bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unified AI framework to uncover deep interrelationships between gene expression and Alzheimer’s disease neuropathologies
Authors: Beebe-Wang Nicasia , Celik Safiye , Weinberger Ethan , Sturmfels Pascal , De Jager Philip L. , Mostafavi Sara , Lee Su-In 
Published: December 2020

ABSTRACTDeep neural networks offer a promising approach for capturing complex, non-linear relationships among variables. Because they require immense sample sizes, their potential has yet to be fully tapped for understanding complex relationships between gene expression and human phenotypes. Encouragingly, a growing number of diseases are being studied through consortium efforts. Here we introduce a new analysis framework, namely MD-AD (Multi-taskDeep learning forAlzheimer’sDisease neuropathology), which leverages an unexpected synergy between deep neural networks and multi-cohort settings. In these settings, true joint analysis can be stymied using conventional statistical methods, which (1) require “harmonized” phenotypes (i.e., measured in a highly consistent manner) and (2) tend to capture cohort-level variations, obscuring the subtler true disease signals. Instead, MD-AD incorporates multiple related phenotypes sparsely measured across cohorts, and learns complex, non-linear interactions between genes and phenotypes not discovered using conventional expression data analysis methods (e.g., component analysis and module detection), enabling the model to capture subtler signals than cohort-level variations. Applied to the largest available collection of brain samples (N=1,758), we demonstrate that MD-AD learns a truly generalizable relationship between gene expression program and AD-related neuropathology. The learned program generalizes in several important ways, including recapitulation of the disease progress in animal models and across tissue types, and we show that such generalizability is not achieved by previous statistical paradigms. Its ability to identify genes with high non-linear relevance to neuropathology enabled us to identify a sex-specific relationship between neuropathology and immune response across microglia, providing a nuanced context for association between inflammatory genes and AD.
A comparison of blood and brain-derived ageing and inflammation-related DNA methylation signatures and their association with microglial burdens
Authors: Stevenson Anna J. , McCartney Daniel L. , Shireby Gemma L. , Hillary Robert F. , King Declan , Tzioras Makis , Wrobel Nicola , McCafferty Sarah , Murphy Lee , McColl Barry W. , Redmond Paul , Taylor Adele M. , Harris Sarah E. , Russ Tom C. , Hannon Eilis J , McIntosh Andrew M. , Mill Jonathan , Smith Colin , Deary Ian J. , Cox Simon R. , Marioni Riccardo E. , Spires-Jones Tara L. 
Published: December 2020

AbstractInflammation and ageing-related DNA methylation patterns in the blood have been linked to a variety of morbidities, including cognitive decline and neurodegenerative disease. However, it is unclear how these blood-based patterns relate to patterns within the brain, and how each associates with central cellular profiles. In this study, we profiled DNA methylation in both the blood and in fivepost-mortembrain regions (BA17, BA20/21, BA24, BA46 and hippocampus) in 14 individuals from the Lothian Birth Cohort 1936. Microglial burdens were additionally quantified in the same brain regions. DNA methylation signatures of five epigenetic ageing biomarkers (‘epigenetic clocks’), and two inflammatory biomarkers (DNA methylation proxies for C-reactive protein and interleukin-6) were compared across tissues and regions. Divergent correlations between the inflammation and ageing signatures in the blood and brain were identified, depending on region assessed. Four out of the five assessed epigenetic age acceleration measures were found to be highest in the hippocampus (β range=0.83-1.14, p≤0.02). The inflammation-related DNA methylation signatures showed no clear variation across brain regions. Reactive microglial burdens were found to be highest in the hippocampus (β=1.32, p=5×10-4); however, the only association identified between the blood- and brain-based methylation signatures and microglia was a significant positive association with acceleration of one epigenetic clock (termed DNAm PhenoAge) averaged over all five brain regions (β=0.40, p=0.002). This work highlights a potential vulnerability of the hippocampus to epigenetic ageing and provides preliminary evidence of a relationship between DNA methylation signatures in the brain and differences in microglial burdens.
Exchange of molecular and cellular information: a hybrid model that integrates stem cell divisions and key regulatory interactions
Authors: Van den Broeck Lisa , Spurney Ryan J. , Fisher Adam P. , Schwartz Michael , Clark Natalie M. , Nguyen Thomas T. , Madison Imani , Gobble Mariah , Long Terri , Sozzani Rosangela 
Published: December 2020

AbstractStem cells give rise to the entirety of cells within an organ. Maintaining stem cell identity and coordinately regulating stem cell divisions is crucial for proper development. In plants, mobile proteins, such as WOX5 and SHR, regulate divisions in the root stem cell niche (SCN). However, how these proteins coordinately function to establish systemic behavior is not well understood. We propose a non-cell autonomous role for WOX5 in the CEI and identify a regulator, AN3/GIF1, that coordinates CEI divisions. Here we show with a multiscale hybrid model integrating ODEs and agent-based modeling that QC and CEI divisions have different dynamics. Specifically, by combining continuous models to describe regulatory networks and agent-based rules, we model systemic behavior, which led us to predict cell-type-specific expression dynamics of SHR, SCR, WOX5, AN3, and CYCD6;1, and experimentally validate CEI cell divisions. Conclusively, our results show an interdependency between CEI and QC divisions.Thumbnail image
White matter alterations in glaucoma and vision-deprived brains differ outside the visual system
Authors: Hanekamp Sandra , Ćurčić-Blake Branislava , Caron Bradley , McPherson Brent , Timmer Anneleen , Prins Doety , Boucard Christine C. , Yoshida Masaki , Ida Masahiro , Jansonius Nomdo M. , Pestilli Franco , Cornelissen Frans W. 
Published: December 2020

AbstractThe degree to which glaucoma has effects beyond the eye –in the brain– is unclear. We investigated white matter microstructure (WMM) alterations in 37 tracts of patients with glaucoma, monocular blindness and controls. We used reproducible methods and the advanced cloud computing platformbrainlife.io. White matter tracts were subdivided into seven categories ranging from primarily involved in vision (the visual white matter) to primarily involved in cognition and motor control. WMM in both glaucoma and monocular blind subjects was lower than controls in the visual white matter, suggesting neurodegenerative mechanisms due to reduced sensory inputs. In glaucoma participants WMM differences from controls decreased outside the visual white matter. A test-retest validation approach was used to validate these results. The pattern of results was different in monocular blind participants, where WMM properties increased outside the visual white matter as compared to controls. The pattern of results suggests that whereas in the blind loss of visual input might promote white matter reorganization outside of the early visual system, such reorganization might be reduced or absent in glaucoma. The results provide indirect evidence that in glaucoma unknown factors might limit the brain plasticity effects that in other patient groups follow visual loss.
Model-based aversive learning in humans is supported by preferential task state reactivation
Authors: Wise Toby , Liu Yunzhe , Chowdhury Fatima , Dolan Raymond J. 
Published: December 2020

AbstractHarm avoidance is critical for survival, yet little is known regarding the underlying neural mechanisms supporting avoidance when we cannot rely on direct trial and error experience. Neural reactivation, and sequential replay, have emerged as potential candidate mechanisms. Here, during an aversive learning task, in conjunction with magnetoencephalography, we show prospective and retrospective reactivation for planning and learning respectively, coupled to evidence for sequential replay. Specifically, when subjects plan in an aversive context, we find preferential reactivation of subsequently chosen goal states and sequential replay of the preceding path. This reactivation was associated with greater hippocampal theta power. At outcome receipt, unchosen goal states are reactivated regardless of outcome valence. However, replay of paths leading to goal states was directionally modulated by outcome valence, with aversive outcomes leading to stronger reverse replay compared to safe outcomes. Our findings suggest that avoidance behaviour involves simulation of alternative future and past outcome states through hippocampally-mediated reactivation and replay.
3D Genome Contributes to Protein-Protein Interactome
Authors: Shi Yi , Cao Song , Zhang Mingxuan , Su Xianbin , Guo Zehua , Wang Jiayi , Liu Tingting , Shi Hui , He Guang 
Published: December 2020

AbstractNumerous computational methods have been proposed to predict protein-protein interactions, none of which however, considers the original DNA loci of the interacting proteins in the perspective of 3D genome. Here we retrospect the DNA origins of the interacting proteins in the context of 3D genome and discovered that 1) if a gene pair is more proximate in 3D genome, their corresponding proteins are more likely to interact. 2) signal peptide involvement of PPI affects the corresponding gene-gene proximity in 3D genome space. 3) by incorporating 3D genome information, existing PPI prediction methods can be further improved in terms of accuracy. Combining our previous discoveries, we conjecture the existence of 3D genome driven cellular compartmentalization, meaning the co-localization of DNA elements lead to increased probability of the co-localization of RNA elements and protein elements.
The ecology of Nipah virus in Bangladesh: a nexus of land use change and opportunistic feeding behavior in bats
Authors: McKee Clifton D. , Islam Ausraful , Luby Stephen P. , Salje Henrik , Hudson Peter J. , Plowright Raina K. , Gurley Emily S. 
Published: December 2020

AbstractNipah virus is a bat-borne paramyxovirus that produces yearly outbreaks of fatal encephalitis in Bangladesh. Understanding the ecological conditions that lead to spillover from bats to humans can assist in designing effective interventions. To investigate the current and historical processes that drive Nipah spillover in Bangladesh, we analyzed the relationship between spillover events and climatic conditions, the spatial distribution and size ofPteropus mediusroosts, and patterns of land use change in Bangladesh over the last 300 years. We found that 53% of annual variation in winter spillovers is explained by winter temperature, which may affect bat behavior, physiology, and human risk behaviors. We infer from changes in forest cover that a progressive shift in bat roosting behavior occurred over hundreds of years, producing the current system where a majority ofP. mediuspopulations are small (median of 150 bats), occupy roost sites for 10 years or more, live in areas of high human population density, and opportunistically feed on cultivated food resources – conditions that promote viral spillover. Without interventions, continuing anthropogenic pressure on bat populations similar to what has occurred in Bangladesh could result in more regular spillovers of other bat viruses, including Hendra and Ebola viruses.
Topological Learning for Brain Networks
Authors: Songdechakraiwut Tananun , Chung Moo K. 
Published: December 2020

AbstractThis paper proposes a novel topological learning framework that can integrate networks of different sizes and topology through persistent homology. This is possible through the introduction of a new topological loss function that enables such challenging task. The use of the proposed loss function bypasses the intrinsic computational bottleneck associated with matching networks. We validate the method in extensive statistical simulations with ground truth to assess the effectiveness of the topological loss in discriminating networks with different topology. The method is further applied to a twin brain imaging study in determining if the brain network is genetically heritable. The challenge is in overlaying the topologically different functional brain networks obtained from the resting-state functional magnetic resonance imaging (fMRI) onto the template structural brain network obtained through the diffusion tensor imaging (DTI).
Major diversification of caribou shaped by glacial cycles before the Last Glacial Maximum
Authors: Taylor Rebecca S. , Manseau Micheline , Klütsch Cornelya F. C. , Polfus Jean L. , Steedman Audrey , Hervieux Dave , Kelly Allicia , Larter Nicholas C. , Gamberg Mary , Schwantje Helen , Wilson Paul J. 
Published: December 2020

AbstractPleistocene glacial cycles influenced the diversification of high-latitude wildlife species through recurrent periods of range contraction, isolation, divergence, and expansion from refugia and subsequent admixture of refugial populations. For many taxa, research has focused on genetic patterns since the Last Glacial Maximum (LGM), however glacial cycles before the LGM likely impacted genomic variation which may influence contemporary genetic patterns. We investigate diversification and the introgressive history of caribou (Rangifer tarandus) in western Canada using 33 high-coverage whole genomes coupled with larger-scale mitochondrial data. Contrary to the well-established paradigm that caribou ecotypes and contemporary genetic diversity arose from two major lineages in separate refugia during the LGM, a Beringian-Eurasian (BEL) and a North American (NAL) lineage, we found that the major diversifications of caribou occurred much earlier at around 110 kya, the start of the last glacial period. Additionally, we found effective population sizes of some caribou reaching ~700,000 to 1,000,000 individuals, one of the highest recorded historical effective population sizes for any mammal species thus far. Mitochondrial analyses dated introgression events prior to the LGM dating to 20-30 kya and even more ancient at 60 kya, coinciding with colder periods with extensive ice coverage, further demonstrating the importance of glacial cycles and events prior to the LGM in shaping demographic history. Reconstructing the origins and differential introgressive history has implications for predictions on species responses under climate change. Our results highlight the need to investigate pre-LGM demographic patterns to fully reconstruct the origin of species diversity, especially for high-latitude species.
Novel TREM2 splicing isoform that lacks the V-set immunoglobulin domain is abundant in the human brain
Authors: Kiianitsa Kostantin , Kurtz Irina , Beeman Neal , Matsushita Mark , Chien Wei-Ming , Raskind Wendy H. , Korvatska Olena 
Published: December 2020

AbstractTREM2 is an immunoglobulin-like receptor expressed by certain myeloid cells, such as macrophages, dendritic cells, osteoclasts and microglia. In the brain, TREM2 plays an important role in the immune function of microglia, and its dysfunction is linked to various neurodegenerative conditions in humans. Ablation of TREM2 or its adaptor protein TYROBP causes Polycystic Lipo-Membranous Osteodysplasia with Sclerosing Leukoencephalopathy (also known as Nasu-Hakola disorder) with early onset of dementia, while some missense variants in TREM2 are associated with an increased risk of late-onset Alzheimer’s disease. Human TREM2 gene is a subject to alternative splicing, and its major, full-length canonical transcript encompasses 5 exons. Herein, we report a novel alternatively spliced TREM2 isoform without exon 2 (Δe2), which constitutes a sizable fraction of TREM2 transcripts and has highly variable inter-individual expression in the human brain (average frequency 10%; range 3.7-35%). The protein encoded by Δe2 lacks a V-set immunoglobulin domain from its extracellular part but retains its transmembrane and cytoplasmic domains. We demonstrated Δe2 protein expression in TREM2-positive THP-1 cells, in which the expression of full-length transcript was precluded by CRISPR/Cas9 disruption of the exon 2 coding frame. In “add-back” experiments, overexpression of full-length, but not Δe2 TREM2, restored phagocytic capacity and promoted interferon type I response in the knockout cells. Our findings suggest that expression of a Δe2 splice isoform may modify the dosage of full-length transcript potentially weakening some TREM2 receptor functions in the human brain.
Mass allelic exchange: enabling sexual genetics inEscherichia coli
Authors: Khetrapal Varnica , Yong Liyana Ow , Chen Swaine L. 
Published: December 2020

AbstractDespite dramatic advances in genomics, connecting genotypes to phenotypes is still challenging. Sexual genetics combined with linkage analysis is a powerful solution to this problem but generally unavailable in bacteria. We build upon a strong negative selection system to invent Mass Allelic Exchange (MAE), which enables hybridization of arbitrary (including pathogenic) strains ofE. coli. MAE reimplements the natural phenomenon of random crossovers, enabling classical linkage analysis. We demonstrate the utility of MAE with virulence-related gain-of-function screens, discovering that transfer of a single operon from a uropathogenic strain is sufficient for enabling a commensalE. colito form large intracellular bacterial collections within bladder epithelial cells. MAE thus enables assaying natural allelic variation inE. coli(and potentially other bacteria), complementing existing loss-of-function genomic techniques.One Sentence SummaryWe create F1 hybrids ofE. coliusing MAE, bringing the power of linkage analysis to bear on phenotypic diversity (including virulence)
A two-arm, randomized, controlled, multi-centric, open-label Phase-2 study to evaluate the efficacy and safety of Itolizumab in moderate to severe ARDS patients due to COVID-19
Authors: Kumar Suresh , de Souza Rosemarie , Nadkar Milind , Guleria Randeep , Trikha Anjan , Joshi Shashank R. , Loganathan Subramanian , Vaidyanathan Sivakumar , Marwah Ashwani , Athalye Sandeep N. 
Published: December 2020

AbstractAn uncontrolled increase in cytokine production may lead to systemic hyperinflammation, vascular hypo-responsiveness, increased endothelial permeability, hypercoagulation, multi-organ dysfunction and eventually death in moderate to severely ill COVID-19 patients. Targeting T-cells, an important driver of the hyperinflammatory response, in the treatment of COVID-19, could potentially reduce mortality and improve survival rates. Itolizumab is an anti-CD6 humanized monoclonal antibody with an immunomodulating action on Teffector cells that downregulates T-cell activation, proliferation and subsequent production of various chemokines and cytokines. The efficacy and safety of Itolizumab for the treatment of cytokine release syndrome in patients with moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19 was evaluated in a multi-centric, open-label, two-arm, controlled, randomized, phase 2 study. Eligible patients were randomized (2:1) to arm A (best supportive care + Itolizumab) and arm B (best supportive care). The primary outcome of interest was reduction in all-cause mortality 30 days after enrolment. Thirty-six patients were screened, 5 were treated as first dose sentinels and the rest were randomized, whilst 4 patients were considered screen failures. Two patients in the Itolizumab treatment arm discontinued prior to receiving the first dose and were replaced. At the end of 1 month, there were 3 deaths in arm B, and none in arm A (p= 0.0296). At the end of the follow-up period, more patients in Arm A had improved SpO2 without increasing FiO2 (p=0.0296), improved PaO2 (p=0.0296), and reduction in IL-6 (43 pg/ml vs 212 pg/ml; p=0.0296) and tumor necrotic factor-α (9 pg/ml vs 39 pg/ml; p=0.0253) levels. Itolizumab was generally safe and well tolerated, and transient lymphopenia (11 patients in Arm A) and infusion reactions (7 patients) were the commonly reported treatment related safety events. These encouraging results indicate that larger clinical trials are warranted to establish the role of Itolizumab in controlling immune hyperactivation in COVID-19.
Rho GTPase transcriptional activity and breast cancer risk: A Mendelian randomization analysis
Authors: Kazmi Nabila , Robinson Tim , Zheng Jie , Kar Siddhartha , Martin Richard M , Ridley Anne J 
Published: December 2020

AbstractBackgroundRho GTPases are a family of 20 intracellular signalling proteins that influence cytoskeletal dynamics, cell migration and cell cycle progression. Rho GTPases are implicated in breast cancer progression but their role in breast cancer aetiology is unknown. As aberrant Rho GTPase activity could be associated with breast cancer, we aimed to determine the potential for a causal role of Rho GTPase gene expression in breast cancer risk, using two-sample Mendelian randomization (MR).MethodsMR was undertaken in 122,977 breast cancer cases and 105,974 controls, including 69,501 estrogen receptor positive (ER+) cases and 105,974 controls, and 21,468 ER negative (ER-) cases and 105,974 controls. Single nucleotide polymorphisms (SNPs) underlying expression quantitative trait loci (eQTLs) obtained from normal breast tissue, breast cancer tissue and blood were used as genetic instruments for Rho GTPase expression. Colocalisation was performed as a sensitivity analysis to examine whether findings reflected shared causal variants or genomic confounding.ResultsWe identified genetic instruments for 14 of the 20 human Rho GTPases. Using eQTLs obtained from normal breast tissue and normal blood, we identified evidence of a causal role of RHOD in overall and ER+ breast cancers (overall breast cancer: odds ratio (OR) per standard deviation (SD) increase in expression level 1.06; (95% confidence interval (CI): 1.03, 1.09; P=5.65×10-5) and OR 1.22 (95% CI: 1.11, 1.35; P=5.22×10−5) in normal breast tissue and blood respectively). The direction of association was consistent for ER- breast cancer, although the effect-estimate was imprecisely estimated. Using eQTLs from breast cancer tissue and normal blood there was some evidence that CDC42 was inversely associated with overall and ER+ breast cancer risk. The evidence from colocalization analyses strongly supported the MR results particularly for RHOD.ConclusionsOur study suggests a potential causal role of increased RHOD gene expression, and a potential protective role for CDC42 gene expression, in overall and ER+ breast cancers. These finding warrant validation in independent samples and further biological investigation to assess whether they may be suitable targets for drug targeting.