bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct 3D contacts and phenotypic consequences of adjacent non-coding loci in the epigenetically quiescent regions
Authors: Wu Peiyao , Wang Wei 
Published: September 2023

AbstractNon-coding regions of the human genome are important for functional regulations, but their mechanisms remain elusive. We used machine learning to guide a CRISPR screening on hubs (i.e. non-coding loci forming many 3D contacts) and significantly increased the discovery rate of hubs essential for cell growth. We found no clear genetic or epigenetic differences between essential and nonessential hubs, but we observed that some neighboring hubs in the linear genome have distinct spatial contacts and opposite effects on cell growth. One such pair in an epigenetically quiescent region showed different impacts on gene expression, chromatin accessibility and chromatin organization. We also found that deleting the essential hub altered the genetic network activity and increased the entropy of chromatin accessibility, more severe than that caused by deletion of the nonessential hub, suggesting that they are critical for maintaining an ordered chromatin structure. Our study reveals new insights into the system-level roles of non-coding regions in the human genome.
Adaptive multipole models of OPM data
Authors: Tierney Tim M , Seedat Zelekha , Pier Kelly St. , Mellor Stephanie , Barnes Gareth R 
Published: September 2023

AbstractMultipole expansions have been used extensively in the Magnetoencephalography (MEG) literature for mitigating environmental interference and modelling brain signal. However, their application to Optically Pumped Magnetometer (OPM) data is challenging due to the wide variety of existing OPM sensor and array designs. We therefore explore how such multipole models can be adapted to provide stable models of brain signal and interference across OPM systems. Firstly, we demonstrate how prolate spheroidal (rather than spherical) harmonics can provide a compact representation of brain signal when sampling on the scalp surface with as few as 100 channels. We then introduce a type of orthogonal projection incorporating this basis set, the Adaptive Multipole Models (AMM), which provides robust interference rejection across systems, even in the presence of spatially structured nonlinearity errors. This projection is always stable, as it is an orthogonal projection, and will only ever decrease the white noise in the data. However, for array designs that are suboptimal for spatially separating brain signal and interference, this method can remove brain signal components. We contrast these properties with the more typically used multipole expansion, Signal Space Separation (SSS), which never reduces brain signal amplitude but is less robust to the effect of sensor nonlinearity errors on interference rejection and can increase noise in the data if the system is sub-optimally designed (as it is an oblique projection). We conclude with an empirical example utilizing AMM to maximize signal to noise ratio (SNR) for the stimulus locked neuronal response to a flickering visual checkerboard in a 128-channel OPM system and demonstrate up to 40dB software shielding in real data.
Retracing Human Genetic Histories and Natural Selection Using Precise Local Ancestry Inference
Authors: Lerga-Jaso Jon , Novković Biljana , Unnikrishnan Deepu , Bamunusinghe Varuna , Hatorangan Marcelinus R. , Manson Charlie , Pedersen Haley , Osama Alex , Terpolovsky Andrew , Bohn Sandra , De Marino Adriano , Mahmoud Abdallah A. , Bircan Karatuğ O. , Khan Umar , Grabherr Manfred G. , Yazdi Puya G. 
Published: September 2023

AbstractIn an increasingly diverse world, including admixed individuals in genomic studies is imperative for equity and portability. A crucial first step is precise local ancestry inference (LAI). We have developed Orchestra, a LAI model with unprecedented accuracy, and trained on over 10,000 single-origin individuals from 35 worldwide populations. We employed Orchestra to delve into genetic relationships and demographic histories, with a focus on Latin Americans, a prime example of admixture, and the Ashkenazi Jewish, whose origins have long been debated. Finally, Orchestra enabled us to map signatures of selection, notably identifying trace Scandinavian ancestry in British samples and unveiling an immune-rich region linked to respiratory infections. Our work advances the field of LAI and holds promise for improvements in future applications for admixed populations.One-Sentence SummaryOrchestra unveils Latino and Ashkenazi ancestral roots and a candidate Viking locus under selection in the British population
Programmed Cell Death Modifies Neural Circuits and Tunes Intrinsic Behavior
Authors: Kochersberger Alison , Torkashvand Mohammad Mahdi , Lee Dongyeop , Baskoylu Saba , Sengupta Titas , Koonce Noelle , Emerson Chloe E. , Patel Nandan V. , Colón-Ramos Daniel , Flavell Steven , Horvitz H. Robert , Venkatachalam Vivek , Hammarlund Marc 
Published: September 2023

AbstractProgrammed cell death is a common feature of animal development. During development of theC. eleganshermaphrodite, programmed cell death (PCD) removes 131 cells from stereotyped positions in the cell lineage, mostly in neuronal lineages. Blocking cell death results in supernumerary “undead” neurons. We find that undead neurons can be wired into circuits, can display activity, and can modify specific behaviors. The two undead RIM-like neurons participate in the RIM-containing circuit that computes movement. The addition of these two extra neurons results in animals that initiate fewer reversals and lengthens the duration of those reversals that do occur. We describe additional behavioral alterations of cell-death mutants, including in turning angle and pharyngeal pumping. These findings reveal that, like too much PCD, too little PCD can modify nervous system function and animal behavior.
Effectiveness of Canadian travel restrictions in reducing burden of SARS-CoV-2 variants of concern
Authors: McLaughlin Angela , Montoya Vincent , Miller Rachel L. ,   Canadian COVID-19 Genomics Network (CanCOGeN) Consortium, Worobey Michael , Joy Jeffrey B. 
Published: September 2023

AbstractEvaluating travel restriction effectiveness in mitigating infectious disease burden is critical for informing public health policy. Here, we quantify where and when variants of SARS-CoV-2 were introduced into Canada to evaluate the extent to which travel restrictions averted viral introductions and COVID-19 case burden. Our results suggest that, across SARS-CoV-2 variants of concern subject to travel restrictions, at least 281 introductions were prevented, accounting for an averted burden of approximately 44,064 cases. This corresponds to approximately 441 averted hospitalizations, 24 averted deaths, and cost savings to Canadian health care systems of approximately 11.2 million Canadian dollars. Travel restrictions were found to be most effective when implemented rapidly during exponential case growth in the focal source and when global circulation was limited. Our analyses reveal that COVID-19 travel restrictions mitigated case burdens and highlight their value in future pandemic response.SummaryCOVID-19 travel restrictions against variants worked and were most effective when implemented rapidly and preceding new variants’ wider circulation.
Determinants of SARS-CoV-2 IgG response and decay in Canadian healthcare workers: a prospective cohort study
Authors: Cherry Nicola , Adisesh Anil , Burstyn Igor , Charlton Carmen , Chen Yan , Durand-Moreau Quentin , Labrèche France , Ruzycki Shannon , Turnbull LeeAnn , Zadunayski Tanis , Yasui Yutaka 
Published: September 2023

AbstractIntroductionHealthcare workers (HCWs) from an interprovincial Canadian cohort were asked to give serial blood samples to identify factors associated with anti-receptor binding domain (anti-RBD) IgG response to the SARS-CoV-2 virus.MethodsMembers of the HCW cohort donated blood samples four months after their first SARS-CoV-2 immunization and again at 7, 10 and 13 months. Date and type of immunizations and dates of SARS-CoV-2 infection were collected at each of four contacts, together with information on immunologically-compromising conditions and current therapies. Blood samples were analyzed centrally for anti-RBD IgG and anti-nucleocapsid IgG (Abbott Architect, Abbott Diagnostics). Records of immunization and SARS-CoV-2 testing from public health agencies were used to assess the impact of reporting errors on estimates from the random-effects multivariable model fitted to the data.Results2752 of 4567 vaccinated cohort participants agreed to donate at least one blood sample. Modelling of anti-RBD IgG titer from 8903 samples showed an increase in IgG with each vaccine dose and with first infection. A decrease in IgG titer was found with the number of months since vaccination or infection, with the sharpest decline after the third dose. An immunization regime that included mRNA1273 (Moderna) resulted in higher anti-RBD IgG. Participants reporting multiple sclerosis, rheumatoid arthritis or taking selective immunosuppressants, tumor necrosis factor inhibitors, calcineurin inhibitors and antineoplastic agents had lower anti-RBD IgG. Supplementary analyses showed higher anti-RBD IgG in those reporting side-effects of vaccination, no relation of anti-RBD IgG to obesity and lower titers in women immunized early in pregnancy. Sensitivity analysis results suggested no important bias in the self-report data.ConclusionCreation of a prospective cohort was central to the credibility of results presented here. Serial serology assessments, with longitudinal analysis, provided effect estimates with enhanced accuracy and a clearer understanding of medical and other factors affecting response to vaccination.
Identification of Cancer Risk Groups through Multi-Omics Integration using Autoencoder and Tensor Analysis
Authors: Braytee Ali , He Sam , Tang Shuxian , Sun Yuxuan , Jiang Xiaoying , Yu Xuanding , Khatri Inder , Prasad Mukesh , Anaissi Ali 
Published: September 2023

Identifying cancer risk groups by integrative multi-omics has attracted researchers in their quest to find biomarkers from diverse risk-related omics. Stratifying the patients into cancer risk groups using genomics is essential for clinicians for pre-prevention treatment to improve the survival time for patients and identify the appropriate therapy strategies. This study proposes an integrative multi-omics framework that can extract the features from various omics simultaneously. The framework employs autoencoders to learn the non-linear representation of the data and applies tensor analysis for feature learning. Further, the clustering method is used to stratify the patients into multiple cancer risk groups. Several omics were included in the experiments, namely methylation, somatic copy-number variation (SCNV), micro RNA (miRNA) and RNA sequencing (RNAseq) from two cancer types, including Glioma and Breast Invasive Carcinoma from the TCGA dataset. The results of this study are promising, as evidenced by the survival analysis and classification models, which outperformed the state-of-art. The patients can be significantly (p-value<0.05) divided into risk groups using extracted latent variables from the fused multi-omics data. The pipeline is open source to help researchers and clinicians identify the patients’ risk groups using genomics.Additional Key Words and Phrases: Multi-omics, Autoencoders, Tensors, Cancer risk groups
Functional connectome through the human life span
Authors: Sun Lianglong , Zhao Tengda , Liang Xinyuan , Xia Mingrui , Li Qiongling , Liao Xuhong , Gong Gaolang , Wang Qian , Pang Chenxuan , Yu Qian , Bi Yanchao , Chen Pindong , Chen Rui , Chen Yuan , Chen Taolin , Cheng Jingliang , Cheng Yuqi , Cui Zaixu , Dai Zhengjia , Deng Yao , Ding Yuyin , Dong Qi , Duan Dingna , Gao Jia-Hong , Gong Qiyong , Han Ying , Han Zaizhu , Huang Chu-Chung , Huang Ruiwang , Huo Ran , Li Lingjiang , Lin Ching-Po , Lin Qixiang , Liu Bangshan , Liu Chao , Liu Ningyu , Liu Ying , Liu Yong , Lu Jing , Ma Leilei , Men Weiwei , Qin Shaozheng , Qiu Jiang , Qiu Shijun , Si Tianmei , Tan Shuping , Tang Yanqing , Tao Sha , Wang Dawei , Wang Fei , Wang Jiali , Wang Pan , Wang Xiaoqin , Wang Yanpei , Wei Dongtao , Wu Yankun , Xie Peng , Xu Xiufeng , Xu Yuehua , Xu Zhilei , Yang Liyuan , Yuan Huishu , Zeng Zilong , Zhang Haibo , Zhang Xi , Zhao Gai , Zheng Yanting , Zhong Suyu ,   Alzheimer’s Disease Neuroimaging Initiative,   Cam-CAN,   Developing Human Connectome Project,   DIDA-MDD Working Group,   MCADI,   NSPN, He Yong 
Published: September 2023

AbstractThe lifespan growth of the functional connectome remains unknown. Here, we assemble task-free functional and structural magnetic resonance imaging data from 33,250 individuals aged 32 postmenstrual weeks to 80 years from 132 global sites. We report critical inflection points in the nonlinear growth curves of the global mean and variance of the connectome, peaking in the late fourth and late third decades of life, respectively. After constructing a fine-grained, lifespan-wide suite of system-level brain atlases, we show distinct maturation timelines for functional segregation within different systems. Lifespan growth of regional connectivity is organized along a primary-to-association cortical axis. These connectome-based normative models reveal substantial individual heterogeneities in functional brain networks in patients with autism spectrum disorder, major depressive disorder, and Alzheimer’s disease. These findings elucidate the lifespan evolution of the functional connectome and can serve as a normative reference for quantifying individual variation in development, aging, and neuropsychiatric disorders.
An interchange property for the rooted Phylogenetic Subnet Diversity on phylogenetic networks
Authors: Coronado Tomás M. , Riera Gabriel , Rosselló Francesc 
Published: September 2023

AbstractFaith’s Phylogenetic Diversity (PD) on rooted phylogenetic trees satisfies the so-called strong exchange property that guarantees that, for every two sets of leaves of different cardinalities, a leaf can always be moved from the largest set to the smallest in such a way that the sum of the PD values does not decrease. This strong exchange property entails a simple polynomial-time greedy solution to the PD optimization problem on rooted phylogenetic trees. In this paper we obtain an exchange property for the rooted Phylogenetic Subnet Diversity (rPSD) on rooted phylogenetic networks of bounded level and reticulations’ in-degree, which involves a more complicated interchange of leaves. We derive from it a polynomial-time greedy solution to the rPSD optimization problem on rooted semibinary level-2 phylogenetic networks.
Lipid peroxidation drives liquid-liquid phase separation and disrupts raft protein partitioning in biological membranes
Authors: Balakrishnan Muthuraj , Kenworthy Anne K. 
Published: September 2023

AbstractThe peroxidation of membrane lipids by free radicals contributes to aging, numerous diseases, and ferroptosis, an iron-dependent form of cell death. Peroxidation changes the structure, conformation and physicochemical properties of lipids, leading to major membrane alterations including bilayer thinning, altered fluidity, and increased permeability. Whether and how lipid peroxidation impacts the lateral organization of proteins and lipids in biological membranes, however, remains poorly understood. Here, we employ cell-derived giant plasma membrane vesicles (GPMVs) as a model to investigate the impact of lipid peroxidation on ordered membrane domains, often termed membrane rafts. We show that lipid peroxidation induced by the Fenton reaction dramatically enhances phase separation propensity of GPMVs into co-existing liquid ordered (raft) and liquid disordered (non-raft) domains and increases the relative abundance of the disordered, non-raft phase. Peroxidation also leads to preferential accumulation of peroxidized lipids and 4-hydroxynonenal (4-HNE) adducts in the disordered phase, decreased lipid packing in both raft and non-raft domains, and translocation of multiple classes of proteins out of rafts. These findings indicate that peroxidation of plasma membrane lipids disturbs many aspects of membrane rafts, including their stability, abundance, packing, and protein and lipid composition. We propose that these disruptions contribute to the pathological consequences of lipid peroxidation during aging and disease, and thus serve as potential targets for therapeutic intervention.
Cas13d-mediated isoform-specific RNA knockdown with a unified computational and experimental toolbox
Authors: Schertzer Megan D. , Stirn Andrew , Isaev Keren , Pereira Laura , Das Anjali , Harbison Claire , Park Stella H. , Wessels Hans-Hermann , Sanjana Neville E. , Knowles David A. 
Published: September 2023

AbstractAlternative splicing is an essential mechanism for diversifying proteins, in which mature RNA isoforms produce proteins with potentially distinct functions. Two major challenges in characterizing the cellular function of isoforms are the lack of experimental methods to specifically and efficiently modulate isoform expression and computational tools for complex experimental design. To address these gaps, we developed and methodically tested a strategy which pairs the RNA-targeting CRISPR/Cas13d system with guide RNAs that span exon-exon junctions in the mature RNA. We performed a high-throughput essentiality screen, quantitative RT-PCR assays, and PacBio long read sequencing to affirm our ability to specifically target and robustly knockdown individual RNA isoforms. In parallel, we provide computational tools for experimental design and screen analysis. Considering all possible splice junctions annotated in GENCODE for multi-isoform genes and our gRNA efficacy predictions, we estimate that our junction-centric strategy can uniquely target up to 89% of human RNA isoforms, including 50,066 protein-coding and 11,415 lncRNA isoforms. Importantly, this specificity spans all splicing and transcriptional events, including exon skipping and inclusion, alternative 5’ and 3’ splice sites, and alternative starts and ends.
Real-world gait and turning in individuals scheduled for total knee arthroplasty
Authors: Boekesteijn R.J. , Keijsers N.L.W. , Defoort K. , Mancini M. , Bruning F.J. , El-Gohary M. , Geurts A.C.H. , Smulders K. 
Published: September 2023

AbstractObjectiveTo compare real-world gait and turning between individuals scheduled for total knee arthroplasty (TKA) and healthy controls, using continuous monitoring with inertial measurement units (IMUs).DesignReal-world gait and turning data were collected for 5-7 days in individuals scheduled for TKA (n=34) and healthy controls in the same age range (n=32) using IMUs on the feet and lower back. Gait and turning parameters were compared between groups using a linear regression model. Data was further analyzed by stratification of gait bouts based on bout length, and turns based on turning angle and turning direction.ResultsDominant real-world gait speed was 0.21 m/s lower in individuals scheduled for TKA compared to healthy controls. The between-group difference in gait speed was -0.10 m/s for bouts containing 0-10 strides and -0.15 m/s for bouts with 160+ strides. Stride time was 0.05 s higher in individuals scheduled for TKA. Step time asymmetry was not different between the groups. Regarding walking activity, individuals scheduled for TKA walked 72 strides/hour less than healthy controls, and maximum bout length was 316 strides shorter. Irrespective of the size of the turn, turning velocity was lower in individuals scheduled for TKA. Turning velocity did not differ between turns over the affected leg compared to the unaffected leg.ConclusionIndividuals scheduled for TKA showed specific walking and turning limitations in the real-world. Parameters derived from IMUs reflected a rich profile of real-world mobility measures indicative of walking limitation of individuals scheduled for TKA, which may provide a relevant outcome dimension for future studies.
Adverse Long-Term Outcomes and an Immune Suppressed Endotype in Sepsis Patients with Reduced Interferon-γ ELISpot: A Multicenter, Prospective Observational Study
Authors: Barrios Evan A. , Mazer Monty B. , McGonagill Patrick , Bergmann Christian B. , Goodman Michael D. , Gould Robert W. , Rao Mahil , Polcz Valerie , Davis Ruth , Del Toro Drew , Dirain Marvin , Dram Alexandra , Hale Lucas , Heidarian Mohammad , Kucaba Tamara A. , Lanz Jennifer P. , McCray Ashley , Meszaros Sandra , Miles Sydney , Nelson Candace , Rocha Ivanna , Silva Elvia E , Ungaro Ricardo , Walton Andrew , Xu Julie , Zeumer-Spataro Leilani , Drewry Anne M. , Liang Muxuan , Bible Letitia E. , Loftus Tyler , Turnbull Isaiah , Efron Philip A. , Remy Kenneth E. , Brakenridge Scott , Badovinac Vladimir P. , Griffith Thomas S. , Moldawer Lyle L. , Hotchkiss Richard S. , Caldwell Charles C. 
Published: September 2023

AbstractBackgroundSepsis remains a major clinical challenge for which successful treatment requires greater precision in identifying patients at increased risk of adverse outcomes requiring different therapeutic approaches. Predicting clinical outcomes and immunological endotyping of septic patients has generally relied on using blood protein or mRNA biomarkers, or static cell phenotyping. Here, we sought to determine whether functional immune responsiveness would yield improved precision.MethodsAnex vivowhole blood enzyme-linked immunosorbent (ELISpot) assay for cellular production of interferon-γ (IFN-γ) was evaluated in 107 septic and 68 non-septic patients from five academic health centers using blood samples collected on days 1, 4 and 7 following ICU admission.ResultsCompared with 46 healthy subjects, unstimulated and stimulated whole blood IFNγ expression were either increased or unchanged, respectively, in septic and nonseptic ICU patients. However, in septic patients who did not survive 180 days, stimulated whole blood IFNγ expression was significantly reduced on ICU days 1, 4 and 7 (all p<0.05), due to both significant reductions in total number of IFNγ−producing cells and amount of IFNγ produced per cell (all p<0.05). Importantly, IFNγ total expression on day 1 and 4 after admission could discriminate 180-day mortality better than absolute lymphocyte count (ALC), IL-6 and procalcitonin. Septic patients with low IFNγ expression were older and had lower ALC and higher sPD-L1 and IL-10 concentrations, consistent with an immune suppressed endotype.ConclusionsA whole blood IFNγ ELISpot assay can both identify septic patients at increased risk of late mortality, and identify immune-suppressed, sepsis patients.Trial RegistryBecause the study is a prospective observational study, and not a clinical trial, registration withclinical trials.govis not required.