bluuebunny/crossref_metadata_2025 huggingface dataset:
Social relationships and depression during the COVID-19 lockdown: longitudinal analysis of the COVID-19 social study
Authors: Sommerlad Andrew , Marston Louise , Huntley Jonathan , Livingston Gill , Lewis Gemma , Steptoe Andrew , Fancourt Daisy
Published: December 2020

Background

The COVID-19 pandemic led to social and physical distancing measures that reduced social contact and support. We explored whether people with more frequent and supportive social contact had fewer depressive symptoms during the UK Spring 2020 ‘lockdown’, whether this applied to face-to-face and remote electronic contact, and whether people with higher empathy levels, or more frequent pre-COVID social contact with others were more protected.

Methods

UK dwelling participants aged ≥18 in the internet-based longitudinal COVID-19 Social Study completed up to 22 weekly questionnaires about frequency of face-to-face and phone/video social contact, perceived social support, and depressive symptoms assessed with the patient health questionnaire (PHQ-9). Mixed linear models examined associations between social contact and support, and depressive symptoms. We examined for interaction by empathic concern and perspective taking and pre-COVID social contact frequency.

Results

In 71,117 people with mean age 49 years (standard deviation 15) we found that daily face-to-face or phone/video contact was associated with lower PHQ-9 scores (mean difference 0.258 (95% confidence interval 0.225, 0.290) and 0.117 (0.080, 0.154) respectively) compared to having no contact. Those with high social support scored 1.836 (1.801, 1.871) PHQ-9 points lower than those with low support. The odds ratio for depression for those with daily face-to-face social contact compared to no face-to-face contact was 0.712 (0.678, 0.747). Daily compared to no phone/video contact was associated with odds ratio for depression 0.825 (0.779, 0.873). And reporting high, compared to low, social support was associated with 0.145 (95%CI 0.138, 0.152) odds ratio for depression. The negative association between social relationships and depressive symptoms was stronger for those with high empathic concern, perspective taking and usual sociability.

Conclusions

Those who had more face-to-face contact during lockdown had fewer depressive symptoms. Phone or video communication were beneficial but less so. People who were usually more sociable or had higher empathy were more likely to have depressive symptoms during enforced reduced social contact. Results have implications both for our management of COVID-19 and potential future pandemics, and for our understanding of the relationship between social factors and mental health.
A Bayesian Susceptible-Infectious-Hospitalized-Ventilated-Recovered Model to Predict Demand for COVID-19 Inpatient Care in a Large Healthcare System
Authors: Self Stella Coker Watson , Huang Rongjie , Amin Shrujan , Ewing Joseph , Rudisill Caroline , McLain Alexander C.
Published: December 2020

The COVID-19 pandemic strained healthcare systems in many parts of the United States. During the early months of the pandemic, there was substantial uncertainty about whether the large number of COVID-19 patients requiring hospitalization would exceed healthcare system capacity. This uncertainty created an urgent need for accurate predictions about the number of COVID-19 patients requiring inpatient and ventilator care at the local level. In this work, we develop a Bayesian Susceptible-Infectious-Hospitalized-Ventilated-Recovered (SIHVR) model to predict the burden of COVID-19 at the healthcare system level. The Bayesian SIHVR model provides daily estimates of the number of new COVID-19 patients admitted to inpatient care, the total number of non-ventilated COVID-19 inpatients, and the total number of ventilated COVID-19 patients at the healthcare system level. The model also incorporates county-level data on the number of reported COVID-19 cases, and county-level social distancing metrics, making it locally customizable. The uncertainty in model predictions is quantified with 95% credible intervals. The Bayesian SIHVR model is validated with an extensive simulation study, and then applied to data from two regional healthcare systems in South Carolina. This model can be adapted for other healthcare systems to estimate local resource needs.
How effective are face coverings in reducing transmission of COVID-19?
Authors: Robinson Joshua F. , de Anda Ioatzin Rios , Moore Fergus J. , Gregson Florence K. A. , Reid Jonathan P. , Husain Lewis , Sear Richard P. , Royall C. Patrick
Published: December 2020

In the COVID–19 pandemic, among the more controversial issues is the use of face coverings. To address this we show that the underlying physics ensures particles with diameters ≳1 µm are efficiently filtered out by a simple cotton or surgical mask. For particles in the submicron range the efficiency depends on the material properties of the masks, though generally the filtration efficiency in this regime varies between 30 to 60 % and multi-layered cotton masks are expected to be comparable to surgical masks.

Respiratory droplets are conventionally divided into coarsedroplets(≳5–10 µm) responsible fordroplet transmissionandaerosols(≳ 5–10 µm) responsible forairborne transmission. Masks are thus expected to be highly effective at preventing droplet transmission, with their effectiveness limited only by the mask fit, compliance and appropriate usage. By contrast, knowledge of the size distribution of bioaerosols and the likelihood that they contain virus is essential to understanding their effectiveness in preventing airborne transmission. We argue from literature data on SARS-CoV-2 viral loads that the finest aerosols (≳ 1 µm) are unlikely to contain even a single virion in the majority of cases; we thus expect masks to be effective at reducing the risk of airborne transmission in most settings.
Diagnosis of SARS-CoV-2 infections in times of material shortage
Authors: Sandri Thaisa Lucas , Inoue Juliana , Geiger Johanna , Griesbaum Johanna-Marie , Heizel Constanze , Burnet Michael , Fendel Rolf , Kremsner Peter G. , Held Jana , Kreidenweiss Andrea
Published: December 2020

The pandemic caused by SARS-CoV-2 resulted in increasing demands for diagnostic tests, leading to a shortage of recommended testing materials and reagents. This study reports on the performance of self-sampled alternative swabbing material (ordinary Q-tips tested against flocked swab and rayon swab), of reagents for classical RNA extraction (phenol/guanidine-based protocol against a commercial kit), and of intercalating dye-based one-step quantitative reverse transcription real-time PCRs (RT-qPCR) compared against the gold standard hydrolysis probe-based assays for SARS-CoV-2 detection. The study found sampling with Q-tips, RNA extraction with classical protocol and intercalating dye-based RT-qPCR as a reliable and comparably sensitive strategy for detection of SARS-CoV-2 - particularly valuable in the current period with a resurgent and dramatic increase in SARS-CoV-2 infections and growing shortage of diagnostic materials as well for regions limited in resources.
The COVID-19 herd immunity threshold is not low: A re-analysis of European data from spring of 2020
Authors: Fox Spencer J. , Potu Pratyush , Lachmann Michael , Srinivasan Ravi , Meyers Lauren Ancel
Published: December 2020

The recent publication of the Great Barrington Declaration (GBD), which calls for relaxing all public health interventions on young, healthy individuals, has brought the question of herd immunity to the forefront of COVID-19 policy discussions, and is partially based on unpublished research that suggests low herd immunity thresholds (HITs) of 10-20%. We re-evaluate these findings and correct a flawed assumption leading to COVID-19 HIT estimates of 60-80%. If policymakers were to adopt a herd immunity strategy, in which the virus is allowed to spread relatively unimpeded, we project that cumulative COVID-19 deaths would be five times higher than the initial estimates suggest. Our re-estimates of the COVID-19 HIT corroborate strong signals in the data and compelling arguments that most of the globe remains far from herd immunity, and suggest that abandoning community mitigation efforts would jeopardize the welfare of communities and integrity of healthcare systems.
Estimating population size when individuals are asynchronous: a model illustrated with northern elephant seal breeding colonies
Authors: Condit Richard , Allen Sarah G. , Costa Daniel P. , Codde Sarah , Goley P. Dawn , Le Boeuf Burney J. , Lowry Mark S. , Morris Patricia
Published: December 2020

Our aim was to develop a method for estimating the number of animals using a single site in an asynchronous species, meaning that not all animals are present at once so that no one count captures the entire population. This is a common problem in seasonal breeders, and in northern elephant seals, we have a model for quantifying asynchrony at the Año Nuevo colony. Here we test the model at several additional colonies having many years of observations and demonstrate how it can account for animals not present on any one day. This leads to correction factors that yield total population from any single count throughout a season. At seven colonies in California for which we had many years of counts of northern elephant seals, we found that female arrival date varied < 2 days between years within sites and by < 5 days between sites. As a result, the correction factor for any one day was consistent, and at each colony, multiplying a female count between 26 and 30 Jan by 1.15 yielded an estimate of total population size that minimized error. This provides a method for estimating the female population size at colonies not yet studied. Our method can produce population estimates with minimal expenditure of time and resources and will be applicable to many seasonal species with asynchronous breeding phenology, particularly colonial birds and other pinnipeds. In elephant seals, it will facilitate monitoring the population over its entire range.
PISCES: a package for rapid quantitation and quality control of large scale mRNA-seq datasets
Authors: Shirley Matthew D. , Radhakrishna Viveksagar K. , Golji Javad , Korn Joshua M.
Published: December 2020

PISCES eases processing of large mRNA-seq experiments by encouraging capture of metadata using simple textual file formats, processing samples on either a single machine or in parallel on a high performance computing cluster (HPC), validating sample identity using genetic fingerprinting, and summarizing all outputs in analysis-ready data matrices. PISCES consists of two modules: 1) compute cluster-aware analysis of individual mRNA-seq libraries including species detection, SNP genotyping, library geometry detection, and quantitation using salmon, and 2) gene-level transcript aggregation, transcriptional and read-based QC, TMM normalization and differential expression analysis of multiple libraries to produce data ready for visualization and further analysis.

PISCES is implemented as a python3 package and is bundled with all necessary dependencies to enable reproducible analysis and easy deployment. JSON configuration files are used to build and identify transcriptome indices, and CSV files are used to supply sample metadata and to define comparison groups for differential expression analysis using DEseq2. PISCES builds on many existing open-source tools, and releases of PISCES are available onGitHubor the python package index (PyPI).
Neuroprotective mechanisms of red clover and soy isoflavones in Parkinson’s disease models
Authors: de Rus Jacquet Aurélie , Ambaw Abeje , Tambe Mitali Arun , Ma Sin Ying , Timmers Michael , Grace Mary H. , Wu Qing-Li , Simon James E. , McCabe George P. , Lila Mary Ann , Shi Riyi , Rochet Jean-Christophe
Published: December 2020

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by nigrostriatal degeneration and the spreading of aggregated forms of the presynaptic protein α-synuclein (aSyn) throughout the brain. PD patients are currently only treated with symptomatic therapies, and strategies to slow or stop the progressive neurodegeneration underlying the disease’s motor and cognitive symptoms are greatly needed. The time between the first neurobiochemical alterations and the initial presentation of symptoms is thought to span several years, and early neuroprotective dietary interventions could delay the disease onset or slow PD progression. In this study, we characterized the neuroprotective effects of isoflavones, a class of dietary polyphenols found in soy products and in the medicinal plant red clover (Trifolium pratense). We found that isoflavone-rich extracts and individual isoflavones rescued the loss of dopaminergic neurons and the shortening of neurites in primary mesencephalic cultures exposed to two PD-related insults, the environmental toxin rotenone and an adenovirus encoding the A53T aSyn mutant. The extracts and individual isoflavones also activated the Nrf2-mediated antioxidant response in astrocytes via a mechanism involving inhibition of the ubiquitin-proteasome system, and they alleviated deficits in mitochondrial respiration. Furthermore, an isoflavone-enriched soy extract reduced motor dysfunction exhibited by rats lesioned with the PD-related neurotoxin 6-OHDA. These findings suggest that plant-derived isoflavones could serve as dietary supplements to delay PD onset in at-risk individuals and mitigate neurodegeneration in the brains of patients.

Graphical Abstract

The isoflavone-rich extracts red clover and soy and the individual isoflavones daidzein and equol protect neuronal cultures against environmental and genetic triggers of Parkinson’s disease, and rescue motor deficits in rats exposed to the neurotoxin 6-OHDA.
Fluorescent protein expression as a proxy of bacterial fitness in a high throughput assay
Authors: Schlechter Rudolf O , Kear Evan J , Remus Daniela M , Remus-Emsermann Mitja NP
Published: December 2020

Bacterial growth is classically assessed by measuring the increase in optical density of pure cultures in shaken liquid media. Measuring growth using optical density has severe limitations when studying multistrain interactions as it is not possible to measure the growth of individual strains within mixed cultures. Here we demonstrated that constitutively expressed fluorescent proteins can be used to track the growth of individual strains in different liquid media. Fluorescence measurements were highly correlated with optical density measurements and cell counts. This allowed us to assess bacterial growth not only in pure cultures, but also in mixed bacterial cultures and determine the impact of competitors on a focal strain, thereby assessing relative fitness. Furthermore, we were able to track the growth of two different strains simultaneously by using fluorescent proteins with differential excitation and emission wavelengths. Bacterial densities measured by fluorescence yielded more consistent data between technical replicates than optical density measurements. Our setup employs fluorescent microplate readers that allow for high throughput and replication.

Importance

We expand on an important limitation of the concept of measuring bacterial growth which is classically limited to one strain at a time. By adopting this approach, it is possible to measure growth of several bacterial strains simultaneously in high temporal resolution and in a high throughput manner. This is important to investigate bacterial interactions such as competition and facilitation.
A multi-omics dataset for the analysis of Frontotemporal Dementia genetic subtypes
Authors: Menden Kevin , Francescatto Margherita , Nyima Tenzin , Blauwendraat Cornelis , Dhingra Ashutosh , Castillo-Lizardo Melissa , Fernandes Noémia , Kaurani Lalit , Kronenberg-Versteeg Deborah , Atasu Burcu , Sadikoglou Eldem , Borroni Barbara , Rodriguez-Nieto Salvador , Simon-Sanchez Javier , Fischer Andre , Craig David Wesley , Neumann Manuela , Bonn Stefan , Rizzu Patrizia , Heutink Peter
Published: December 2020

Understanding the molecular mechanisms underlying frontotemporal dementia (FTD) is essential for the development of successful therapies. Systematic studies on human post-mortem brain tissue of patients with genetic subtypes of FTD are currently lacking. The Risk and Modyfing Factors of Frontotemporal Dementia (RiMod-FTD) consortium therefore has generated a multi-omics dataset for genetic subtypes of FTD to identify common and distinct molecular mechanisms disturbed in disease. Here, we present multi-omics datasets generated from the frontal lobe of post-mortem human brain tissue from patients with mutations in MAPT, GRN and C9orf72 and healthy controls. This data resource consists of four datasets generated with different technologies to capture the transcriptome by RNA-seq, and small RNA-seq, and supplemented this date with CAGE-seq, and methylation profiling. We show concrete examples on how to use the resulting data and confirm current knowledge about FTD and identify new processes for further investigation. This extensive multi-omics dataset holds great value to reveal new research avenues for this devastating disease.
Prediction of Michaelis constants from structural features using deep learning
Authors: Kroll Alexander , Heckmann David , Lercher Martin J.
Published: December 2020

The Michaelis constantKMdescribes the affinity of an enzyme for a specific substrate, and is a central parameter in studies of enzyme kinetics and cellular physiology. As measurements ofKMare often difficult and time-consuming, experimental estimates exist for only a minority of enzyme-substrate combinations even in model organisms. Here, we build and train an organism-independent model that successfully predictsKMvalues for natural enzyme-substrate combinations using machine and deep learning methods. Predictions are based on a task-specific molecular fingerprint of the substrate, generated using a graph neural network, and the domain structure of the enzyme. Model predictions can be used to estimate enzyme efficiencies, to relate metabolite concentrations to cellular physiology, and to fill gaps in the parameterization of kinetic models of cellular metabolism.
HLA-E restricted, HIV-1 suppressing, Gag specific CD8+ T cells offer universal vaccine opportunities
Authors: Yang Hongbing , Rei Margarida , Brackenridge Simon , Brenna Elena , Sun Hong , Abdulhaqq Shaheed , Liu Michael K P , Ma Weiwei , Kurupati Prathiba , Xu Xiaoning , Cerundolo Vincenzo , Jenkins Edward , Davis Simon J. , Sacha Jonah B. , Früh Klaus , Picker Louis J. , Borrow Persephone , Gillespie Geraldine , McMichael Andrew J.
Published: December 2020

Human leukocyte antigen-E (HLA-E) normally presents a HLA class Ia signal peptide to the NKG2A/C-CD94 regulatory receptors on natural killer (NK) cells and T cell subsets. Rhesus macaques immunized with a cytomegalovirus vectored simian immunodeficiency virus (SIV) vaccine, generated Mamu-E (HLA-E homolog) restricted T cell responses that mediated post-challenge SIV replication arrest in >50% of animals. However, human immunodeficiency virus type 1 (HIV-1) specific HLA-E restricted T cells have not been observed in HIV-1-infected individuals. Here we primed HLA-E restricted HIV-1 specific CD8+ T cellsin vitro.These T cell clones, and allogeneic CD8+ T cells transduced with their T cell receptors, suppressed HIV-1 replication in CD4+ T cellsin vitro. Vaccine induction of efficacious HLA-E restricted HIV-1 specific T cells should therefore be possible.

One Sentence Summary

CD8+T cells that recognize a Gag peptide presented by HLA-E suppress HIV-1 replicationin vitro.
Strong selective environments determine evolutionary outcome in time-dependent fitness seascapes
Authors: Cairns Johannes , Borse Florian , Mononen Tommi , Hiltunen Teppo , Mustonen Ville
Published: December 2020

The impact of fitness landscape features on evolutionary outcomes has attracted considerable interest in recent decades. However, evolution often occurs under time-dependent selection in so-called fitness seascapes where the landscape is under flux. Fitness seascapes are an inherent feature of natural environments, where the landscape changes owing both to the intrinsic fitness consequences of previous adaptations and extrinsic changes in selected traits caused by new environments. The complexity of such seascapes may curb the predictability of evolution. However, empirical efforts to test this question utilising a comprehensive set of regimes are lacking. Here we employed anin vitromicrobial model system to investigate differences in evolutionary outcomes between time-invariant and -dependent environments, including all possible temporal permutations, with three subinhibitory antimicrobials and a viral parasite (phage) as selective agents. Expectedly, time-invariant environments caused stronger directional selection for resistances compared to time-dependent environments. Intriguingly, however, multidrug resistance outcomes in both cases were largely driven by two strong selective agents (rifampicin and phage) out of four agents in total. These agents either caused cross-resistance or obscured the phenotypic effect of other resistance mutations, modulating the evolutionary outcome overall in time-invariant environments and as a function of exposure epoch in time-dependent environments. This suggests that identifying strong selective agents and their pleiotropic effects is critical for predicting evolution in fitness seascapes, with ramifications for evolutionarily informed strategies to mitigate drug resistance evolution.
Profiling of extracellular small RNAs highlights a strong bias towards non-vesicular secretion
Authors: Sork Helena , Conceicao Mariana , Corso Giulia , Nordin Joel , Lee Yi Xin Fiona , Krjutskov Kaarel , Westholm Jakub Orzechowski , Vader Pieter , Pauwels Marie , Vandenbroucke Roosmarijn , Wood Matthew JA , Andaloussi Samir EL , Mäger Imre
Published: December 2020

Extracellular environment consists of a plethora of different molecules, including extracellular miRNA that can be secreted in association with extracellular vesicles (EVs) or soluble protein complexes (non-EVs). Yet, it is generally accepted that most of the biological activity is attributed to EV-associated miRNAs. The capability of EVs to transport cargoes has attracted much interest towards developing EVs as therapeutic short RNA carriers by using endogenous loading strategies for miRNA enrichment. Here, by overexpressing miRNA and shRNA sequences of interest in source cells and using size exclusion liquid chromatography (SEC) to separate the cellular secretome into EV and non-EV fractions, we saw that strikingly, <2% of all secreted overexpressed miRNA were found in association with EVs. To see whether the prominent non-EV miRNA secretion also holds true at the basal expression level of native miRNA transcripts, both fractions were further analysed by small RNA sequencing. This revealed a global correlation of EV and non-EV miRNA abundance to that of their parent cells and showed an enrichment only for miRNAs with a relatively low cellular expression level. Further quantification showed that similarly to the transient overexpression context, an outstanding 96.2-99.9% of total secreted miRNA at its basal level was secreted to the non-EV fraction. Yet, even though EVs contain only a fraction of secreted miRNAs, these molecules were found stable at 37°C in serum-containing environment, indicating that if sufficient miRNA loading to EVs is achieved, EVs can remain miRNA delivery-competent for a prolonged period of time. This study suggests that the passive endogenous EV loading strategy can be a relatively wasteful way of loading miRNA to EVs and active miRNA loading approaches are needed for developing advanced EV miRNA therapies in the future.
HOCMO: A Tensor-based Higher-Order Correlation Model to Deconvolute Epigenetic Microenvironment in Breast Cancer
Authors: Lu Charles , Sherpa Rintsen , Klindziuk Liubou , Kriel Stefanie , Mollah Shamim
Published: December 2020

An in-depth understanding of epithelial breast cell response to growth-promoting ligands is required to elucidate how signals from the microenvironment affect cell-intrinsic regulatory networks and their resultant cellular phenotypes, such as cell growth, progression, and differentiation. Understanding the cellular response to these signals is particularly important in understanding the mechanisms of breast cancer initiation and progression. There is increasing evidence that aberrant epigenetic marks are present in cells of the breast tumor microenvironment and are known to affect these cellular processes. However, the mechanisms by which epigenetic microenvironment signals influence these cellular phenotypes are complex and currently not well established. To deconvolute the complexity of the epigenetic microenvironment signals in breast cancer, we developed a novel tensor-based correlation method: HOCMO (Higher-Order Correlation Model), applying to proteomics time series data to reveal the four-way regulatory dynamics among signaling proteins, histones, and growth-promoting ligands across multiple time points in the breast epithelial cells. HOCMO reveals two functional modules and the onset of specific protein-histone signatures in response to growth ligands contributing to distinct cellular phenotypes indicative of breast cancer initiation and progression. We evaluate robustness of our tensor model against baseline method TensorLy and achieved slight improvement in terms of reconstruction error and execution time. HOCMO is a data independent self-supervised learning method with superior interpretability that can capture the strength of complex interactions such as inter- and intra-pathway cellular signaling networks in any diseases or biological systems.
Postnatal persistence of sex-dependent renal developmentally programmed structural and molecular changes in nonhuman primates
Authors: Bishop Andrew C. , Spradling-Reeves Kimberly D. , Shade Robert E. , Lange Kenneth J. , Birnbaum Shifra , Favela Kristin , Dick Edward J. , Nijland Mark J. , Li Cun , Nathanielsz Peter W. , Cox Laura A.
Published: December 2020

Background

Poor nutrition during development programs kidney function. No studies on postnatal consequences of decreased perinatal nutrition exist in nonhuman primates (NHP) for translation to human renal disease. Our baboon model of moderate maternal nutrient restriction (MNR) produces intrauterine growth restricted (IUGR) and programs renal fetal phenotype. We hypothesized that the IUGR phenotype persists postnatally, influencing responses to a high-fat, high-carbohydrate, high-salt (HFCS) diet.

Methods

Pregnant baboons ate chow (Control; CON) or 70% of control intake (MNR) from 0.16 gestation through lactation. MNR offspring were IUGR at birth. At weaning, all offspring (CON and IUGR females and males, n=3/group) ate chow. At ~4.5 years of age, blood, urine, and kidney biopsies were collected before and after a 7-week HFCS diet challenge. Kidney function, unbiased kidney gene expression, and untargeted urine metabolomics were evaluated.

Results

IUGR female and male kidney transcriptome and urine metabolome differed from CON at 3.5 years, prior to HFCS. After the challenge, we observed sex-specific and fetal exposure-specific responses in urine creatinine, urine metabolites, and renal signaling pathways.

Conclusions

We previously showed mTOR signaling dysregulation in IUGR fetal kidneys. Before HFCS, gene expression analysis indicated that dysregulation persists postnatally in IUGR females. IUGR male offspring response to HFCS showed uncoordinated signaling pathway responses suggestive of proximal tubule injury. To our knowledge, this is the first study comparing CON and IUGR postnatal juvenile NHP and the impact of fetal and postnatal life caloric mismatch. Perinatal history needs to be taken into account when assessing renal disease risk.
The blast pathogen effector AVR-Pik binds and stabilizes rice heavy metal-associated (HMA) proteins to co-opt their function in immunity
Authors: Oikawa Kaori , Fujisaki Koki , Shimizu Motoki , Takeda Takumi , Nemoto Keiichiro , Saitoh Hiromasa , Hirabuchi Akiko , Hiraka Yukie , Miyaji Naomi , Białas Aleksandra , Langner Thorsten , Kellner Ronny , Bozkurt Tolga O , Cesari Stella , Kroj Thomas , Banfield Mark J , Kamoun Sophien , Terauchi Ryohei
Published: December 2020

Intracellular nucleotide-binding domain and leucine-rich repeat-containing (NLR) receptors play crucial roles in immunity across multiple domains of life. In plants, a subset of NLRs contain noncanonical integrated domains that are thought to have evolved from host targets of pathogen effectors to serve as pathogen baits. However, the functions of host proteins with similarity to NLR integrated domains and the extent to which they are targeted by pathogen effectors remain largely unknown. Here, we show that the blast fungus effector AVR-Pik binds a subset of related rice proteins containing a heavy metal-associated (HMA) domain, one of the domains that has repeatedly integrated into plant NLR immune receptors. We find that AVR-Pik binding stabilizes the rice small HMA (sHMA) proteins OsHIPP19 and OsHIPP20. Knockout ofOsHIPP20causes enhanced disease resistance towards the blast pathogen, indicating thatOsHIPP20is a susceptibility gene (S-gene). We propose that AVR-Pik has evolved to bind HMA domain proteins and co-opt their function to suppress immunity. Yet this binding carries a trade-off, it triggers immunity in plants carrying NLR receptors with integrated HMA domains.

Significance Statement

Rice blast disease, caused by the fungusMagnaporthe oryzae, is one of the most devastating diseases of rice. Therefore, understanding the mechanisms of blast fungus infection and resistance of rice against the disease is important for global food security. In this study, we show that theM. oryzaeeffector protein AVR-PikD binds rice sHMA proteins and stabilizes them, presumably to enhance pathogen infection. We show that loss-of-function mutants in one rice sHMA, OsHIPP20, reduced the level of susceptibility against a compatible isolate ofM. oryzae, suggesting thatM. oryzaerequires host sHMA to facilitate invasion. Remarkably,OsHIPP20knockout rice line showed no growth defect, suggesting editing sHMA genes may present a novel source of resistance against blast disease.
Cumulative impacts across Australia’s Great Barrier Reef: A mechanistic evaluation
Authors: Bozec Yves-Marie , Hock Karlo , Mason Robert A. B. , Baird Mark E. , Castro-Sanguino Carolina , Condie Scott A. , Puotinen Marji , Thompson Angus , Mumby Peter J.
Published: December 2020

Cumulative impacts assessments on marine ecosystems have been hindered by the difficulty of collecting environmental data and identifying drivers of community dynamics beyond local scales. On coral reefs, an additional challenge is to disentangle the relative influence of multiple drivers that operate at different stages of coral ontogeny. We integrated coral life history, population dynamics and spatially-explicit environmental drivers to assess the relative and cumulative impacts of multiple stressors across 2,300 km of the world’s largest coral reef ecosystem, Australia’s Great Barrier Reef (GBR). Using literature data, we characterized relationships between coral life history processes (reproduction, larval dispersal, recruitment, growth and mortality) and environmental variables. We then simulated coral demographics and stressor impacts at the organism (coral colony) level on >3,800 individual reefs linked by larval connectivity, and exposed to temporally- and spatially-realistic regimes of acute (crown-of-thorns starfish outbreaks, cyclones and mass coral bleaching) and chronic (water quality) stressors. Model simulations produced a credible reconstruction of recent (2008–2020) coral trajectories consistent with monitoring observations, while estimating the impacts of each stressor at reef and regional scales. Overall, corals declined by one third across the GBR, from an average ∼29% to ∼19% hard coral cover. By 2020, less than 20% of the GBR had coral cover higher than 30%. Global annual rates of coral mortality were driven by bleaching (48%) ahead of cyclones (41%) and starfish predation (11%). Beyond the reconstructed status and trends, the model enabled the emergence of complex interactions that compound the effects of multiple stressors while promoting a mechanistic understanding of coral cover dynamics. Drivers of coral cover growth were identified; notably, water quality (suspended sediments) was estimated to delay recovery for at least 25% of inshore reefs. Standardized rates of coral loss and recovery allowed the integration of all cumulative impacts to determine the equilibrium cover for each reef. This metric, combined with maps of impacts, recovery potential, water quality thresholds and reef state metrics, facilitates strategic spatial planning and resilience-based management across the GBR.
PPalign: Optimal alignment of Potts models representing proteins with direct coupling information
Authors: Talibart Hugo , Coste François
Published: December 2020

Abstract

Background

To assign structural and functional annotations to the ever increasing amount of sequenced proteins, the main approach relies on sequence-based homology search methods, e.g. BLAST or the current state-of-the-art methods based on profile Hidden Markov Models (pHMM), which rely on significant alignments of query sequences to annotated proteins or protein families. While powerful, these approaches do not take coevolution between residues into account. Taking advantage of recent advances in the field of contact prediction, we propose here to represent proteins by Potts models, which model direct couplings between positions in addition to positional composition, and to compare proteins by aligning these models. Due to non-local dependencies, the problem of aligning Potts models is hard and remains the main computational bottleneck for their use.

Results

We introduce here an Integer Linear Programming formulation of the problem and PPalign, a program based on this formulation, to compute the optimal pairwise alignment of Potts models representing proteins in tractable time. The approach is assessed with respect to a non-redundant set of reference pairwise sequence alignments from SISYPHUS benchmark which have lowest sequence identity (between 3% and 20%) and enable to build reliable Potts models for each sequence to be aligned. This experimentation confirms that Potts models can be aligned in reasonable time (1′37″ in average on these alignments). The contribution of couplings is evaluated in comparison with HHalign and PPalign without couplings. Although Potts models were not fully optimized for alignment purposes and simple gap scores were used, PPalign yields a better meanF1score and finds significantly better alignments than HHalign and PPalign without couplings in some cases.

Conclusions

These results show that pairwise couplings from protein Potts models can be used to improve the alignment of remotely related protein sequences in tractable time. Our experimentation suggests yet that new research on the inference of Potts models is now needed to make them more comparable and suitable for homology search. We think that PPalign’s guaranteed optimality will be a powerful asset to perform unbiased investigations in this direction.
Chemical inhibition of ENL/AF9 YEATS domains in acute leukemia
Authors: Garnar-Wortzel Leopold , Bishop Timothy R. , Kitamura Seiya , Milosevich Natalia , Asiaban Joshua N. , Zhang Xiaoyu , Zheng Qinheng , Chen Emily , Ramos Anissa R. , Ackerman Christopher J. , Hampton Eric N. , Chatterjee Arnab K. , Young Travis S. , Hull Mitchell V. , Sharpless K. Barry , Cravatt Benjamin F. , Wolan Dennis W. , Erb Michael A.
Published: December 2020

Transcriptional co-regulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional co-activator, ENL, as a selective requirement for the survival of acute leukemia and highlighted an essential role for its chromatin reader YEATS domain. Motivated by these discoveries, we executed a screen of nearly 300,000 small molecules and identified an amido-imidazopyridine inhibitor of the ENL YEATS domain (IC50= 7 µM). Leveraging a SuFEx-based high-throughput approach to medicinal chemistry optimization, we discovered SR-0813 (IC50= 25 nM), a potent and selective ENL/AF9 YEATS domain inhibitor that exclusively inhibits the growth of ENL-dependent leukemia cell lines. Armed with this tool and a first-in-class ENL PROTAC, SR-1114, we detailed the response of AML cells to pharmacological ENL disruption for the first time. Most notably, displacement of ENL from chromatin by SR-0813 elicited a strikingly selective suppression of ENL target genes, includingHOXA9/10, MYB, MYCand a number of other leukemia proto-oncogenes. Our study reproduces a number of key observations previously made by CRISPR/Cas9 loss of function and dTAG-mediated degradation, and therefore, both reinforces ENL as an emerging leukemia target and validates SR-0813 as a high-quality chemical probe.
Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension
Authors: Lakk Monika , Hoffmann Grace F. , Gorusupudi Aruna , Enyong Eric , Lin Amy , Bernstein Paul S. , Toft-Bertelsen Trine , MacAulay Nanna , Elliott Michael H. , Križaj David
Published: December 2020

Despite the association of cholesterol with debilitating pressure-related diseases, its role in mechanotransduction is not well understood. We investigated the relationship between mechanical strain, free membrane cholesterol, actin cytoskeleton, and activation of stretch- activated TRPV4 (transient receptor potential vanilloid isoform 4) channel in human trabecular meshwork (TM) cells. Physiological levels of cyclic stretch resulted in time- dependent decreases in membrane cholesterol/phosphatidylcholine ratio and upregulation of stress fibers. Depletion of free membrane cholesterol with m-β-cyclodextrin (MβCD) augmented TRPV4 activation by the agonist GSK1016790A, swelling and strain, with the effects reversed by cholesterol supplementation. MβCD increased membrane expression of TRPV4, caveolin-1 and flotillin. Caveolin-1 antibody partially precipitated a truncated ∼75 kDa variant whereas the majority of TRPV4 did not colocalize or interact with caveolae or lipid rafts, indicating that TRPV4 is mainly localized outside of cholesterol-enrichedmembrane domains. MβCD induced currents in TRPV4-expressingXenopus laevisoocytes. Thus, while the membrane C/P ratio reflects the biomechanical milieu, trabecular transduction of mechanical information is modulated by the membrane cholesterol content. Diet, cholesterol metabolism and mechanical stress might modulate the conventional outflow pathway and intraocular pressure in glaucoma and diabetes.
Scaling effects of temperature on parasitism from individuals to host–parasite systems
Authors: Kirk Devin , O’Connor Mary I. , Mordecai Erin A.
Published: December 2020

Parasitism is expected to change in a warmer future, but whether warming leads to substantial increases in parasitism remains unclear. Understanding how warming effects on parasitism in individual hosts (e.g., parasite load) translate to effects on population-level parasitism (e.g., prevalence, R0) remains a major knowledge gap. We analyzed the temperature dependence of parasitism at both host and population levels in thirteen empirical vector-borne host–parasite systems and found a strong, significant positive correlation between the thermal optima of individual- and population-level parasitism. We also found a significant, positive correlation in eleven environmentally-transmitted parasite systems, though several of these systems exhibited thermal optima >5ºC apart between individual and population levels. Similarly, parasitism thermal optima were close to host performance thermal optima in vector-borne systems but not in environmentally-transmitted systems. We then adapted and simulated simple models for both transmission modes and found a similar pattern to the empirical systems: thermal optima in vector-borne systems were more strongly correlated across scales compared to environmentally-transmitted systems. Generally, our results suggest that information on the temperature-dependence, and specifically the thermal optimum, at either the individual- or population-level should provide a useful—though not quantitatively exact—baseline for predicting temperature dependence at the other level, especially in vector-borne parasite systems. Environmentally-transmitted parasitism may operate by a different set of rules, in which temperature-dependence is decoupled in some systems, requiring the need for trait-based studies of temperature-dependence at individual and population levels.
MTX-COVAB, a human-derived antibody with potent neutralizing activity against SARS-CoV-2 infectionin vitroand in a hamster model of COVID-19
Authors: Schmitt Simone , Weber Marcel , Hillenbrand Matthias , Seidenberg Jemima , Zingg Andreas , Townsend Catherine , Eicher Barbara , Rutkauskaite Justina , Riese Peggy , Guzman Carlos A. , Fischer Karsten , Esslinger Christoph
Published: December 2020

Fast track microfluidic screening of the antibody repertoires of 12 convalescent COVID-19 donors comprising 2.8mio antibodies yielded MTX-COVAB, a human-derived monoclonal antibody with low picomolar neutralization IC50 of SARS-CoV-2. COVAB neutralization potency is on par with the Regeneron cocktail as demonstrated in a comparative neutralization assay. MTX-COVAB shows strong efficacyin vivoand binds to all currently identified clinically relevant variants of SARS-CoV-2. MTX-COVAB completes GMP manufacturing by the end of this year and will be tested in the clinic in March 2021.
Humans optimally anticipate and compensate for an uneven step during walking
Authors: Darici Osman , Kuo Arthur D.
Published: December 2020

The simple task of walking up a sidewalk curb is actually a dynamic prediction task. The curb is a disturbance that causes a loss of momentum, to be anticipated and compensated for. For example, the compensation might regain momentum and ensure undisturbed time of arrival. But without a selection criterion, there are infinite possible strategies. Here we show that humans compensate with an anticipatory pattern of forward speed adjustments, with a criterion of minimizing mechanical energy input. This is predicted by optimal control for a simple model of walking dynamics, with each leg’s push-off work as input. Optimization predicts a tri-phasic trajectory of speed (and thus momentum) adjustments, including an anticipatory, feedforward phase. In experiment, human subjects successfully regain time relative to undisturbed walking, with the predicted tri-phasic trajectory. They also scale the pattern with up- or down-steps, and inversely with average speed, as also predicted by model. Humans can reason about the dynamics of walking to plan anticipatory and economical control, even with a sidewalk curb in the way.
PhenoBR: a model to phenotype body condition dynamics in meat sheep
Authors: Macé Tiphaine , González-García Eliel , Kövér György , Hazard Dominique , Taghipoor Masoomeh
Published: December 2020

In situations of negative energy balance (NEB) due to feed scarcity or high physiological demands, body energy reserves (BR), mainly stored in adipose tissues, become the main sources of energy for ruminants. The capacity to mobilize and restore such BRs in response to different challenges is of major concern in the current context of breeding for resilience. Body condition score (BCS) is a common, practical indicator of BR variations throughout successive productive cycles, and quantitative tools for characterizing such dynamics at the individual level are still lacking. The main objective of this work was to characterize body condition dynamics in terms of BR mobilization and accretion capacities of meat sheep during their productive lifespan through a modelling approach.

The animal model used in this work was the reproductive meat ewe (n= 1478) reared in extensive rangeland. Regular measurements of BCS for each productive cycle were used as the indicator of BR variations. A hybrid mathematical model and a web interface, called PhenoBR, was developed to characterize ewes’ BCS variations through four synthetic and biologically meaningful parameters for each productive cyclei: BR accretion rate, BR mobilization rate, plus the time of onset and the duration of the BR mobilization,and ΔTi, respectively.

The model converged for all the ewes included in the analysis. Estimation of the parameters indicated the inter-individual variability for BR accretion and mobilization rates, and for the length of the mobilization period. Body reserve mobilization rates were closely correlated between productive cycles. Significant correlations between BR mobilization and accretion rates suggest that the two processes are biologically linked. Parameterskpandkbdecreased as parity increased. BR mobilization rate and duration increased as litter size increased, while BR accretion rate decreased.

Individual characterization of animals by these parameters makes it possible to rank them for their efficiency in the use of body reserves when facing NEB challenges. Such parameters could contribute to better management and decision-making by farmers and advisors, e.g. by adapting feeding systems to the individual characteristics of BR dynamics, or by geneticists as criteria to develop future animal breeding programs including BR dynamics for more robust and resilient animals.
Atomic force microscopy reveals the role of vascular smooth muscle cell elasticity in hypertension
Authors: Zhu Yi
Published: December 2020

The vascular smooth muscle cell (VSMC) mechanical properties not only provide intrinsic cellular functions, but also influence many vascular and circulation functions in physiology. In this report, the VSMCs of thoracic aorta from 16 week age Wistar-Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHR) were used as research subjects to reveal hypertension mechanism at a single cell level using atomic force microscopy (AFM). The apparent elastic modulus was significantly increased in VSMCs from SHRs compared to those from WKYs. Treatment with cytochalasin D (CD), ML7, Y27632 and lysophosphatidic acid (LPA) modulated VSMC stiffness of WKYs and SHRs. A spectral analysis approach was applied to further investigate the time-dependent change in VSMC elasticity of WKYs and SHRs. This report demonstrated the efficacy of real-time analysis of VSMC elasticity by AFM nano-indentation, and revealed real-time functional differences in biomechanical characteristics of VSMCs with drug treatments.