bluuebunny/crossref_metadata_2025_split huggingface dataset:
Doublecortin-like kinase 1 is a therapeutic target in squamous cell carcinoma
Authors: Standing David , Arnold Levi , Dandawate Prasad , Ottemann Brendan , Snyder Vusala , Ponnurangam Sivapriya , Sayed Afreen , Subramaniam Dharmalingam , Srinivasan Pugazhendhi , Choudhury Sonali , New Jacob , Kwatra Deep , Ramamoorthy Prabhu , Roy Badal C. , Shadoin Melissa , Al-Rajabi Raed , O’Neil Maura , Gunewardena Sumedha , Ashcraft John , Umar Shahid , Weir Scott J. , Tawfik Ossama , Padhye Subhash B. , Anant Shrikant , Thomas Sufi Mary 
Published: May 2022

AbstractDoublecortin like kinase 1 (DCLK1) plays a crucial role in several cancers including colon and pancreatic adenocarcinomas. However, its role in squamous cell carcinoma (SCC) remains unknown. To this end, we examined DCLK1 expression in head and neck squamous cell carcinoma (HNSCC) and anal squamous cell carcinoma (ASCC). We found that DCLK1 is elevated in patient SCC tissue, which correlated with cancer progression and poorer overall survival. Furthermore, DCLK1 expression is significantly elevated in HPV negative cancer tissues, which are typically aggressive with poor responses to radiation therapy. To understand the role of DCLK1 in tumorigenesis, we used specific shRNA to suppress DCLK1 expression. This significantly reduced tumor growth, spheroid formation, and migration of HNSCC cancer cells. To further the translational relevance of our studies, we sought to identify a selective DCLK1 inhibitor. Current attempts to target DCLK1 using pharmacologic approaches have relied on non-specific suppression of DCLK1 kinase activity. Here, we demonstrate that DiFiD [3,5-bis (2,4-difluorobenzylidene)-4-piperidone] binds to DCLK1 with high selectivity. Moreover, DiFiD mediated suppression of DCLK1 led to G2/M arrest and apoptosis and significantly suppressed tumor growth of HNSCC xenografts and ASCC patient derived xenografts, supporting that DCLK1 is critical for SCC growth.
Whole-exome sequencing study identifies novel rare variants and genes associated with intraocular pressure and glaucoma
Authors: Gao Xiaoyi Raymond , Chiariglione Marion , Arch Alexander J. 
Published: May 2022

AbstractElevated intraocular pressure (IOP) is a major risk factor for glaucoma, the leading cause of irreversible blindness worldwide. IOP is also the only modifiable risk factor for glaucoma. Previous genome-wide association studies have established the contribution of common genetic variants to IOP. The role of rare variants for IOP was unknown. Using whole exome sequencing data from 454,756 participants in the UK Biobank (UKB), we conducted the largest exome-wide association study of IOP to date. In addition to confirming known IOP genes, we identified 40 novel rare-variant genes for IOP, such as BOD1L1, ACAD10 and HLA-B, demonstrating the power of including and aggregating rare variants in gene discovery. About half of these IOP genes are also associated with glaucoma phenotypes in UKB and the FinnGen cohort. Six of these genes, i.e. ADRB1, PTPRB, RPL26, RPL10A, EGLN2, and MTOR, are drug targets that are either established for clinical treatment or in clinical trials. Furthermore, we constructed a rare-variant polygenic risk score and showed its significant association with glaucoma in independent subjects. We demonstrated the value of rare variants to enhance our understanding of the biological mechanisms regulating IOP, and uncovered potential novel therapeutic targets for glaucoma.
Statistical segmentation and correlation analysis of the EEG between the different phases of general anesthesia
Authors: Sun C. , Longrois D. , Holcman D. 
Published: May 2022

AbstractElectroencephalography (EEG) is routinely used to monitor general anesthesia (GA). Unanswered questions concern the possibility of using the EEG signal to classify patients as more or less sensitive to anesthetic drugs from the onset of anesthesia. We investigate here possible statistical correlation between different phases of general anesthesia. We test whether it could be possible to predict the speed of return to consciousness from the induction or the maintenance phases. For that goal, we tracked the maximum power of theα−band and follow its time course. Using an optimization procedure, we quantify the characteristic shift of theα−band during recovery and the associated duration. Interestingly, we found no correlation (Pearson coefficient) between these shifts and the amount ofα−band or iso-electric suppressions (flat EEG epochs) present in the maintenance phase or induced by a propofol injection during induction. To quantify the instability of theα−band, we introduce the total variation theα−band that accounts for all possible deviation from a flat line. To conclude, the present analysis shows that it would not be possible to anticipate the duration of recovery of consciousness from previous phases of general anesthesia in children and adults. Possibly the involved neuronal mechanisms during the different phases are not comparable.
Multi-ancestry GWAS deciphers genetic architecture of abdominal aortic aneurysm and highlightsPCSK9as a therapeutic target
Authors: Roychowdhury Tanmoy , Klarin Derek , Levin Michael G , Spin Joshua M , Rhee Yae Hyun , Deng Alicia , Headley Colwyn A , Surakka Ida , Tsao Noah L , Gellatly Corry , Zuber Verena , Shen Fred , Hornsby Whitney E , Laursen Ina Holst , Verma Shefali S , Locke Adam E , Einarsson Gudmundur , Thorleifsson Gudmar , Graham Sarah E , Dikilitas Ozan , Pattee Jack W , Judy Renae L , Pauls-Verges Ferran , Nielsen Jonas B , Wolford Brooke N , Brumpton Ben M , Dilmé Jaume , Peypoch Olga , Juscafresa Laura Calsina , Edwards Todd L , Li Dadong , Banasik Karina , Brunak Søren , Jacobsen Rikke L , Garcia-Barrio Minerva T , Zhang Jifeng , Rasmussen Lars M , Lee Regent , Handa Ashok , Wanhainen Anders , Mani Kevin , Lindholt Jes S , Obel Lasse M , Strauss Ewa , Oszkinis Grzegorz , Nelson Christopher P , Saxby Katie , van Herwaarden Joost A , van der Laan Sander W , van Setten Jessica , Camacho Mercedes , Davis Frank M , Wasikowski Rachael , Tsoi Lam C , Gudjonsson Johann E , Eliason Jonathan L , Coleman Dawn M , Henke Peter K , Ganesh Santhi K , Chen Y Eugene , Guan Weihua , Pankow James S , Pankratz Nathan , Pedersen Ole B , Erikstrup Christian , Tang Weihong , Hveem Kristian , Gudbjartsson Daniel , Gretarsdottir Solveig , Thorsteinsdottir Unnur , Holm Hilma , Stefansson Kari , Ferreira Manuel A , Baras Aris , Kullo Iftikhar J , Ritchie Marylyn D , Christensen Alex H , Iversen Kasper K , Eldrup Nikolaj , Sillesen Henrik , Ostrowski Sisse R , Bundgaard Henning , Ullum Henrik , Burgess Stephen , Gill Dipender , Gallagher Katherine , Sabater-Lleal Maria ,   DiscovEHR,   Regeneron Genetics Center,   UK Aneurysm Growth Study,   DBDS Genomic Consortium,   VA Million Veteran Program, Jones Gregory T , Bown Matthew J , Tsao Philip S , Willer Cristen J , Damrauer Scott M 
Published: May 2022

SummaryAbdominal aortic aneurysm (AAA) is a common disease with significant heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 144 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis was able to explain AAA beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in the pathogenesis of AAA. We further integrated functional data to elucidate expression of genes associated with AAA. These genes also indicate crossover between the development of AAA and other monogenic aortopathies, particularly via TGF-β signaling pathways. Motivated by the strong evidence for the role of lipid levels in AAA by PheWAS, we identified therapeutic opportunities using Mendelian Randomization and, in pre-clinical studies, we demonstrated thatPCSK9inhibition in mice prevented the development of AAA.
Identifying COVID-19 phenotypes using cluster analysis and assessing their clinical outcomes
Authors: Yamga Eric , Mullie Louis , Durand Madeleine , Cadrin-Chenevert Alexandre , Tang An , Montagnon Emmanuel , Chartrand-Lefebvre Carl , Chassé Michaël 
Published: May 2022

AbstractMultiple clinical phenotypes have been proposed for COVID-19, but few have stemmed from data-driven methods. We aimed to identify distinct phenotypes in patients admitted with COVID-19 using cluster analysis, and compare their respective characteristics and clinical outcomes.We analyzed the data from 547 patients hospitalized with COVID-19 in a Canadian academic hospital from January 1, 2020, to January 30, 2021. We compared four clustering algorithms: K-means, PAM (partition around medoids), divisive and agglomerative hierarchical clustering. We used imaging data and 34 clinical variables collected within the first 24 hours of admission to train our algorithm. We then conducted survival analysis to compare clinical outcomes across phenotypes and trained a classification and regression tree (CART) to facilitate phenotype interpretation and phenotype assignment.We identified three clinical phenotypes, with 61 patients (17%) in Cluster 1, 221 patients (40%) in Cluster 2 and 235 (43%) in Cluster 3. Cluster 2 and Cluster 3 were both characterized by a low-risk respiratory and inflammatory profile, but differed in terms of demographics. Compared with Cluster 3, Cluster 2 comprised older patients with more comorbidities. Cluster 1 represented the group with the most severe clinical presentation, as inferred by the highest rate of hypoxemia and the highest radiological burden. Mortality, mechanical ventilation and ICU admission risk were all significantly different across phenotypes.We conducted a phenotypic analysis of adult inpatients with COVID-19 and identified three distinct phenotypes associated with different clinical outcomes. Further research is needed to determine how to properly incorporate those phenotypes in the management of patients with COVID-19.
Identification of Disease-Specific Turning Movement Hallmarks: A Systematic Review towards Establishment of Disease Screening Algorithm
Authors: Ogawa Ami , Takeda Takanori , Yoshino Kohei , Iijima Hirotaka 
Published: May 2022

AbstractBackgroundPatients with nervous system and musculoskeletal diseases display gait disturbance that is a leading cause of falls. Identification of disease-specific movement hallmarks is therefore an essential first step in preventing falls. Since turning, a common daily activity, is a unique movement that requires inter-limb spatial coordination, turning may be a suitable observational target for the identification of disease-specific movement disorder. However, to date, few comprehensive systematic review regarding disease-specific alterations in turning movement is available.Research questionThis systematic review with meta-analysis summarized the level of knowledge regarding movement disorders during turning in patients with nervous system and musculoskeletal diseases.MethodsA systematic review was conducted of papers throughout 2021 in accordance with PRISMA guideline. Including criteria were (1) were published in a peer-reviewed journal, (2) were written in English, (3) included adult patients who were diagnosed with musculoskeletal or nervous system diseases, (4) had a control group of age-matched healthy adults, and (5) outcomes included turning parameters.ResultsMeta-analysis revealed a significantly larger step number, longer turn duration, and shorter step length in patients with Parkinson’s disease (PD) than in controls during the 180° turn, suggesting that these biomechanical alterations may be, at least in part, movement disorders associated with PD. Notably, this review identified methodological heterogeneity for turning movement assessments, which limited the identification of disease-specific movement disorders.SignificanceThis work serves as a call to action for the establishment of a standard assessment protocol towards the identification of disease-specific turning movement disorders and effective disease screening.
Circular RNA RORβ regulates TGFBR1 by decoying miR-140 in alcohol-exposed lungs and fibroblasts
Authors: Sueblinvong Viranuj , Fan Xian , Williams Raven , Kang Bum-Yong 
Published: May 2022

AbstractAlcohol ingestion exaggerates transforming growth factor-beta 1 (TGFβ1) expression and signaling leading to fibroproliferation. Inhibition of TGFβ receptor type 1 (TGFβR1) mitigates the effect of TGFβ1 signaling. We showed that alcohol can modulate microRNA (miRNA) expressions. The mechanism by which alcohol modulates microRNA and how it ties to TGFβ1 signaling has not been well elucidated. Circular RNA (circRNAs or circ) emerges as a potential therapeutic target based on its stability, tissue specificity, and its ability to modify miRNAs. In this study, we showed that alcohol upregulates TGFβR1 and circRNA form of retinoic acid receptor-related orphan receptor beta (circ-RORβ) in lung fibroblasts (LF) and the lung. We identified miR-140 to have binding sites for both TGFβR1 3’ UTR and circ-RORβ and alcohol attenuated miR-140 expression in LF and the lung. We demonstrated that inhibition of circ-RORβ upregulated miR-140 and completely abrogated alcohol-induced miR-140 suppression. We further showed that inhibition of circ-RORβ attenuated alcohol-induced TGFβR1, fibronectin (FN1), and α-smooth muscle actin (αSMA) expressions and myofibroblast development as seen by an attenuation of αSMA stress fiber formation in LF. Taken together, these findings identify circ-RORβ-miR-140-TGFβR1 axis as a novel mechanism by which alcohol induces TGFβ1 signaling and promotes FMD.HighlightsAlcohol induces circ-RORβ expression in lung fibroblastsCirc-RORβ regulates TGFβR1 by decoying miR-140 in lung fibroblastsInhibition of Circ-RORβ restores miR-140 expressionInhibition of Circ-RORβ mitigates alcohol-mediated myofibroblast differentiationThis is the first description of circ-RORβ functional significance in lung fibroblast
sMAP: An interactive microarray data analysis tool for early-stage researchers
Authors: Bharti Samuel , Krishnan Nikita , Veyssi Arian , Momeni Maryam , Raj Sneha 
Published: May 2022

AbstractMicroarray data enables biologists to extract differentially expressed genes (DEGs) across multiple phenotypes. While several pipelines and tools exist to perform microarray data analysis, they are targeted to users with moderate to advanced computational understanding and lack an easy-to-use, interactive and dynamic methodology to perform analysis assisted with comprehensive learning resources. In this study, we developed an interactive application “sMAP” (Standard Microarray Analysis Pipeline) to make transcriptome microarray data analysis more accessible in learning environments and to enable the identification of significant pathological biomarkers. In a case study of colorectal cancer, we showed that sMAP enabled us to reproduce previous findings and discover relevant pathways. sMAP provides a comprehensive set of tutorials and learning documentation to help early-stage researchers. The latest URLs of sMAP’s hosting, tutorial, and frequently updated documentation can be found at https://github.com/BI-STEM-Away/sMAP.
Peritoneal autoantibody landscape in endometriosis
Authors: Harden Sarah , Tan Tse Yeun , Ku Chee Wai , Zhou Jieliang , Chen Qingfeng , Chan Jerry Kok Yen , Brosens Jan , Lee Yie Hou 
Published: May 2022

ABSTRACTWomen with endometriosis have a profound association with autoimmunity. An excess of autoantigens in the peritoneal cavity resulting from retrograde menstruation could lead to inflammation and pathologic autoimmunity. Using a native-conformation protein array, proteome-wide analysis of autoantibodies (AAbs) against 1623 proteins were profiled in peritoneal fluids (PF) of 25 women with endometriosis and 25 endometriosis-negative women. 46% of endometriotic women have five or more AAbs. Diverse cognate autoantigens were identified and corresponding AAbs against proteins involved in implantation, B-cell activation/development, and aberrant migration and mitogenicity. AAbs recognizing tumour suppressor protein p53 were the most frequent at 35% and were targeted against native and citrullinated p53 forms. Further, unsupervised hierarchical clustering and integrative pathway analysis, we observed clusters of endometriosis-associated infertile women with 60% positive for two or more AAbs which are involved in PDGF, TGF-β, RAC1/PAK1/p38/MMP2 signaling, LAT2/NTAL/LAB-mediated calcium mobilisation and integrin-mediated cell adhesion. Together, our data identifies peritoneal autoimmunity in a significant subset of women with endometriosis, with diverse impact on infertility and disease pathophysiology.
Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I
Authors: Rodríguez-Nuevo Aida , Torres-Sanchez Ariadna , Duran Juan M , De Guirior Cristian , Martínez-Zamora Maria Angeles , Böke Elvan 
Published: May 2022

SUMMARYOocytes form before birth and remain viable for several decades before fertilisation. Although poor oocyte quality accounts for the majority of female fertility problems, little is known about how oocytes maintain cellular fitness, nor why they eventually decline with age. Reactive oxygen species (ROS) produced as by-products of mitochondrial activity are associated with lower rates of fertilisation and embryo survival. Yet, how healthy oocytes balance essential mitochondrial activity with the production of ROS is unknown. Here, we show that oocytes evade ROS by remodelling the mitochondrial electron transport chain (ETC) through elimination of complex I. Combining live-cell imaging and proteomics in human and Xenopus oocytes, we find that early oocytes exhibit greatly reduced levels of complex I. This is accompanied by a highly active mitochondrial unfolded protein response, which is indicative of an imbalanced ETC. Biochemical and functional assays confirm that complex I is neither assembled nor active in early oocytes. Thus, we report the first physiological cell type without complex I in animals. Our findings clarify why patients suffering from complex I related hereditary mitochondrial diseases do not experience subfertility, in contrast to diseases involving other mitochondrial complexes. Complex I suppression represents an evolutionary-conserved strategy that allows longevity while maintaining biological activity in long-lived oocytes.
Adgrg6/Gpr126 is required for myocardial Notch activity and N-cadherin localization to attain trabecular identity
Authors: Srivastava Swati , Gunawan Felix , Gentile Alessandra , Petersen Sarah C. , Stainier Didier Y.R. , Engel Felix B. 
Published: May 2022

AbstractHow adhesion G protein-coupled receptors (aGPCRs) control development remains unclear. The aGPCR Adgrg6/Gpr126 has been associated with heart trabeculation. Defects in this process cause cardiomyopathies and embryonic lethality. Yet, how cardiomyocytes attain trabecular identity is poorly understood. Here, we show that Gpr126 regulates Notch activity and N-cadherin localization that are necessary for attaining trabecular identity in zebrafish. Maternal zygotic gpr126stl47 early truncation mutants exhibit hypotrabeculation whereby N-cadherin distributes randomly at apical/basal membranes of compact layer cardiomyocytes. In contrast, gpr126st49 mutants expressing a N-terminal fragment lacking the GPS motif (NTFΔGPS) exhibit a multilayered ventricular wall consisting of polarized cardiomyocytes with normal N-cadherin expression and increased Notch signaling. Notably, endocardially expressed C-terminal fragment (CTF) reinstates trabeculation in gpr126st49 mutants. Collectively, our data indicate domain-specific roles of Gpr126 during trabeculation whereby the NTF maintains cell-cell adhesion and is required for compact wall integrity, while the CTF is essential to provide trabecular identity
A Role for Nup153 in Nuclear Assembly Reveals Differential Requirements for Targeting of Nuclear Envelope Constituents
Authors: LaJoie Dollie , Turkmen Ayse M. , Mackay Douglas R. , Jensen Christopher C. , Aksenova Vasilisa , Niwa Maho , Dasso Mary , Ullman Katharine S. 
Published: May 2022

AbstractAssembly of the nucleus following mitosis requires rapid and coordinate recruitment of diverse constituents to the inner nuclear membrane. We have identified an unexpected role for the nucleoporin Nup153 in promoting the continued addition of a subset of nuclear envelope proteins during initial expansion of nascent nuclei. Specifically, disrupting the function of Nup153 interferes with ongoing addition of B-type lamins, lamin B receptor (LBR), and SUN1 early in telophase, after the nuclear envelope (NE) has initially enclosed chromatin. In contrast, effects on lamin A and SUN2 were minimal, pointing to differential requirements for the ongoing targeting of nuclear envelope proteins. Further, distinct mis-targeting phenotypes arose among the proteins that require Nup153 for NE targeting. Thus, disrupting the function of Nup153 in nuclear formation reveals several previously undescribed features important for establishing nuclear architecture: 1) a role for a nuclear basket constituent in ongoing recruitment of nuclear envelope components, 2) two functionally separable phases of nuclear envelope formation in mammalian cells, and 3) distinct requirements of individual nuclear envelope residents for continued targeting during the expansion phase of NE reformation.
Mapping Structural Drivers of Insulin Analogs Using Molecular Dynamics and Free Energy Calculations at Insulin Receptor
Authors: Sena Mohan Maruthi , Ramakrishnan C , Gromiha M. Michael , Chatterji Monalisa , Khedkar Anand , Ranganathan Anirudh 
Published: May 2022

AbstractA century on from the discovery of insulin, a complete understanding of insulin interactions with the insulin receptor (IR) at atomic level remains elusive. In this work, we have leveraged recent advancements in structural biology that have resulted in multiple high-resolution structures of the insulin-IR complex. As a first step, we employed molecular dynamics (MD) simulations to unravel atomic insights into the interactions between insulin-IR complexes in order to better understand ligand recognition at the receptor. The MD simulations were followed up with free energy perturbation (FEP) calculations to discriminate between and elucidate the drivers for ligand association for various natural and man-made insulin analogs. As an example, these calculations were utilized to understand the molecular mechanisms that characterized the loss-of-function seen in disease-associated insulin mutations seen in different populations. Further, multiple man-made insulin analogs spanning a range of potencies, mutations, and sequence lengths were studied using FEP and a comprehensive molecular level map of potency determinants were established. ∼85% of FEP calculations captured the direction of shift of potency, and in ∼53% of cases the predictions were within 1 kcal/mol of experiment. The impressive accuracy of FEP in recapitulating functional profiles across such a span of insulin analogs and potency profiles provided clear evidence of its utility in computational mutagenesis. In addition to the impressive accuracy, the ability of FEP to provide a dissected understanding of protein residue, solvent and solvent-mediated contributions to binding energy clearly establishes its utility in the design of novel insulins and peptides in general.