bluuebunny/crossref_metadata_2025 huggingface dataset:
Widespread exposure to SARS-CoV-2 in wildlife communities
Authors: Goldberg Amanda R. , Langwig Kate E. , Brown Katherine L. , Marano Jeffrey , Rai Pallavi , King Kelsie M. , Sharp Amanda K. , Ceci Alessandro , Kailing Christopher D. , Kailing Macy J. , Briggs Russell , Urbano Matthew G. , Roby Clinton , Brown Anne M. , Weger-Lucarelli James , Finkielstein Carla V. , Hoyt Joseph R.
Published: November 2022

Pervasive SARS-CoV-2 infections in humans have led to multiple transmission events to captive animals. While SARS-CoV-2 has a potential broad wildlife host range, most documented infections to date are found in a single species, the white-tailed deer. The extent of SARS-CoV-2 exposure among wildlife species and the factors that influence wildlife transmission risk remain unknown. We sampled 23 wildlife species for SARS-CoV-2 and examined the effects of urbanization and human use on seropositivity. Here, we document positive detections of SARS-CoV-2 RNA in six species, including the deer mouse, Virginia opossum, raccoon, groundhog, Eastern cottontail, and Eastern red bat. In addition, we found that sites with high human activity had three times higher seroprevalence than low human-use areas. We detected SARS-CoV-2 genomic sequences from nine individuals of six species which were assigned to seven Pango lineages of the Omicron variant. The close match to variants circulating in humans at the time suggests at least seven recent human-to-animal transmission events. Our data support that exposure to SARS-CoV-2 has been widespread in wildlife communities and suggests that areas with high human activity may serve as points of contact for cross-species transmission.
Distinct energy-coupling factor transporter subunits enable flavin acquisition and extracytosolic trafficking for extracellular electron transfer inListeria monocytogenes
Authors: Rivera-Lugo Rafael , Huang Shuo , Lee Frank , Méheust Raphaël , Iavarone Anthony T. , Sidebottom Ashley M. , Oldfield Eric , Portnoy Daniel A. , Light Samuel H.
Published: November 2022

A variety of electron transfer mechanisms link bacterial cytosolic electron pools with functionally diverse redox activities in the cell envelope and extracellular space. InListeria monocytogenes, the ApbE-like enzyme FmnB catalyzes extracytosolic protein flavinylation, covalently linking a flavin cofactor to proteins that transfer electrons to extracellular acceptors.L. monocytogenesuses an energy-coupling factor (ECF) transporter complex that contains distinct substrate-binding, transmembrane, ATPase A, and ATPase A’ subunits (RibU, EcfT, EcfA, and EcfA’) to import environmental flavins, but the basis of extracytosolic flavin trafficking for FmnB flavinylation remains poorly defined. In this study, we show that the proteins EetB and FmnA are related to ECF transporter substrate-binding and transmembrane subunits, respectively, and are essential for exporting flavins from the cytosol for flavinylation. Comparisons of the flavin import versus export capabilities ofL. monocytogenesstrains lacking different ECF transporter subunits demonstrates a strict directionality of substrate-binding subunit transport but partial functional redundancy of transmembrane and ATPase subunits. Based on these results, we propose that ECF transporter complexes with different subunit compositions execute directional flavin import/export through a broadly conserved mechanism. Finally, we present genomic context analyses which show that related ECF exporter genes are distributed across the Firmicutes phylum and frequently co-localize with genes encoding flavinylated extracytosolic proteins. These findings clarify the basis of ECF transporter export and extracytosolic flavin cofactor trafficking in Firmicutes.
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

Introduction

A 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.

Objective

To develop and evaluate a test for measuring glucagon sensitivity towards amino acid and glucose metabolism in humans.

Methods and analysis

The 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.

Results

These data will be published in peer-reviewed scientific journals and presented at scientific conferences.

Ethics and dissemination

The 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 study

The glucagon sensitivity test is based on several pilot experiments

Liver 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 production

The 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

The 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

Background

Some payors and clinicians require alcohol abstinence for direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection.

Objective

To evaluate whether alcohol use at DAA treatment initiation was associated with decreased odds of sustained virologic response (SVR).

Design

Observational cohort study using electronic health records.

Setting

US Department of Veterans Affairs (VA), the largest integrated national healthcare system that provides unrestricted access to HCV treatment.

Patients

All patients born between 1945 and 1965 who were dispensed DAA therapy between 1 January 2014 and 30 June 2018.

Measurements

We 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.

Results

Among 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).

Limitations

Predominately male population.

Conclusion

Alcohol 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 source

National 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

Breeding 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

Biofuels 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 statement

Current 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

The 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

This 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

Anemonefish 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

All 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

The 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

Background and aims

Immunocompromised 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.

Methods

Two 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.

Results

17 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.

Conclusions

There 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.
Bivalent BNT162b2mRNA original/Omicron BA.4-5 booster vaccination: adverse reactions and inability to work compared to the monovalent COVID-19 booster
Authors: Wagenhäuser Isabell , Reusch Julia , Gabel Alexander , Krone Lukas B. , Kurzai Oliver , Petri Nils , Krone Manuel
Published: November 2022

In the light of emerging SARS-CoV-2 variants of concern (VOC), bivalent COVID-19 vaccines combining the wild-type spike mRNA with an Omicron VOC BA.1 or BA.4-5 spike mRNA became available. This non-randomized controlled study examined adverse reactions, PRN (pro re nata) medication intake and inability to work after a fourth COVID-19 vaccination among 76 healthcare workers. As fourth dose either the original, monovalent BNT162b2mRNA (48.7%) or the bivalent BNT162b2mRNA original/Omicron BA.4-5 vaccine (51.3%) was administered. The rate of adverse reactions for the second booster dose was significantly higher among participants receiving the bivalent 84.6% (95% CI 70.3%-92.8%; 33/39) compared to the monovalent 51.4% (95% CI 35.9-66.6%; 19/37) vaccine (p=0.0028). Also, there was a trend towards an increased rate of inability to work and intake of PRN medication following bivalent vaccination. In view of preprints reporting inconclusive results in neutralizing antibody levels between the compared vaccines, our results and further studies on safety and reactogenicity of bivalent COVID-19 booster vaccines are highly important to aid clinical decision making in the choice between bivalent and monovalent vaccinations.
Patient Clustering and Classification for Vital Organ Failure Using ICD Code with Graph Attention
Authors: Liu Zhangdaihong , Hu Ying , Mertes Gert , Yang Yang , Clifton David A.
Published: November 2022

Objective

Heart failure, respiratory failure and kidney failure are three severe organ failures (OF) that have high mortalities and are most prevalent in intensive care units. The objective of this work is to offer insights on OF clustering from the aspects of graph neural network and diagnosis history.

Methods

This paper proposes a neural network-based pipeline to cluster three types of organ failure patients by incorporating embedding pre-train using an ontology graph of International Classification of Diseases (ICD) codes. We employ an autoencoder-based deep clustering architecture jointly trained with a K-means loss, and a non-linear dimension reduction is performed to obtain patient clusters on the MIMIC-III dataset.

Results

The clustering pipeline shows superior performance on a public-domain image dataset. For MIMIC-III, the model gives two distinct clusters that are related to the severity of the diseases. The learnt ICD embeddings present strong power in identifying the OF type in supervised learning.

Conclusion

Our proposed pipeline gives stable clusters, however, they do not correspond to the type of OF which indicates these OF share significant hidden characteristics in diagnosis. These clusters can be used to signal possible complications and severity of illness.

Significance

We are the first to apply an unsupervised approach to offer insights from a biomedical engineering perspective on these three types of organ failure, and publish the pre-trained embeddings for future transfer learning.
dATP Elevation Induces Myocardial Metabolic Remodeling to Support Improved Cardiac Function
Authors: Mhatre Ketaki N , Murray Jason D , Flint Galina , McMillen Timothy S. , Weber Gerhard , Shakeri Majid , Tu An-Yue , Steczina Sonette , Weiss Robert , Marcinek David J. , Murry Charles E , Raftery Daniel , Tian Rong , Moussavi-Harami Farid , Regnier Michael
Published: November 2022

Hallmark features of systolic heart failure are reduced contractility and impaired metabolic flexibility of the myocardium. Cardiomyocytes (CMs) with elevated deoxy ATP (dATP) via overexpression of ribonucleotide reductase (RNR) enzyme robustly improve contractility. However, the effect of dATP elevation on cardiac metabolism is unknown. Here, we developed proteolysis-resistant versions of RNR and demonstrate that elevation of dATP/ATP to ~1% in CMs in a transgenic mouse (TgRRB) resulted in robust improvement of cardiac function. Pharmacological approaches showed that CMs with elevated dATP have greater basal respiratory rates by shifting myosin states to more active forms, independent of its isoform, in relaxed CMs. Targeted metabolomic profiling revealed a significant reprogramming towards oxidative phosphorylation in TgRRB-CMs. Higher cristae density and activity in the mitochondria of TgRRB-CMs improved respiratory capacity. Our results revealed a critical property of dATP to modulate myosin states to enhance contractility and induce metabolic flexibility to support improved function in CMs.

Highlights

Ubiquitylation-resistant variant RRB in a transgenic mice model (TgRRB) elevates dATP level up to 1% (of the total ATP pool) in the heart and improves function.

TgRRB-CMs show greater basal oxygen consumption due to changes in myosin state by dATP.

TgRRB-CMs respond to elevated function with a metabolic shift, such that there are higher pools of oxidative metabolites, with elevated OXPHOS, FAO, and energy reserve.

Long-term mitochondrial remodeling may occur to accommodate for the higher energy demands of the high functioning TgRRB-CMs.

Graphical abstract
Functional characterization ofBotrytis cinereaABC transporter geneBcatrBin response to phytoalexins produced in plants belonging to families Solanaceae, Brassicaceae and Fabaceae
Authors: Bulasag Abriel Salaria , Camagna Maurizio , Kuroyanagi Teruhiko , Ashida Akira , Ito Kento , Tanaka Aiko , Sato Ikuo , Chiba Sotaro , Ojika Makoto , Takemoto Daigo
Published: November 2022

Botrytis cinerea, a generalist fungal pathogen of economically important crop species, has been shown to exhibit reduced sensitivity to fungicides and plant toxins. Specifically, previous reports indicateB. cinerea’s efficacy in tolerating a wide array of phytoalexins, toxic plant metabolites that play key role in plant immune defense strategies. Previously, we have shown that a distinct set of genes was induced inB. cinereawhen treated with phytoalexins derived from different plant species such as rishitin (tomato and potato), capsidiol (tobacco and bell pepper) or resveratrol (grape and blueberry). In this study, we focused on the functional analyses ofB. cinereagenes induced by rishitin treatment.B. cinereacan metabolize rishitin to at least 4 oxidized forms. Heterologous expression of rishitin-inducedB. cinereagenes in the plant symbiotic fungus,Epichloë festucae, revealed that oxidoreductase (Bcin08g04910) and cytochrome P450 (Bcin16g01490) genes are involved in the oxidation of rishitin. BcatrB is an exporter of structurally unrelated anti-microbial compounds such as resveratrol, camalexin and fungicide fenpicionil. Expression ofBcatrBis upregulated by rishitin, but not by structurally resembling capsidiol.BcatrBknock out transformants (ΔbcatrB) showed enhanced sensitivity to rishitin, but not to capsidiol. Likewise,ΔbcatrBshowed reduced virulence on tomato fruits (which produce rishitin), but showed full virulence onNicotiana benthamiana(which mainly produces capsidiol), suggesting thatB. cinereadistinguishes phytoalexins and activates expression of appropriate transporter genes during the infection. Activation ofBcatrBpromoter was detected using P_BcatrB:GFPtransformant during theB. cinereainfection in plant tissues. Surveying of 26 plant species across 13 families revealed that theBcatrBpromoter is mainly activated during the infection of plants belonging to the Solanaceae, Fabaceae and Brassicaceae families. TheBcatrBpromoter is activated by the treatment with Fabaceae phytoalexins medicarpin and glyceollin, andΔbcatrBshowed reduced virulence on red clover, which produces medicarpin. These results suggest thatBcatrBplays a critical role in the strategy employed byB. cinereato bypass the plant innate immune responses in a wide variety of important crops belonging to the Solanaceae, Brassicaceae and Fabaceae families.
A F420-dependent single domain chemogenetic tool for protein de-dimerization
Authors: Antoney James , Kainrath Stephanie , Ahmed F. Hafna , Kang Suk Woo , Mackie Emily R. R. , Soares da Costa Tatiana P. , Jackson Colin J. , Janovjak Harald
Published: November 2022

Protein-protein interactions (PPIs) mediate many fundamental cellular processes and their control through optically or chemically responsive protein domains has a profound impact on basic research and some clinical applications. Most available chemogenetic methods induce the association, i.e., dimerization or oligomerization, of target proteins, and the few available dissociation approaches either break large oligomeric protein clusters or heteromeric complexes. Here, we have exploited the controlled dissociation of a dimeric oxidoreductase from mycobacteria (MSMEG_2027) by its native cofactor, F420, which is not present in mammals, as a bioorthogonal monomerization switch. We found that in the absence of F420, MSMEG_2027 forms a unique domain-swapped dimer that occludes the cofactor binding site. Substantial remodelling of the intertwined N-terminal helix upon F420binding results in the dissolution of the dimer. We then show that MSMEG_2027 can be expressed as fusion proteins in human cells and apply it as a tool to induce and release MAPK/ERK signalling downstream of a chimeric fibroblast growth factor receptor 1 (FGFR1) tyrosine kinase. This F420-dependent chemogenetic de-dimerization tool is stoichiometric, based on a single domain and presents a novel mechanism to investigate protein complexesin situ.
Methylated Cycloalkanes Fuel a Novel Genera in thePorticoccaceaeFamily and Inform Substrate Affinity for a Unique Copper Membrane Monooxygenase
Authors: Arrington Eleanor C. , Tarn Jonathan , Kittner Hailie , Kivenson Veronika , Liu Rachel M. , Valentine David L.
Published: November 2022

Cycloalkanes are an abundant and toxic class of compounds in subsurface petroleum reservoirs and their fate is quantitatively important to ecosystems impacted by natural oil seeps and spills. In this study, we focus on the microbial metabolism of methylcyclohexane (MCH) and methylcyclopentane (MCP) in the deep Gulf of Mexico. MCH and MCP are often the most abundant cycloalkanes observed in petroleum and a substantial portion of these compounds will dissolve into the water column when introduced at the seafloor via a spill or natural seep. Once dissolved into the water column, the environmental fate of MCH and MCP is presumably controlled by microbial consumption, but little is known about this environmental process. We conducted incubations using fresh Gulf of Mexico (GOM) seawater amended with MCH and MCP at four stations along a transect with a gradient in the influence of natural oil seepage. We observe microbial blooms via optical oxygen sensors that occur at all stations with bloom occurrence among replicate incubations impacted by the proximity of natural seepage. Within all incubations with active respiration of MCH and MCP, we find thatB045, a novel genus of bacteria belonging to thePorticoccaceaefamily dominates the microbial community. Using seven high-quality metagenome-assembled genomes recovered from microbial blooms on MCH and MCP, we reconstruct the biodegradation pathways and central carbon metabolism ofB045, identifying a novel clade of the particulate hydrocarbon monooxygenase (pmo) that may play a key role in MCH and MCP metabolism. Through comparative analysis of 176 genomes, we parse the taxonomy of thePorticoccaceaefamily and find evidence suggesting the acquisition ofpmoand other genes related to the degradation of cyclic and branched hydrophobic compounds were likely key events in the ecology and evolution of this group of organisms.
Using unlabeled information of embryo siblings from the same cohort cycle to enhance in vitro fertilization implantation prediction
Authors: Tzukerman Noam , Rotem Oded , Shapiro Maya Tsarfati , Maor Ron , Meseguer Marcos , Gilboa Daniella , Seidman Daniel S. , Zaritsky Assaf
Published: November 2022

High content time-lapse embryo imaging assessed by machine learning is revolutionizing the field of in vitro fertilization (IVF). However, the vast majority of IVF embryos are not transferred to the uterus, and these masses of embryos with unknown implantation outcomes are ignored in current efforts that aim to predict implantation. Here, we explore whether, and to what extent the information encoded within “sibling” embryos from the same IVF cohort contribute to the performance of machine learning-based implantation prediction. First, we show that the implantation outcome is correlated with attributes derived from the cohort siblings. Second, we demonstrate that this unlabeled data boosts implantation prediction performance. Third, we characterize the cohort properties driving embryo prediction, especially those that rescued erroneous predictions. Our results suggest that predictive models for embryo implantation can benefit from the overlooked, widely available unlabeled data of sibling embryos by reducing inherent noise of the individual transferred embryo.

Significance statement

We use in vitro fertilization (IVF) as a model to study the effect of genotypic and environmental variation on phenotype and demonstrate a potential translational application. This is achieved by associating the implantation potential of transferred embryos and the visual information encoded within their non-transferred “sibling” embryos from the same IVF cohort, and establishing that these cohort features contribute to consistent improvement in machine learning implantation prediction regardless of the embryo-focused model. Our results suggest a general concept where the uncertainty in the implantation potential for the transferred embryo can be reduced by information encapsulated in the correlated cohort embryos. Since the siblings’ data are routinely collected, incorporating cohort features in AI-driven embryo implantation prediction can have direct translational implications.
Rac1, Rac3 GTPases and TPC2 are required for axonal outgrowth and migration of cortical interneurons
Authors: Kounoupa Zouzana , Tivodar Simona , Theodorakis Kostas , Kyriakis Dimitrios , Denaxa Myrto , Karagogeos Domna
Published: November 2022

Rho GTPases, among them Rac1 and Rac3, are major transducers of extracellular signals and are involved in multiple cellular processes. In cortical interneurons, the neurons that control excitation/inhibition balance of cortical circuits, Rac1 and Rac3 are essential for their development. Ablation of both, leads to a severe reduction in the numbers of mature interneurons found in the murine cortex, which is partially due to abnormal cell cycle progression of interneuron precursors and defective formation of their growth cones. Here we present new evidence that upon Rac1 and Rac3 ablation, centrosome, Golgi complex and lysosome positioning are significantly perturbed, thus affecting both interneuron migration and axon growth. Moreover, for the first time we provide evidence of altered expression and localization of the two-pore channel 2 (TPC2) voltage-gated ion channel that mediates Ca2+release. Pharmacological inhibition of TPC2 negatively affected axonal growth and migration of interneurons. Our data taken together suggest that TPC2 contributes to the severe phenotype in axon growth initiation, extension and interneuron migration in the absence of Rac1 and Rac3.

SUMMARY STATEMENT

Rac1/3 severely affect cortical interneuron migration by affecting centrosome, Golgi and lysosome positioning. TPC2 likely contributes to the phenotype by decreasing axonogenesis and somatic migration.
DNA methylation regulates sex-biased gene expression in the house sparrow
Authors: Lundregan Sarah L. , Mäkinen Hannu , Viitaniemi Heidi , Rønning Bernt , Jensen Henrik , Husby Arild
Published: November 2022

Sexual dimorphism is often mediated by tissue-specific, differential gene expression, but the mechanisms that regulate these gene expression patterns are not well understood. Here, we investigate DNA methylation as a potential regulator of sex-biased gene expression in the house sparrow (Passer domesticus). First, we examine whether sex-bias in gene expression or DNA methylation is present in this species, and whether any sex differences are tissue-general or tissue-specific. Second, we assess the correlation between gene expression and DNA methylation at different genomic features in several tissues. Samples clustered by tissue type when looking at both gene expression and DNA methylation, and in gonads samples clustered according to sex. We demonstrate sex-bias in DNA methylation and gene expression on the Z-chromosome as well as on autosomes, but find that most of the sex-biased genes are tissue-specific and that the majority of sex-bias occurs in gonads, although some tissue-general sex differences were observed. This underscores the importance of choosing a tissue relevant to the studied phenotype in DNA methylation or gene expression studies. We find strong negative correlation between DNA methylation and gene expression at the transcription start site (TSS), and that the TSS of highly expressed genes is hypomethylated in comparison to the TSS of genes with low expression. Furthermore, we show that sex-biased DNA methylation can account for 14% of the sex differences in gene expression in gonads. Together these results indicate that DNA methylation differences between the sexes can provide a mechanistic explanation for sex-biased gene expression that likely contributes to trait sexual dimorphism in nature.
Long-range Hill-Robertson effect in adapting populations with recombination and standing variation
Authors: Rouzine Igor M.
Published: November 2022

In sexual populations, closely-situated genes have linked evolutionary fates, while genes spaced far in genome are commonly thought to evolve independently due to recombination. In the case where evolution depends essentially on supply of new mutations, this assumption has been confirmed by mathematical modeling. Here I examine it in the case of pre-existing genetic variation, where mutation is not important. A haploid population withNgenomes,Lloci, a fixed selection coefficient, and a small initial frequency of beneficial allelesf0is simulated by a Monte-Carlo algorithm. The results demonstrate the existence of extremely strong linkage effects, including clonal interference and genetic background effects, that depend neither on the distance between loci nor on the average number of recombination crossovers. When the number of loci,L, is larger than 4log2(Nf0), beneficial alleles become extinct at most loci. The substitution rate varies broadly between loci, with the fastest rate exceeding the one-locus model prediction. All observables and the transition to the independent-locus limit are controlled by single composite parameter log2(Nf0)/L. The potential link between these findings and the emergence of new Variants of Concern of SARS CoV-2 is discussed.
Long-term recoveries of forest ecosystem components after shallow landslides were asynchronized among slope positions
Authors: Hotta Wataru , Morimoto Junko , Yanai Seiji , Uchida Yoshitaka , Nakamura Futoshi
Published: November 2022

Landslides are a common disturbance in mountainous areas of the world. Transporting and accumulating landslide debris, i.e., disturbance legacies, such as coarse woody debris (CWD), vegetation patches, and surface soils, generate a heterogeneous environment along slopes (zones), which are suggested to affect forest recovery. However, the long-term changes in forest ecosystems after landslides remain unknown, particularly zone-dependent change patterns. We aimed to reveal the differences in the changes in live trees, understory vegetation, CWD, and soils among zones by surveying forests with landslide ages (years since the landslide) ranging from 3 to 74 years and reference stands. The increase in live tree aboveground biomass occurred at a faster rate at the lower part of the slopes where the disturbance legacies were rich and surface soils were stabilized due to the smaller slope angle. Chronological patterns of understory vegetation amounts were determined by the differences in disturbance legacy richness and the timing of subsequent canopy closure. The amounts and decay-class diversity of CWD were determined by the differences in legacy richness and mortality through stand development. These zone-dependent chronological changes influenced litter production and determined the recovery rates of surface soil carbon stocks and nitrogen contents. The increase in the dominance rates of forest herbaceous species was faster in the lower part of the slopes due to the faster surface soil development and canopy closure. Our results illustrate that long-term forest ecosystem succession and recovery after landslides occurs more rapidly at the lower parts than at the upper parts of slopes.

Highlights

Rich landslide legacies and low slope angles promoted vegetation and soil recovery

Legacy richness and timing of canopy closure determined changes in the understory

Landslide mortality and stand development mortality determined changes in dead wood