bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic determination of regional connectivity in modelling the spread of COVID-19 outbreak for improved mitigation strategies
Authors: Salichos Leonidas , Warrell Jonathan , Cevasco Hannah , Chung Alvin , Gerstein Mark 
Published: February 2021

ABSTRACTCovid-19 has resulted in the death of more than 1,500,000 individuals. Due to the pandemic’s severity, thousands of genomes have been sequenced and publicly stored with extensive records, an unprecedented amount of data for an outbreak in a single year. Simultaneously, prediction models offered region-specific and often contradicting results, while states or countries implemented mitigation strategies with little information on success, precision, or agreement with neighboring regions. Even though viral transmissions have been already documented in a historical and geographical context, few studies aimed to model geographic and temporal flow from viral sequence information. Here, using a case study of 7 states, we model the flow of the Covid-19 outbreak with respect to phylogenetic information, viral migration, inter- and intra- regional connectivity, epidemiologic and demographic characteristics. By assessing regional connectivity from genomic variants, we can significantly improve predictions in modeling the viral spread and intensity.Contrary to previous results, our study shows that the vast majority of the first outbreak can be traced to very few lineages, despite the existence of multiple worldwide transmissions. Moreover, our results show that while the distance from hotspots is initially important, connectivity becomes increasingly significant as the virus establishes itself. Similarly, isolated local strategies-such as relying on herd immunity-can negatively impact neighboring states. Our work suggests that we can achieve more efficient unified mitigation strategies with selective interventions.
A specific agonist of the orphan nuclear receptor NR2F1 suppresses metastasis through the induction of cancer cell dormancy
Authors: Khalil Bassem D. , Sanchez Roberto , Rahman Tasrina , Rodriguez-Tirado Carolina , Moritsch Stefan , Martinez Alba Rodriguez , Miles Brett , Farias Eduardo , Mezei Mihaly , Cheung Julie F. , Nobre Ana Rita , Kale Nupura , Sproll Karl Christoph , Sosa Maria Soledad , Aguirre-Ghiso Julio A. 
Published: February 2021

AbstractDisseminated tumor cells (DTCs) in secondary organs often remain dormant for a long period of time before re-awakening and growing into overt metastases. We have previously identified NR2F1/COUP-TF1, an orphan nuclear receptor, as a master regulator of tumor cell dormancy in head and neck squamous cell carcinoma (HNSCC) and other cancer types. Here we describe the identification and function of a novel NR2F1 agonist herein referred to as compound 26 (C26). C26 was found to specifically activate NR2F1 in HNSCC cells, leading to increased NR2F1 transcription and nuclear protein accumulation. C26-mediated activation of NR2F1 induced growth arrest of HNSCC PDX line and cell lines in 3D culturesin vitroand on chicken embryo chorioallantoic membrane (CAM)in vivo. The effect of C26 on growth arrest was lost when NR2F1 was knocked out by CRISPR/Cas9. C26-induced growth arrest was mediated by activation of an NR2F1-regulated dormancy program, including upregulation of cyclin-dependent kinase (CDK) inhibitor p27 and the transcription factors retinoic acid receptor β (RARβ) and Sox9. In mice bearing HNSCC PDX tumors, combined adjuvant and neo-adjuvant treatment with C26 resulted in complete inhibition of lethal lung metastasis. Mechanistic analysis showed that lung DTCs in C26-treated mice displayed an NR2F1hi/p27hi/Ki-67lophenotype, which kept them dormant in a single-cell state preventing their outgrowth into overt metastases. Our work reveals a novel NR2F1 agonist and provides a proof of principle strategy supporting that inducing DTC dormancy using NR2F1 agonists could be used as a therapeutic strategy to prevent metastasis.
Non-invasively measured brain activity and radiological progression in diffuse glioma
Authors: Numan T. , Kulik S.D. , Moraal B. , Reijneveld J.C. , Stam CJ. , de Witt Hamer P.C. , Derks J. , Bruynzeel A.M.E. , van Linde M.E. , Wesseling P. , Kouwenhoven M.C.M. , Klein M. , Würdinger T. , Barkhof F. , Geurts J.J.G. , Hillebrand A. , Douw L. 
Published: February 2021

AbstractNon-invasively measured brain activity is related to progression-free survival in glioma patients, suggesting its potential as a marker of glioma progression. We therefore assessed the relationship between brain activity and increasing tumor volumes on routine clinical magnetic resonance imaging (MRI) in glioma patients. Postoperative magnetoencephalography (MEG) was recorded in 45 diffuse glioma patients. Brain activity was estimated using three measures (absolute broadband power, offset and slope) calculated at three spatial levels: global average, averaged across the peritumoral areas, and averaged across the homologues of these peritumoral areas in the contralateral hemisphere. Tumors were segmented on MRI. Changes in tumor volume between the two scans surrounding the MEG were calculated and correlated with brain activity. Brain activity was compared between patient groups classified into having increasing or stable tumor volume. Results show that brain activity was significantly increased in the tumor hemisphere in general, and in peritumoral regions specifically. However, none of the measures and spatial levels of brain activity correlated with changes in tumor volume, nor did they differ between patients with increasing versus stable tumor volumes. Longitudinal studies in more homogeneous subgroups of glioma patients are necessary to further explore the clinical potential of non-invasively measured brain activity.
Extracellular matrix stiffness regulates degradation of the Hippo kinase MST2 via SCFβTrCP
Authors: Fiore Ana Paula Zen Petisco , da Silva Ana Maria Rodrigues , Filho Helder Veras Ribeiro , Manucci Antonio Carlos , de Freitas Ribeiro Pedro , Botelho Mayara Carolinne Silva , de Oliveira Paulo Sergio Lopes , Pagano Michele , Bruni-Cardoso Alexandre 
Published: February 2021

AbstractTumor microenvironments display disrupted mechanical properties, including altered extracellular matrix (ECM) rigidity. ECM stiffening perturbs cell tensional homeostasis resulting in activation of mechanosensing transcriptional co-activators, such as the Hippo pathway effectors YAP and TAZ. The Hippo pathway plays central roles in development and tumorigenesis, but how the proteostasis of the Hippo kinase MST2 is regulated remains unknown. Here, we show that ECM stiffness induces MST2 degradation via proteasome degradation. MST2 degradation is enhanced in human breast epithelial cells (HMEC) that are cultured in stiffer microenvironments due to integrin and integrin-linked kinase activation. MST2 knockdown resulted in increased nucleus-to-cytoplasm ratio of YAP in physiological and breast tumor rigidities and altered mechanoregulated cellular processes in HMEC. We found that MST2 is ubiquitinated by the SCFβTrCPubiquitin ligase. Site-directed mutagenesis combined with computational molecular dynamics studies revealed that βTrCP binds MST2 via a noncanonical degradation motif. Our study uncovers the underlying biochemical mechanisms controlling MST2 degradation and demonstrates how changes in the microenvironment rigidity regulate the proteostasis of a central Hippo pathway component.
Neonatal-onset autoinflammation and immunodeficiency caused by heterozygous missense mutation of the proteasome subunit β-type 9
Authors: Kanazawa Nobuo , Hemmi Hiroaki , Kinjo Noriko , Ohnishi Hidenori , Hamazaki Jun , Mishima Hiroyuki , Kinoshita Akira , Mizushima Tsunehiro , Hamada Satoru , Hamada Kazuya , Kawamoto Norio , Kadowaki Saori , Honda Yoshitaka , Izawa Kazushi , Nishikomori Ryuta , Tsumura Miyuki , Yamashita Yusuke , Tamura Shinobu , Orimo Takashi , Ozasa Toshiya , Kato Takashi , Sasaki Izumi , Fukuda-Ohta Yuri , Wakaki-Nishiyama Naoko , Inaba Yutaka , Kunimoto Kayo , Okada Satoshi , Taketani Takeshi , Nakanishi Koichi , Murata Shigeo , Yoshiura Koh-ichiro , Kaisho Tsuneyasu 
Published: February 2021

ABSTRACTBACKGROUNDDefective proteasome activities due to genetic mutations lead to an autoinflammatory disease, termed as proteasome-associated autoinflammatory syndromes (PRAAS). In PRAAS relapsing inflammations and progressive wasting are common, but immunodeficiency has not been reported.METHODSWe studied two unrelated Japanese infants with PRAAS-like manifestations. We have also generated and analyzed the mice carrying the candidate mutation found in the patients.RESULTSBoth patients showed neonatal-onset skin rash, myositis and basal ganglia calcification, similar to PRAAS patients. Meanwhile, they manifested distinct phenotypes, including pulmonary hypertension and immunodeficiency without lipoatrophy. We identified a novel de novo heterozygous missense mutation, G156D, in a proteasome subunit gene, PSMB9, encoding β1i, in the two patients. Maturation and activity of the immunoproteasome were impaired, but ubiquitin accumulation was hardly detected not only in patient-derived cells and samples but also in Psmb9G156D/+ mice. As an immunodeficient phenotype, one patient showed decrease of B cells and increase of monocytes, while the other patient showed decrease of CD8 T cells. The proteasome defects and immunodeficient phenotypes were recapitulated in Psmb9G156D/+ mice.CONCLUSIONSThe PSMB9 G156D is a unique mutation in proteasome subunits in causing defects by its heterozygosity, affecting two β rings interaction and leading to immunodeficiency. The mutant mice are the first mice model for analyzing proteasome dysfunctions in PRAAS. We here propose the term, proteasome-associated autoinflammation and immunodeficiency disease (PRAID), as an umbrella name for our cases, PRAAS with immunodeficiency, as well as PRAAS described so far.
Comparing effect estimates in randomized trials and observational studies from the same population: an application to percutaneous coronary intervention
Authors: Matthews Anthony A , Szummer Karolina , Dahabreh Issa J , Lindahl Bertil , Erlinge David , Feychting Maria , Jernberg Tomas , Berglund Anita , Hernán Miguel A 
Published: February 2021

AbstractBackgroundThe ability for real world data to deliver similar results as a trial that asks the same question about the risks or benefits of a clinical intervention can be restricted not only by lack of randomization, but also limited information on eligibility criteria and outcomes. To understand when results from observational studies and randomized trials are comparable, we carried out an observational emulation of a target trial designed to ask similar questions as the VALIDATE randomized trial. VALIDATE compared the effect of bivalirudin and heparin during percutaneous coronary intervention on the risk of death, myocardial infarction, and bleeding across Sweden.MethodsWe specified the protocol of a target trial similar to the VALIDATE trial protocol, then emulated the target trial in the period before the trial took place using data from the SWEDEHEART registry; the same registry in which the trial was undertaken.ResultsThe target trial emulation and the VALIDATE trial both estimated no difference in the effect of bivalirudin and heparin on the risk of death or myocardial infarction by 180 days: emulation risk ratio for death 1.21 (0.88, 1.54); VALIDATE hazard ratio for death 1.05 (0.78, 1.41). The observational data, however, could not capture less severe cases of bleeding, resulting in an inability to define a bleeding outcome like the trial, and could not account for intractable confounding early in follow-up (risk ratio for death by 14 days 1.85 (0.95, 3.63)).ConclusionUsing real world data to emulate a target trial can deliver accurate long-term effect estimates. Yet, even with rich observational data, it is not always possible to estimate the short-term effect of interventions, or the effect on outcomes for which data are not routinely collected. If registries included information on reasons for treatment decisions, researchers may be better positioned to identify important confounders.
A Rapid Realist Review of the Role of Community Pharmacy in the Public Health Response to COVID-19
Authors: Maidment Ian , Young Emma , MacPhee Maura , Booth Andrew , Zaman Hadar , Breen Juanita , Hilton Andrea , Kelly Tony , Wong Geoff 
Published: February 2021

ABSTRACTIntroductionCommunity pharmacists and their teams have remained accessible to the public providing essential services despite immense pressures during the COVID-19 pandemic. They have successfully expanded the influenza vaccination programme and are now supporting the delivery of the COVID-19 vaccination roll-out.AimThis rapid realist review aims to understand how community pharmacy can most effectively deliver essential and advanced services, with a focus on vaccination, during the pandemic and in the future.MethodAn embryonic programme theory was generated using four diverse and complementary documents along with the expertise of the project team. Academic databases, preprint services and grey literature were searched and screened for documents meeting our inclusion criteria. The data was extracted from 103 documents to develop and refine a programme theory using a realist logic of analysis. Our analysis generated 13 context-mechanism-outcome configurations explaining when, why and how community pharmacy can support public health vaccination campaigns, maintain essential services during pandemics, and capitalise on opportunities for expanded, sustainable public health service roles. The views of stakeholders including pharmacy users, pharmacists, pharmacy teams and other healthcare professionals were sought throughout to refine the 13 explanatory configurations.ResultsThe 13 context-mechanism-outcome configurations are organised according to decision makers, community pharmacy teams and community pharmacy users as key actors. Review findings include: supporting a clear role for community pharmacies in public health; clarifying pharmacists’ legal and professional liabilities; involving pharmacy teams in service specification design; providing suitable guidance, adequate compensation and resources; and leveraging accessible, convenient locations of community pharmacy.DiscussionCommunity pharmacy has been able to offer key services during the pandemic. Decision makers must endorse, articulate and support a clear public health role for community pharmacy. We provide key recommendations for decision makers to optimise such a role during these unprecedented times and in the future.
IN-HOSPITAL CONTINUATION WITH ANGIOTENSIN RECEPTOR BLOCKERS IS ASSOCIATED WITH A LOWER MORTALITY RATE THAN CONTINUATION WITH ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN COVID-19 PATIENTS: A RETROSPECTIVE COHORT STUDY
Authors: de Abajo Francisco J. , Rodríguez-Miguel Antonio , Rodríguez-Martín Sara , Lerma Victoria , García-Lledó Alberto 
Published: February 2021

ABSTRACTBackgroundSeveral studies have reported a reduced risk of death associated with the inpatient use of angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) in COVID-19 patients, but have been criticized for incurring in several types of bias. Also, most studies have pooled ACEIs and ARBs as if they were a unique group, overlooking their pharmacological differences. We aimed to assess whether the in-hospital continuation of ARBs and ACEIs, in regular users of these drugs, was associated with a reduced risk of death as compared to their discontinuation and also to compare head-to-head ARBs with ACEIs.MethodsAdult patients with a PCR-confirmed diagnosis of COVID-19 requiring admission during March, 2020 were consecutively selected from 7 hospitals in Madrid, Spain. Among them, we identified outpatient users of ACEIs/ARBs and divided them in two cohorts depending on treatment discontinuation/continuation at admission. Then, they were followed-up until discharge or in-hospital death. An intention-to-treat survival analysis was carried out and hazard ratios (HRs) and their 95%CI were computed through a Cox regression model adjusted for propensity scores of discontinuation and controlled by potential mediators.ResultsOut of 625 ACEI/ARB users, 340(54.4%) discontinued treatment. The in-hospital mortality rates were 27.6% and 27.7% in discontinuation and continuation cohorts, respectively (HR=1.01; 95%CI:0.70-1.46). No difference in mortality was observed between ARB and ACEI discontinuation (28.6% vs. 27.1%, respectively), while a significantly lower mortality rate was found among patients who continued with ARBs (20.8%,N=125) as compared to those who continued with ACEIs (33.1%,N=136; p=0.03). The head-to-head comparison (ARB vs. ACEI continuation) yielded an adjusted HR of 0.52 (95%CI:0.29-0.93), being especially notorious among males (HR=0.34; 95%CI:0.12-0.93), subjects older than 74 years (HR=0.46; 95%CI:0.25-0.85), and patients with obesity (HR=0.22; 95%CI:0.05-0.94), diabetes (HR=0.36; 95%CI:0.13-0.97) and heart failure (HR=0.12; 95%CI:0.03-0.97).ConclusionsAmong regular users of ARBs admitted for COVID-19, the in-hospital continuation with them was associated with an improved survival, while this was not observed with ACEIs. Regular users of ARBs should continue with this treatment if admitted for COVID-19, unless medically contraindicated. In admitted ACEI users, a switching to ARBs should be considered, especially among high-risk patients.GRAPHICAL ABSTRACT
RAY: CRISPR diagnostic for rapid and accurate detection of SARS-CoV2 variants on a paper strip
Authors: Kumar Manoj , Gulati Sneha , Ansari Asgar Hussain , Phutela Rhythm , Acharya Sundaram , Kathpalia Poorti , Kanakan Akshay , Maurya Ranjeet , Vasudevan Janani Srinivasa , Murali Aparna , Pandey Rajesh , Maiti Souvik , Chakraborty Debojyoti 
Published: February 2021

ABSTRACTThe COVID-19 pandemic originating in the Wuhan province of China in late 2019 has impacted global health, causing increased mortality among elderly patients and individuals with comorbid conditions. During the passage of the virus through affected populations, it has undergone mutations- some of which have recently been linked with increased viral load and prognostic complexities. Interestingly, several of these variants are point mutations that are difficult to diagnose using the gold standard quantitative real-time PCR (qPCR) method. This necessitates widespread sequencing which is expensive, has long turn-around times, and requires high viral load for calling mutations accurately. In this study, we show that the high specificity of Francisella novicida Cas9 (FnCas9) to point mismatches can be successfully adapted for the simultaneous detection of SARS-CoV2 infection as well as for detecting point mutations in the sequence of the virus obtained from patient samples. We report the detection of the mutation N501Y (earlier shown to be present in the British N501Y.V1, South African N501Y.V2, and Brazilian N501Y.V3 variants of SARS-CoV2) within an hour using paper strip chemistry. The results were corroborated using deep sequencing. Our design principle can be rapidly adapted for other mutations, highlighting the advantages of quick optimization and roll-out of CRISPR diagnostics (CRISPRDx) for disease surveillance even beyond COVID-19.
Inference on the dynamics of the COVID pandemic from observational data
Authors: Bhattacharjee Satarupa , Liao Shuting , Paul Debashis , Chaudhuri Sanjay 
Published: February 2021

AbstractWe describe a time dependent stochastic dynamic model in discrete time for the evolution of the COVID-19 pandemic in various states of USA. The proposed multi-compartment model is expressed through a system of difference equations that describe their temporal dynamics. Various compartments in our model is connected to the social distancing measures and diagnostic testing rates. A nonparametric estimation strategy is employed for obtaining estimates of interpretable temporally static and dynamic epidemiological rate parameters. The confidence bands of the parameters are obtained using a residual bootstrap procedure. A key feature of the methodology is its ability to estimate latent compartments such as the trajectory of the number of asymptomatic but infected individuals which are the key vectors of COVID-19 spread. The nature of the disease dynamics is further quantified by the proposed epidemiological markers, which use estimates of such key latent compartments.
Exempting low-risk health research from ethics reviews to better serve the interests of the patients and public: a qualitative analysis of survey responses
Authors: Scott Anna Mae , Chalmers Iain , Barnett Adrian , Stephens Alexandre , Kolstoe Simon E. , Clark Justin , Matthews Richard , Glasziou Paul 
Published: February 2021

AbstractBackgroundWe conducted a survey to identify what types of health research could be exempted from research ethics reviews in Australia.MethodsWe surveyed active Australian health researchers and members of Human Research Ethics Committees (HREC). We presented the respondents with eight hypothetical research scenarios, involving: N of 1 trials, no treatment studies, linked data sets, surplus samples, audits, surveys, interviews with patients, and professional opinion. We asked whether these scenarios should or should not be exempt from ethics review, and to provide (optional) explanations. We analysed the reasons thematically, to identify Top 3 reasons underlying the decisions.ResultsMost frequent reasons for requiring ethics reviews, included: the need for independent oversight, privacy/confidentiality issues, review of scientific rigour, and publishing considerations. Most frequent reasons for exempting scenarios from reviews, included: level of risk, study design, privacy/confidentiality issues, and standard clinical practice. Four research scenarios listed the same Top 3 reasons for requiring ethics reviews: need for independent oversight, review of scientific rigour, privacy/confidentiality. Reasons for exempting were less uniform, but low risk was a Top 3 reason for 7 scenarios, and study design for 4 scenarios. Privacy/confidentiality was given as a Top 3 reason for both requiring and exempting from ethics the same two scenarios.ConclusionsThe most frequently offered reasons in support of requiring ethics reviews for research scenarios are more uniform than those for exempting them. However, considerable disagreement exists about when the risks of research are so minimal that the exemption is appropriate.
How coiled-coil assemblies accommodate multiple aromatic residues
Authors: Rhys Guto G. , Dawson William M. , Beesley Joseph L. , Martin Freddie J. O. , Brady R. Leo , Thomson Andrew R. , Woolfson Derek N. 
Published: February 2021

ABSTRACTRational protein design requires understanding the contribution of each amino acid to a targeted protein fold. For a subset of protein structures, namely theα;-helical coiled coils (CCs), knowledge is sufficiently advanced to allow the rationalde novodesign of many structures, including entirely new protein folds. However, current CC design rules center on using aliphatic hydrophobic residues predominantly to drive the folding and assembly of amphipathicαhelices. The consequences of using aromatic residues—which would be useful for introducing structural probes, and binding and catalytic functionalities—into these interfaces is not understood. There are specific examples of designed CCs containing such aromatic residues,e.g., phenylalanine-rich sequences, and the use of polar aromatic residues to make buried hydrogen-bond networks. However, it is not known generally if sequences rich in tyrosine can form CCs, or what CC assemblies these would lead to. Here we explore tyrosine-rich sequences in a general CC-forming background and resolve new CC structures. In one of these, an antiparallel tetramer, the tyrosine residues are solvent accessible and pack at the interface between the core and the surface. In the other more-complex structure, the residues are buried and form an extended hydrogen-bond network.