omics for Precision Medicine to be used. Our protocol involves phasing, imputation, and filtering. We illustrated its ability to control type I error and recover known disease-associated signals across technologies, independent datasets, and ancestries in smoking-related cohorts. GAWMerge enables genetic studies to leverage existing cohorts to validly increase sample size and enhance discovery.
Similar geographic patterns but distinct assembly processes of abundant and rare bacterioplankton communities in river networks of the Taihu Basin
Authors: Xu Sai 
Published: October 2021

AbstractBacterioplankton play an important role in the biochemical cycling in rivers. The dynamics of hydrologic conditions in rivers were believed to affect geographic pattern and assembly process of these microorganisms, which have not been widely investigated. In this study, the geographic pattern and community assembly process of bacterioplankton in river networks of the Taihu Basin were systematically explored using amplicon sequencing of the 16S rRNA gene. The results showed that community structure, diversity, and taxonomic composition of bacterioplankton all exhibited significant temporal variation during wet, normal, and dry seasons (p<0.01). The neutral community model and null model were applied to reveal the assembly process of bacterioplankton community. The stochastic process and deterministic process both shaped the bacterioplankton community with greater influence of deterministic process. In addition, the abundant and rare bacterioplankton communities were comparatively analyzed. The abundant and rare bacterioplankton communities exhibited similar temporal dynamics (principal coordinates analysis) and spatial variations (distance-decay relationship), indicating similar geographic patterns. Meanwhile, distinct assembly processes were observed for the abundant and rare bacterioplankton communities. Stochastic process (dispersal limitation) shaped the abundant bacterioplankton community while deterministic process (heterogeneous selection) dominated the assembly process of rare bacterioplankton community. Mantel test, redundancy analysis, and correlation analysis together indicated that pH and dissolved oxygen were the major environmental attributes that affected the bacterioplankton community structure and assembly process. These results expanded our understanding of the geographic patterns, assembly processes, and driving factors of the bacterioplankton community in river networks and provided clues provided clues for the underlying mechanisms.
Integrative system biology analysis of barley transcriptome – hormonal signaling against biotic stress
Authors: Soltani Zahra , Moghadam Ali , Tahmasebi Ahmad , Niazi Ali 
Published: October 2021

AbstractBiotic stresses are environmental factors that cause a variety of crop diseases and damages. In contrast, crops trigger specific transduction signaling pathways that the hormones are the central players. Integrative OMICS for systems genetic engineering approach contributes in the understanding of molecular mechanisms. In this research, the system biology approaches were applied to discover particular molecular interactions between biotic stresses and hormonal signaling in barley. The meta-analysis of the data identified a total of 1232 and 304 differentially expressed genes (DEGs) respectively so that were significantly involved in defense processes and hormone signaling. A total of 24 TFs belonged to 15 conserved families and 6 TFs belonged to 6 conserved families were identified for biotic and hormonal data respectively, whereas NF-YC, GNAT, and whirly families were the most abundant groups. The functional analysis of the upstream regions for over-represented cis-acting elements revealed that were involved activation of transcription factors in response to pathogens and hormones. Based on the co-expression analysis, 6 and 7 distinct co-expression modules related to biotic stresses and hormonal signaling were respectively uncovered. The gene network analysis also identified novel hub genes such as TIM10, DRT101, ADG1, and TRA2 which may be involved in regulating defense responses to biotic stresses. In addition, many new genes with unknown function were obtained. Since this study represents a first preliminary curated system biology analysis of barley transcriptomic responses to biotic stresses and hormone treatments, introduces important candidate genes that may be beneficial to crop biotechnologists to accelerate genetic engineering programs.
Multiple Sex Chromosome Drivers in a Mammal with Three Sex Chromosomes
Authors: Saunders Paul A. , Perez Julie , Ronce Ophélie , Veyrunes Frédéric 
Published: October 2021

AbstractA few mammals have unusual sex determining systems whereby fertile XY females live alongside XX females and XY males. These systems are regarded as evolutionary paradoxes because of the production of sex-reversed individuals and non-viable embryos, but they nevertheless seem stable over evolutionary time. Several hypotheses have been proposed to account for their stability, including models involving sex chromosome drive (i.e., biased transmission of sex chromosomes to the next generation). Here we corroborate this hypothesis inMus minutoides, a close relative of the house mouse in which the presence of XY females is due to the evolution of a third sex chromosome: a feminizing X. Through extensive molecular sexing of pups at weaning, we reveal the existence of a remarkable male sex chromosome drive system in this species, whereby direction and strength of drive is conditional upon the genotype of males’ partners: males transmit their Y to almost 80% of their offspring when mating with XX females, and only 36% when mating with XY females. Using mathematical modelling, we explore the joint evolution of these unusual sex-determining and drive systems, revealing that different sequences of events could have led to the evolution of this bizarre system, and that the “conditional” nature of sex chromosome drive stabilizes the feminizing X, and even precludes a return to a standard XX/XY system.
Knock-down of a regulatory barcode shifts macrophage polarization destination from M1 to M2 and increases pathogen burden uponS. aureusinfection
Authors: Ravichandran Sathyabaarathi , Bhatt Bharat , Shah Awantika , Balaji Kithiganahalli Narayanaswamy , Chandra Nagasuma 
Published: October 2021

AbstractMacrophages are driven to form distinct functional phenotypes in response to different immunological stimuli, in a process widely referred to as macrophage polarization. Transcriptional regulators that guide macrophage polarization in response to a given trigger remain largely unknown. In this study, we interrogate the programmable landscape in macrophages to find regulatory panels that determine the precise polarization state that a macrophage is driven to. Towards this, we configure an integrative network analysis pipeline that utilizes macrophage transcriptomes in response to 28 distinct stimuli and reconstructs contextualized human gene regulatory networks, and identifies epicentres of perturbations in each case. We find that these contextualized regulatory networks form a spectrum of thirteen distinct clusters with M1 and M2 at the two ends. Using our computational pipeline, we identify combinatorial panels of epicentric regulatory factors (RFs) for each polarization state. We demonstrate that a set of three RFs i.e.,CEBPB,NFE2L2andBCL3, is sufficient to change the polarization destination from M1 to M2. siRNA knockdown of the 3-RF set in THP1 derived M0 cells, despite exposure to an M1 stimulant, significantly attenuated the shift to M1 phenotype, and instead increased the expression of M2 markers. Single knockdown of each RF also showed a similar trend. The siRNA-mediated knockdown of the 3-RF set rendered the macrophages hyper-susceptible toStaphylococcus aureusinfection, demonstrating the importance of these factors in modulating immune responses. Overall, our results provide insights into the transcriptional mechanisms underlying macrophage polarization and identify key regulatory factors that may be targeted to modulate immune responses.
Overexpression of Zinc finger (GpZF) promotes drought tolerance in grass pea (Lathyrus sativus)
Authors: Parsa Mitra , Kashanchi Mona , Zeinali Amineh , pourfakhraei Elaheh 
Published: October 2021

ABSTRACTThe genes encoding Cys2/His2-type zinc finger proteins constitute a large family in higher plants consisting of a family of plant transcription factors. GpZF encodes a Cys2/His2-type zinc finger protein. The purposes of this study are to elucidate further the functions of a novel zinc finger transcription factor in the grass pea (GpZF) gene involved in the drought stress response in the grass pea (Lathyrus sativus) and to investigate its biochemical and physiological parameters under stress conditions. GpZF was expressed in grass pea. Relative gene expression analysis showed the GpZF gene in independent transgenic lines was more under drought mild and severe treatments (50% and 25% field capacity-FC). Furthermore, overexpression of this gene in grass pea results in more relative water content, free proline, and soluble sugars than the wild-type (WT) plants under 50% and 25% FC stresses. Moreover, in 25% FC, the independent transgenic lines revealed an increase in survival rates and dry weight than the WT plants. GpZF thus implies the positive role in drought stress tolerance in Lathyrus sativus. In conclusion, the transgenic grass pea plants generated in this study could be used to farm arid areas.HighlightGpZF is a positive regulator in drought stress tolerance in grass pea.
Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities
Authors: Esposito Roberta , Polidori Taisia , Meise Dominik F. , Pulido-Quetglas Carlos , Chouvardas Panagiotis , Forster Stefan , Schaerer Paulina , Kobel Andrea , Schlatter Juliette , Roemmele Michaela , Westemeier Emily S. , Zhu Lina , Lanzós Andrés , Guillen-Ramirez Hugo A. , Basile Giulia , Carrozzo Irene , Vancura Adrienne , Ullrich Sebastian , Andrades Alvaro , Harvey Dylan , Medina Pedro P. , Ma Patrick C. , Haefliger Simon , Wang Xin , Martinez Ivan , Ochsenbein Adrian , Riether Carsten , Johnson Rory 
Published: October 2021

AbstractLong noncoding RNAs (lncRNAs) are widely dysregulated in cancer, yet their functional roles in cellular disease hallmarks remain unclear. Here we employ pooled CRISPR deletion to perturb all 831 lncRNAs in KRAS-mutant non-small cell lung cancer (NSCLC), and measure their contribution to proliferation, chemoresistance and migration across two cell backgrounds. Integrative analysis of this data outperforms conventional “dropout” screens in identifying cancer genes, while prioritising disease-relevant lncRNAs with pleiotropic and background-independent roles. Altogether 60 high-confidence oncogenic lncRNAs are active in NSCLC, the majority identified here for the first time, and which tend to be amplified and overexpressed in tumours. A follow-up antisense oligonucleotide (ASO) screen shortlisted two candidates, Cancer Hallmarks in Lung LncRNA (CHiLL 1&2), whose knockdown consistently suppressed cancer hallmarks in a variety of 2D and 3D tumour models. Molecular phenotyping reveals that CHiLL 1&2 control cellular-level phenotypes via distinct transcriptional networks converging on common oncogenic pathways. In summary, this work reveals a multi-dimensional functional lncRNA landscape underlying NSCLC that contains potential therapeutic vulnerabilities.