bluuebunny/crossref_metadata_2025 huggingface dataset:
Coordinating directional switches in pigeon flocks: the role of nonlinear interactions
Authors: Chen Duxin , Sun Yongzheng , Shao Guanbo , Yu Wenwu , Zhang Hai-Tao , Lin Wei
Published: September 2021

The mechanisms inducing unpredictably directional switches in collective and moving biological entities are largely unclear. Deeply understanding such mechanisms is beneficial to delicate design of biologically inspired devices with particular functions. Here, articulating a framework that integrates data-driven, analytical and numerical methods, we investigate the underlying mechanism governing the coordinated rotational flight of pigeon flocks with unpredictably directional switches. Particularly using the sparse Bayesian learning method, we extract the inter-agent interactional dynamics from the high-resolution GPS data of three pigeon flocks, which reveals that the decision-making process in rotational switching flight performs in a more nonlinear manner than in smooth coordinated flight. To elaborate the principle of this nonlinearity of interactions, we establish a data-driven particle model with two potential wells and estimate the mean switching time of rotational direction. Our model with its analytical and numerical results renders the directional switches of moving biological groups more interpretable and predictable. Actually, an appropriate combination of natures, including high density, stronger nonlinearity in interactions, and moderate strength of noise, can enhance such highly ordered, less frequent switches.
Lipopolysaccharide core type diversity in the Escherichia coli species in association with phylogeny, virulence gene repertoire and distribution of type VI secretion systems
Authors: Leclercq Sébastien O. , Branger Maxime , Smith David G. E. , Germon Pierre
Published: September 2021

Escherichia coli

is a very versatile species for which diversity has been explored from various perspectives highlighting, for example, phylogenetic groupings and pathovars, as well as a wide range of O serotypes. The highly variable O-antigen, the most external part of the lipopolysaccharide (LPS) component of the outer membrane of

E. coli

, is linked to the innermost lipid A through the core region of LPS of which five different structures, denominated K-12, R1, R2, R3 and R4, have been characterized so far. The aim of the present study was to analyse the prevalence of these LPS core types in the

E. coli

species and explore their distribution in the different

E. coli

phylogenetic groups and in relationship with the virulence gene repertoire. Results indicated an uneven distribution of core types between the different phylogroups, with phylogroup A strains being the most diverse in terms of LPS core types, while phylogroups B1, D and E strains were dominated by the R3 type, and phylogroups B2 and C strains were dominated by the R1 type. Strains carrying the LEE virulence operon were mostly of the R3 type whatever the phylogroup while, within phylogroup B2, strains carrying a K-12 core all belonged to the complex STc131, one of the major clones of extraintestinal pathogenic

E. coli

(ExPEC) strains. The origin of this uneven distribution is discussed but remains to be fully explained, as well as the consequences of carrying a specific core type on the wider aspects of bacterial phenotype.
Role of Solvent Compatibility in the Phase Behavior of Binary Solutions of Weakly Associating Multivalent Polymers
Authors: Michels Jasper J. , Brzezinski Mateusz , Scheidt Tom , Lemke Edward A. , Parekh Sapun H.
Published: September 2021

Condensate formation of biopolymer solutions, prominently those of various intrinsically disordered proteins (IDPs), is determined by “sticky” interactions between associating residues, multivalently present along the polymer backbone. Using a ternary mean field “stickers-and-spacers” model, we demonstrate that if sticker association is of the order of a few times the thermal energy, a delicate balance between specific binding and non-specific polymer-solvent interactions gives rise to a particularly rich ternary phase behavior under physiological circumstances. For a generic system represented by a solution comprising multi-associative scaffold and client polymers, the difference in solvent compatibility between the polymers modulates the nature of isothermal liquid-liquid phase separation (LLPS) between associative and segregative. The calculations reveal regimes of dualistic phase behavior, where both types of LLPS occur within the same phase diagram, either associated with the presence of multiple miscibility gaps, or a flip in the slope of the tie-lines belonging to a single coexistence region.
Detecting a History of Repetitive Head Impacts from a Short Voice Recording
Authors: Tauro Michael G. , Ravanelli Mirco , Droppelmann Cristian A.
Published: September 2021

Repetitive head impacts (RHI) are associated with an increased risk of developing various neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and most notably, chronic traumatic encephalopathy (CTE). While the clinical presentation of AD and PD is well established, CTE can only be diagnosed post-mortem. Therefore, a distinction can be made between the pathologically defined CTE and RHI-related functional or structural brain changes (RHI-BC) which may result in CTE. Unfortunately, there are currently no accepted biomarkers of CTE nor RHI-BC, a major hurdle to achieving clinical diagnoses. Interestingly, speech has shown promise as a potential biomarker of both AD and PD, being used to accurately classify individuals with AD and PD from those without. Given the overlapping symptoms between CTE, RHI-BC, PD and AD, we aimed to determine if speech could be used to identify individuals with a history of RHI from those without. We therefore created the Verus dataset, consisting of 13 second voice recordings from 605 professional fighters (RHI group) and 605 professional athletes in non-contact sports (control group) for a total of 1210 recordings. Using a deep learning approach, we achieved 85% accuracy in detecting individuals with a history of RHI from those without. We then used our model trained on the Verus dataset to fine-tune on publicly available AD and PD speech datasets and achieved new state-of-the-art accuracies of 84.99% on the AD dataset and 89% on the PD dataset. Finding a biomarker of CTE and RHI-BC that presents early in disease progression is critical to improve risk management and patient outcome. Our study is the first we are aware of to investigate speech as such a candidate biomarker of RHI-BC.
Towards Understanding Comprehensive Morphometric Changes and Its Correlation with Cognition and Exposure to Fighting in Active Professional Boxers
Authors: Mishra Virendra R. , Zhuang Xiaowei , Sreenivasan Karthik R. , Cordes Dietmar , Ritter Aaron , Banks Sarah J. , Bernick Charles
Published: September 2021

Professional athletes exposed to repetitive head impacts are at increased risk for developing a progressive neurological syndrome known as traumatic encephalopathy syndrome and neuropathology seen on autopsy called chronic traumatic encephalopathy (CTE). The early identification of individuals at increased risk for CTE is important and the search for biomarkers is underway. In this study, we utilized data from a large cohort study to compare differences in regional brain volumes, cortical thickness, voxel-based morphometric (VBM)-derived measures, and graph-theoretical measures derived from large-scale topographical maps in active professional boxers. We compared the above morphometric measures between active professional boxers with low cognitive scores (impaired boxers) and active professional boxers with intact cognitive scores (nonimpaired boxers). The cognitive scores were evaluated through neuropsychological evaluation. As an exploratory analysis, we also examined the power of various machine-learning algorithms to identify impaired and nonimpaired boxers using both group-level regression-driven analysis and previously identified hypothesis-driven cortical thickness and volumetric measures. We found significant group-level differences between impaired and nonimpaired boxers in cortical thickness in a single brain region (right precuneus), differences in VBM-derived gray matter density encompassing the caudate, putamen, and thalamus; and white matter density encompassing the right paracentral lobule, but no differences in any graph-theoretical network properties. Additionally, we found that a priori hypothesis-driven T1-derived cortical thickness and volumetric analysis performed better than traditional regression-based analysis. Overall, this study suggests that neuroanatomical differences exist between impaired and nonimpaired active professional boxers, and that hypothesis-driven techniques are likely necessary to become reliable biomarkers.
Methods for Estimation of SARS-CoV-2 Seroprevalence and Reported COVID-19 Cases in U.S. Children, August 2020—May 2021
Authors: Couture Alexia , Lyons Casey , Mehrotra Megha L. , Sosa Lynn , Ezike Ngozi , Brown Catherine M. , Yendell Stephanie , Azzam Ihsan A. , Katić Božena J , Cope Anna , Dickerson Kristen , Dunn John , Traxler L. Brannon , Davis Lora B. , Ahmed Farah S. , Stone Jolianne , Reed Carrie , Clarke Kristie E. N. , Flannery Brendan , Charles Myrna D.
Published: September 2021

Background and Objectives

Case-based surveillance of pediatric COVID-19 cases underestimates the prevalence of SARS-CoV-2 infections among children and adolescents. Our objectives were to: 1) estimate monthly SARS-CoV-2 antibody seroprevalence among children aged 0-17 years and 2) calculate ratios of SARS-CoV-2 infections to reported COVID-19 cases among children and adolescents in 14 U.S. states.

Methods

Using data from commercial laboratory seroprevalence surveys, we estimated monthly SARS-CoV-2 antibody seroprevalence among children aged 0-17 years from August 2020 through May 2021. Seroprevalence estimates were based on SARS-CoV-2 anti-nucleocapsid immunoassays from February to May 2021. We compared estimated numbers of children infected with SARS-CoV-2 by May 2021 to cumulative incidence of confirmed and probable COVID-19 cases from case-based surveillance, and calculated infection: case ratios by state and type of anti-SARS-CoV-2 nucleocapsid immunoassay used for seroprevalence testing.

Results

Analyses included 67,321 serum specimens tested for SARS-CoV-2 antibodies among children in 14 U.S. states. Estimated ratios of SARS-CoV-2 infections to reported confirmed and probable COVID-19 cases among children and adolescents varied by state and type of immunoassay, ranging from 0.8-13.3 in May 2021.

Conclusions

Through May 2021, the majority of children in selected states did not have detectable SARS-CoV-2 nucleocapsid antibodies. Case-based surveillance underestimated the number of children infected with SARS-CoV-2, however the predicted extent of the underestimate varied by state, immunoassay, and over time. Continued monitoring of pediatric SARS-CoV-2 antibody seroprevalence should inform prevention and vaccination strategies.
Combination of Mifepristone and Methotrexate for the Treatment of Ectopic Pregnancy: A Systematic Review Protocol
Authors: Su Qiling , Feng Huiyan , Tian Tian , Liao Xiaoqian , Li Yunhui , Li Xiaomao
Published: September 2021

Aim

The increase in ectopic pregnancies (EP) in recent years and their impact on female fertility forces physicians to find an effective medical treatment that can avoid surgery as soon as possible. Methotrexate and mifepristone are widely used in conservative treatments, but the effectiveness of this combination is not completely clear. Therefore, the aims in this meta-analysis are to systematically analyze the efficacy of mifepristone combined with methotrexate in the treatment of EP through existing studies and draw a conclusion, to evaluate the advantages and disadvantages of inclusion trials and propose improvement measures and scientific designing schemes.

Methods

Six databases will be searched, including PubMed, Embase, Cochrane Library, the China National Knowledge Infrastructure(CNKI), Chinese Science and Technology Periodical Database (VIP), and Wanfang Database (WF). Randomized controlled trials published up to October 2020 will be selected. Search terms include mifepristone, methotrexate, EP, and random (free word/synonym expansion). We will include trials in which the experimental group was treated with combination of mifepristone and methotrexate, and the control group was treated with mifepristone alone. Revman 5.4 will be used to evaluate the quality of the trials, and the effect model will be selected to analyze the results. Cure rate will be the main outcome index.

Result

Only when we finish this meta analysis can we get the result.

Discussion

The results of this study will provide evidence for the efficacy of mifepristone combined with methotrexate therapy in the treatment of EP. The site of onset of pregnancy should be taken into account.

PROSPERO registration number

CRD42021246757
Systemic and Genetic Risk Factors for Reticular Macular Disease and Soft Drusen in Age-Related Macular Degeneration
Authors: Thomson Robert J. , Chazaro Joshua , Otero-Marquez Oscar , Ledesma-Gil Gerardo , Tong Yuehong , Coughlin Arielle C. , Teibel Zachary R. , Alauddin Sharmina , Tai Katy , Lloyd Harriet , Scolaro Maria , Govindaiah Arun , Bhuiyan Alauddin , Dhamoon Mandip S. , Deobhakta Avnish , Narula Jagat , Rosen Richard B. , Yannuzzi Lawrence A. , Freund K. Bailey , Smith R. Theodore
Published: September 2021

Purpose

Soft drusen and subretinal drusenoid deposits (SDD) aka reticular macular disease (RMD) characterize two pathways to advanced age-related macular degeneration (AMD). We propose these pathways are distinct diseases, with distinct genetic risks, serum risks and associated systemic diseases.

Methods

126 Subjects with AMD had: retinal imaging for RMD status, serum risks, genetic testing, and histories of cardiovascular disease (CVD) and stroke.

Results

62 subjects had RMD, 64 were nonRMD (drusen only), 51 had CVD or Stroke. RMD correlated significantly with: ARMS2 risk allele (p= 0.019); lower mean serum HDL (61±18 vs. 69±22 mg/dl, p= 0.038, t test); CVD and troke (34/51 RMD, p= 0.001).NonRMD correlated/trended with APOE2 (p= 0.032) and CETP (p= 0.072) risk alleles. 97 subjects total had some drusen, which correlated with CFH risk (p= 0.016). Multivariate independent risks for RMD were: CVD and Stroke (p= 0.008), and ARMS2 homozygous risk (p= 0.038).

Conclusion

The RMD and soft drusen AMD pathways have distinct systemic associations, serum and genetic risks. RMD is associated with CVD and stroke, ARMS2 risk, and lower HDL; drusen with CFH risk and two lipid risk genes. These pathways appear to be distinct diseases leading to advanced AMD.

Summary Statement

Two phenotypes of age-related macular degeneration, soft drusen and reticular macular disease (the combination of subretinal drusenoid deposits and choriocapillaris insufficiency), are shown here to have distinct systemic vascular, serum, and genetic risks. These findings support the concept that these phenotypes actually represent distinct disease processes.
Linguistic fairness in the U.S.: The case of multilingual public health information about COVID-19
Authors: Blasi Damián E. , Mishra Vishala , García Adolfo M. , Dexter Joseph P.
Published: September 2021

Lack of high-quality multilingual resources can contribute to disparities in the availability of medical and public health information. The COVID-19 pandemic has required rapid dissemination of essential guidance to diverse audiences and therefore provides an ideal context in which to study linguistic fairness in the U.S. Here we report a cross-sectional study of official non-English information about COVID-19 from the Centers for Disease Control and Prevention, the Food and Drug Administration, and the health departments of all 50 U.S. states. We find that multilingual information is limited in many states, such that almost half of all individuals not proficient in English or Spanish lack access to state-specific COVID-19 guidance in their primary language. Although Spanish-language information is widely available, we show using automated readability formulas that most materials do not follow standard recommendations for clear communication in medicine and public health. In combination, our results provide a snapshot of linguistic unfairness across the U.S. and highlight an urgent need for the creation of plain language, multilingual resources about COVID-19.
ChAdOx1 nCoV-19 (AZD1222) vaccine elicits monoclonal antibodies with potent cross-neutralizing activity against SARS-CoV-2 viral variants
Authors: Seow Jeffrey , Graham Carl , Hallett Sadie R. , Lechmere Thomas , Maguire Thomas J.A. , Huettner Isabella , Cox Daniel , Roberts Rebekah , Waters Anele , Ward Christopher C. , Mant Christine , Pitcher Michael J. , Spencer Jo , Fox Julie , Malim Michael H. , Doores Katie J.
Published: September 2021

Although the antibody response to COVID-19 vaccination has been studied extensively at the polyclonal level using immune sera, little has been reported on the antibody response at the monoclonal level. Here we isolate a panel of 44 anti-SARS-CoV-2 monoclonal antibodies (mAbs) from an individual who received two doses of the ChAdOx1 nCoV-19 (AZD1222) vaccine at a 12-week interval. We show that despite a relatively low serum neutralization titre, mAbs with potent neutralizing activity against the current SARS-CoV-2 variants of concern (B.1.1.7, P.1, B.1.351 and B.1.617.2) were obtained. The vaccine elicited neutralizing mAbs form 8 distinct competition groups and bind epitopes overlapping with neutralizing mAbs elicited following SARS-CoV-2 infection. AZD1222 elicited mAbs are more mutated than mAbs isolated from convalescent donors 1-2 months post infection. Spike reactive IgG+ B cells were still detectable 9-months post boost. These findings give molecular insights into AZD1222 elicited antibody response.
Disentangling heterogeneity of Malignant Pleural Mesothelioma through deep integrative omics analyses
Authors: Mangiante Lise , Alcala Nicolas , Di Genova Alex , Sexton-Oates Alexandra , Gonzalez-Perez Abel , Khandekar Azhar , Bergstrom Erik N. , Kim Jaehee , Giacobi Colin , Le Stang Nolwenn , Boyault Sandrine , Cuenin Cyrille , Tabone-Eglinger Severine , Damiola Francesca , Voegele Catherine , Ardin Maude , Michallet Marie-Cecile , Soudade Lorraine , Delhomme Tiffany M. , Poret Arnaud , Brevet Marie , Copin Marie-Christine , Giusiano-Courcambeck Sophie , Damotte Diane , Girard Cecile , Hofman Veronique , Hofman Paul , Mouroux Jérôme , Lacomme Stephanie , Mazieres Julien , de Montpreville Vincent Thomas , Perrin Corinne , Planchard Gaetane , Rouquette Isabelle , Sagan Christine , Scherpereel Arnaud , Thivolet Francoise , Vignaud Jean-Michel , Jean Didier , Gilg Soit Ilg Anabelle , Olaso Robert , Meyer Vincent , Boland Anne , Deleuze Jean-Francois , Altmuller Janine , Nuernberg Peter , Lantuejoul Sylvie , Ghantous Akram , Maussion Charles , Courtiol Pierre , Hernandez-Vargas Hector , Caux Christophe , Girard Nicolas , Lopez-Bigas Nuria , Alexandrov Ludmil B. , Salle Françoise Galateau , Foll Matthieu , Fernandez-Cuesta Lynnette
Published: September 2021

Malignant Pleural Mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Using the largest series of whole-genome sequencing data integrated with transcriptomic and epigenomic data using multi-omic factor analysis, we demonstrate that MPM heterogeneity arises from four sources of variation: tumor cell morphology, ploidy, adaptive immune response, and CpG island methylator phenotype. Previous genomic studies focused on describing only the tumor cell morphology factor, although we robustly find the three other sources in all publicly available cohorts. We prove how these sources of variation explain the biological functions performed by the cancer cells, and how genomic events shape MPM molecular profiles. We show how these new sources of variation help understand the heterogeneity of the clinical behavior of MPM and drug responses measured in cell lines. These findings unearth the interplay between MPM functional biology and its genomic history, and ultimately, inform classification, prognostication and treatment.

Graphical abstract
Tuning epithelial cell-cell adhesion and collective dynamics with functional DNA-E-cadherin hybrid linkers
Authors: Schoenit Andreas , Giudice Cristina Lo , Hahnen Nina , Ollech Dirk , Jahnke Kevin , Göpfrich Kerstin , Cavalcanti-Adam Elisabetta Ada
Published: September 2021

The binding strength between epithelial cells is crucial for tissue integrity, signal transduction and collective cell dynamics. However, there is no experimental approach to precisely modulate cell-cell adhesion strength at the cellular and molecular level. Here, we establish DNA nanotechnology as tool to control cell-cell adhesion of epithelial cells. We designed a DNA-E-cadherin hybrid system consisting of complementary DNA strands covalently bound to a truncated E-cadherin with a modified extracellular domain. DNA sequence design allows to tune the DNA-E-cadherin hybrid molecular binding strength, while retaining its cytosolic interactions and downstream signaling capabilities. The DNA-E-cadherin hybrid facilitates strong and reversible cell-cell adhesion in E-cadherin deficient cells by forming mechanotransducive adherens junctions. We assess the direct influence of cell-cell adhesion strength on intracellular signaling and collective cell dynamics. This highlights the scope of DNA nanotechnology as a precision technology to study and engineer cell collectives.
Immune function of the serosa in hemimetabolous insect eggs
Authors: Jacobs Chris G.C. , van der Hulst Remy , Chen Yen-Ta , Williamson Ryan P. , Roth Siegfried , van der Zee Maurijn
Published: September 2021

Insects comprise more than a million species and many authors have attempted to explain this success by evolutionary innovations. A much overlooked evolutionary novelty of insects is the serosa, an extraembryonic epithelium around the yolk and embryo. We have shown previously that this epithelium provides innate immune protection to eggs of the beetle Tribolium castaneum. It remained elusive, however, whether this immune competence evolved in the Tribolium lineage or is ancestral to all insects. Here, we expand our studies to two hemimetabolous insects, the bug Oncopeltus fasciatus and the swarming grasshopper Locusta migratoria. For Oncopeltus, RNA sequencing reveals an extensive response upon infection, including the massive upregulation of antimicrobial peptides (AMPs). We demonstrate antimicrobial activity of these peptides using in vitro bacterial growth assays, and describe two novel AMP families called Serosins and Ovicins. For both insects, qPCRs show immune competence of the eggs when the serosa is present, and in situ hybridizations demonstrate that immune gene expression is localized in the serosa. This first evidence from hemimetabolous insect eggs suggests that immune competence is an ancestral property of the serosa. The evolutionary origin of the serosa with its immune function might have facilitated the spectacular radiation of the insects.
DIDO3 acts at the interface of RNAPII transcription and chromatin structure regulation
Authors: Pons Tirso , Serra Francois , Pazos Florencio , Valencia Alfonso , Martínez-A Carlos
Published: September 2021

Chromatin structure and organization has a key role in gene expression regulation. Here, we integrated ChIP-seq, RNA-seq, Hi-C, epigenetic, and cancer-related mutations data to get insight into the role of Death Inducer Obliterator gene (Dido1) in RNA pol II (RNAPII) transcription and chromatin structure regulation. Analysis of ChIP-seq data of DIDO3, the largest protein isoform ofDido1, revealed binding-sites overlap about 70% with RNAPII and H3K36me3 in the mouse genome, but also significant overlap 10-30% with Polycomb, CTCF, H3K4me3, and H3K27ac. Based on this analysis we propose that DIDO3’s PHD domain interacts with H3K36me3 posttranslational modification. Integrating multi-omics data we describe how DIDO3 potentially recruit several transcription factors, including RNAPII, and also regulates genes transcribing those same transcription factors. DIDO3 regulation of the genes traduced into proteins to which it binds puts DIDO3 in the center of intricate feedback loops. We showed, by using data from a DIDO3 mutant, that DIDO3 C-terminus is responsible for most of these transcriptional regulation, and is also implicated in other very important pathways by regulating genes encoding for Polycomb-accessory proteins, subunits of the SWI/SNF chromatin remodelling, or Set1/COMPASS chromatin modifier complexes. These multi-protein complexes control gene activation or silencing and also play a role in tumour development. DIDO3 C-terminus region and splice-site for alternative DIDO2/DIDO3 protein isoforms tended to accumulate recurrent truncating mutations identified in the TCGA Pan-Cancer dataset. We hypothesize that deregulation of DIDO3, as it happens with large epigenetic complexes and long-range interactions, leads to cell differentiation deficiency and cancer development. Overall, we propose here a molecular mechanism by which DIDO3, favour RNAPII pausing and long-range chromatin interactions.
A Mediterranean-like fat blend protects against the development of severe colitis in the mucin-2 deficient murine model
Authors: Haskey Natasha , Ye Jiayu , Estaki Mehrbod , Verdugo Meza Andrea A. , Barnett Jacqueline A. , Yousefi Mitra , Birnie Blake W. , Gruenheid Samantha , Ghosh Sanjoy , Gibson Deanna L.
Published: September 2021

The Mediterranean diet (MD) is a health-promoting, moderate fat diet (~ 40% energy). It is not known if the blend of fats found in the MD contribute to the beneficial protective effects. We compared the MD fat blend (high monounsaturated, 2:1 n-6:n-3 polyunsaturated and moderate saturated fat) to isocaloric diets composed with corn oil (CO, n-6 polyunsaturated-rich), olive oil (high monounsaturated-rich) or milk fat (MF, saturated-rich) on spontaneous colitis development in Muc2−/− mice. The MD resulted in lower clinical and histopathological scores, and induced tolerogenic CD103+CD11b+ dendritic, Th22 and IL-17+IL-22+ cells important for intestinal barrier repair. MD also reduced attendant insulin resistance and a shift to a higher health-promoting gut microbes including Lactobacillus B. animalis and Muribaculaceae, whereas CO showed higher prevalence of mucin-degraders (Akkermansia muciniphila) and colitis promoters (Enterobacteriaceae). Our findings suggest that the MD fat blend could be recommended as a maintenance diet for colitis.
Plant neighborhood shapes diversity and reduces interspecific variation of the phyllosphere microbiome
Authors: Meyer Kyle M. , Porch Robert , Muscettola Isabella E. , Vasconcelos Ana Luisa S. , Sherman Julia K. , Metcalf C. Jessica E. , Lindow Steven E. , Koskella Britt
Published: September 2021

Microbial communities associated with plant leaf surfaces (i.e. the phyllosphere) are increasingly recognized for their role in plant health. While accumulating evidence suggests a role for host filtering of its microbiota, far less is known about how community composition is shaped by dispersal, including from neighboring plants. We experimentally manipulated the local plant neighborhood within which tomato, pepper, or bean plants were grown in a three-month field trial. Focal plants were grown in the presence of con- or hetero-specific neighbors (or no neighbors) in a fully factorial combination. At 30-day intervals, focal plants were harvested and replaced with a new age- and species-matched cohort while allowing neighborhood plants to continue growing. 16S community profiling revealed that the strength of host filtering effects (i.e. interspecific differences in composition) decreased over time. In contrast, the strength of neighborhood effects increased over time, suggesting dispersal from neighboring plants becomes more important as neighboring plant biomass increases. We next implemented a cross-inoculation study in the greenhouse using inoculum generated from the field plants to directly test host filtering of microbiomes while controlling for directionality and source of dispersal. This experiment further demonstrated that focal host species, the host from which the microbiome came, and in one case the donor hosts’ neighbors, contribute to variation in phyllosphere bacterial composition. Overall, our results suggest that local dispersal is a key factor in phyllosphere assembly, and that demographic factors such as nearby neighbor identity and biomass or age are important determinants of phyllosphere microbiome diversity.
PlasmidHostFinder: Prediction of plasmid hosts using random forest
Authors: Aytan-Aktug Derya , Clausen Philip TLC , Szarvas Judit , Munk Patrick , Otani Saria , Nguyen Marcus , Davis James J , Lund Ole , Aarestrup Frank M
Published: September 2021

Plasmids play a major role facilitating the spread of antimicrobial resistance between bacteria. Understanding the host range and dissemination trajectories of plasmids is critical for surveillance and prevention of antimicrobial resistance. Identification of plasmid host ranges could be improved using automated pattern detection methods, compared to homology-based methods due to the diversity and genetic plasticity of plasmids. In this study, we developed a method for predicting the host range of plasmids based on the random forest machine learning method. We trained the models with 8,519 plasmids from 359 different bacterial species per taxonomic level, where the models achieved 0.662 and 0.867 Matthews correlation coefficients at the species and order levels, respectively. Our results suggest that despite the diverse nature and genetic plasticity of plasmids, our random forest model can accurately distinguish between plasmid hosts. This tool can be used online through Center for Genomic Epidemiology (https://cge.cbs.dtu.dk/services/PlasmidHostFinder/).

Importance

Antimicrobial resistance is a global health threat to humans and animals causing high mortality and morbidity, and effectively ending decades of success in fighting against bacterial infections. Plasmids confer extra genetic capabilities to the host organisms through accessory genes, which can encode antimicrobial resistance and virulence factors. In addition to lateral inheritance, plasmids can be transferred horizontally between bacterial taxa. Therefore, detecting the host range of plasmids is crucial for understanding and predicting the dissemination trajectories of extrachromosomal genes and bacterial evolution, as well as for taking effective counter measures against antimicrobial resistance.
Pharmacogenomic study of heart failure and candesartan response from the CHARM programme
Authors: Dubé Marie-Pierre , Chazara Olympe , Lemaçon Audrey , Asselin Géraldine , Provost Sylvie , Barhdadi Amina , Perreault Louis-Philippe Lemieux , Mongrain Ian , Wang Quanli , Carss Keren , Paul Dirk S , Cunningham Jonathan W , Rouleau Jean , Solomon Scott D , McMurray John J V , Yusuf Salim , Granger Chris B , Haefliger Carolina , de Denus Simon , Tardif Jean-Claude
Published: September 2021

Aims

The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme consisted of three parallel, randomised, double-blind clinical trials comparing candesartan with placebo in patients with heart failure (HF) categorised according to left ventricular ejection fraction and tolerability to an ACE inhibitor. We conducted a pharmacogenomic study of the CHARM studies to identify genetic predictors of heart failure progression and the efficacy and safety of treatment with candesartan.

Methods

We performed genome-wide association studies (GWAS) with the composite endpoint of cardiovascular death or hospitalisation for heart failure in 2727 patients from CHARM-Overall and stratified by CHARM study according to preserved and reduced ejection fraction. The safety endpoints were hyperkalaemia, renal dysfunction, hypotension, and change in systolic blood pressure. We also conducted a genome-wide gene-level collapsing analysis from whole-exome sequencing data with the composite cardiovascular endpoint.

Results

We found the genetic variant rs66886237 at 8p21.3 near the gene GFRA2 to be associated with the composite cardiovascular endpoint in 1029 HF patients with preserved ejection fraction from the CHARM-Preserved study [hazard ratio (HR): 1.91, 95% confidence interval (CI): 1.55-2.35; P=1.7×10-9], but not in patients with reduced ejection fraction. None of the GWAS for candesartan safety or efficacy passed the significance threshold.

Conclusions

We have identified a candidate genetic variant potentially predictive of the progression of heart failure in patients with preserved ejection fraction. The findings require further replication and we cannot exclude the possibility that the results may be chance findings.
Precision Diagnostic Approach to Predict 5-Year Risk for Microvascular Complications in Type 1 Diabetes
Authors: Al-Sari Naba , Kutuzova Svetlana , Suvitaival Tommi , Henriksen Peter , Pociot Flemming , Rossing Peter , McCloskey Douglas , Legido-Quigley Cristina
Published: September 2021

OBJECTIVE: Our aim was to apply state-of-the-art machine learning algorithms to predict the risk of future progression to diabetes complications, including diabetic kidney disease (≥30% decline in eGFR) and diabetic retinopathy (mild, moderate or severe).

RESEARCH DESIGN AND METHODS: Using data in a cohort of 537 adults with type 1 diabetes we predicted diabetes complications emerging during a median follow-up of 5.4 years. Prediction models were computed first with clinical risk factors at baseline (17 measures) and then with clinical risk factors and blood-derived metabolomics and lipidomics data (965 molecular features) at baseline. Participants were first classified into two groups: type 1 diabetes stable (n=195) or type 1 diabetes with progression to diabetes complications (n=190). Furthermore, progression of diabetic kidney disease (≥30% decline in eGFR; n=79) and diabetic retinopathy (mild, moderate or severe; n=111) were predicted in two complication-specific models. Models were compared by 5-fold cross-validated area under the receiver operating characteristic (AUROC) curves. The Shapley additive explanations algorithm was used for feature selection and for interpreting the models. Accuracy, precision, recall, and F-score were used to evaluate clinical utility.

RESULTS: During a median follow-up of 5.4 years, 79 (21 %) of the participants (mean+-SD: age 54.8 +- 13.7 years) progressed in diabetic kidney disease and 111 (29 %) of the participants progressed to diabetic retinopathy. The predictive models for diabetic kidney disease progression were highly accurate with clinical risk factors: the accuracy of 0.95 and AUROC of 0.92 (95% CI 0.857;0.995) was achieved, further improved to the accuracy of 0.98 and AUROC of 0.99 (95% CI 0.876;0.997) when omics-based predictors were included. The predictive panel composition was: albuminuria, retinopathy, estimated glomerular filtration rate, hemoglobin A1c, and six metabolites (five identified as ribitol, ribonic acid, myo-inositol, 2,4- and 3,4-dihydroxybutanoic acids).
Models for diabetic retinopathy progression were less predictive with clinical risk predictors at, AUROC of 0.81 (95% CI 0.754;0.958) and with omics included at AUROC of 0.87 (95% CI 0.781;0.996) curve. The final retinopathy-panel included: hemoglobin A1c, albuminuria, mild degree of retinopathy, and seven metabolites, including one ceramide and the 3,4-dihydroxybutanoic acid).

CONCLUSIONS: Here we demonstrate the application of machine learning to effectively predict five-year progression of complications, in particular diabetic kidney disease, using a panel of known clinical risk factors in combination with blood small molecules. Further replication of this machine learning tool in a real-world context or a clinical trial will facilitate its implementation in the clinic.
Transmission clusters, predominantly associated with men who have sex with men, play a main role in the propagation of HIV-1 in Northern Spain (2013-2018)
Authors: Gil Horacio , Delgado Elena , Benito Sonia , Georgalis Leonidas , Montero Vanessa , Sánchez Mónica , Cañada-García Javier E. , García-Bodas Elena , Díaz Asunción , Thomson Michael M. ,   the Spanish Group for the Study of New HIV Diagnoses
Published: September 2021

Viruses of HIV-1-infected individuals whose transmission is related group phylogenetically in transmission clusters (TCs). The study of the phylogenetic relations of these viruses and the factors associated with these individuals is essential to analyze the HIV-1 epidemic. In this study, we examine the role of TCs in the epidemiology of HIV-1 infection in Galicia and the Basque County, two regions of Northern Spain. A total of 1158 newly HIV-1-diagnosed patients (NDs) from both regions diagnosed in 2013-2018 were included in the study. Partial HIV-1 pol sequences were analyzed phylogenetically by approximately-maximum-likelihood with FastTree 2. In this analysis, 10,687 additional sequences from samples from HIV-1-infected individuals collected in Spain in 1999-2019 were also included to assign and determine the TCs’ sizes. TCs were defined as those which included viruses from ≥4 individuals, at least 50% of them Spaniards, and with ≥0.95 Shimodaira-Hasegawa-like node support in the phylogenetic tree. Factors associated to TCs were evaluated using odds ratios (OR) and their 95% confidence intervals (CI). Fifty one percent of NDs grouped in 162 TCs. Male patients (OR: 2.6; 95% CI: 1.5-4.7) and men having sex with men (MSM) (OR: 2.1; 95% CI: 1.4-3.2) had higher odds of belonging to a TC compared to female and heterosexual patients, respectively. Individuals from Latin America (OR: 0.3; 95% CI: 0.2-0.4), North Africa (OR: 0.4; 95% CI: 0.2-1.0), and especially Sub-Saharan Africa (OR: 0.02; 95% CI: 0.003-0.2) were inversely associated to belonging to TCs compared to native Spaniards. Differences in distribution and sizes of local TCs were observed in both regions reflecting a different epidemic pattern. Our results show that TCs play an important role in the spread of HIV-1 infection in the two Spanish regions studied, where transmission between MSM is predominant. The majority of migrants were infected with viruses not belonging to TCs that expand in Spain. Molecular epidemiology is essential to identify local peculiarities of HIV-1 propagation. The early detection of TCs and prevention of their expansion, implementing effective control measures, could reduce HIV-1 infections.
Contribution of Schools to Covid-19 Pandemic: Evidence from Czechia
Authors: Brom Cyril , Drbohlav Jakub , Šmíd Martin , Zajíček Milan
Published: September 2021

Purpose

It is unclear how much opening of schools during Covid-19 pandemic contributes to new SARS-CoV-2 infections among children. We investigated the impact of school opening with various mitigation measures (masks, rotations, mass testing) on growth rate of new cases in child cohorts ranging from kindergartens to upper secondary in Czechia, a country heavily hit by Covid-19, since April 2020 to June 2021.

Methods

Our primary method is comparison of the reported infections in age cohorts corresponding to school grades undergoing different regimes. When there is no opportunity for such a comparison, we estimate corresponding coefficients from a regression model. In both the cases, we assume that district-level infections in particular cohorts depend on the school attendance and the external environment in dependence on the current overall risk contact reduction.

Results

The estimates of in-cohort growth rates were significantly higher for normally opened schools compared to closed schools. When prevalence is comparable in the cohorts and general population, and no further measures are applied, the in-cohort growth reduction for closed kindergartens is 29% (SE=11%); primary: 19% (7%); lower secondary: 39% (6%); upper secondary: 47% (6%). For secondary education, mitigation measures reduce school-related growth 2-6 times.

Conclusion

Considering more infectious SARS-CoV-2 variants and the ‘long covid’ risk, mitigation measures in schools, especially in secondary levels, should be implemented for the next school year. Some infections, however, are inevitable, even in kindergartens (where mitigation measures are difficult to implement) and primary schools (where they may not work due to low adherence).
Reduced antibody activity against SARS-CoV-2 B.1.617.2 Delta virus in serum of mRNA-vaccinated patients receiving TNF-α inhibitors
Authors: Chen Rita E. , Gorman Matthew J. , Zhu Daniel Y. , Carreño Juan Manuel , Yuan Dansu , VanBlargan Laura A. , Burdess Samantha , Lauffenburger Douglas A. , Kim Wooseob , Turner Jackson S. , Droit Lindsay , Handley Scott A. , Chahin Salim , Deepak Parakkal , O’Halloran Jane A. , Paley Michael , Presti Rachel M. , Wu Gregory F. , Krammer Florian , Alter Galit , Ellebedy Ali H. , Kim Alfred H. J. , Diamond Michael S.
Published: September 2021

Although vaccines effectively prevent COVID-19 in healthy individuals, they appear less immunogenic in individuals with chronic inflammatory diseases (CID) and/or under chronic immunosuppression, and there is uncertainty of their activity against emerging variants of concern in this population. Here, we assessed a cohort of 74 CID patients treated as monotherapy with chronic immunosuppressive drugs for functional antibody responses in serum against historical and variant SARS-CoV-2 viruses after immunization with Pfizer mRNA BNT162b2 vaccine. Longitudinal analysis showed the greatest reductions in neutralizing antibodies and Fc effector function capacity in individuals treated with TNF-α inhibitors, and this pattern appeared worse against the B.1.617.2 Delta virus. Within five months of vaccination, serum neutralizing titers of the majority of CID patients fell below the presumed threshold correlate for antibody-mediated protection. Thus, further vaccine boosting or administration of long-acting prophylaxis (e.g., monoclonal antibodies) likely will be required to prevent SARS-CoV-2 infection in this susceptible population.
A Multidisciplinary Prematurity Research Cohort Study
Authors: Stout Molly J. , Chubiz Jessica , Raghuraman Nandini , Zhao Peinan , Tuuli Methodius G. , Wang Lihong V. , Cahill Alison G. , Cuculich Phillip S. , Wang Yong , Jungheim Emily S. , Herzog Erik D. , Fay Justin , Schwartz Alan L. , Macones George A. , England Sarah K.
Published: September 2021

Background

Worldwide, 10% of babies are born preterm, defined as a live birth before 37 weeks of gestation. Preterm birth is the leading cause of neonatal death, and survivors face lifelong risks of adverse outcomes. New approaches with large sample sizes are needed to identify strategies to predict and prevent preterm birth. The primary aims of the Washington University Prematurity Research Cohort Study were to conduct three prospective projects addressing possible causes of preterm birth and provide data and samples for future research.

Study Design

Pregnant patients were recruited into the cohort between January 2017 and January 2020. Consenting patients were enrolled into the study before 20 weeks’ gestation and followed through delivery. Participants completed demographic and lifestyle surveys; provided maternal blood, placenta samples, and cord blood; and participated in up to three projects focused on underlying physiology of preterm birth: cervical imaging (Project 1), circadian rhythms (Project 2), and uterine magnetic resonance imaging and electromyometrial imaging (Project 3).

Results

A total of 1260 participants were enrolled and delivered during the study period. Of the participants, 706 (56%) were Black/African American, 494 (39%) were nulliparous, and 185 (15%) had a previous preterm birth. Of the 1260 participants, 1220 (97%) delivered a live infant. Of the 1220 with a live birth, 163 (14.1%) had preterm birth, of which 74 (6.1%) were spontaneous preterm birth. Of the 1220 participants with a live birth, 841 participated in cervical imaging, 1047 contributed data and/or samples on circadian rhythms, and 39 underwent uterine magnetic resonance imaging. Of the 39, 25 underwent electromyometrial imaging.

Conclusion

We demonstrate feasibility of recruiting and retaining a diverse cohort in a complex prospective, longitudinal study throughout pregnancy. The extensive clinical, imaging, survey, and biologic data obtained will be used to explore cervical, uterine, and endocrine physiology of preterm birth and can be used to develop novel approaches to predict and prevent preterm birth.
HIV-specific CD8 T cells from elite controllers have an epigenetic imprint that preserves effector functions
Authors: Frias Adolfo B. , Rutishauser Rachel L. , Sharma Ashish A. , Mi Tian , Abdelsamed Hossam , Zebley Caitlin , Constantz Christian M. , Stone Mars , Busch Michael P. , Deeks Steven G. , Sékaly Rafick-Pierre , Youngblood Ben
Published: September 2021

Several lines of evidence support a central role for CD8 T cells as key determinants in the control of HIV, particularly in rare “elite controllers” who control the virus to undetectable levels in the blood in the absence of antiretroviral therapy (ART). While HIV-specific CD8 T cells isolated from elite controllers have enhanced antiviral cytokine production and proliferative capacity in response to antigen stimulation when compared to cells isolated from viremic or even aviremic ART-suppressed non-controllers, the cell-intrinsic mechanisms underlying the enhanced T cell memory-like function of HIV-specific CD8 T cells in elite controllers remain largely undefined. To identify the transcriptional and epigenetic pathways that regulate functional capacity in HIV-specific CD8 T cells in elite controllers, we performed genome-wide transcriptional and DNA methylation analysis of MHC Class I multimer+ CD8 T cells sorted from aviremic elite controllers compared to aviremic non-controllers on suppressive ART. Co-omics analysis revealed enrichment for gene signatures that support a multipotent differentiation state, cell survival, and a long-lived effector cell fate in HIV-specific CD8 T cells from elite controllers. Specifically, we observed DNA methylation programs at the transcription factor binding sites of the stem-associated factors TCF-1 and LEF1 that delineate HIV-specific CD8 T cells from elite controllers versus ART-treated individuals. HIV-specific CD8 T cells in elite controllers also maintain T cell receptor and IL-12/STAT4 pathway signaling and have suppressed pro-apoptotic TNFα pathway signaling. These findings show that HIV-specific CD8 T cells from elite controllers have enhanced expression and DNA methylation programs that maintain developmental potential and in turn promote long-term survival, proliferative potential, and effector capacity. These data also provide new insights into the relationship between stem-associated transcription factors and stable epigenetic restriction of T cell developmental capacity.