bluuebunny/crossref_metadata_2025_split huggingface dataset:
Colocalization of blood cell traits GWAS associations and variation in PU.1 genomic occupancy prioritizes causal noncoding regulatory variants
Authors: Jeong Raehoon , Bulyk Martha L. 
Published: March 2023

AbstractGenome-wide association studies (GWAS) have uncovered numerous trait-associated loci across the human genome, most of which are located in noncoding regions, making interpretations difficult. Moreover, causal variants are hard to statistically fine-map at many loci because of widespread linkage disequilibrium. To address this challenge, we present a strategy utilizing transcription factor (TF) binding quantitative trait loci (bQTLs) for colocalization analysis to identify trait associations likely mediated by TF occupancy variation and to pinpoint likely causal variants using motif scores. We applied this approach to PU.1 bQTLs in lymphoblastoid cell lines and blood cell traits GWAS data. Colocalization analysis revealed 69 blood cell trait GWAS loci putatively driven by PU.1 occupancy variation. We nominate PU.1 motif-altering variants as the likely shared causal variants at 51 loci. Such integration of TF bQTL data with other GWAS data may reveal transcriptional regulatory mechanisms and causal noncoding variants underlying additional complex traits.
Caenorhabditis elegansSEL-5/AAK1 regulates cell migration and cell outgrowth independently of its kinase activity
Authors: Knop Filip , Zounarová Apolena , Šabata Vojtěch , Middelkoop Teije Corneel , Macůrková Marie 
Published: March 2023

AbstractDuringCaenorhabditis elegansdevelopment multiple cells migrate long distances or extend processes to reach their final position and/or attain proper shape. Wnt signalling pathway stands out as one of the major coordinators of cell migration or cell outgrowth along the anterior-posterior body axis. Wnt signalling outcome is fine-tuned by various mechanisms including endocytosis. In this study, we show that SEL-5, theC. elegansorthologue of mammalian AP2-associated kinase AAK1, acts together with the retromer complex as a positive regulator of EGL-20/Wnt signalling during the migration of QL neuroblast daughter cells. At the same time, SEL-5 in cooperation with the retromer complex is also required during excretory canal cell outgrowth. Importantly, SEL-5 kinase activity is not required for its role in either neuronal migration or excretory cell outgrowth and neither of these processes is dependent on DPY-23/AP2M1 phosphorylation. We further establish that Wnt proteins CWN-1 and CWN-2 together with Frizzled receptor CFZ-2 positively regulate excretory cell outgrowth, while LIN-44/Wnt and LIN-17/Frizzled together generate a stop signal inhibiting its extension.
Plant cellulose synthase membrane protein isolation directly fromPichia pastorisprotoplasts, liposome reconstitution, and its enzymatic characterization
Authors: Jayachandran Dharanidaran , Banerjee Shoili , Chundawat Shishir P. S. 
Published: March 2023

AbstractThe most abundant renewable biopolymer on earth, viz., cellulose, acts as carbon storage reserve in plant and microbial cell walls that could potentially be converted into biofuels or other valuable bioproducts. Cellulose is synthesized by a plant cell membrane-integrated processive glycosyltransferase (GT) called cellulose synthase (CesA). Since only a few of these plant CesAs have been purified and characterized to date, there are huge gaps in our mechanistic understanding of these enzymes. Furthermore, the coordination between different CesAs involved in primary and secondary cell wall formation is yet to be unveiled. The biochemistry and structural biology studies of CesAs are currently hampered by challenges associated with their expression and extraction at high yields. To aid in understanding CesA reaction mechanisms and to provide a more efficient CesA extraction method, two putative plant CesAs – PpCesA5 fromPhyscomitrella patensand PttCesA8 fromPopulus tremula x tremuloidesthat are involved in primary and secondary cell wall formation in plants were expressed usingPichia pastorisas an expression host. We developed a protoplast-based membrane protein extraction approach to directly isolate both these membrane-bound enzymes for purification, as detected by immunoblotting and mass spectrometry-based analyses. Our method results in a higher purified protein yield by 3-4-fold than the standard cell homogenization protocol. Our purified CesAs were reconstituted into liposomes to yield active enzymes that gave similar biochemical characteristics (e.g., substrate utilization and cofactor requirements, no primer needed to initiate polymerization reaction) as enzymes isolated using the standard protocol. This method resulted in reconstituted CesA5 and CesA8 with similar Michaelis-Menten kinetic constants, Km= 167 μM, 108 μM and Vmax= 7.88×10−5μmol/min, 4.31×10−5μmol/min, respectively, in concurrence with the previous studies. Taken together, these results suggest that CesAs involved in primary and secondary cell wall formation can be expressed and purified using a simple and more efficient extraction method. This could potentially help unravel the mechanism of native and engineered cellulose synthase complexes involved in plant cell wall biosynthesis.
A method to improve the reproducibility of findings from epigenome- and transcriptome-wide association studies
Authors: van den Oord Edwin JCG , Guintivano Jerry D , Aberg Karolina A. 
Published: March 2023

AbstractReproducibility is a cornerstone of scientific progress. In epigenome- and transcriptome-wide association studies (E/TWAS) failure to reproduce may be the result of false discoveries. Whereas multiple methods exist to control false discoveries due to sampling error, minimizing false discoveries due to outliers and other data artefacts remains challenging. We propose a robust E/TWAS approach that outperforms alternative methods to improve reproducibility such as split-half replication. Furthermore, robust E/TWAS results in only a minor loss of power if there are no outliers and can in the presence of outliers, likely a more realistic scenario, even be more powerful than regular E/TWAS.
Structural Covariance of the Duplicated Heschl’s Gyrus: A Sulcal/Gyral Template Morphology Approach
Authors: Eckert Mark A. ,   Dyslexia Data Consortium
Published: March 2023

AbstractHeschl’s gyrus (HG) can occur as a single gyrus or with a completely duplicated posterior HG that has been related to a variety of abilities and disorders. Voxel-based studies typically involve the normalization of these qualitatively different HG types, thus making it difficult to evaluate the contribution of sulcal/gyral variability to voxel-based effects and perhaps obscuring some effects. To examine the structural covariance of single and duplicated HG, templates were created for the left single and duplicated HG. Structural covariance analysis with a Jacobian measure of volumetric displacement demonstrated consistent spatial covariance with homologous structure in the right hemisphere across qualitatively different HG morphology. These results suggest that HG duplication is aptly named with respect to cortical structure variation and demonstrate a multi-template approach for studying qualitatively unique brain function and structure linked to perceptual and cognitive functions.HighlightsQualitatively unique sulcal/gyral features can affect voxel-based analyses.Heschl’s gyrus is highly variable across people.Morphology-specific templates were created to study Heschl’s gyrus structural covariance.Single and duplicated Heschl’s gyrus exhibited a similar pattern of covariance.
Feature-specific salience maps in human cortex
Authors: Thayer Daniel D. , Sprague Thomas C. 
Published: March 2023

ABSTRACTPriority maps are representations of visual space that determine the relative importance of scene locations. Computational theories suggest that priority maps identify salient locations based on individual feature dimensions (e.g., color, motion), which are integrated into an aggregate priority map. While widely accepted, a core assumption of this framework—the existence of independent feature dimension maps in visual cortex—remains untested. Here, we tested the hypothesis that feature-selective retinotopic regions in human cortex act as neural feature dimension maps, indexing salience based on their preferred feature. We used fMRI activation patterns to reconstruct spatial maps while participants viewed stimuli with salient regions defined by color or motion direction. Reconstructed spatial maps selectively represented salient locations defined by each region’s preferred feature. These findings identify spatially organized feature dimension maps that characterize the salience of scene locations based on a specific visual feature, confirming a key prediction of priority map theory.
Kaposi’s sarcoma-associated herpesvirus ORF67.5 functions as a component of the terminase complex
Authors: Iwaisako Yuki , Watanabe Tadashi , Suzuki Youichi , Nakano Takashi , Fujimuro Masahiro 
Published: March 2023

ABSTRACTKaposi’s sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA gammaherpesvirus, with a poorly characterized lytic replication cycle. However, the lytic replication cycle of the alpha- and betaherpesviruses are well characterized. During lytic infection of alpha- and betaherpesviruses, the viral genome is replicated as a precursor form, which contains tandem genomes linked via terminal repeats (TRs). One genomic unit of the precursor form is packaged into a capsid and is cleaved at the TR by the terminase complex. While the alpha- and betaherpesvirus terminases are well characterized, the KSHV terminase remains poorly understood. KSHV ORF7, ORF29, and ORF67.5 are presumed to be components of the terminase complex based on their homology to other terminase proteins. We previously reported that ORF7-deficient KSHV formed numerous immature soccer ball-like capsids and failed to cleave the TRs. ORF7 interacted with ORF29 and ORF67.5, however ORF29 and ORF67.5 did not interact with each other. While these results suggested that ORF7 is important for KSHV terminase function and capsid formation, the function of ORF67.5 was completely unknown. Therefore, to analyze the function of ORF67.5, we constructed ORF67.5-deficient BAC16. ORF67.5-deficient KSHV failed to produce infectious virus, failed to cleave the TRs, and numerous soccer ball-like capsids were observed in ORF67.5-deficient KSHV-harboring cells. Furthermore, ORF67.5 promoted the interaction between ORF7 and ORF29, and ORF29 increased the interaction between ORF67.5 and ORF7. Thus, our data indicated that ORF67.5 functions as a component of the KSHV terminase complex by contributing to TR cleavage, terminase complex formation, capsid formation, and virus production.IMPORTANCEAlthough the formation and function of the alpha- and betaherpesvirus terminase complexes are well understood, the KSHV terminase complex is still largely uncharacterized. This complex presumably contains KSHV ORF7, ORF29, and ORF67.5. We were the first to report the presence of soccer ball-like capsids in ORF7-deficient KSHV-harboring lytic-induced cells. Here, we demonstrated that ORF67.5-deficient KSHV also formed the soccer ball-like capsids in lytic-induced cells. Moreover, ORF67.5 was required for TR cleavage, infectious virus production, and enhancement of the interaction between ORF7 and ORF29. ORF67.5 has several highly conserved regions among its human herpesviral homologs. These regions were necessary for virus production and for the interaction of ORF67.5 with ORF7, which was supported by the AI-predicted structure model. Importantly, our results provide the first evidence showing that ORF67.5 is essential for terminase complex formation and TR cleavage.
Auditory Complications among Childhood Cancer Survivors and Health-related Quality of Life: A PanCareLIFE study
Authors: Strebel Sven , Baust Katja , Grabow Desiree , Byrne Julianne , Langer Thorsten , Zehnhoff-Dinnesen Antoinette am , Kuonen Rahel , Weiss Annette , Kepak Tomas , Kruseova Jarmila , Berger Claire , Calaminus Gabriele , Sommer Grit , Kuehni Claudia E. 
Published: March 2023

ABSTRACTAuditory complications are potential side effects from childhood cancer treatment. Yet, limited evidence exists about the impact of auditory complications—particularly tinnitus—on health-related quality of life (HRQoL) among childhood cancer survivors (CCS). We determined the prevalence of hearing loss and tinnitus in the large European PanCareLIFE cohort of CCS and examined its effect on HRQoL. We included CCS from four European countries who were diagnosed at age ≤ 18 years; survived ≥ 5 years; and aged 25–44 years at study. We assessed HRQoL (Short Form 36), hearing loss, and tinnitus using questionnaires. We used multivariable linear regression to examine associations between these two auditory complications and HRQoL adjusting for socio-demographic and clinical factors. Our study population consisted of 6,318 CCS (53% female; median age at cancer diagnosis 9 years interquartile range [IQR] 5–13 years) with median age at survey of 31 years (IQR 28–35 years). Prevalence was 7.5% (confidence interval [CI]: 6.9–8.2) for hearing loss and 7.6% (CI: 6.4–9.0) for tinnitus. CCS with hearing loss had impaired physical (coefficient [coef.] - 4.3, CI: -7.0 to -1.6) and mental (coef. -3.2, CI: -5.5 to -0.8) HRQoL when compared with CCS with normal hearing. Tinnitus was also associated with impaired physical (coef. -8.2, CI: -11.8 to -4.7) and mental (coef. -5.9, CI: -8.8 to -3.1) HRQoL. We observed the lowest HRQoL among CCS with both hearing loss and tinnitus. Our findings indicate timely treatment of hearing loss and tinnitus may contribute to quality of life of survivors.
Viral and Host Mediators of Non-Suppressible HIV-1 Viremia
Authors: Mohammadi Abbas , Etemad Behzad , Zhang Xin , Li Yijia , Bedwell Gregory J. , Sharaf Radwa , Kittilson Autumn , Melberg Meghan , Wong Colline , Fajnzylber Jesse , Worrall Daniel P. , Rosenthal Alex , Jordan Hannah , Jilg Nikolaus , Kaseke Clarety , Giguel Francoise , Lian Xiaodong , Deo Rinki , Gillespie Elisabeth , Chishti Rida , Abrha Sara , Adams Taylor , Siagian Abigail , Anderson Peter L. , Deeks Steven G. , Lederman Michael M. , Yawetz Sigal , Kuritzkes Daniel R. , Lichterfeld Mathias D. , Tsibris Athe , Carrington Mary , Brumme Zabrina L. , Castillo-Mancilla Jose R. , Engelman Alan N. , Gaiha Gaurav D. , Li Jonathan Z. 
Published: March 2023

AbstractNon-suppressible HIV-1 viremia (NSV) can occur in persons with HIV despite adherence to combination antiretroviral therapy (ART) and in the absence of significant drug resistance. Here, we show that plasma NSV sequences are comprised primarily of large clones without evidence of viral evolution over time. We defined proviruses that contribute to plasma viremia as “producer”, and those that did not as “non-producer”. Compared to ART-suppressed individuals, NSV participants had a significantly larger producer reservoir. Producer proviruses were enriched in chromosome 19 and in proximity to the activating H3K36me3 epigenetic mark. CD4+cells from NSV participants demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, NSV participants showed no elevation in HIV-specific CD8+cell responses and producer proviruses were enriched for HLA escape mutations. We identified critical host and viral mediators of NSV that represent potential targets to disrupt HIV persistence and promote viral silencing.
Tumor-specific activity of precision medicines in the NCI-MATCH trial
Authors: Zhou Ivvone , Plana Deborah , Palmer Adam C. 
Published: March 2023

Structured AbstractBackgroundNCI-MATCH is a precision medicine basket trial designed to test the effectiveness of treating cancers based on specific genetic changes in patients’ tumors, regardless of cancer type. Multiple subprotocols have each tested different targeted therapies matched to specific genetic aberrations. Most subprotocols exhibited low rates of tumor shrinkage as evaluated across all tumor types enrolled. We hypothesized that these results may arise because these precision cancer therapies have tumor type-specific efficacy, as is common among other cancer therapies.MethodsTo test the hypothesis that certain tumor types are more sensitive to specific therapies than other tumor types, we applied permutation testing to tumor volume change and progression-free survival data from ten published NCI-MATCH subprotocols (together n=435 patients). False discovery rate was controlled by the Benjamini-Hochberg procedure.ResultsSix of ten subprotocols exhibited statistically significant evidence of tumor-specific drug sensitivity, four of which were previously considered negative based on response rate across all tumors. This signal-finding analysis highlights potential uses of FGFR tyrosine kinase inhibition in urothelial carcinomas with actionableFGFRaberrations, MEK inhibition in lung cancers withBRAFnon-V600Emutations, and MEK inhibition in cholangiocarcinomas withNRASmutations.ConclusionsThese findings support the value of basket trials because even when precision medicines do not have tumor-agnostic activity, basket trials can identify tumor-specific activity for future study.
The Role of Sacubitril/Valsartan and Gliflozins in Heart Failure with Reduced Ejection Fraction after Cardiac Resynchronization Therapy
Authors: Fonderico Celeste , Pergola Valerio , Faccenda Daniele , Comparone Gianluigi , Marrese Aldo , Salucci Alfonsomaria , Ammirati Giuseppe , Cocchiara Luigi , Varriale Alfonso , Esposito Giovanni , Rapacciuolo Antonio , Strisciuglio Teresa 
Published: March 2023

ABSTRACTBACKGROUNDThe angiotensin receptor-neprilysin inhibitor (ARNi) and the sodium- glucose co-transporter 2 inhibitors (SGLT2i) have improved the outcome of patients with heart failure and reduced ejection fraction (HFrEF). However, data characterizing their effectiveness after cardiac resynchronization therapy (CRT) implant are relatively scarce. This study investigated the impact of ARNi and SGLT2i treatment 1) on CRT response at 12 months 2) on the cardiac function and the clinical functional status (NYHA class) at mid- and long-term follow-up 3) on the cardiac and overall survival at long-term follow-up.METHODS AND RESULTSHFrEF patients referred for CRT implant were enrolled in the study and were grouped by the ARNi/SGLT2i therapy. A first analysis investigated the synergistic impact of these drugs started at implant on 1-year CRT response and included all 172 patients enrolled. In order to evaluate whether the time of ARNi/SGLT2i initiation after CRT response assessment is meaningful, a second analysis considered 100 patients with a follow-up ≥ 24 months. The median follow-up was 63.1 (confidence interval [CI] 95%, 52.7 - 73.8) months.At 1-year follow-up, 40 of 51 (78.4%) patients in ARNi or SGLT2i group and 66 of 121 (54.5%) in the no treatment group were classified as responders (p = 0.006). In multivariable analysis, ARNi/SGLT2i use was an independent predictor of CRT response (odds ratio, 5.38; CI 95%, 2-16.2; p = 0.001). At mid-term follow-up (median time [interquartile range, IQR] 40.6 [25.2; 58.3] months), 61 patients started to assume these drugs. NYHA functional class improved in 23 (37.7%) patients and decreased in only 2 (3.3%) in ARNi/SGLT2i patients vs 13 (33.3%) in no treatment group (p < 0.001). ARNi and SGLT2i improved significantly also the Δ LVEF, with a median [IQR] increase of 4 [2; 8] % compared to the no treatment group - 1.8 [-4; 0.2] % (p < 0.001) and were independently associated with a NYHA functional class II or I at long-term (hazard ratio [HR], 3.67; CI 95%, 1.37-10.2; p < 0.001). Their estimated effectiveness was consistent over the entire follow-up period (Schoenfeld residuals test, p = 0.10), although without reaching statistical significance effects on cardiovascular survival (HR, 0.61; CI 95%, 0.25-1.50; p = 0.22).CONCLUSIONSThe ARNi and SGLT2i treatment in CRT patients improves the clinical and echocardiographic response at 12-month and long-term follow-up, independently from the time of initiation. These drugs also confer benefit on survival, however further studies are needed to confirm these data.
Deep Learning using Susceptibility-Weighted MR Sequence to Detect Microbleeds and Classify Cerebral Small Vessel Disease
Authors: Wu Ruizhen , Liu Huaqing , Li Hao , Chen Lifen , Wei Lei , Huang Xuehong , Liu Xu , Men Xuejiao , Li Xidan , Han Lanqing , Lu Zhengqi , Qin Bing 
Published: March 2023

AbstractBackgroundMicrobleeds (CMBs) serve as neuroimaging biomarkers to assess risk of intracerebral hemorrhage and diagnose cerebral small vessel disease (CSVD). Therefore, detecting CMBs can evaluate the risk of intracerebral hemorrhage and use its presence to support CSVD classification, both are conducive to optimizing CSVD management. This study aimed to develop and test a deep learning (DL) model based on susceptibility-weighted MR sequence (SWS) to detect CMBs and classify CSVD to assist neurologists in optimizing CSVD management.MethodsPatients with arteriolosclerosis (aSVD), cerebral amyloid angiopathy (CAA), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) treated at three centers were enrolled between January 2017 and May 2022 in this retrospective study. The SWSs of patients from two centers were used as the development set, and the SWSs of patients from the remaining center were used as the external test set. The DL model contains a Mask R-CNN for detecting CMBs and a multi-instance learning (MIL) network for classifying CSVD. The metrics for model performance included intersection over union (IoU), Dice score, recall, confusion matrices, receiver operating characteristic curve (ROC) analysis, accuracy, precision, and F1-score.ResultsA total of 364 SWS were recruited, including 336 in the development set and 28 in the external test set. IoU for the model was 0.523 ± 0.319, Dice score 0.627 ± 0.296, and recall 0.706 ± 0.365 for CMBs detection in the external test set. For CSVD classification, the model achieved a weighted-average AUC of 0.908 (95% CI: 0.895-0.921), accuracy of 0.819 (95% CI: 0.768-0.870), weighted-average precision of 0.864 (95% CI: 0.831-0.897), and weighted-average F1-score of 0.829 (95% CI: 0.782-0.876) in the external set, outperforming the performance of the neurologist group.ConclusionThe DL model based on SWS can detect CMBs and classify CSVD, thereby assisting neurologists in optimizing CSVD management.