Search

Your search keyword '"Charaka, A."' showing total 456 results
Start Over Author "Charaka, A."
456 results on '"Charaka, A."'

1. No Size Fits All: The Perils and Pitfalls of Leveraging LLMs Vary with Company Size

Author

Urlana, Ashok, Kumar, Charaka Vinayak, Garlapati, Bala Mallikarjunarao, Singh, Ajeet Kumar, and Mishra, Rahul

Subjects
Computer Science - Computers and Society, Computer Science - Artificial Intelligence
Abstract

Large language models (LLMs) are playing a pivotal role in deploying strategic use cases across a range of organizations, from large pan-continental companies to emerging startups. The issues and challenges involved in the successful utilization of LLMs can vary significantly depending on the size of the organization. It is important to study and discuss these pertinent issues of LLM adaptation with a focus on the scale of the industrial concerns and brainstorm possible solutions and prospective directions. Such a study has not been prominently featured in the current research literature. In this study, we adopt a threefold strategy: first, we conduct a case study with industry practitioners to formulate the key research questions; second, we examine existing industrial publications to address these questions; and finally, we provide a practical guide for industries to utilize LLMs more efficiently., Comment: 17 pages, 3 figures

Published
2024

2. TrustAI at SemEval-2024 Task 8: A Comprehensive Analysis of Multi-domain Machine Generated Text Detection Techniques

Author

Urlana, Ashok, Saibewar, Aditya, Garlapati, Bala Mallikarjunarao, Kumar, Charaka Vinayak, Singh, Ajeet Kumar, and Chalamala, Srinivasa Rao

Subjects
Computer Science - Computation and Language, I.2.7
Abstract

The Large Language Models (LLMs) exhibit remarkable ability to generate fluent content across a wide spectrum of user queries. However, this capability has raised concerns regarding misinformation and personal information leakage. In this paper, we present our methods for the SemEval2024 Task8, aiming to detect machine-generated text across various domains in both mono-lingual and multi-lingual contexts. Our study comprehensively analyzes various methods to detect machine-generated text, including statistical, neural, and pre-trained model approaches. We also detail our experimental setup and perform a in-depth error analysis to evaluate the effectiveness of these methods. Our methods obtain an accuracy of 86.9\% on the test set of subtask-A mono and 83.7\% for subtask-B. Furthermore, we also highlight the challenges and essential factors for consideration in future studies., Comment: 8 pages, 1 Figure

Published
2024

3. LLMs with Industrial Lens: Deciphering the Challenges and Prospects -- A Survey

Author

Urlana, Ashok, Kumar, Charaka Vinayak, Singh, Ajeet Kumar, Garlapati, Bala Mallikarjunarao, Chalamala, Srinivasa Rao, and Mishra, Rahul

Subjects
Computer Science - Computation and Language
Abstract

Large language models (LLMs) have become the secret ingredient driving numerous industrial applications, showcasing their remarkable versatility across a diverse spectrum of tasks. From natural language processing and sentiment analysis to content generation and personalized recommendations, their unparalleled adaptability has facilitated widespread adoption across industries. This transformative shift driven by LLMs underscores the need to explore the underlying associated challenges and avenues for enhancement in their utilization. In this paper, our objective is to unravel and evaluate the obstacles and opportunities inherent in leveraging LLMs within an industrial context. To this end, we conduct a survey involving a group of industry practitioners, develop four research questions derived from the insights gathered, and examine 68 industry papers to address these questions and derive meaningful conclusions., Comment: 25 pages, 7 figures

Published
2024

5. Cluster analysis of cancer knowledge, attitudes and behaviors in the Moroccan population

Author

Mohamed Khalis, Imad Elbadisy, Oumnia Bouaddi, Amy Luo, Amina Bendriouich, Badr Addahri, Hafida Charaka, Mohamed Chahboune, Jérôme Foucaud, Abdallah Badou, Lahcen Belyamani, and Inge Huybrechts

Subjects
Cancer, Morocco, Risk factors, Cluster analysis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Cancer has become a major health concern due to the increasing morbidity and mortality rates, and its negative social, economic consequences and the heavy financial burden incurred by cancer patients. About 40% of cancers are preventable. The aim of this study was to assess the knowledge, attitudes, and practices regarding cancer prevention, and associated characteristics to inform the development of targeted cancer prevention campaigns and policies. Methods We conducted a cross-sectional survey of adult patients at Mohamed Sekkat and Sidi Othmane Hospitals in Casablanca, Morocco. Data collection was conducted by two trained interviewers who administered the questionnaire in-person in the local language. An unsupervised clustering approach included 17 candidate variables for the cluster analysis. The variables covered a wide range of characteristics, including demographics, health perceptions and attitudes. Survey answers were calculated to compose qualitative ordinal categories, including a cancer attitude score and knowledge score. Results The cluster-based analysis showed that participants in cluster 1 had the highest mean attitude score (13.9 ± 2.15) and percentage of individuals with a high level of knowledge (50.8%) whereas the lowest mean attitude score (9.48 ± 2.02) and knowledge level (7.5%.) were found in cluster 3. The participants with the lowest cancer attitude scores and knowledge levels were aged 34 to 47 years old (middle age group), predominantly females, living in rural settings, and were least likely to report health professionals as a source of health information. Conclusions The findings showed that female individuals living in rural settings, belonging to an older age group, who were least likely to use health professionals as an information source had the lowest levels of knowledge and attitudes. These groups are amenable to targeted and tailored interventions aiming to modify their understanding of cancer in order to enhance the outcomes of Morocco’s on-going efforts in cancer prevention and control strategies.

Published
2024
Full Text
View/download PDF

11. Aortic flow is abnormal in HFpEF [version 2; peer review: 2 approved]

Author

Pankaj Garg, Vassilios S Vassiliou, Peter Swoboda, Steffen Peterson, Christopher Miller, Andrew J. Swift, Rob J. van der Geest, Hosamadin Assadi, Zia Mehmood, Bahman Kasmai, Rui Li, Ciaran Grafton-Clarke, Gareth Matthews, Xiaodan Zhao, Aureo Sanz-Cepero, Nay Aung, Liang Zhong, Charaka Hadinnapola, and Kristian Skinner

Subjects
Magnetic Resonance Imaging, Aortic Flow, Haemodynamics, HFpEF, Cardiac Output, eng, Medicine, Science
Abstract

Aims Turbulent aortic flow makes the cardiovascular system less effective. It remains unknown if patients with heart failure with preserved ejection fraction (HFpEF) have disturbed aortic flow. This study sought to investigate advanced markers of aortic flow disturbances in HFpEF. Methods This case-controlled observational study used four-dimensional flow cardiovascular magnetic resonance derived, two-dimensional phase-contrast reformatted plane data at an orthogonal plane just above the sino-tubular junction. We recruited 10 young healthy controls (HCs), 10 old HCs and 23 patients with HFpEF. We analysed average systolic aortic flow displacement (FDsavg), systolic flow reversal ratio (sFRR) and pulse wave velocity (PWV). In a sub-group analysis, we compared old HCs versus age-gender-matched HFpEF (N=10). Results Differences were significant in mean age (P 17.7% achieved 74% sensitivity, 70% specificity for differentiating them. sFRR was notably higher in HFpEF (11±10% vs 7±6%, P 7.3% yielded 78% sensitivity, 70% specificity in differentiating these groups. In sub-group analysis, FDsavg remained distinctly elevated in HFpEF (22.4±9.7% vs 16±4.9%, P=0.029). FDsavg of >16% showed 100% sensitivity and 70% specificity (P=0.01). Similarly, sFRR remained significantly higher in HFpEF (11.3±9.5% vs 6.6±6.4%, P=0.007). A sFRR of >7.2% showed 100% sensitivity and 60% specificity (P

Published
2024
Full Text
View/download PDF

14. Affective Dynamic Based Technique for Facial Emotion Recognition (FER) to Support Intelligent Tutors in Education

Author

Ruan, Xingran, Palansuriya, Charaka, Constantin, Aurora, Goos, Gerhard, Founding Editor, Hartmanis, Juris, Founding Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Yung, Moti, Editorial Board Member, Wang, Ning, editor, Rebolledo-Mendez, Genaro, editor, Matsuda, Noboru, editor, Santos, Olga C., editor, and Dimitrova, Vania, editor

Published
2023
Full Text
View/download PDF

16. EXO5-DNA structure and BLM interactions direct DNA resection critical for ATR-dependent replication restart

Author

Hambarde, Shashank, Tsai, Chi-Lin, Pandita, Raj K, Bacolla, Albino, Maitra, Anirban, Charaka, Vijay, Hunt, Clayton R, Kumar, Rakesh, Limbo, Oliver, Le Meur, Remy, Chazin, Walter J, Tsutakawa, Susan E, Russell, Paul, Schlacher, Katharina, Pandita, Tej K, and Tainer, John A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Human Genome, Generic health relevance, Ataxia Telangiectasia Mutated Proteins, Cell Line, Cell Line, Tumor, DNA, DNA Damage, DNA Helicases, DNA Mutational Analysis, DNA Repair, DNA Replication, DNA-Binding Proteins, Exonucleases, Genomic Instability, HEK293 Cells, HeLa Cells, Humans, Mutation, Oncogenes, Phosphorylation, RecQ Helicases, Up-Regulation, Hela Cells, ATR phosphorylation, Bloom, Fanconi anemia, SCE, exonuclease, fork restart, genetic instability, interstrand crosslink repair, replication stress, sister chromatid exchange, tumor proliferation, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Stalled DNA replication fork restart after stress as orchestrated by ATR kinase, BLM helicase, and structure-specific nucleases enables replication, cell survival, and genome stability. Here we unveil human exonuclease V (EXO5) as an ATR-regulated DNA structure-specific nuclease and BLM partner for replication fork restart. We find that elevated EXO5 in tumors correlates with increased mutation loads and poor patient survival, suggesting that EXO5 upregulation has oncogenic potential. Structural, mechanistic, and mutational analyses of EXO5 and EXO5-DNA complexes reveal a single-stranded DNA binding channel with an adjacent ATR phosphorylation motif (T88Q89) that regulates EXO5 nuclease activity and BLM binding identified by mass spectrometric analysis. EXO5 phospho-mimetic mutant rescues the restart defect from EXO5 depletion that decreases fork progression, DNA damage repair, and cell survival. EXO5 depletion furthermore rescues survival of FANCA-deficient cells and indicates EXO5 functions epistatically with SMARCAL1 and BLM. Thus, an EXO5 axis connects ATR and BLM in directing replication fork restart.

Published
2021

17. Autism-Associated Vigilin Depletion Impairs DNA Damage Repair.

Author

Banday, Shahid, Pandita, Raj, Mushtaq, Arjamand, Bacolla, Albino, Mir, Ulfat, Singh, Dharmendra, Jan, Sadaf, Bhat, Krishna, Hunt, Clayton, Rao, Ganesh, Charaka, Vijay, Tainer, John, Pandita, Tej, and Altaf, Mohammad

Subjects
DNA repair, Rad51, autism-related disorders, cancer, histone acetylation, homologous recombination, replicative stress, vigilin, Autistic Disorder, BRCA1 Protein, DNA Breaks, Double-Stranded, DNA Repair, DNA Replication, Genomic Instability, Humans, Proto-Oncogene Mas, RNA-Binding Proteins, Rad51 Recombinase
Abstract

Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. Conserved from yeast to humans, vigilin is an RNA-binding protein with 14 tandemly arranged nonidentical hnRNP K-type homology (KH) domains. Here, we report that vigilin depletion increased cell sensitivity to cisplatin- or ionizing radiation (IR)-induced cell death and genomic instability due to defective DNA repair. Vigilin depletion delayed dephosphorylation of IR-induced γ-H2AX and elevated levels of residual 53BP1 and RIF1 foci, while reducing Rad51 and BRCA1 focus formation, DNA end resection, and double-strand break (DSB) repair. We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites. Transient hydroxyurea (HU)-induced replicative stress in vigilin-depleted cells increased replication fork stalling and blocked restart of DNA synthesis. Furthermore, histone acetylation promoted vigilin recruitment to DSBs preferentially in the transcriptionally active genome. These findings uncover a novel vigilin role in DNA damage repair with implications for autism and cancer-related disorders.

Published
2021

18. Human-In-The-Loop Automatic Program Repair

Author

Böhme, Marcel, Geethal, Charaka, and Pham, Van-Thuan

Subjects
Computer Science - Software Engineering, Computer Science - Artificial Intelligence
Abstract

We introduce Learn2fix, the first human-in-the-loop, semi-automatic repair technique when no bug oracle--except for the user who is reporting the bug--is available. Our approach negotiates with the user the condition under which the bug is observed. Only when a budget of queries to the user is exhausted, it attempts to repair the bug. A query can be thought of as the following question: "When executing this alternative test input, the program produces the following output; is the bug observed"? Through systematic queries, Learn2fix trains an automatic bug oracle that becomes increasingly more accurate in predicting the user's response. Our key challenge is to maximize the oracle's accuracy in predicting which tests are bug-exposing given a small budget of queries. From the alternative tests that were labeled by the user, test-driven automatic repair produces the patch. Our experiments demonstrate that Learn2fix learns a sufficiently accurate automatic oracle with a reasonably low labeling effort (lt. 20 queries). Given Learn2fix's test suite, the GenProg test-driven repair tool produces a higher-quality patch (i.e., passing a larger proportion of validation tests) than using manual test suites provided with the repair benchmark., Comment: Accepted as full paper (10+2 pages) at ICST'20 (https://icst2020.info/) *** Tool and Replication Package at: https://github.com/mboehme/learn2fix

Published
2019

24. A Framework for Big Data Sovereignty: The European Industrial Data Space (EIDS)

Author

Mertens, Christoph, Alonso, Jesús, Lázaro, Oscar, Palansuriya, Charaka, Böge, Gernot, Nizamis, Alexandros, Rousopoulou, Vaia, Ioannidis, Dimosthenis, Tzovaras, Dimitrios, Touma, Rizkallah, Tarzán, Miquel, Mallada, Diego, Figueiras, Paulo, Costa, Ruben, Graça, Diogo, Garcia, Gisela, Laibarra, Begoña, Celaya, Aitor, Sobonski, Piotr, Naeem, Azzam, Mozo, Alberto, Vakaruk, Stanislav, Sierra-García, J. Enrique, Pastor, Antonio, Rodriguez, Juan, Hildebrand, Marlène, Luniewski, Tomasz, Zietak, Wojciech, Lange, Christoph, Sipsas, Konstantinos, Poulakidas, Athanasios, Curry, Edward, editor, Scerri, Simon, editor, and Tuikka, Tuomo, editor

Published
2022
Full Text
View/download PDF

25. Phenotype-genotype associations in a large cohort of patients with pulmonary arterial hypertension

Author

Hadinnapola, Charaka Mayura Bandara, Morrell, Nicholas, and Stefan, Graf

Subjects
616.2, Pulmonary arterial hypertension, Pulmonary veno-occlusive disease, BMPR2, EIF2AK4
Abstract

Idiopathic and heritable pulmonary arterial hypertension (PAH) are rare diseases with a poor prognosis. There is significant heterogeneity in clinical features at diagnosis, and in a proportion of patients there is a genetic cause of the disease. This clinical and genetic heterogeneity has hindered accurate risk stratification and the development of personalised treatments. The National Institute of Health Research BioResource - Rare Diseases PAH Study and the Medical Research Council/British Heart Foundation National Cohort Study of Idiopathic and Heritable PAH were established to investigate disease pathogenesis through whole genome sequencing and deep phenotyping. One thousand and seventy patients were sequenced and 391 clinical variables were captured for each patient. In patients with idiopathic PAH the age at diagnosis, gender, right atrial pressure and the transfer coefficient for carbon monoxide were identified as independent prognostic variables. However, the presence of rare and predicted deleterious variants in BMPR2 was not of prognostic significance. Variants in genes previously associated with disease pathogenesis were identified in 204 patients (19 %). Patients with variants in BMPR2 were younger at diagnosis and had more severe pulmonary haemodynamic impairment compared to patients with idiopathic PAH. Novel associations between BMPR2 variant status and both haemoglobin concentration and white blood cell count were observed. Four patients carried variants in both SMAD9 and either BMPR2 or EIF2AK4. The clinical significance of this requires further study. Unexpectedly, biallelic variants in EIF2AK4 were identified in patients with a clinical diagnosis of idiopathic PAH. These patients had a significantly worse prognosis compared to patients with idiopathic PAH. The spectrum of phenotypic, radiological and histological changes associated with biallelic EIF2AK4 variants was broader than previously recognised. As these datasets mature, further analyses assessing the response to specific treatments and the outcomes of specific subgroups will be possible.

Published
2019
Full Text
View/download PDF

28. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Author

Rhodes, Christopher J, Batai, Ken, Bleda, Marta, Haimel, Matthias, Southgate, Laura, Germain, Marine, Pauciulo, Michael W, Hadinnapola, Charaka, Aman, Jurjan, Girerd, Barbara, Arora, Amit, Knight, Jo, Hanscombe, Ken B, Karnes, Jason H, Kaakinen, Marika, Gall, Henning, Ulrich, Anna, Harbaum, Lars, Cebola, Inês, Ferrer, Jorge, Lutz, Katie, Swietlik, Emilia M, Ahmad, Ferhaan, Amouyel, Philippe, Archer, Stephen L, Argula, Rahul, Austin, Eric D, Badesch, David, Bakshi, Sahil, Barnett, Christopher, Benza, Raymond, Bhatt, Nitin, Bogaard, Harm J, Burger, Charles D, Chakinala, Murali, Church, Colin, Coghlan, John G, Condliffe, Robin, Corris, Paul A, Danesino, Cesare, Debette, Stéphanie, Elliott, C Gregory, Elwing, Jean, Eyries, Melanie, Fortin, Terry, Franke, Andre, Frantz, Robert P, Frost, Adaani, Garcia, Joe GN, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, J Simon R, Harley, John, He, Hua, Hill, Nicholas S, Hirsch, Russel, Houweling, Arjan C, Howard, Luke S, Ivy, Dunbar, Kiely, David G, Klinger, James, Kovacs, Gabor, Lahm, Tim, Laudes, Matthias, Machado, Rajiv D, Ross, Robert V MacKenzie, Marsolo, Keith, Martin, Lisa J, Moledina, Shahin, Montani, David, Nathan, Steven D, Newnham, Michael, Olschewski, Andrea, Olschewski, Horst, Oudiz, Ronald J, Ouwehand, Willem H, Peacock, Andrew J, Pepke-Zaba, Joanna, Rehman, Zia, Robbins, Ivan, Roden, Dan M, Rosenzweig, Erika B, Saydain, Ghulam, Scelsi, Laura, Schilz, Robert, Seeger, Werner, Shaffer, Christian M, Simms, Robert W, Simon, Marc, Sitbon, Olivier, Suntharalingam, Jay, Tang, Haiyang, Tchourbanov, Alexander Y, Thenappan, Thenappan, Torres, Fernando, Toshner, Mark R, Treacy, Carmen M, Noordegraaf, Anton Vonk, Waisfisz, Quinten, and Walsworth, Anna K

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Genetics, Human Genome, Lung, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotyping Techniques, HLA-DP alpha-Chains, HLA-DP beta-Chains, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Pulmonary Arterial Hypertension, Risk Assessment, SOXF Transcription Factors, Signal Transduction, Survival Analysis, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortium, Public Health and Health Services, Other Medical and Health Sciences, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundRare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.MethodsWe did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.FindingsA locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity.InterpretationThis is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.FundingUK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.

Published
2019

32. Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

Author

Gräf, Stefan, Haimel, Matthias, Bleda, Marta, Hadinnapola, Charaka, Southgate, Laura, Li, Wei, Hodgson, Joshua, Liu, Bin, Salmon, Richard M, Southwood, Mark, Machado, Rajiv D, Martin, Jennifer M, Treacy, Carmen M, Yates, Katherine, Daugherty, Louise C, Shamardina, Olga, Whitehorn, Deborah, Holden, Simon, Aldred, Micheala, Bogaard, Harm J, Church, Colin, Coghlan, Gerry, Condliffe, Robin, Corris, Paul A, Danesino, Cesare, Eyries, Mélanie, Gall, Henning, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, J Simon R, Girerd, Barbara, Houweling, Arjan C, Howard, Luke, Humbert, Marc, Kiely, David G, Kovacs, Gabor, MacKenzie Ross, Robert V, Moledina, Shahin, Montani, David, Newnham, Michael, Olschewski, Andrea, Olschewski, Horst, Peacock, Andrew J, Pepke-Zaba, Joanna, Prokopenko, Inga, Rhodes, Christopher J, Scelsi, Laura, Seeger, Werner, Soubrier, Florent, Stein, Dan F, Suntharalingam, Jay, Swietlik, Emilia M, Toshner, Mark R, van Heel, David A, Vonk Noordegraaf, Anton, Waisfisz, Quinten, Wharton, John, Wort, Stephen J, Ouwehand, Willem H, Soranzo, Nicole, Lawrie, Allan, Upton, Paul D, Wilkins, Martin R, Trembath, Richard C, and Morrell, Nicholas W

Subjects
Humans, Genetic Predisposition to Disease, Transforming Growth Factor beta, Membrane Transport Proteins, Prognosis, Case-Control Studies, Signal Transduction, Gene Expression Regulation, Base Sequence, Mutation, Models, Molecular, Adult, Female, Male, Aquaporin 1, Bone Morphogenetic Protein Receptors, Type II, Adenosine Triphosphatases, Growth Differentiation Factors, SOXF Transcription Factors, HEK293 Cells, Familial Primary Pulmonary Hypertension, Whole Genome Sequencing, Bone Morphogenetic Protein Receptors, Type II, Models, Molecular
Abstract

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

Published
2018

33. Acceptability of COVID-19 vaccination among health care workers: a cross-sectional survey in Morocco

Author

Mohamed Khalis, Asmaa Hatim, Latifa Elmouden, Mory Diakite, Abdelghafour Marfak, Soukaina Ait El Haj, Rachid Farah, Mohamed Jidar, Kaba Kanko Conde, Kenza Hassouni, Hafida Charaka, Mark Lacy, Fatima-Zahra Aazi, and Chakib Nejjari

Subjects
covid-19, health care workers, vaccine, vaccine acceptance, morocco, Immunologic diseases. Allergy, RC581-607, Therapeutics. Pharmacology, RM1-950
Abstract

Introduction This study aimed to evaluate the acceptability of COVID-19 vaccination among health care workers prior to the start of the COVID-19 vaccination campaign in Morocco. Methods This cross-sectional study was conducted in the Cheikh Khalifa University Hospital of Casablanca-Morocco. Utilizing a web-based platform surveys were distributed over a 3-week period via professional mailing list and social media. Odds ratios and 95% confidence intervals were estimated by using logistic regression models. Results A total of 303 health care workers participated in this study. The results showed a relatively high rate of vaccination acceptability (62.0%) among health care workers included in this study. Participants were more likely to accept the COVID-19 vaccine if they were physician, nurse, or technician (OR 1.79; 95% CI: 1.09–2.95), had high score of confidence in the information circulating about COVID-19 (OR 1.91; 95% CI: 1.36–2.69), or had high score of perceived severity of COVID-19 (OR 1.55; 95% CI: 1.11–2.15). Reasons of hesitation/or refusal of COVID-19 vaccine were fear of the likely side effects of the vaccine for 74.8% of participants, and concern about the effectiveness of the vaccine for 47.8%. Conclusion This study showed a relatively high rate of the COVID-19 vaccination acceptance among health care workers in Morocco. Willingness to be vaccinated was significantly associated with job category, confidence in the information circulating about COVID-19, and perceived severity of COVID-19. These results could be useful in the development of educational interventions to increase the acceptance of COVID-19 vaccine among health care workers in Morocco and similar settings.

Published
2021
Full Text
View/download PDF

34. Aortic flow is abnormal in HFpEF

Author

Mehmood, Zia, primary, Assadi, Hosamadin, additional, Li, Rui, additional, Kasmai, Bahman, additional, Matthews, Gareth, additional, Grafton-Clarke, Ciaran, additional, Sanz-Cepero, Aureo, additional, Zhao, Xiaodan, additional, Zhong, Liang, additional, Aung, Nay, additional, Skinner, Kristian, additional, Hadinnapola, Charaka, additional, Swoboda, Peter, additional, Swift, Andrew J., additional, Vassiliou, Vassilios S, additional, Miller, Christopher, additional, van der Geest, Rob J., additional, Peterson, Steffen, additional, and Garg, Pankaj, additional

Published
2024
Full Text
View/download PDF

38. Heat-induced SIRT1-mediated H4K16ac deacetylation impairs resection and SMARCAD1 recruitment to double strand breaks

Author

Sharmistha Chakraborty, Mayank Singh, Raj K. Pandita, Vipin Singh, Calvin S.C. Lo, Fransisca Leonard, Nobuo Horikoshi, Eduardo G. Moros, Deblina Guha, Clayton R. Hunt, Eric Chau, Kazi M. Ahmed, Prayas Sethi, Vijaya Charaka, Biana Godin, Kalpana Makhijani, Harry Scherthan, Jeanette Deck, Michael Hausmann, Arjamand Mushtaq, Mohammad Altaf, Kenneth S. Ramos, Krishna M. Bhat, Nitika Taneja, Chandrima Das, and Tej K. Pandita

Subjects
Biological sciences, Molecular biology, Epigenetics, Science
Abstract

Summary: Hyperthermia inhibits DNA double-strand break (DSB) repair that utilizes homologous recombination (HR) pathway by a poorly defined mechanism(s); however, the mechanisms for this inhibition remain unclear. Here we report that hyperthermia decreases H4K16 acetylation (H4K16ac), an epigenetic modification essential for genome stability and transcription. Heat-induced reduction in H4K16ac was detected in humans, Drosophila, and yeast, indicating that this is a highly conserved response. The examination of histone deacetylase recruitment to chromatin after heat-shock identified SIRT1 as the major deacetylase subsequently enriched at gene-rich regions. Heat-induced SIRT1 recruitment was antagonized by chromatin remodeler SMARCAD1 depletion and, like hyperthermia, the depletion of the SMARCAD1 or combination of the two impaired DNA end resection and increased replication stress. Altered repair protein recruitment was associated with heat-shock-induced γ-H2AX chromatin changes and DSB repair processing. These results support a novel mechanism whereby hyperthermia impacts chromatin organization owing to H4K16ac deacetylation, negatively affecting the HR-dependent DSB repair.

Published
2022
Full Text
View/download PDF

39. Whole-genome sequencing of patients with rare diseases in a national health system.

Author

Ernest Turro, William J. Astle, Karyn Megy, Stefan Gräf, Daniel Greene, Olga Shamardina, Hana Lango Allen, Alba Sanchis-Juan, Mattia Frontini, Chantal Thys, Jonathan Stephens, Rutendo Mapeta, Oliver S. Burren, Kate Downes, Matthias Haimel, Salih Tuna, Sri V. V. Deevi, Timothy J. Aitman, David L. H. Bennett, Paul Calleja, Keren Carss, Mark J. Caulfield, Patrick F. Chinnery, Peter H. Dixon, Daniel P. Gale, Roger James, Ania Koziell, Michael A. Laffan, Adam P. Levine, Eamonn R. Maher, Hugh S. Markus, Joannella Morales, Nicholas W. Morrell, Andrew D. Mumford, Elizabeth Ormondroyd, Stuart Rankin, Augusto Rendon, Sylvia Richardson, Irene Roberts, Noemi B. A. Roy, Moin A. Saleem, Kenneth G. C. Smith, Hannah Stark, Rhea Y. Y. Tan, Andreas C. Themistocleous, Adrian J. Thrasher, Hugh Watkins, Andrew R. Webster, Martin R. Wilkins, Catherine Williamson, James Whitworth, Sean Humphray, David R. Bentley, Stephen Abbs, Lara Abulhoul, Julian Adlard, Munaza Ahmed, Hana Alachkar, David J. Allsup, Jeff Almeida-King, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, Anthony Attwood, Paul Aurora, Christian Babbs, Chiara Bacchelli, Tamam Bakchoul, Siddharth Banka, Tadbir Bariana, Julian Barwell, Joana Batista, Helen E. Baxendale, Phil L. Beales, Agnieszka Bierzynska, Tina Biss, Maria A. K. Bitner-Glindzicz, Graeme C. M. Black, Marta Bleda, Iulia Blesneac, Detlef Bockenhauer, Harm Bogaard, Christian J. Bourne, Sara Boyce, John R. Bradley, Eugene Bragin, Gerome Breen, Paul Brennan, Carole Brewer, Matthew Brown, Andrew C. Browning, Michael J. Browning, Rachel J. Buchan, Matthew S. Buckland, Teofila Bueser, Carmen Bugarin Diz, John Burn, Siobhan O. Burns, Nigel Burrows, Carolyn Campbell, Gerald Carr-White, Ruth Casey, Jenny Chambers, John Chambers, Melanie M. Y. Chan, Calvin Cheah, Floria Cheng, Manali Chitre, Martin T. Christian, Colin Church, Jill Clayton-Smith, Maureen Cleary, Naomi Clements Brod, Gerry Coghlan, Elizabeth Colby, Trevor R. P. Cole, Janine Collins, Peter W. Collins, Camilla Colombo, Cecilia J. Compton, Robin Condliffe, Stuart A. Cook, H. Terence Cook, Nichola Cooper, Paul A. Corris, Abigail Furnell, Fiona Cunningham, Nicola S. Curry, Antony J. Cutler, Matthew J. Daniels, Mehul Dattani, Louise C. Daugherty, John Davis, Anthony De Soyza, Timothy Dent, Charu Deshpande, Eleanor F. Dewhurst, Sofia Douzgou, Anna M. Drazyk, Elizabeth Drewe, Daniel Duarte, Tina Dutt, J. David M. Edgar, Karen Edwards, William Egner, Melanie N. Ekani, Perry Elliott, Wendy N. Erber, Marie Erwood, Maria C. Estiu, Dafydd Gareth Evans, Gillian Evans, Tamara Everington, Mélanie Eyries, Hiva Fassihi, Remi Favier, Jack Findhammer, Debra Fletcher, Frances A. Flinter, R. Andres Floto, Tom Fowler, James Fox, Amy J. Frary, Courtney E. French, Kathleen Freson, Henning Gall, Vijeya Ganesan, Michael Gattens, Claire Geoghegan, Terence S. A. Gerighty, Ali G. Gharavi, Stefano Ghio, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Kate Gibson, Kimberly C. Gilmour, Barbara Girerd, Nicholas S. Gleadall, Sarah Goddard, David B. Goldstein, Keith Gomez, Pavels Gordins, David Gosal, Jodie Graham, Luigi Grassi, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip Griffiths, Sofia Grigoriadou, Russell J. Grocock, Detelina Grozeva, Mark Gurnell, Scott Hackett, Charaka Hadinnapola, William M. Hague, Rosie Hague, Matthew Hall, Helen L. Hanson, Eshika Haque, Kirsty Harkness, Andrew R. Harper, Claire L. Harris, Daniel Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Archana Herwadkar, Jonathan Hoffman, Simon Holden, Rita Horvath, Henry Houlden, Arjan C. Houweling, Luke S. G. E. Howard, Fengyuan Hu, Gavin Hudson, Joseph Hughes, Aarnoud P. Huissoon, Marc Humbert, Sarah Hunter, Matthew E. Hurles, Melita Irving, Louise Izatt, Sally A. Johnson, Stephen Jolles, Jennifer Jolley, Dragana Josifova, Neringa Jurkute, Tim Karten, Johannes Karten, Mary A. Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, Anne M. Kelly, Wilf Kelsall, Carly Kempster, David G. Kiely, Nathalie Kingston, Robert Klima, Nils Koelling, Myrto Kostadima, Gabor Kovacs, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju A. Kurian, Fiona Lalloo, Michele Lambert, Allan Lawrie, D. Mark Layton, Nick Lench, Claire Lentaigne, Tracy Lester, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Eleni Louka, Paul A. Lyons, Rajiv D. Machado, Robert V. MacKenzie Ross, Bella Madan, Jesmeen Maimaris, Samantha Malka, Sarah Mangles, Kevin J. Marchbank, Stephen Marks, Hanns-Ulrich Marschall, Andrew G. Marshall, Jennifer Martin, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Harriet McKinney, Aoife McMahon, Stuart Meacham, Adam J. Mead, Ignacio Medina Castello, Sarju G. Mehta, Michel Michaelides, Carolyn Millar, Shehla N. Mohammed, Shahin Moledina, David Montani, Anthony T. Moore, Monika Mozere, Keith W. Muir, Andrea H. Nemeth, William G. Newman, Michael Newnham, Sadia Noorani, Paquita Nurden, Jennifer O'Sullivan, Samya Obaji, Chris Odhams, Steven Okoli, Andrea Olschewski, Horst Olschewski, Kai Ren Ong, S. Helen Oram, Willem H. Ouwehand, Claire Palles, Sofia Papadia, Soo-Mi Park, David Parry 0003, Smita Patel, Joan Paterson, Andrew Peacock, Simon H. Pearce, John Peden, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, Romina Petersen, Clarissa Pilkington, Kenneth E. S. Poole, Radhika Prathalingam, Bethan Psaila, Angela Pyle, Richard Quinton, Shamima Rahman, Anupama Rao, F. Lucy Raymond, Paula J. Rayner-Matthews, Christine Rees, Tara Renton, Christopher J. Rhodes, Andrew S. C. Rice, Alex Richter, Leema Robert, Anthony Rogers, Sarah J. Rose, Robert Ross-Russell, Catherine Roughley, Deborah M. Ruddy, Omid Sadeghi-Alavijeh, Nilesh J. Samani, Crina Samarghitean, Ravishankar B. Sargur, Robert N. Sarkany, Simon Satchell, Sinisa Savic, John A. Sayer, Genevieve Sayer, Laura Scelsi, Andrew M. Schaefer, Sol Schulman, Richard Scott, Marie Scully, Claire Searle, Werner Seeger, Arjune Sen, W. A. Carrock Sewell, Denis Seyres, Neil Shah, Susan E. Shapiro, Adam C. Shaw, Patrick J. Short, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A. Simpson, Matthew C. Sims, Suthesh Sivapalaratnam, Damian Smedley, Katherine R. Smith, Katie Snape, Nicole Soranzo, Florent Soubrier, Laura Southgate, Olivera Spasic-Boskovic, Simon Staines, Emily Staples, Charles A. Steward, Kathleen E. Stirrups, Alex Stuckey, Jay Suntharalingam, Emilia M. Swietlik, Petros Syrris, R. Campbell Tait, Kate Talks, Katie Tate, John M. Taylor, Jenny C. Taylor, James E. Thaventhiran, Ellen Thomas, David Thomas 0004, Moira J. Thomas, Patrick Thomas, Kate Thomson, Glen Threadgold, Tobias Tilly, Marc Tischkowitz, Catherine Titterton, John A. Todd, Cheng-Hock Toh, Bas Tolhuis, Ian P. Tomlinson, Mark Toshner, Matthew Traylor, Carmen Treacy, Paul Treadaway, Richard Trembath, Wojciech Turek, Philip Twiss, Tom Vale, Chris Van Geet, Natalie van Zuydam, Maarten Vandekuilen, Anthony M. Vandersteen, Marta Vazquez-Lopez, Julie von Ziegenweidt, Anton Vonk-Noordegraaf, Annette Wagner, Quinten Waisfisz, Suellen M. Walker, Neil Walker, Klaudia Walter, James S. Ware, Christopher Watt, Lucy Wedderburn, Wei Wei, Steven B. Welch, Julie Wessels, Sarah K. Westbury, John-Paul Westwood, John Wharton, Deborah Whitehorn, Andrew O. M. Wilkie, Brian T. Wilson, Edwin K. S. Wong, Nicholas W. Wood, Yvette Wood, Christopher Geoffrey Woods, Emma R. Woodward, Stephen J. Wort, Austen Worth, Michael Wright, Katherine Yates, Patrick F. K. Yong, Timothy Young, Ping Yu, Patrick Yu-Wai-Man, and Eliska Zlamalova

Published
2020
Full Text
View/download PDF

48. Angiopoietin 2 and hsCRP are associated with pulmonary hemodynamics and long-term mortality respectively in CTEPH-Results from a prospective discovery and validation biomarker study

Author

Charaka M. Hadinnapola, Mark Southwood, Jules Hernández – Sánchez, Katherine Bunclark, Michael Newnham, Emilia M. Swietlik, John Cannon, Stephen D. Preston, Karen Sheares, Dolores Taboada, Nicholas Screaton, David P. Jenkins, Nicholas W. Morrell, Mark Toshner, Joanna Pepke-Zaba, Hadinnapola, Charaka M [0000-0002-7794-3432], Southwood, Mark [0000-0002-3493-9599], Preston, Stephen D [0000-0002-6836-3591], Toshner, Mark [0000-0002-3969-6143], Pepke-Zaba, Joanna [0000-0003-3764-3563], and Apollo - University of Cambridge Repository

Subjects
Pulmonary and Respiratory Medicine, Vascular Endothelial Growth Factor A, Transplantation, Hypertension, Pulmonary, CTEPH, Hemodynamics, Endarterectomy, angiopoietin 2, Angiopoietin-2, angiogenesis, C-Reactive Protein, inflammation, Humans, Surgery, Cardiology and Cardiovascular Medicine, Biomarkers
Abstract

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed disease of uncertain etiology. Altered endothelial homeostasis, defective angiogenesis and inflammation are implicated. Angiopoietin 2 (Ang2) impairs acute thrombus resolution and is associated with vasculopathy in idiopathic pulmonary arterial hypertension. METHODS: We assessed circulating proteins associated with these processes in serum from patients with CTEPH (n = 71) before and after pulmonary endarterectomy (PEA), chronic thromboembolic pulmonary disease without pulmonary hypertension (CTEPD, n = 9) and healthy controls (n = 20) using Luminex multiplex arrays. Comparisons between groups were made using multivariable rank regression models. Ang2 and high-sensitivity C-reactive protein (hsCRP) were measured in a larger validation dataset (CTEPH = 277, CTEPD = 26). Cox proportional hazards models were used to identify markers predictive of survival. RESULTS: In CTEPH patients, Ang2, interleukin (IL) 8, tumor necrosis factor α, and hsCRP were elevated compared to controls, while vascular endothelial growth factor (VEGF) c was lower (p < 0.05). Ang2 fell post-PEA (p < 0.05) and was associated with both pre- and post-PEA pulmonary hemodynamic variables and functional assessments (p < 0.05). In the validation dataset, Ang2 was significantly higher in CTEPH compared to CTEPD. Pre-operative hsCRP was an independent predictor of mortality. CONCLUSIONS: We hypothesize that CTEPH patients have significant distal micro-vasculopathy and consequently high circulating Ang2. Patients with CTEPD without pulmonary hypertension have no discernible distal micro-vasculopathy and therefore have low circulating Ang2. This suggests Ang2 may be critical to CTEPH disease pathogenesis (impaired thrombus organization and disease severity).

Published
2023

49. Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

Author

Stefan Gräf, Matthias Haimel, Marta Bleda, Charaka Hadinnapola, Laura Southgate, Wei Li, Joshua Hodgson, Bin Liu, Richard M. Salmon, Mark Southwood, Rajiv D. Machado, Jennifer M. Martin, Carmen M. Treacy, Katherine Yates, Louise C. Daugherty, Olga Shamardina, Deborah Whitehorn, Simon Holden, Micheala Aldred, Harm J. Bogaard, Colin Church, Gerry Coghlan, Robin Condliffe, Paul A. Corris, Cesare Danesino, Mélanie Eyries, Henning Gall, Stefano Ghio, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Arjan C. Houweling, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Robert V. MacKenzie Ross, Shahin Moledina, David Montani, Michael Newnham, Andrea Olschewski, Horst Olschewski, Andrew J. Peacock, Joanna Pepke-Zaba, Inga Prokopenko, Christopher J. Rhodes, Laura Scelsi, Werner Seeger, Florent Soubrier, Dan F. Stein, Jay Suntharalingam, Emilia M. Swietlik, Mark R. Toshner, David A. van Heel, Anton Vonk Noordegraaf, Quinten Waisfisz, John Wharton, Stephen J. Wort, Willem H. Ouwehand, Nicole Soranzo, Allan Lawrie, Paul D. Upton, Martin R. Wilkins, Richard C. Trembath, and Nicholas W. Morrell

Subjects
Science
Abstract

Pulmonary arterial hypertension (PAH) is a rare lung disorder characterised by narrowing and obliteration of small pulmonary arteries ultimately leading to right heart failure. Here, the authors sequence whole genomes of over 1000 PAH patients and identify likely causal variants in GDF2, ATP13A3, AQP1 and SOX17.

Published
2018
Full Text
View/download PDF

50. SMARCAD1 Phosphorylation and Ubiquitination Are Required for Resection during DNA Double-Strand Break Repair

Author

Sharmistha Chakraborty, Raj K. Pandita, Shashank Hambarde, Abid R. Mattoo, Vijaya Charaka, Kazi M. Ahmed, Swaminathan P. Iyer, Clayton R. Hunt, and Tej K. Pandita

Subjects
Science
Abstract

Summary: The chromatin remodeling factor SMARCAD1, an SWI/SNF ATPase family member, has a role in 5′ end resection at DNA double-strand breaks (DSBs) to produce single-strand DNA (ssDNA), a critical step for subsequent checkpoint and repair factor loading to remove DNA damage. However, the mechanistic details of SMARCAD1 coupling to the DNA damage response and repair pathways remains unknown. Here we report that SMARCAD1 is recruited to DNA DSBs through an ATM-dependent process. Depletion of SMARCAD1 reduces ionizing radiation (IR)-induced repairosome foci formation and DSB repair by homologous recombination (HR). IR induces SMARCAD1 phosphorylation at a conserved T906 by ATM kinase, a modification essential for SMARCAD1 recruitment to DSBs. Interestingly, T906 phosphorylation is also important for SMARCAD1 ubiquitination by RING1 at K905. Both these post-translational modifications are critical for regulating the role of SMARCAD1 in DNA end resection, HR-mediated repair, and cell survival after DNA damage. : In Vitro Toxicology Including 3D Culture; Bioengineering; Tissue Engineering Subject Areas: In Vitro Toxicology Including 3D Culture, Bioengineering, Tissue Engineering

Published
2018
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results