bluuebunny/crossref_metadata_2025_split huggingface dataset:
Studies to develop a glucagon sensitivity test in humans: The GLUSENTIC study protocol
Authors: Kjeldsen Sasha A. S. , Richter Michael M. , Jensen Nicole J. , Nilsson Malin S. D. , Heinz Niklas , Nybing Janus D. , Linden Frederik H. , Høgh-Schmidt Erik , Boesen Mikael P. , Madsbad Sten , Vilstrup Hendrik , Schiødt Frank Vinholt , Møller Andreas , Nørgaard Kirsten , Schmidt Signe , Rashu Elias B. , Gluud Lise L. , Haugaard Steen B. , Holst Jens J. , Rungby Jørgen , Wewer Albrechtsen Nicolai J. 
Published: November 2022

AbstractIntroductionA physiological feedback system exists between hepatocytes and the alpha cells termed the liver-alpha cell axis and signifies the role between amino acid-stimulated glucagon secretion and glucagon-stimulated amino acid catabolism. Several reports indicate that metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) disrupts this feedback system, because of impaired glucagon receptor (GCGR) signaling (glucagon resistance). However, no experimental test exists to assess glucagon resistance in humans.ObjectiveTo develop and evaluate a test for measuring glucagon sensitivity towards amino acid and glucose metabolism in humans.Methods and analysisThe study protocol is based on several pilot studies presented in this paper. The study will include 65 participants including 20 individuals with a BMI 18.6-25 kg/m2, 30 individuals with a BMI ≥25-40 kg/m2, and 15 individuals with type 1 diabetes with a BMI between 18.6-40 kg/m2. Participants will be grouped according to their percentage of hepatic steatosis measured by whole-liver magnetic resonance imaging (MRI). The primary outcome measure will be differences in a novel ‘glucagon sensitivity’ index between individuals with and without hepatic steatosis (<5.6 % vs ≥5.6 %) without diabetes. Secondary outcomes include between-group differences regarding the glucagon-alanine-index, incremental and decremental area under the curve (AUC) and association analyses between hepatic steatosis and glucagon sensitivity. This report describes the design of the cross-sectional study currently taking place at Copenhagen University hospital Bispebjerg and Frederiksberg.ResultsThese data will be published in peer-reviewed scientific journals and presented at scientific conferences.Ethics and disseminationThe study was approved by the scientific-ethical committee of the Capital region of Denmark (H-20023717) and registered with Danish Data protection Agency (P-2021-39) andClinicalTrials.gov(NCT04907721). Written and oral consent will be obtained from all participants, and the study will adhere to the principles of the Declaration of Helsinki.Strengths and limitations of this studyThe glucagon sensitivity test is based on several pilot experimentsLiver fat is based on whole-liver imaging and not region of interest (ROI)The glucagon sensitivity test may be limited to assess glucagon sensitivity towards amino acid catabolism and glucose productionThe glucagon sensitivity test does not use amino acid or glucose tracers which expands the generalizability of such test but also may impair its accuracy
A mechanical atlas for Ascidian gastrulation
Authors: Liu Siqi , Lemaire Patrick , Munro Edwin , Mani Madhav 
Published: November 2022

ABSTRACTThe intricate three-dimensional (3D) structures of multicellular organisms emerge through genetically encoded spatio-temporal patterns of mechanical stress. Cell atlases of gene expression during embryogenesis are now available for many organisms, but connecting these to the mechanical drivers of embryonic shape requires physical models of multicellular tissues that identify the relevant mechanical and geometric constraints, and an ability to measure mechanical stresses at single-cell resolution over time. Here we report significant steps towardsboththese goals. We describe a new mathematical theory for the mechanics of 3D multicellular aggregates involving the quasi-static balance of cellular pressures, surface tensions, and line tensions. Our theory yields a quantitatively accurate low-dimensional description for the time-varying geometric dynamics of 3D multicellular aggregates and, through the solution of a mechanical inverse problem, an image-based strategy for constructing spatio-temporal maps of the mechanical stresses driving morphogenesis in 3D. Using synthetic image data, we confirm the accuracy and robustness of our geometric and mechanical approaches. We then apply these approaches to segmented light sheet data, representing cellular membranes with isotropic resolution, to construct a 3D mechanical atlas for ascidian gastrulation. The atlas captures a surprisingly accurate low-dimensional description of ascidian gastrulation, revealing the adiabatic nature of the underlying mechanical dynamics. Mapping the inferred forces onto the invariant embryonic lineage reveals a rich correspondence between dynamically evolving cell states, patterns of cell division, and local regulation of cellular pressure and contractile stress. Thus, our mechanical atlas reveals a new view of ascidian gastrulation in which lineage-specific control over a complex heterogenous pattern of cellular pressure and contractile stress, integrated globally, governs the emergent dynamics of ascidian gastrulation.
Alcohol Use and Sustained Virologic Response to Hepatitis C Virus Direct-Acting Antiviral Therapy: A National Observational Cohort Study
Authors: Cartwright Emily J. , Pierret Chloe , Minassian Caroline , Esserman Denise A. , Tate Janet P. , Goetz Matthew B. , Bhattacharya Debika , Fiellin David A. , Justice Amy C. , Re Vincent Lo , Rentsch Christopher T. 
Published: November 2022

AbstractBackgroundSome payors and clinicians require alcohol abstinence for direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection.ObjectiveTo evaluate whether alcohol use at DAA treatment initiation was associated with decreased odds of sustained virologic response (SVR).DesignObservational cohort study using electronic health records.SettingUS Department of Veterans Affairs (VA), the largest integrated national healthcare system that provides unrestricted access to HCV treatment.PatientsAll patients born between 1945 and 1965 who were dispensed DAA therapy between 1 January 2014 and 30 June 2018.MeasurementsWe used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of SVR associated with alcohol category. SVR was defined as undetectable HCV RNA ≥12 weeks after completion of DAA therapy. Alcohol category was determined using information on alcohol use disorder diagnoses and Alcohol Use Disorders Identification Test - C (AUDIT-C) at DAA initiation.ResultsAmong 69,229 patients who initiated DAA therapy (mean age 63 years; 97% men; 50% non-Hispanic White; 41% non-Hispanic Black; 85% HCV genotype 1), 65,355 (94.4%) of patients achieved SVR. After multivariable adjustment, we found no difference in SVR across alcohol use categories (lowest OR 0.92, 95% CI 0.82-1.04). There was no evidence of interaction by stage of hepatic fibrosis measured by FIB-4 (p-interaction=0.3001).LimitationsPredominately male population.ConclusionAlcohol use was not associated with lower odds of SVR, suggesting that DAA therapy should not be withheld due to alcohol use. Restricting access to DAA therapy based on alcohol use creates an unnecessary barrier to patients and challenges HCV elimination goals.Funding sourceNational Institute on Alcohol Abuse and Alcoholism
Disruption ofOsLAT5is sufficient to endow rice tolerance to dihydropyridine herbicides at commercial application concentrations
Authors: Chen Ronghua , Zhao Di , Yu Diya , Li Chaozheng , Wang Siwei , Xu Hanhong , Lin Fei 
Published: November 2022

AbstractBreeding non-selective herbicide-resistant crops is important constituent of weed management system in modern rice production. Non-selective dihydropyridine herbicide shares transporters with polyamine (PA), making construction of a dihydropyridine herbicide-resistant rice line possible by inactivating the PA transporter function via gene editing. Success depends on understanding substrate selection for homologues in the PA transporter family and amino acid sites that play critical roles. Here,OsLAT1was mainly responsible for root uptake and root-to-shoot transport; whereas,OsLAT5was more responsible for intracellular transport to chloroplasts. Theoslat5disruption line tolerated relevant concentrations, whileoslat1did not. Compared to GY11 wild type, plant height, 1000-grain weight, and spermidine, spermine, and putrescine content changes occurred inGY11-oslat5lines, implying involvement ofOsLAT5in yield and quality regulation.OsLAT5P44F, P44Y and P44Rshowed declined dihydropyridine herbicide uptake but no spermidine and putrescine transport competence disruption in yeast, providing a candidate site for precisely editing in breeding a dihydropyridine herbicide-resistant rice cultivar without impairing rice yield and grain quality.
Proteomics and constraint-based modelling reveal enzyme kinetic properties ofChlamydomonas reinhardtiion a genome scale
Authors: Arend Marius , Zimmer David , Xu Rudan , Sommer Frederick , Mühlhaus Timo , Nikoloski Zoran 
Published: November 2022

AbstractBiofuels produced from microalgae offer a promising solution for carbon neutral economy, and integration of turnover numbers into metabolic models can improve the design of metabolic engineering strategies towards achieving this aim. However, the coverage of enzyme turnover numbers forChlamydomonas reinhardtii, a model eukaryotic microalga accessible to metabolic engineering, is 17-fold smaller compared to the heterotrophic modelSaccharomyces cerevisiaeoften used as a cell factory. Here we generated protein abundance data fromChlamydomonas reinhardtiicells grown in various experiments, covering between 2337 and 3708 proteins, and employed these data with constraint-based metabolic modeling approaches to estimatein vivomaximum apparent turnover numbers for this model organism. The gathered data allowed us to estimate maximum apparent turnover numbers for 568 reactions, of which 46 correspond to transporters that are otherwise difficult to characterize. The resulting, largest-to-date catalogue of proxies forin vivoturnover numbers increased the coverage forC. reinhardtiiby more than 10-fold. We showed that incorporation of thesein vivoturnover numbers into a protein-constrained metabolic model ofC. reinhardtiiimproves the accuracy of predicted enzyme usage in comparison to predictions resulting from the integration onin vitroturnover numbers. Together, the integration of proteomics and physiological data allowed us to extend our knowledge of previously uncharacterized enzymes in theC. reinhardtiigenome and subsequently increase predictive performance for biotechnological applications.Significance statementCurrent metabolic modelling approaches rely on the usage ofin vitroturnover numbers (kcat) that provide limited information on enzymes operating in their native environment. This knowledge gap can be closed by data-integrative approaches to estimatein vivo kcatvalues that can improve metabolic modelling and design of metabolic engineering strategies. In this work, we assembled a high-quality proteomics data set containing 27 samples of various culture conditions and strains ofChlamydomonas reinhardtii. We used this resource to create the largest data set of estimates forin vivoturnover numbers to date. Subsequently, we showed that metabolic models parameterized with these estimates provide better predictions of enzyme abundance than those obtained by usingin vitroturnover numbers.
Spatially resolved single-cell multiomics map of human trophoblast differentiation in early pregnancy
Authors: Arutyunyan Anna , Roberts Kenny , Sheridan Megan A , Kats Ilia , Garcia-Alonso Luz , Velten Britta , Hoo Regina , Lozano Kevin Troulé , Handfield Louis-Francois , Marconato Luca , Tuck Elizabeth , Gardner Lucy , Mazzeo Cecilia Icoresi , Kelava Iva , Prigmore Elena , Teichmann Sarah A , Bayraktar Omer Ali , Moffett Ashley , Stegle Oliver , Turco Margherita Y , Vento-Tormo Roser 
Published: November 2022

AbstractThe relationship between the human placenta, the extraembryonic organ built by the fetus, and the decidua, the mucosal layer of the uterus, is essential to nurture and protect the fetus during pregnancy. Extravillous trophoblast cells (EVTs) anchor the placenta and infiltrate the decidua, transforming the maternal arteries into high conductance vessels. Defects in trophoblast invasion and arterial transformation established during early pregnancy underlie common pregnancy disorders such as pre-eclampsia. Despite its importance, how EVT invasion is regulated in humans is still unclear due the inaccessibility of the entire pregnant uterus and, until recently, a lack of reliablein vitromodels. Here, we have generated a spatially-resolved multiomics single-cell atlas of the entire maternal-fetal interface including the myometrium, allowing us to resolve the full trajectory of trophoblast differentiation. We have used this cellular map to elucidate the main regulatory programmes mediating EVT invasion and show that they are preserved in trophoblast organoids. We define the transcriptomes of the final cell states of trophoblast invasion: placental bed giant cells (fused multinucleated EVTs) and endovascular EVTs (which form plugs inside the maternal arteries). We reconstruct the cell-cell communication events contributing to trophoblast invasion and GC formation, and define the dual role of interstitial EVTs and endovascular EVTs in mediating arterial transformation during early pregnancy. Together, our data provides a comprehensive analysis of postimplantation trophoblast differentiation in humans that can be used as a blueprint to design accurate multilineage placentalin vitromodels.
Temporal Vascular Endothelial Growth Factor Sub-type Gene Switching in SARS-CoV-related Inflammation - Basis for a Dual Gene Biomarker Approach
Authors: Rashid Asrar , Benakati Govind , Al-Obeidat Feras , Malik Zainab A. , Brierley Joe , Sharma Varun , Sharma Anuka , Gupta Love , Alkhazaimi Hoda , Shaikh Guftar , Al-Dubai Ahmed , Quraishi Nasir , Zaki Syed A. , Hafez Wael , Hussain Amir 
Published: November 2022

AbstractThis study examines temporal gene expression (GE) patterns in a murine model of SARS-CoV infection. We focused on a Temporal Gene Set (TGS) comprising pro-inflammatory genes (TNF, NFKB1, VEGF-A) and VEGF-B. A systematic search of the NCBI Geo database for MA15 (SARS-CoV) pulmonary studies using C57BL Wild (WT) mice and filtering according to TGS GE patterns eluded seven datasets for further analysis. Encompassing the GE profiles from these datasets alluded to a rising and falling pattern in TNF and NFKB1 GE. Also, our findings reveal a temporal decrease in VEGF-A GE coinciding with an increase in VEGF-B GE post-immunogenic stimulation. Notably, differential responses were observed with the MA15 dosage and in comparison, to other antigens (dORF6 and NSP16). Further, the human SARS-CoV-2 gene enrichment in this murine study confirms the MA15 murine model’s relevance for SARS research. Our study also suggests potential interactions between SARS-CoV-2 Spike protein and VEGF-related receptors, hinting at other pathophysiological mechanisms. Our results indicate severe inflammation may lead to a flattened VEGF-B GE response, influencing VEGF-B’s cell survival role. We underline the significance of considering VEGF-A/B interactions, particularly temporal differences, in manipulating angiogenic processes. Future research needs to consider temporal changes in VEGF-A and VEGF-B GE, in terms of time-associated gene-switching, in line with changing host inflammation.
Megacolonies: an alternative social organization in anemonefishes?
Authors: Mercader Manon , Zwahlen Jann , Hayashi Kina , Takamiyagi Hiroki , Tseng Yung-Che , Nguyen Hai-Thanh T. , Asada Keishu , Sowinski Jérome , Reimer James , Lecchini David , Laudet Vincent 
Published: November 2022

AbstractAnemonefish are iconic examples of marine fishes living in mutualistic symbiosis with sea anemones. In a given sea anemone, the anemonefishes have a stereotyped social organization with a dominant female, a semi-dominant male, and several juveniles. A strict size-based hierarchy governs the social interactions within these colonies, with each individual differing from the previous or next fish in the order by +/- 20% size. This social organization is conserved across the Indo-Pacific in all 28 species of anemonefish found on any of ten giant sea anemone species. We report the existence of huge “megacolonies” of up to 100 fish living in large carpets of sea anemones. This alternative organization was observed for different fish and anemone species in different coral reef locations (French Polynesia, Japan, Taiwan, and Vietnam). In these colonies, the strict size-based hierarchy is no longer recognizable, and the level of aggressivity of the different members appears lower than in “normal” colonies. These megacolonies may correspond to a previously overlooked type of social organization that could be linked to host availability and offer a unique opportunity to understand anemonefish’s behavioral, social, and hormonal plasticity.
Orphan quality control shapes network dynamics and gene expression
Authors: Mark Kevin G. , Kolla SriDurgaDevi , Garshott Danielle M. , Martínez-González Brenda , Xu Christina , Akopian David , Haakonsen Diane L. , See Stephanie K. , Rapé Michael 
Published: November 2022

AbstractAll eukaryotes require intricate protein networks to translate developmental signals into accurate cell fate decisions. Mutations that disturb crucial interactions between network components often result in disease, but how the composition and dynamics of complex networks are established is unknown. Here, we identify the tumor suppressor E3 ligase UBR5 as a quality control enzyme that helps degrade unpaired subunits of multiple transcription factors that operate within a single network. By constantly turning over orphan subunits, UBR5 forces cells to continuously replenish network components through new protein synthesis. The resulting cycles of transcription factor synthesis and degradation allow cells to effectively execute the gene expression program, while remaining susceptible to environmental signals. We conclude that orphan quality control plays an essential role in establishing the dynamics of protein networks, which may explain the conserved need for protein degradation in transcription and offers unique opportunities to modulate gene expression in disease.
A fast computational model for circulatory dynamics: Effects of left ventricle-aorta coupling
Authors: Moulton Michael J. , Secomb Timothy W. 
Published: November 2022

AbstractThe course of diseases such as hypertension, systolic heart failure and heart failure with a preserved ejection fraction are affected by interactions between the left ventricle (LV) and the vasculature. To study these interactions, a computationally efficient, biophysically based mathematical model for the circulatory system is presented. In a four-chamber model of the heart, the LV is represented by a previously described low-order, wall volume-preserving model that includes torsion and base-to-apex and circumferential wall shortening and lengthening, and the other chambers are represented using spherical geometries. Active and passive myocardial mechanics of all four chambers are included. The cardiac model is coupled with a wave-propagation model for the aorta and a closed lumped-parameter circulation model. Parameters for the normal heart and aorta are determined by fitting to experimental data. Changes in the timing and magnitude of pulse wave reflections by the aorta are demonstrated with changes in compliance and taper of the aorta as seen in aging (decreased compliance, increased diameter and length), and resulting effects on LV pressure-volume loops and LV fiber stress and sarcomere shortening are predicted. Effects of aging of the aorta combined with reduced LV contractile force (failing heart) are examined. In the failing heart, changes in aortic properties with aging affect stroke volume and sarcomere shortening without appreciable augmentation of aortic pressure, and the reflected pressure wave contributes an increased proportion of aortic pressure.
Systematic review of the clinical effectiveness of Tixagevimab/Cilgavimab for prophylaxis of COVID-19 in immunocompromised patients
Authors: Suribhatla Rhea , Starkey Thomas , Ionescu Maria C , Pagliuca Antonio , Richter Alex , Lee Lennard YW 
Published: November 2022

AbstractBackground and aimsImmunocompromised patients have a reduced ability to generate antibodies after COVID-19 vaccination and are at higher risk of SARS-CoV-2 infection, complications and mortality. Tixagevimab/Cilgavimab (Evusheld) is a monoclonal antibody combination which bind to the SARS-CoV-2 spike protein, preventing the virus entering human cells. The phase III PROVENT trial reported that immunocompromised patients given Tixagevimab/Cilgavimab had a significantly reduced risk of COVID-19 infection. However, PROVENT was conducted before the SARS-CoV-2 Omicron became prevalent. This systematic review provides an updated summary of real-world clinical evidence of Tixagevimab/Cilgavimab effectiveness in immunocompromised patients.MethodsTwo independent reviewers conducted PubMed and medRxiv searches for the period of 01/01/2021 to 01/10/2022. Clinical studies which reported the primary outcome of breakthrough COVID-19 infections after Tixagevimab/Cilgavimab administration were included in the review. COVID-19-related hospitalisations, ITU admissions and mortality were assessed as secondary outcomes. Clinical effectiveness was determined using the case-control clinical effectiveness methodology. The GRADE tool was used to ascertain the level of certainty for the primary outcome in each study.Results17 clinical studies were included, comprising 24,773 immunocompromised participants of whom 10,775 received Tixagevimab/Cilgavimab. Most studies reported clinical outcomes during the SARS-CoV-2 Omicron wave. Six studies compared a Tixagevimab/Cilgavimab intervention group to a control group. Overall, the clinical effectiveness of prophylactic Tixagevimab/Cilgavimab against COVID-19 breakthrough infection, hospitalisation and ITU admission were 40.47%, 69.23% and 87.89%, respectively. For prevention of all-cause and COVID-19-specifc mortality, overall clinical effectiveness was 81.29% and 86.36%, respectively.ConclusionsThere is a growing body of real-world evidence validating the original PROVENT phase III study regarding the clinical effectiveness of Tixagevimab/Cilgavimab as prophylaxis for immunocompromised patients, notably demonstrating effectiveness during the Omicron wave. This review demonstrates the clinical effectiveness of prophylactic Tixagevimab/Cilgavimab at reducing COVID-19 infection, hospitalisation, ITU admission and mortality for immunosuppressed individuals. It is important that ongoing larger-scale and better-controlled real world studies are initiated and evaluated to provide ongoing certainty of the clinical benefit of prophylactic antibody treatment for immunocompromised patients in the face of new variants.