bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alzheimer’s Disease Heterogeneity Explained by Polygenic Risk Scores Derived from Brain Transcriptomic Profiles
Authors: Chung Jaeyoon , Sahelijo Nathan , Maruyama Toru , Hu Junming , Panitch Rebecca , Xia Weiming , Mez Jesse , Stein Thor D. ,   the Alzheimer’s Disease Neuroimaging Initiative, Saykin Andrew J. , Takeyama Haruko , Farrer Lindsay A. , Crane Paul K. , Nho Kwangsik , Jun Gyungah R. 
Published: December 2022

AbstractINTRODUCTIONAlzheimer’s disease (AD) is heterogeneous, both clinically and neuropathologically. We investigated whether polygenic risk scores (PRSs) integrated with transcriptome profiles from AD brains can explain AD clinical heterogeneity.METHODSWe conducted co-expression analysis and identified gene-sets (modules) which were preserved in three AD transcriptome datasets and associated with AD-related neuropathological traits for neuritic plaques (NPs) or neurofibrillary tangles (NFTs). We computed the module-based PRS (mbPRS) for each module and tested associations for mbPRSs with cognitive test scores, cognitively-defined AD subgroups, and brain imaging data.RESULTSOf the modules significantly associated with NPs and/or NFTs, the mbPRSs from two modules (M6 and M9) showed distinct associations with language and visuospatial functioning as well as their matching AD-subgroups and brain atrophy at specific regions.DISCUSSIONOur findings demonstrate that polygenic profiling based on co-expressed gene-sets can explain heterogeneity in AD patients, enabling to genetically-informed patient stratification and precision medicine in AD.
Systematic Review and Meta-analysis of Rate of Major Amputation Following Endovascular Intervention in Chronic Limb-Threatening Ischaemia
Authors: Bergman Henry I , Elghazaly Hussein , Thapar Ankur , Davies Alun H. 
Published: December 2022

AbstractBackgroundDespite significant improvements in endovascular technology and anaesthetic practice over the last 20 years, patients with CLTI remain at high risk of major limb amputation and overall mortality. The aim of this systematic review was to provide a contemporary review of the rate of major amputation and key clinical outcomes following all endovascular interventions in CLTI.MethodsA systematic review and meta-analysis of prospective studies from 2010-2020 reporting the risk of major lower limb amputation in patients with CLTI. MEDLINE, EMBASE, the Cochrane Database for Systematic Reviews andClinicalTrials.govwere searched for relevant studies by 2 reviewers. The primary endpoint was rate of major limb amputation at 1 year and 2 years. Meta-analysis of proportions was employed using the random effects model. Studies were quality assessed using the ROBINS-I tool. To investigate factors associated with major limb amputations, subgroup analyses and meta-regression for clinical-demographic and lesion characteristics were employed.ResultsA total of 28 studies, from 24 manuscripts were eligible for inclusion. These included a total of 49,756 patients. At one-year post-revascularisation, the pooled rate of major lower limb amputations at 1 year was 8.6% (95% CI 6.7% - 11.0%). At two years, the rate of major amputations was 11.1% (95% CI 7.6% - 16.0%). Subgroup analysis showed that in studies that mandated stent deployment for all patients, there was a significantly lower rate of major amputations of 5.1% (95% CI 4.7% - 5.5%). Meta-regression showed that none of the clinical-demographic and lesion characteristics were associated with major lower limb amputations, and no volume-outcome relationship was observed.ConclusionsThis review provides important benchmarking information on the outcomes of endovascular intervention in a frail CLTI cohort. This provides a realistic evaluation of risk to facilitate full informed consent and the setting of realistic expectations regarding the need for reintervention, major and minor amputation and overall mortality.
Treatment Success and associated factors among patients with Pulmonary Tuberculosis attending Kampala Capital City Authority health facilities: A retrospective cohort study
Authors: Tumusiime Cathbert , Katamba Achilles , Nakiyingi Lydia , Kalyango Joan 
Published: December 2022

ABSTRACTBackgroundTB treatment success remains low in Uganda at 82%, below the recommended WHO target (≥90%). Consequences of poor treatment outcome include; increased MDR-TB prevalence, treatment costs and death. Kampala Capital City Authority (KCCA) public health facilities are congested which compromises the care given to pulmonary tuberculosis patients (PTB) that affects the treatment success of patients. However, there is scarce information regarding factors that are associated with treatment success among PTB patients in KCCA public health facilities.General ObjectiveTo determine the treatment success and associated factors among patients with pulmonary tuberculosis attending KCCA public health facilities in Kampala between July 2019 and June 2020.MethodsA retrospective cohort study that involved review of records for 772 PTB patients who were enrolled on TB treatment in five KCCA health facilities from July 2019 to June 2020. Data on socio-demographic and clinical factors was abstracted from health facility TB registers. Data was entered in epidata and analyzed using STATA_v14 software. A modified poison regression model with robust standard errors was used in analysis and risk ratios were reported.ResultsTreatment success was 87.2% (CI: 84.2%-89.1%), PTB patients who cured accounted for 413 (53.5%) and 260 (33.7%) completed treatment. Factors associated with PTB treatment success were: being classified as a clinically diagnosed PTB patients (aRR= 0.8, CI: 0.53 - 0.94, P value =0.021) and having a positive HIV/AIDS status (aRR= 0.7, CI: 0.43 - 0.88, P value =0.006) reduced treatment success and having a community volunteer as a treatment supporter was associated with increased treatment success (aRR= 1.2, CI: 1.06 - 3.28, P value =0.028).ConclusionOver 80% of PTB patients in KCCA public health facilities achieve treatment success although this is still below the WHO target. Factors associated with TB treatment success include; being classified as a clinically diagnosed PTB patient, having a positive HIV/AIDS status as factors that reduce treatment success and having a community volunteer as a treatment supporter improves treatment success. Efforts such as consistent follow-ups should be encouraged among clinically diagnosed and HIV/AIDS positive PTB patients. Additionally, community volunteers should be empowered to support PTB patients.
Coronary vessel assembly involves patterned endocardial sprouting and tip-cell-to artery specification
Authors: Cano Elena , Paech Jennifer , Kanda Masatoshi , Lindberg Eric L. , Hollfinger Irene , Brauening Caroline , Fischer Cornelius , Hübner Norbert , Gerhardt Holger 
Published: December 2022

AbstractThe coronary vasculature comprises superficial coronary veins and deeper coronary arteries and capillaries that critically support the high metabolic activity of the beating heart. Understanding how different endothelial progenitor sources jointly shape and remodel the coronary vasculature into its adult pattern has recently attracted great research interest, and spurred much debate. Here, using lineage tracing tools in combination with three-dimensional imaging, live-imaging in explants and single-cell transcriptional profiling, we demonstrate that sprouting angiogenesis drives both sinus venosus and endocardial contribution to coronary plexus. Whereas previous studies limit endocardial contribution to coronary vessels to the interventricular septum and ventral aspect of the heart, our study demonstrates extensive endocardial sprouting angiogenesis in the free ventricular walls. In particular, we identify a distinct subpopulation of endocardial cells that express future coronary markers and reside in both the embryonic and adult ventricular wall endocardium. Most importantly, we provide evidence for sprouting angiogenesis from both endocardium and subepicardial plexus towards the inner myocardial wall to determine pre-arterial specification. Additionally, sprouting from the endocardium leads to the establishment of perfused connections to the advancing coronary plexus, also followed by transitioning to the pre-arterial cell state. Distinct molecular profiles characterize sprouting populations in the intramyocardial and subepicardial layers that shape the prospective coronary arteries and veins, respectively. Harnessing the endocardial progenitors and targeting the distinct sprouting populations may in the future serve to tailor cardiac vascular adaptations for therapeutic purposes.
Discovery and molecular basis of chloride as an allosteric activator and catalytic inhibitor for Class-D β-lactamases
Authors: Zhou Qi , Catalán Pablo , Bell Helen , Baumann Patrick , Evans Rhodri , Yang Jianhua , Zhang Zhen , Zappalà Davide , Zhang Ye , Blackburn George Michael , He Yuan , Jin Yi 
Published: December 2022

AbstractOxacillinase (OXA)-48-like carbapenemases are epidemic class D β-lactamases inEnterobacterales, resulting in high mortality. Though the chemical mechanism has been clearly established, for decades, the link between the biphasic kinetic behaviour of these enzymes, which significantly impacts antibiotic efficacy, and the state of carbamylated lysine has been elusive. Here, substitutingN-carbamylated lysine73 with a chemically-stableN-acetyl lysine allows us to prove the origin of catalytic inhibition is not decarbamylation and enables us to capture an unprecedented inactive acyl-intermediate wedged in place by a chloride ion against the conserved residue arginine250. We here identify chloride as a “Janus effector” acting by allosteric activation of the burst phase and inhibition of the steady-state for a series of β-lactam substrates in kinetic assays. Chloride ions are necessarily present in both laboratory and clinical OXA activity assays and their inseparable role is now identified. Our finding suggests a new direction for the discovery of next-generation antibiotics specific for β-lactamases of Class D.
Proximity-dependent recruitment of Polycomb Repressive Complexes by the lncRNAAirn
Authors: Braceros Aki K. , Schertzer Megan D. , Omer Arina , Trotman Jackson B. , Davis Eric S. , Dowen Jill M. , Phanstiel Douglas H. , Aiden Erez Lieberman , Calabrese J. Mauro 
Published: December 2022

ABSTRACTDuring mouse embryogenesis, expression of the lncRNAAirninduces gene silencing and recruits Polycomb Repressive Complexes (PRCs) to varying extents over a 15 megabase domain. The mechanisms remain unclear. Using high-resolution approaches, we show in mouse trophoblast stem cells thatAirnexpression induces long-range changes to chromatin architecture that coincide with PRC-directed modifications and center around CpG island promoters that contact theAirnlocus even in the absence ofAirnexpression. Intensity of contact betweenAirnlncRNA and target chromatin correlated with underlying intensity of PRC-directed chromatin modifications. Deletion of CpG islands that form contacts withAirnaltered long-distance silencing and PRC activity in a manner that correlated with changes in chromatin architecture. We conclude thatAirnis a potentcis-acting lncRNA whose primary functions of transcriptional repression and PRC recruitment are controlled by an equilibratory network of DNA regulatory elements that modulate its frequency of contact with target chromatin.
Acquired and intrinsic resistance to vemurafenib in BRAFV600E-driven melanoma brain metastases
Authors: Zhang Ping , Kuil Laura E. , Buil Levi C.M. , Freriks Stephan , Beijnen Jos H. , van Tellingen Olaf , de Gooijer Mark C. 
Published: December 2022

ABSTRACTPurposeBRAFV600-mutated melanoma brain metastases (MBMs) are responsive to BRAF inhibitors, but responses are generally less durable than those of extracranial metastases. We here tested the hypothesis that the drug efflux transporters P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP;ABCG2) expressed at the blood–brain barrier (BBB) offer MBMs protection from therapy.MethodsWe intracranially implanted A375 tumor cells in wild-type andAbcb1a/b;Abcg2-/-mice. We characterized the tumor BBB, analyzed drug levels in plasma and brain lesions after oral vemurafenib administration and determined the efficacy against brain metastases and subcutaneous lesions.ResultsAlthough contrast-enhanced MRI demonstrated that the integrity of the BBB is disrupted in A375 MBMs, vemurafenib achieved greater antitumor efficacy against MBMs inAbcb1a/b;Abcg2-/-mice compared to wild-type mice. Concordantly, P-gp and BCRP are expressed in MBM-associated brain endothelium both in patients and in A375 xenografts and limited vemurafenib penetration into A375 MBMs. Confirming the BBB-specific context of this protection, vemurafenib was equally effective against subcutaneous A375 tumors in WT andAbcb1a/b;Abcg2-/-mice. Intriguingly, although initially responsive, A375 MBMs rapidly developed therapy resistance, even inAbcb1a/b;Abcg2-/-mice, and this was unrelated to pharmacokinetic or target inhibition issues. Rather, MBMs likely resorted to noncanonical growth signaling, as target inhibition of canonical MAPK pathway signaling components was maintained in resistant intracranial A375 tumors.ConclusionsWe demonstrate that BRAFV600E-driven MBMs are partly intrinsically protected from vemurafenib by the BBB. Intriguingly, MBMs can also rapidly acquire resistancein situ, likely by resorting to non-canonical growth signaling.
Leveraging a Billion-Edge Knowledge Graph for Drug Re-purposing and Target Prioritization using Genomically-Informed Subgraphs
Authors: Martin Brian , Jacob Howard J. , Hajduk Philip , Wolfe Elaine , Chen Loren , Crosby Henry , Lefever Matthew , Wendell Richard 
Published: December 2022

AbstractDrug development is a resource and time-intensive process resulting in attrition rates of up to 90%. As a result, repurposing existing drugs with established safety and pharmacokinetic profiles is gaining traction as a way of accelerating therapeutics development. Here we have developed unique machine learning-driven Natural Language Processing and biomedical semantic technologies that mine over 53 million biomedical documents to automate the generation of a 911M edge knowledge graph. We then applied subgraph queries that relate drugs to diseases using genetic evidence to identify potential drug repurposing candidates for a broad range of diseases. We use Carney Complex, a disease with no known treatment, to illustrate our approach. This analysis revealed Ruxolitinib (Incyte, trade name Jakafi), a JAK1/2 inhibitor with an established safety and efficacy profile approved to treat myelofibrosis, as a potential candidate for the treatment of Carney Complex through off-target drug activity.
MODELING POLARITY SITE MOVEMENT IN YEAST VIA CALCIUM-MEDIATED REGULATION OF GAP ACTIVITY
Authors: Parikh Vatsal 
Published: December 2022

AbstractSymmetry-breaking polarization is a process that occurs in many cells. In budding yeast cells specifically, this polarization is possible due to the presence of a positive feedback loop, which allows for one and only one front to develop. Furthermore, in mating yeast cells the detection of pheromones plays a crucial role in the cell’s development of a polarity site; however, due to the microscopic size of yeast cells, there is often error in the initial polarity site’s accuracy. As a result, yeast cells can correct their polarity site by allowing the GTP-Cdc42 cluster to “wander”. This is typically considered as the indecisive phase of a cell. Recent studies have identified that cytosolic Ca2+bursts, caused by sexual pheromones, increase the activity of GTPase-activating protein (GAP). This project tests this from a modeling perspective by adding a module of code to an already established positive feedback model that allows periodic spikes of GAP activity to occur. The model was successfully able to simulate the effects of calcium-mediated GAP spikes by portraying oscillating polarity sites and “wandering” polarity sites, using specific parameters based on biochemical data.
Benchmarking single-cell hashtag oligo demultiplexing methods
Authors: Howitt George , Feng Yuzhou , Tobar Lucas , Vassiliadis Dane , Hickey Peter , Dawson Mark A. , Ranganathan Sarath , Shanthikumar Shivanthan , Neeland Melanie , Maksimovic Jovana , Oshlack Alicia 
Published: December 2022

AbstractSample multiplexing is often used to reduce cost and limit batch effects in single-cell RNA sequencing (scRNA-seq) experiments. A commonly used multiplexing technique involves tagging cells prior to pooling with a hashtag oligo (HTO) that can be sequenced along with the cells’ RNA to determine their sample of origin. Several tools have been developed to demultiplex HTO sequencing data and assign cells to samples. In this study, we critically assess the performance of seven HTO demultiplexing tools:hashedDrops, HTODemux, GMM-Demux, demuxmix, deMULTIplex, BFFandHashSolo. The comparison uses data sets where each sample has also been demultiplexed using genetic variants from the RNA, enabling comparison of HTO demultiplexing techniques against complementary data from the genetic “ground truth”. We find that all methods perform similarly where HTO labelling is of high quality, but methods that assume a bimodal counts distribution perform poorly on lower quality data. We also suggest heuristic approaches for assessing the quality of HTO counts in a scRNA-seq experiment.
Multimodal learning of noncoding variant effects using genome sequence and chromatin structure
Authors: Tan Wuwei , Shen Yang 
Published: December 2022

AbstractMotivationA growing amount of noncoding genetic variants, including single-nucleotide polymorphisms (SNPs), are found to be associated with complex human traits and diseases. Their mechanistic interpretation is relatively limited and can use the help from computational prediction of their effects on epigenetic profiles. However, current models often focus on local, 1D genome sequence determinants and disregard global, 3D chromatin structure that critically affects epigenetic events.ResultsWe find that noncoding variants of unexpected high similarity in epigenetic profiles, with regards to their relatively low similarity in local sequences, can be largely attributed to their proximity in chromatin structure. Accordingly we have developed a multimodal deep learning scheme that incorporates both data of 1D genome sequence and 3D chromatin structure for predicting noncoding variant effects. Specifically, we have integrated convolutional and recurrent neural networks for sequence embedding and graph neural networks for structure embedding despite the resolution gap between the two types of data, while utilizing recent DNA language models. Numerical results show that our models outperform competing sequence-only models in predicting epigenetic profiles and their use of long-range interactions complement sequence-only models in extracting regulatory motifs. They prove to be excellent predictors for noncoding variant effects in gene expression and pathogenicity, whether in unsupervised “zero-shot” learning or supervised “few-shot” learning.AvailabilityCodes and data access can be found athttps://github.com/Shen-Lab/ncVarPred-1D3DContactyshen@tamu.eduSupplementary informationSupplementary data are available atBioinformaticsonline.
Bacillus subtilisencodes a discrete flap endonuclease that cleaves RNA-DNA hybrids
Authors: Lowder Frances Caroline , Simmons Lyle A. 
Published: December 2022

AbstractCurrent models for Okazaki fragment maturation in eubacteria invoke RNA cleavage by RNase H, followed by strand displacement synthesis and 5′ RNA flap removal by DNA polymerase I (Pol I). RNA removal by Pol I is thought to occur through the 5′-3′ flapendo/exonuclease (FEN) domain, located in the N-terminus of the protein. In addition to Pol I, many bacteria encode a second, Pol I-independent FEN. The contribution of Pol I and Pol I-independent FENs to DNA replication and genome stability remains unclear. In this work we purified Pol I and FEN, then assayed these proteins on a variety of RNA-DNA hybrid and DNA-only substrates. We found that FEN is far more active than Pol I on 5′ flapped and nicked RNA-DNA hybrid substrates. We found that the 5′ nuclease activity ofB. subtilisPol I is feeble, even during DNA synthesis when a 5′ flapped substrate is formed modeling an Okazaki fragment intermediate. Examination of Pol I and FEN on DNA-only substrates shows that FEN is more active than Pol I on most substrates tested. Further experiments show that ΔpolAphenotypes are completely rescued by expressing the C-terminal polymerase domain while expression of the N-terminal 5′ nuclease domain fails to complement ΔpolA. Cells lacking FEN (ΔfenA) show a phenotype in conjunction with an RNase HIII defect, providing genetic evidence for the involvement of FEN in Okazaki fragment processing. With these results, we propose a model where cells remove RNA primers using FEN while upstream Okazaki fragments are extended through synthesis by Pol I. Our model is similar to models for Okazaki fragment processing in eukaryotes, where Pol d catalyzes strand displacement synthesis followed by 5′ flap cleavage using FEN-1.Author Summary5′ flap endo/exonuclease (FEN) activity provides an essential contribution to DNA replication and repair in all cellular life. In bacteria, DNA polymerase I is thought to be the central enzyme involved in Okazaki fragment processing, using its DNA polymerase and 5′ nuclease activities to generate and then remove the 5’ ssRNA segment of an Okazaki fragment. Many bacterial genomes encode a second, discrete FEN in addition to Pol I. We show that FEN is the primary 5′ nuclease used byB. subtilisfor primer removal. FEN activity exceeds that of Pol I on most substrates, including several that mimic Okazaki fragment intermediates. Additionally, we provide genetic evidence showing that FEN is involved in Okazaki fragment processing and that it is the DNA polymerase domain of Pol I rather than its 5′ nuclease domain that is importantin vivo. With our results, we propose a new model for Okazaki fragment processing inB. subtilis, which may be prevalent in a wider group of bacteria.