bluuebunny/crossref_metadata_2025 huggingface dataset:
Rates of COVID-19-related Outcomes in Cancer compared to non-Cancer Patients
Authors: Sun Lova , Surya Sanjna , Le Anh N. , Desai Heena , Doucette Abigail , Gabriel Peter , Ritchie Marylyn , Rader Daniel , Maillard Ivan , Bange Erin , Huang Alexander , Vonderheide Robert H. , DeMichele Angela , Verma Anurag , Mamtani Ronac , Maxwell Kara N.
Published: August 2020

Cancer patients are a vulnerable population postulated to be at higher risk for severe COVID-19 infection. Increased COVID-19 morbidity and mortality in cancer patients may be attributable to age, comorbidities, smoking, healthcare exposure, and cancer treatments, and partially to the cancer itself. Most studies to date have focused on hospitalized patients with severe COVID-19, thereby limiting the generalizability and interpretability of the association between cancer and COVID-19 severity. We compared outcomes of SARS-CoV-2 infection in 323 patients enrolled prior to the pandemic in a large academic biobank (n=67 cancer patients and n=256 non-cancer patients). After adjusting for demographics, smoking status, and comorbidities, a diagnosis of cancer was independently associated with higher odds of hospitalization (OR 2.16, 95% CI 1.12-4.18) and 30-day mortality (OR 5.67, CI 1.49-21.59). These associations were primarily driven by patients with active cancer. These results emphasize the critical importance of preventing SARS-CoV-2 exposure and mitigating infection in cancer patients.
Depression following traumatic brain injury is characterised by dominant and recurring brain loops in self-referential areas
Authors: Pappas Ioannis , Moreno-López Laura , Carroll Ellen L. , Manktelow Anne , Outtrim Joanne G. , Coles Jonathan P. , Newcombe Virginia F. , Sahakian Barbara J. , Menon David K. , Stamatakis Emmanuel A.
Published: August 2020

Depression is a major albeit neglected complication in patients with traumatic brain injury (TBI). Elucidating its neural correlates remains an important milestone with respect to understanding the disorder and helping with the rehabilitation process. Towards this direction, neuropsychological theories have proposed abnormal brain dynamics as the neural basis of depressive symptomatology. This observational study addressed the question of whether depression in TBI patients is related to abnormal brain dynamics using a sample of 81 TBI patients with depressive symptomatology. To explore brain dynamics we employed the Hidden Markov model that utilises resting-state fMRI data to identify the states that the brain visits sequentially during scanning. Spatial (highest activated regions) and temporal (occupancy, switching rate) characteristics of these states were used to analyse the networks involved and probe differences between depressed and non-depressed TBI patients. We found a significant positive association between depression score and the fractional occupancy and switching rate of two specific states that distinguished between depressed and non-depressed TBI patients. These states spanned default mode, subcortical and cerebellar regions while also forming a temporally coherent “metastate” that the depressed brain would recurrently visit. Depression in TBI patients is characterised by abnormal recruitment and repetitive sequencing between certain neural networks. These results point to the existence of a reinforced, self-referential circuitry that could provide the basis for targeted therapies during the recovery process.
The medical signature of musicians: A Phenome-wide association study using an Electronic Health Record database
Authors: Niarchou Maria , Lin George , Lense Miriam D. , Gordon Reyna , Davis Lea
Published: August 2020

Background

Being a musician is a physically and psychologically demanding undertaking. A limited set of previous studies suggest musicians may be at higher risk for a unique set of medical and mental health problems. To address the limitations of previous studies, we examined trends in the medical care of musicians in Vanderbilt’s Electronic Health Record research database.

Methods

We mined clinical notes for a principled collection of keywords and regular expressions which indicated that the patient was a musician. We identified 9,803 “musicians” that we matched for sex, median age (across the medical record), ethnicity, race, length of record (in days) and number of visits with 49,015 controls. We fitted 1,263 logistic regression models (one for each phenotype classification).

Results

257 medical diagnoses were significantly more prevalent in musicians than controls after strict Bonferroni adjustment for the total number of phenotypes tested (p-value<7.6 × 10−6). Diseases of the larynx and the vocal cords (OR=2.32, p<2.84 × 10−191), and hearing loss (OR=1.36, p=5.98 × 10−97) were among the top associations. Anxiety disorder (OR=1.25, p=7.67 × 10−71), and Major depressive disorder (OR=1.21, p=4.88 × 10−36) were also strongly associated with musician status. However, 15 phenotypes were significantly more prevalent in non-musicians than musicians, including Coronary atherosclerosis (OR=0.91, p=1.77 × 10−10), and Ischemic Heart Disease (OR=0.92, p=1.65 × 10−09).

Conclusions

Although being a musician was related to a large number of occupational health problems, we also identified protective effects of musicianship in which certain diagnoses were less common in musicians than in non-musicians, indicating that active musical engagement could have similar health benefits to athletic engagement.

Key messages

In a sample of 14,379 musician cases and 71,895 matched controls identified in an Electronic Health Record database, we conducted the first and largest study to date to identify the medical diagnoses associated with musician patients in an EHR context.

We replicated previous associations of musician status with medical problems, including respiratory and hearing problems as well as mental health problems.

We identified a number of protective effects by observing diagnoses such as cardiovascular disease, respiratory failure, and renal failure, that were less common in musicians than in controls, in line with literature indicating that active musical engagement has similar health benefits to athletic engagement.
Responsible modelling: Unit testing for infectious disease epidemiology
Authors: Lucas Tim CD , Pollington Timothy M , Davis Emma L , Hollingsworth T Déirdre
Published: August 2020

Infectious disease epidemiology is increasingly reliant on large-scale computation and inference. Models have guided health policy for epidemics including COVID-19 and Ebola and endemic diseases such as malaria and tuberculosis. Yet a single coding bug may bias results, leading to incorrect conclusions and wrong actions that could cause avoidable harm. We are ethically obliged to ensure our code is as free of error as possible. Unit testing is a coding method to avoid such bugs, but unit testing is rarely used in epidemiology. We demonstrate through simple examples how unit testing can handle the particular quirks of infectious disease models.
The Common Interests of Health Protection and the Economy: Evidence from Scenario Calculations of COVID-19 Containment Policies
Authors: Dorn Florian , Khailaie Sahamoddin , Stoeckli Marc , Binder Sebastian C. , Lange Berit , Lautenbacher Stefan , Peichl Andreas , Vanella Patrizio , Wollmershäuser Timo , Fuest Clemens , Meyer-Hermann Michael
Published: August 2020

Several countries use shutdown strategies to contain the spread of the COVID-19 epidemic, at the expense of massive economic costs. While this suggests a conflict between health protection and economic objectives, we examine whether the economically optimal exit strategy can be reconciled with the containment of the epidemic. We use a novel combination of epidemiological and economic simulations for scenario calculations based on empirical evidence from Germany. Our findings suggest that a prudent opening is economically optimal, whereas costs are higher for a more extensive opening process. This rejects the view that there is a conflict with health protection. Instead, it is in the common interest of public health and the economy to relax non-pharmaceutical interventions in a manner that keeps the epidemic under control.
The limits of estimating COVID-19 intervention effects using Bayesian models
Authors: Bryant Patrick , Elofsson Arne
Published: August 2020

To limit the rapid spread of COVID-19, most governments have introduced different non-pharmaceutical interventions, which might have severe costs for society. Therefore, it is crucial to evaluate the most cost-effective interventions, using, for instance, Bayesian modelling. Such modelling efforts have deemed lockdown to account for 81% of the reduction in R​0, contributing to government policies. Here, we show that these conclusions are unsupported and that policies therefore should not be based on these studies.

https://www.eurosurveillance.org/for-authors
Vaccine optimization for COVID-19, who to vaccinate first?
Authors: Matrajt Laura , Eaton Julie , Leung Tiffany , Brown Elizabeth R.
Published: August 2020

A vaccine, when available, will likely become our best tool to control the current COVID-19 pandemic. Even in the most optimistic scenarios, vaccine shortages will likely occur. Using an age-stratified mathematical model, we determined optimal vaccine allocation for four different metrics (deaths, symptomatic infections, and maximum non-ICU and ICU hospitalizations) under a wide variety of assumptions. We find that a vaccine with effectiveness ≥50% would be enough to substantially mitigate the ongoing pandemic provided that a high percentage of the population is optimally vaccinated. When minimizing deaths, we find that for low vaccine effectiveness, it is optimal to allocate vaccine to high-risk (older) age-groups first. In contrast, for higher vaccine effectiveness, there is a switch to allocate vaccine to high-transmission (younger) age-groups first for high vaccination coverage. While there are other societal and ethical considerations, this work can provide an evidence-based rationale for vaccine prioritization.
Probing nanoscale diffusional heterogeneities in cellular membranes through multidimensional single-molecule and super-resolution microscopy
Authors: Yan Rui , Chen Kun , Xu Ke
Published: August 2020

Diffusion properties notably determine the behavior of biomembranes. Here we report the concurrent nanoscale fine-mapping of membrane topography, diffusivity, and packing order in live mammalian cells through a synergy of single-molecule and super-resolution methods. By identifying a bright, lipophilic fluorescence turn-on probe that enables sustained single-molecule imaging of cellular membranes under stroboscopic excitation, we accumulate the positions and transient displacements of >106probe molecules to achieve super-resolution topography and diffusivity mapping. We thus determine a trend that the membrane diffusivity drops with increased lipid packing order when comparing the endoplasmic reticulum (ER) membrane, plasma membrane, and nanodomains induced by cholera toxin B. Utilizing our nanoscale mapping capability, we further unveil reduced diffusivity in the ER membrane at ER-plasma membrane contact sites. By next integrating spectrally resolved single-molecule imaging, we show this localized diffusion slowdown is not due to altered lipid packing order, but may instead be attributed to local protein crowding. Our integrated multidimensional single-molecule approach thus unveils and differentiates between nanoscale diffusional heterogeneities of different origins in live-cell membranes.
Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 main protease by tafenoquinein vitro
Authors: Chen Yeh , Yang Wen-Hao , Huang Li-Min , Wang Yu-Chuan , Yang Chia-Shin , Liu Yi-Liang , Hou Mei-Hui , Tsai Chia-Ling , Chou Yi-Zhen , Huang Bao-Yue , Hung Chian-Fang , Hung Yu-Lin , Chen Jin-Shing , Chiang Yu-Ping , Cho Der-Yang , Jeng Long-Bin , Tsai Chang-Hai , Hung Mien-Chie
Published: August 2020

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the current pandemic, coronavirus disease 2019 (COVID-19), has taken a huge toll on human lives and the global economy. Therefore, effective treatments against this disease are urgently needed. Here, we established a fluorescence resonance energy transfer (FRET)-based high-throughput screening platform to screen compound libraries to identify drugs targeting the SARS-CoV-2 main protease (Mpro), in particular those which are FDA-approved, to be used immediately to treat patients with COVID-19. Mpro has been shown to be one of the most important drug targets among SARS-related coronaviruses as impairment of Mproblocks processing of viral polyproteins which halts viral replication in host cells. Our findings indicate that the anti-malarial drug tafenoquine (TFQ) induces significant conformational change in SARS-CoV-2 Mproand diminishes its protease activity. Specifically, TFQ reduces the α-helical content of Mpro, which converts it into an inactive form. Moreover, TFQ greatly inhibits SARS-CoV-2 infection in cell culture system. Hence, the current study provides a mechanistic insight into the mode of action of TFQ against SARS-CoV-2 Mpro. Moreover, the low clinical toxicity of TFQ and its strong antiviral activity against SARS-CoV-2 should warrant further testing in clinical trials.
De NovoDesigned Peptide and Protein Hairpins Self-assemble into Sheets and Nanoparticles
Authors: Galloway Johanna M. , Bray Harriet E. V. , Shoemark Deborah K. , Hodgson Lorna R. , Coombs Jennifer , Mantell Judith M. , Rose Ruth S. , Ross James F. , Morris Caroline , Harniman Robert L. , Wood Christopher W. , Arthur Christopher , Verkade Paul , Woolfson Derek N.
Published: August 2020

The design and assembly of peptide based materials has advanced considerably, leading to a variety of fibrous, sheet and nanoparticle structures. A remaining challenge is to account for and control different possible supramolecular outcomes accessible to the same or similar peptide building blocks. Here we present ade novopeptide system that forms nanoparticles or sheets depending on the strategic placement of a ‘disulfide pin’ between two elements of secondary structure that drive self-assembly. Specifically, we join homodimerizing and homotrimerizingde novocoiled-coil α-helices with a flexible linker to generate a series of linear peptides. The helices are pinned back-to-back, constraining them as hairpins by a disulfide bond placed either proximal or distal to the linker. Computational modeling and advanced microscopy show that the proximally pinned hairpins self-assemble into nanoparticles, whereas the distally pinned constructs form sheets. These peptides can be made synthetically or recombinantly to allow both chemical modifications and the introduction of whole protein cargoes as required.
Systems Biology behind immunoprotection of both Sheep and Goats after Sungri/96 PPRV vaccination
Authors: Wani Sajad Ahmad , Praharaj Manas Ranjan , Sahu Amit R , Khan Raja Ishaq Nabi , Rajak Kaushal Kishor , Muthuchelvan Dhanavelu , Sahoo Aditya , Mishra Bina , Singh R. K. , Mishra Bishnu Prasad , Gandham Ravi Kumar
Published: August 2020

Immune response is a highly coordinated cascade involving all the subsets of PBMCs. In this study, RNA-Seq analysis of PBMC subsets - CD4+, CD8+, CD14+, CD21+ and CD335+ cells from day 0 and day 5 of Sungri/96 Peste des Petits Ruminants vaccinated sheep and goats was done to delineate the systems biology behind immune - protection of the vaccine in sheep and goats. Assessment of the immune response processes enriched by the differentially expressed genes in all the subsets suggested a strong dysregulation towards development of early inflammatory microenvironment, which is very much required for differentiation of monocytes to macrophages, and for activation and migration of dendritic cells into the draining lymph nodes. The protein - protein interaction networks among the antiviral molecules (IFIT3, ISG15, MX1, MX2, RSAD2, ISG20, IFIT5 and IFIT1) and common DEGs across PBMCs subsets in both the species identified ISG15 to be an ubiquitous hub, that helps in orchestrating antiviral host response against PPRV. IRF7 was found to be the key master regulator activated in most of the subsets in sheep and goats. Most of the pathways were found to be inactivated in B - lymphocytes of both the species indicating that 5 dpv is too early a time point for the B - lymphocytes to react. The cell mediated immune response and humoral immune response pathways were found more enriched in goats than in sheep. Though, animals from both the species survived the challenge, a contrast in pathway activation was observed in CD335+ cells.

Importance

Peste des petits ruminants (PPR) by PPRV is an OIE listed acute, contagious transboundary viral disease of small ruminants. Attenuated Sungri/96 PPRV vaccine used all over India against this PPR, provides long-lasting robust innate and adaptive immune response. The early antiviral response was found mediated through type I interferon independent ISGs expression. However, systems biology behind this immune response is unknown. In this study, in vivo transcriptome profiling of PBMC subsets (CD4+, CD8+, CD14+, CD21+ and CD335+) in vaccinated goats and sheep (at 5 days of post vaccination) was done to understand this systems biology. Though there are a few differences in the systems biology across cells (specially the NK cells) between sheep and goats, the co-ordinated response that is inclusive of all the cell subsets was found to be towards induction of strong innate immune response, which is needed for an appropriate adaptive immune response.
Design, Performance Evaluation and Investigation of the Dynamic Mechanisms of Earthworm-Microorganisms interactions for wastewater treatment through Vermifiltration technology
Authors: Arora Sudipti , Saraswat Sakshi , Mishra Rinki , Rajvanshi Jayana , Sethi Jasmine , Nag Aditi , Saxena Sonika
Published: August 2020

The present study points to the relevance of the earthworms-microorganism’s symbiotic and synergistic interactions that drive the wastewater treatment by identifying the most essential mechanisms underlying the removal of contaminants during vermifiltration technology. Previous studies have showed the presence of earthworms improves treatment performance of vermifilter (VF), but earthworm microbial community dynamics, their structure and functional characteristics in VF were not fully investigated. To investigate the effects of earthworms on the inherent microbial community of the VF, the present study envisages the dynamics of the complex symbiosis of earthworms & microorganisms associated to the treatment mechanisms. In this study, the design, operations and performance evaluation and influent, effluent and filter media layer were investigated for microbial diversity inside the earthworm population, along with the antimicrobial activity, enzymatic activity, and protein profiling assays. The results showed that earthworm gut microbial communities were dominated byGammaproteobacteria, and the percentages arrived to 59–60% of the microbial species detected, while filter media layer showed presence ofFirmicutesandActinobacteria. The protein profiling of the microbiota associated with the VF showed that earthworms feeding and earthworm–microorganism interaction were responsible for enhanced treatment performance. The finding provides an insight into the complex earthworm microbial dynamics and mechanisms for wastewater treatment in VF. Furthermore, earthworm predation strongly regulated microbial biomass while improving microbial activity, and is deciphered as the possible mechanisms behind the vermifiltration technology.
nMAGMA: a network enhanced method for inferring risk genes from GWAS summary statistics and its application to schizophrenia
Authors: Yang Anyi , Chen Jingqi , Zhao Xing-Ming
Published: August 2020

Motivation

Annotating genetic variants from summary statistics of genome-wide association studies (GWAS) is crucial for predicting risk genes of various disorders. The multi-marker analysis of genomic annotation (MAGMA) is one of the most popular tools for this purpose, where MAGMA aggregates signals of single nucleotide polymorphisms (SNPs) to their nearby genes. However, SNPs may also affect genes in a distance, thus missed by MAGMA. Although different upgrades of MAGMA have been proposed to extend gene-wise variant annotations with more information (e.g. Hi-C or eQTL), the regulatory relationships among genes and the tissue-specificity of signals have not been taken into account.

Results

We propose a new approach, namely network-enhanced MAGMA (nMAGMA), for gene-wise annotation of variants from GWAS summary statistics. Compared with MAGMA and H-MAGMA, nMAGMA significantly extends the lists of genes that can be annotated to SNPs by integrating local signals, long-range regulation signals, and tissue-specific gene networks. When applied to schizophrenia, nMAGMA is able to detect more risk genes (217% more than MAGMA and 57% more than H-MAGMA) that are reasonably involved in schizophrenia compared to MAGMA and H-MAGMA. Some disease-related functions (e.g. the ATPase pathway in Cortex) tissues are also uncovered in nMAGMA but not in MAGMA or H-MAGMA. Moreover, nMAGMA provides tissue-specific risk signals, which are useful for understanding disorders with multi-tissue origins.
Utilizing Computational Machine Learning Tools to Understand Immunogenic Breadth in the Context of a CD8 T-Cell Mediated HIV Response
Authors: McGowan Ed , Rosenthal Rachel , Fiore-Gartland Andrew , Macharia Gladys , Balinda Sheila , Kapaata Anne , Umviligihozo Gisele , Muok Erick , Dalel Jama , Streatfield Claire , Coutinho Helen , Monaco Daniela C. , Morrison David , Yue Ling , Hunter Eric , Nielsen Morten , Gilmour Jill , Hare Jonathan
Published: August 2020

Predictive models are becoming more and more commonplace as tools for candidate antigen discovery to meet the challenges of enabling epitope mapping of cohorts with diverse HLA properties. Here we build on the concept of using two key parameters, diversity metric of the HLA profile of individuals within a population and consideration of sequence diversity in the context of an individual’s CD8 T-cell immune repertoire to assess the HIV proteome for defined regions of immunogenicity. Using this approach, Analysis of HLA adaptation and functional immunogenicity data enabled the identification of regions within the proteome that offer significant conservation, HLA recognition within a population, low prevalence of HLA adaptation and demonstrated immunogenicity. We believe this unique and novel approach to vaccine design that, in combination with in vitro functional assays, offers a bespoke pipeline for expedited and rational CD8 T-cell vaccine design for HIV and potentially other pathogens with the potential for both global and local coverage.
Fibroblasts close a void in free space by a purse-string mechanism
Authors: Da Costa Avelino Dos Santos , Subbiah Ramesh , Oh Seung Ja , Jeong Hyun Tae , Na Jung-Im , Park Kwideok , Shin Jennifer Hyunjong , Choi In-Suk
Published: August 2020

How stromal cells fill voids in wounded tissue remains one of the most fundamental questions in regenerative medicine. Fibroblasts are known to fill voids by depositing extracellular matrix (ECM) proteins while migrating towards the wound site; however, their ability to adopt an epithelial-like purse-string behaviour remains unexplored. Here, we fabricated an artificial wound with a deep void space to investigate fibroblasts’ behaviour during gap closure. We found that fibroblasts can form a free-standing bridge on deep microvoids and consequently close the void through the purse-string contraction, which was previously believed to be exclusively an epithelial wound closure mechanism. The results also revealed that the fibroblast gap closure in our fabricated 3D artificial wound depends on myosin II-mediated contractility and intercellular adherent junctions. Our study reveals that stromal cells can gain the structural features of epithelial cells, namely, intercellular contractile rings, to fulfil their functions under the specific microenvironmental conditions of tissue repair. Furthermore, fibroblasts can close artificial wounds with gap widths up to 300 μm, approximately twice as large as the critical epithelial gap closure size on non-adherent substrates. Fibroblasts exhibited a zip-up gap closure mechanism with a geometrical size effect. These findings reveal a new mechanism for gap closure by stromal cells during wound healing and pave a way to groundbreaking therapeutic strategies for tissue repair.
TISCH: a comprehensive web resource enabling interactive single-cell transcriptome visualization of tumor microenvironment
Authors: Sun Dongqing , Wang Jin , Han Ya , Dong Xin , Zheng Rongbin , Ge Jun , Shi Xiaoying , Wang Binbin , Li Ziyi , Ren Pengfei , Sun Liangdong , Yan Yilv , Zhang Peng , Zhang Fan , Li Taiwen , Wang Chenfei
Published: August 2020

Cancer immunotherapy targeting co-inhibitory pathways by checkpoint blockade shows remarkable efficacy in a variety of cancer types. However, only a minority of patients respond to treatment due to the stochastic heterogeneity of tumor microenvironment (TME). Recent advances in single-cell RNA-seq technologies enabled comprehensive characterization of the immune system heterogeneity in tumors, but also posed computational challenges on how to integrate and utilize the massive published datasets to inform immunotherapy. Here, we present Tumor Immune Single Cell Hub (TISCH,http://tisch.comp-genomics.org), a large-scale curated database that integrates single-cell transcriptomic profiles of nearly two million cells from 76 high-quality tumor datasets across 28 cancer types. All the data were uniformly processed with a standardized workflow, including quality control, batch effect removal, malignant cell classification, cell clustering, cell-type annotation, differential expression analysis, and functional enrichment analysis. TISCH provides interactive gene expression visualization across multiple datasets at the single-cell level or cluster level, allowing systematic comparison between different cell-types, patients, tissue origins, treatment and response groups, and even different cancer-types. In summary, TISCH provides a user-friendly interface for systematically visualizing, searching, and downloading gene expression atlas in the TME from multiple cancer types, enabling fast, flexible and comprehensive exploration of the TME.
Antioxidant nanozyme counteracts HIV-1 by modulating intracellular redox potential
Authors: Singh Shalini , Ghosh Sourav , Pal Virender Kumar , Munshi MohamedHusen , Rajmani Raju S , Mugesh Govindasamy , Singh Amit
Published: August 2020

Reactive oxygen species (ROS) regulates the proliferation of human immunodeficiency virus (HIV-1) andMycobacterium tuberculosis(Mtb) inside the infected immune cells. However, the application of this knowledge to develop therapeutic strategies remained unsuccessful due to unfavorable consequences of manipulating cellular antioxidant systems that respond to ROS. Here, we show that vanadium pentoxide (V2O5) nanosheets functionally mimic the activity of natural glutathione peroxidase (GPX) to mitigate ROS associated with HIV-1 infection without triggering detrimental changes in cellular physiology. Using genetic reporters of glutathione (GSH) redox potential (EGSH; Grx1-roGFP2) and H2O2(Orp1-roGFP2), we showed that V2O5-nanosheets catalyze GSH-dependent neutralization of ROS in HIV-1 infected cells. Notably, V2O5-nanosheets uniformly blocked HIV-1 reactivation, multiplication, and impaired survival of drug-resistantMtbduring HIV-TB co-infection. Mechanistically, V2O5-nanosheets suppressed HIV-1 by affecting the expression of pathways coordinating redox balance, virus transactivation (e.g.,NF-κB and FOS), inflammation, and apoptosis. Importantly, a combination of V2O5-nanosheets with a pharmacological inhibitor of NF-κB (BAY11-7082) abrogated activation of HIV-1 from latency. Lastly, V2O5-nanosheets counteracted ROS, disease pathophysiology, and virus expression in HIV-1 transgenic mice. Our data successfully revealed the usefulness of V2O5-nanosheets against human pathogens and suggest nanozymes as future platforms to develop interventions against infectious diseases.

Significance Statement

Redox stress, such as those caused by the deregulation of the antioxidant glutathione, promotes the multiplication of human immunodeficiency virus-1 (HIV-1) andMycobacterium tuberculosis(Mtb). Here we present a vanadium pentoxide (V2O5)-based antioxidant nanozyme that targets cells infected with HIV-1. The nanozyme, by mimicking the activity of glutathione peroxidase, reprograms redox signaling to subvert HIV-1 from monocytes, lymphocytes, and HIV-1 transgenic mice. Treatment with nanozyme bolsters the antiviral potential of immune cells by reducing the expression of genes involved in virus activation, inflammation, and apoptosis. The nanozyme also inhibited the proliferation ofMtb, which is a major cause of lethality in HIV patients. These V2O5-based nanozymes may be applied to numerous human pathogens where redox signaling contributes to disease progression.
Structural evolution of the tissue-specific U2AF2 paralog and alternative splicing factor LS2
Authors: Kawale Ashish Ashok , Taliaferro J. Matthew , Kang Hyun-Seo , Hartmüller Christoph , Geerlof Arie , Stehle Ralf , Burge Christopher , Rio Donald C. , Sattler Michael
Published: August 2020

TheDrosophila melanogasterLS2 protein is a tissue-specific paralog of U2AF2 that mediates testis-specific alternative splicing. In order to understand the structural mechanisms underlying the distinct RNA binding specificity we determined the solution structures of the LS2 RNA recognition motif (RRM) domains and characterized their interaction withcis-regulatory guanosine-rich RNA motifs found in intron regions upstream of alternatively spliced exons. We show that the guanosine-rich RNA adopts a G quadruplex (G4) foldin vitro. The LS2 tandem RRMs adopt canonical RRM folds that are connected by a 38-residue linker that harbors a small helical motif α0. The LS2 RRM2 domain and the α0helix in the interdomain linker mediate interactions with the G4 RNA. The functional importance of these unique molecular features in LS2 is validated by mutational analysisin vitroand RNA splicing assaysin vivo. RNA sequencing data confirm the enrichment of G4-forming LS2 target motifs near LS2-affected exons. Our data indicate a role of G quadruplex structures ascis-regulatory motifs in introns for the regulation of alternative splicing, that engage non-canonical interactions with a tandem RRM protein. These results highlight the intriguing molecular evolution of a tissue-specific splicing factor from its conserved U2AF2 paralog as a result of (retro-) gene duplication inD. melanogaster.
A universal formula for avian egg shape
Authors: Narushin Valeriy G. , Romanov Michael N. , Griffin Darren K.
Published: August 2020

The bird’s oomorphology has far escaped mathematical formulation universally applicable. All bird egg shapes can be laid in four basic geometric figures: sphere, ellipsoid, ovoid, and pyriform (conical/pear-shaped). The first three have a clear mathematical definition, each derived from expression of the previous, but a formula for the pyriform profile has yet to be inferred. To rectify this, we introduced an additional function into the ovoid formula. The subsequent mathematical model fits a completely novel geometric shape that can be characterized as the last stage in the evolution of the sphere—ellipsoid—Hügelschäffer’s ovoid transformation applicable to any avian egg shape geometry. Required measurements are the egg length, maximum breadth, and diameter at the terminus from the pointed end. This mathematical description is invariably a significant step in understanding not only the egg shape itself, but how and why it evolved, thus making widespread biological and technological applications theoretically possible.
Climate change and the migration of a pastoralist people c.3500 cal. years BP inferred from palaeofire and lipid biomarker records in the montane Western Ghats, India
Authors: Kavil Sarath Pullyottum , Ramya Bala Prabhakaran , Kumar Pankaj , Ghosh Devanita , Sukumar Raman
Published: August 2020

Human migration in response to climate change during the Holocene has been recorded in many regions of the world. The Todas are a pastoralist people who are believed to have colonized the higher elevations (>2000 m asl) of the Nilgiris in the Western Ghats, India, not earlier than about 2000 cal. yr BP. Vegetation shifts in response to changing climate in tropical montane forest-grassland mosaic of the Ghats have been well documented using stable carbon isotopes and pollen profiles; however, there have been no corresponding investigations of human presence and activity at the highest elevations. We used a number of other proxies to infer the human ecology of this montane region. Radiocarbon dated (~22,000 cal. BP to the present) peat samples from the Sandynallah basin (2200m asl, Nilgiri hills, Tamil Nadu State) were used to reconstruct fire history, animal abundance, and human presence since the Last Glacial Maximum (LGM). While the macro-charcoal record indicates fires at the LGM, macro- and micro-charcoal counts indicate intense fire at ~3500 cal. yr BP, coprophilous fungal spores indicate a large population of herbivorous mammals, and steroid biomarkers indicate human faecal remains for the first time. This period is also characterized by dry arid conditions and dominant grassy vegetation as inferred from n-alkane signatures. We thus infer that a pastoralist people, most likely the Todas, migrated to the highest elevations of the Western Ghats along with their buffalo herds in response to prolonged or abrupt climate change in peninsular India, about 3500 cal. yr BP or at least 1500 years prior to what historical accounts assume.
Comparative morphology of the corpus callosum across the adult lifespan in chimpanzees (Pan troglodytes) and humans
Authors: Westerhausen René , Fjell Anders M. , Kompus Kristiina , Schapiro Steven J. , Sherwood Chet , Walhovd Kristine B. , Hopkins William D.
Published: August 2020

The human corpus callosum exhibits substantial atrophy in old age, which is stronger than what would be predicted from parallel changes in overall brain anatomy. To date, however, it has not been conclusively established whether this accentuated decline represents a common feature of brain aging across species, or whether it is a specific characteristic of the aging human brain. In the present cross-sectional study, we address this question by comparing age-related difference in corpus callosum morphology of chimpanzees and humans. For this purpose, we measured total midsagittal area and regional thickness of the corpus callosum from T1-weighted MRI data from 213 chimpanzees, aged between 9 and 54 years. The results were compared with data drawn from a large-scale human samples which was age-range matched using two strategies: (a) matching by chronological age (human sample size: n = 562), or (b) matching by accounting for differences in longevity and various maturational events between the species (i.e., adjusted human age range: 13.6 to 80.9 years; n = 664). Using generalized additive modelling to fit and compare aging trajectories, we found significant differences between the two species. The chimpanzee aging trajectory compared to the human trajectory was characterized by a slower increase from adolescence to middle adulthood, and by a lack of substantial decline from middle to old adulthood, which, however, was present in humans. Thus, the accentuated decline of the corpus callosum found in aging humans, is not an universal characteristic of the aging brain, and appears to be human-specific.
Wavelet coherence phases decode the universal switching mechanism of Ras GTPase superfamily
Authors: Motiwala Zenia , Sandholu Anand S. , Sengupta Durba , Kulkarni Kiran
Published: August 2020

Ras superfamily GTPases are molecular switches which regulate critical cellular processes. Extensive structural and computational studies on these G proteins have established a general framework for their switching mechanism, which involves conformational changes in their two loops, Switch I and Switch II, upon GTP binding and hydrolysis. Since the extent of these conformational changes is not uniform amongst the members of the Ras superfamily, there is no genericmodus operandidefining their switching mechanism. Here, we have developed a novel approach employing wavelet coherence analysis to correlate the structural changes with their functional states. Our analysis shows that the structural coupling between the Switch I and Switch II regions is manifested in terms of conserved wavelet coherence phases, which could serve as useful parameters to define functional states of the GTPases. In oncogenic GTPases mutants, this phase coupling gets disentangled, which perhaps provides an alternative explanation for their aberrant function. We have tested the statistical significance of the observed phase angle correlations on multiple switch region conformers, generated through MD simulations.
Bixafen, a succinate dehydrogenase inhibitor fungicide, causes microcephaly and motor neuron axon defects during development
Authors: Brenet Alexandre , Hassan-Abdi Rahma , Soussi-Yanicostas Nadia
Published: August 2020

Succinate dehydrogenase inhibitors (SDHIs), the most widely used fungicides in agriculture today, act by blocking succinate dehydrogenase (SDH), an essential and evolutionarily conserved component of mitochondrial respiratory chain. Recent results showed that several SDHIs used as fungicides not only inhibit the SDH activity of target fungi but also block this activity in human cells inin vitromodels, revealing a lack of specificity and thus a possible health risk for exposed organisms, including humans. Despite the frequent detection of SDHIs in the environment and on harvested products and their increasing use in modern agriculture, their potential toxic effectsin vivo, especially on neurodevelopment, are still under-evaluated. Here we assessed the neurotoxicity of bixafen, one of the latest-generation SDHIs, which had never been tested during neurodevelopment. For this purpose, we used a well-known vertebrate model for toxicity testing, namely zebrafish transparent embryos, and live imaging using transgenic lines labelling the brain and spinal cord. Here we show that bixafen causes microcephaly and defects on motor neuron axon outgrowth and their branching during development. Our findings show that the central nervous system is highly sensitive to bixafen, thus demonstratingin vivothat bixafen is neurotoxic in vertebrates and causes neurodevelopmental defects. This work adds to our knowledge of the toxic effect of SDHIs on neurodevelopment and may help us take appropriate precautions to ensure protection against the neurotoxicity of these substances.
Evidence-based gene expression modulation correlates with transposable element knock-down
Authors: Hernandes-Lopes José , Quintanilha Danielle M. , de Jesus Erika M. , Lopes Fabrício M. , Parmigiani Raphael B. , Karolski Bruno , Dias Henrique M. , Jacobs Thomas B. , Camargo Anamaria A. , Kitajima João P. , Van Sluys Marie-Anne
Published: August 2020

Background

Transposable elements (TEs) are major components of plant genomes. Despite being regarded as “junk DNA” at first, TEs play important roles for the organisms they are found in. The most obvious and easily recognizable effects caused by TEs result from their mobility, which can disrupt coding sequences or promoter regions. However, with the recent advances in transcriptomics, it is becoming increasingly evident that TEs can act as an additional layer of gene expression regulation through a number of processes, which can involve production of non-coding RNAs. Here, we describe how Tnt1, a stress-responsive LTR-retrotransposon, interferes with gene expression and modulate a number of developmental aspects in tobacco.

Results

Through an RNAi approach, we generated tobacco (HP) lines knocked-down for Tnt1 expression. Quantitative RT-PCR experiments confirm that Tnt1 is downregulated in HP lines after ethylene exposure. A RNA-seq experiment was performed and through two independent bioinformatic approaches (with different stringencies) we found 932 and 97 differentially expressed genes in HP lines. A number of phenotypes were observed in such lines, namely lesion mimicry in leaves, underdevelopment of the root system, overproduction of root hairs and early loss of seed viability. Folding prediction of part of the Tnt1 mRNA reveals putative stem-loop secondary structures containing transcriptional regulation sequences, suggesting it could be a source of small RNAs. We also propose a model to explain the Tnt1 expression in both homeostatic and stress conditions, and how it could interact with stress-responsive genes.

Conclusions

Our results are consistent that interferences with Tnt1 transcript levels correlate with transcriptomic and phenotypic changes, suggesting a functional role for this element during plant development and stress response.
Human Embryonic Expression Identifies Novel Essential Gene Candidates
Authors: Penon-Portmann Monica , Chang Jiyoo , Blair David R. , Rodriguez-Alonso Beatriz , Cakmak Hakan , Rajkovic Aleksandar , Shieh Joseph T.
Published: August 2020

Disruption of essential genes leads to pregnancy loss, early lethality, or severe disease. Current methods to predict genes that underlie severe phenotypes include knockout animal model systems, evolutionary conservation, and variation intolerance metrics. With existing methods, human lethal genes are missed due to interspecies differences or paucity of gene characterization. We analyzed global gene expression in stages of early human development (1-cell to the blastocyst). These data were integrated with all 4049 current murine knockout phenotypes, genome-wide evolutionary gene conservation, and human genic intolerance metrics. We found that currently established human essential genes and orthologs of murine essential genes demonstrate higher gene expression across developmental stages compared to non-essential genes (Wilcoxon rank sum test, p<8.5e-10), indicating that higher expression correlates with essentiality. Of 1438 unique genes candidates with the highest expression, an estimated 1115 (78%) have not yet been associated with human disease and are thus novel candidates. The essential gene candidates concur with four prediction metrics, further supporting essentiality. We also assessed gene-specific expression changes during early development for their ability to predict essentiality. Genes that increase in expression were more likely to be essential (Fishers exact test, p<2.4e-06), suggesting that dynamic temporal expression during development may be particularly important. We find that embryonic gene expression can be used to prioritize genes that currently lack a Mendelian phenotype. Human embryonic gene expression is readily available, and applied as a novel tool, it may identify highly conserved processes vital in development.
Ligand Effects on Phase Separation of Multivalent Macromolecules
Authors: Ruff Kiersten M. , Dar Furqan , Pappu Rohit V.
Published: August 2020

Biomolecular condensates enable spatial and temporal control over cellular processes by concentrating biomolecules into non-stoichiometric assemblies. Many condensates form via reversible phase transitions of condensate-specific multivalent macromolecules known as scaffolds. Phase transitions of scaffolds can be regulated by changing the concentrations of ligands, which are defined as non-scaffold molecules that bind to specific sites on scaffolds. Here, we use theory and computation to uncover rules that underlie ligand-mediated control over scaffold phase behavior. We use thestickers-and-spacersmodel wherein reversible non-covalent crosslinks among stickers drive phase transitions of scaffolds, and spacers modulate the driving forces for phase transitions. We find that the modulatory effects of ligands are governed by: the valence of ligands; whether they bind directly to stickers versus spacers; and the relative affinities of ligand-scaffold versus scaffold-scaffold interactions. In general, all ligands have a diluting effect on the concentration of scaffolds within condensates. Whereas monovalent ligands destabilize condensates, multivalent ligands can stabilize condensates by binding directly to spacers or destabilize condensates by binding directly to stickers. Bipartite ligands that bind to stickers and spacers can alter the structural organization of scaffold molecules within condensates even when they have a null effect on condensate stability. Our work highlights the importance of measuring dilute phase concentrations of scaffolds as a function of ligand concentration in cells. This can reveal whether ligands modulate scaffold phase behavior by enabling or suppressing phase separation at endogeneous levels thereby regulating the formation and dissolution of condensatesin vivo.

Significance

Phase transitions of multivalent macromolecules known as scaffolds help drive the formation of functional biomolecular condensates in cells. The formation and dissolution of condensates is tightly regulated, as aberrant phase behavior is associated with disease. Here, we show that distinct types of ligands can exert control over the formation and dissolution of condensates by binding to distinct sites on scaffold molecules. We further show that the extent and direction of regulation can be inferred through direct measurements of how ligands impact scaffold phase boundaries. Our findings have broad implications for understanding and modeling ligand-mediated regulation of condensates in cells, and for designing novel molecules that exert regulatory control over condensates.
Evolution of multicellularity and unicellularity in yeastS. cerevisiaeto study reversibility of evolutionary trajectories
Authors: Alugoju Phaniendra , Mahilkar Anjali , Saini Supreet
Published: August 2020

Adaptive trajectories of populations have been focus of number of studies. However, adaptive trajectories have not been studied in the context of reverse evolution. By reverse evolution, we mean a scenario where selection is reversed. In this work, we use evolution (and reversal from) of multicellularity inS. cerevisiaeas a model to answer this question. When selected for fast-settling variants, multicellularity evolves rapidly in the organism. On reversing selection, unicellularity evolves from the multicellular clusters. However, the dynamic trajectories of the two processes are different. In this context, evolution is not reversed dynamically at a phenotypic level. The phenotypic reversal is not driven by reversal of the original mutations during the forward evolution. Overall, our results show that the dynamics of molecular and phenotypic trajectories of evolution are distinct, and reversal of selection leads to unique trajectories of phenotypic reversal.
Does participation in acoustic experiments improve welfare in captive animals? A case study of three grey seals (Halichoerus grypus)
Authors: Ortiz Sara T. , Maxwell Alyssa , Hernandez Ariana , Hansen Kirstin Anderson
Published: August 2020

Both mental and physiological conditions determine the well-being state in an animal. Enrichment is a way to increase an animals’ well-being and may require problem solving through thinking, tolerance of ambiguity, openness, and intrinsic motivation. It is unclear if it is enriching when an animal participates in different types of research. Therefore, it is important to answer the question of whether research can be used as an enrichment tool in zoological facilities. Here, we examine if participation in psychophysical research affected the mental stimulation of three grey seals under human care. The effects varied amongst the three individuals that took part in the research, and indicated that their participation in the research task was dependent on their individual personalities and life history. Two seals indicated that their involvement in the research was positive and motivating, and therefore can be considered enriching. In comparison, the third seal displayed a tendency for frustration and low motivation. Our results indicate that research can be a powerful enrichment tool with animals that find research motivating.