bluuebunny/crossref_metadata_2025 huggingface dataset:
Transmission Dynamics of the COVID-19 Epidemics in England
Authors: Liu Yang , Tang Julian W , Lam Tommy TY
Published: July 2020

Abstract

The ongoing COVID-19 pandemic has caused a tremendous health burden and impact on the world economy. As one of the European countries experiencing one of the worst COVID-19 epidemics, the UK government at the end of March 2020 implemented the biggest lockdown of society during peacetime in British history, aiming to contain the rapid spread of the virus. While the lockdown has been maintained for seven weeks in UK, the effectiveness of the control measures in suppressing the transmission of the disease remains incompletely understood. Here we applied a Bayesian SEIR (susceptible-exposed-infected-removed) epidemiological model to rebuild the local transmission dynamics of the spread of COVID-19 in nine regions of England. We found that the basic reproduction number (R0) in England is relatively high compared with China. Our estimation of the temporally varying effective reproduction number (Rt) suggests that the control measures, especially the forceful lockdown, were effective to reduce the transmissibility and curb the COVID-19 epidemic. Although the overall incidence rate in the UK has declined, our forecasting highlights the possibility of a second wave of the disease in several regions, which may be currently underway in one of the cities there (e.g. Leicester, East Midlands). This study enhances our understanding of the current outbreak and effectiveness of control measures in the UK.
Investigating the effect of respiratory indices to predict mortality and the status of trauma patients using artificial neural networks
Authors: Hafezi Zahra , Sabouri Mohammad , Shayan Milad , Paydar Shahram
Published: July 2020

Introduction

Knowing the final status of trauma patients and clearly understanding their condition are always significant due to the complexity of injuries and the high dependence of the patient’s condition on various factors. That is why it allows doctors to be able to provide required facilities in a broader perspective and perform appropriate action. In addition, it can avoid wasting time and energy and then increasing patient mortality. While, there are several ways to measure and predict the final status of patients but all of them have some defects. Therefore, it is very important for the significance of the system design with high accuracy and reliability to be able to help physicians investigate the final status of trauma patients.

Method

In this study, a method, a sub-branch of data science and artificial intelligence, is presented and studied based on artificial neural networks to estimate the final status of trauma patients and predict their survival and death probabilities during the treatment and care process. In the proposed method, the final status of patients is predicted using 13 respiratory indices. This method is run in Matlab and its efficiency is studied.

Results

Research subjects include 3073 patients, 494 females and 2579 males, from Shahid Rajaei Medical Center in Shiraz. In general, according to the results from testing the method, it has been able to accurately predict the mortality of patients based on respiratory indices. The proposed structure has been able to predict patients’ survival and death probabilities with an accuracy of %73.75 and %99.71 respectively. Therefore, we can conclude that the presented and examined method can make a significant relevance between calculated respiratory indices and final status of patients.

Discussion and Conclusion

Due to the present study and the obtained results and investigating the mortality relevance with the other 13 respiratory indices using artificial intelligence-based methods, it can be stated that these indicators are good criteria for predicting mortality.
Exploring Epidemiological Behavior of Novel Coronavirus Outbreak through the Development and Analysis of COVID-19 Daily Dataset in Bangladesh
Authors: Dey Samrat Kumar , Rahman Md. Mahbubur , Siddiqi Umme Raihan , Howlader Arpita
Published: July 2020

Background

Globally, there is an obvious concern about the fact that the evolving 2019-nCoV coronavirus is a worldwide public health threat. The appearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China at the end of 2019 triggered a major global epidemic, which is now a major community health issue. As of April 17, 2020, according to Institute of Epidemiology, Disease Control and Research (IEDCR) Bangladesh has reported 1838 confirmed cases in between 8 March to 17 April 2020, with > 4.08% of mortality rate and >3.15% of recovery rate. COVID-19 outbreak is evolving so rapidly in Bangladesh; therefore, the availability of epidemiological data and its sensible analysis are essential to direct strategies for situational awareness and intervention.

Method

This article presents an exploratory data analysis approach to collect and analyze COVID-19 data on epidemiological outbreaks based on first publicly available COVID-19 Daily Dataset of Bangladesh. Various publicly open data sources on the outbreak of COVID-19 provided by the IEDCR, World Health Organization (WHO), Directorate General of Health Services (DGHS), and Ministry of Health and Family Welfare (MHFW) of Bangladesh have been used in this research.

Results

A Visual Exploratory Data Analysis (V-EDA) techniques have been followed in this research to understand the epidemiological characteristics of COVID-19 outbreak in different districts of Bangladesh in between 8 March 2020 to 12 April 2020 and these findings were compared with those of other countries.

Conclusions

In all, this is extremely important to promptly spread information to understand the risks of this pandemic and begin containment activities in the country.
Potential role of Mercury pollutants in the success of Methicillin-ResistantStaphylococcus aureusUSA300 in Latin America
Authors: Gustave C. A. , Rasigade J.P. , Martins-Simões Patricia , Couzon F. , Bourg Chloe , Tristan Anne , Laurent Frédéric , Wirth T. , Vandenesch F.
Published: July 2020

Community-acquired methicillin-resistantStaphylococcus aureus(CA-MRSA) lineage known as USA300-North American (NA) has become highly prevalent in North America whilst a USA300 variant known as USA300-LV, harboring a mercury resistance element (COMER), has become dominant in South America. We investigated whether mercury pollution, which is common in South America notably because of artisanal gold mining, may explain the local dominance pattern of USA300-LV. Density-based estimation of epidemic success in 250 genomes of the ST8 lineage revealed that the acquisition of COMER in USA300 progenitors increased success in South American countries but decreased success elsewhere. The fitness of USA300-LV was impairedin vitrocompared with USA300-NA, but the addition of sub-inhibitory concentration of mercury provided a strong fitness advantage to USA300-LV and triggered an overexpression of major virulence factors. The success of USA300-LV in South America may result from low-level mercury exposure selecting resistant and virulent strains.
Hyperrealistic neural decoding: Reconstructing faces from fMRI activations via the GAN latent space
Authors: Dado Thirza , Güçlütürk Yağmur , Ambrogioni Luca , Ras Gabriëlle , Bosch Sander E. , van Gerven Marcel , Güçlü Umut
Published: July 2020

Neural decoding can be conceptualized as the problem of mapping brain responses back to sensory stimuli via a feature space. We introduce (i) a novel experimental paradigm which uses well-controlled yet highly naturalistic stimuli with a priori known feature representations and (ii) an implementation thereof for HYPerrealistic reconstruction of PERception (HYPER) of faces from brain recordings. To this end, we embrace the use of generative adversarial networks (GANs) at the earliest step of our neural decoding pipeline by acquiring fMRI data as subjects perceive face images synthesized by the generator network of a GAN. We show that the latent vectors used for generation effectively capture the same defining stimulus properties as the fMRI measurements. As such, GAN latent vectors can be used as features underlying the perceived images that can be predicted for (re-)generation, leading to the most accurate reconstructions of perception to date.
VELCRO-IP RNA-seq explores ribosome expansion segment function in translation genome-wide
Authors: Leppek Kathrin , Byeon Gun Woo , Fujii Kotaro , Barna Maria
Published: July 2020

Roles for ribosomal RNA (rRNA) in gene regulation remain largely unexplored. With hundreds of rDNA units scattered across multiple chromosomal loci, it is not possible to genetically modify rRNA in mammalian cells, hindering understanding of ribosome function. Emerging evidence suggests that expansion segments (ESs), tentacle-like rRNA extensions that vary in sequence and size across eukaryotic evolution, may provide platforms for the binding of proteins and mRNAs. Here, we develop VELCRO-IP RNA-seq: a versatile methodology to generate species-adapted ESs and map specific mRNA regions across the transcriptome that preferentially associate with ESs. By applying VELCRO-IP RNA-seq to a mammalian ES, ES9S, we identified a large array of mRNAs that are selectively recruited to ribosomes via an ES. We further characterize a set of specific 5’ UTRs that facilitate cap-independent translation through ES9S-mediated ribosome recruitment. These data provide a novel technology for studying the enigmatic ESs of the ribosome in gene-specific translation.
MORT, a locus for apoptosis in the human immunodeficiency virus-type 1 antisense gene: implications for AIDS, Cancer, and Covid-19
Authors: Ludwig Linda B. , Albert Michael S.
Published: July 2020

Apoptosis, or programmed cell death, is a fundamental requirement for life in multicellular organisms, including humans, and a mechanism to maintain homeostasis and prevent unwarranted cellular proliferations such as cancer. An antisense gene in HIV-1 (Hap) induces apoptosis in human cells. Apoptotic T cell death following HIV-1 infection leads to a compromised immune system and eventually AIDS (acquired immunodeficiency syndrome). A review of several studies that focused on long-term survivors of HIV-1 reveals that these survivors had deletion-mutations inHap. A subset of these survivors changed course and experienced CD4+ T cell death and progression to AIDS. These individuals had virus that regainedHapgene sequence that had previously been deleted. Analysis of the changes in the genetic sequences within vivoprogression of the revertant HIV-1 virus allowed identification of a specific region inHapwe are calling MORT. MORT, inHapRNA forms a primary microRNA-like structure. Potential human mRNAs targeted by MORT mi/siRNAs include gene/RNA sequences of X-linked inhibitor of apoptosis (XIAP), survivin, and apollon, along with many other human gene sites/RNAs. Thus MORT may be acting as an RNA antagonist to cellular IAPs thereby inducing apoptotic cell death. Surprisingly, additional potential MORT targets include viral sites in human SARS-CoV-2, including the protease, nsp5 RNA. Future uses for RNA therapy and a hypothesis for an HIV intrinsic mechanism utilizing MORT for viral anti-viral (or anti-microbial) and HIV anti-immune cell defense are proposed.
The Sec1/Munc18 protein Vps45 holds the Qa-SNARE Tlg2 in an open conformation
Authors: Eisemann Travis , Allen Frederick , Lau Kelly , Shimamura Gregory R. , Jeffrey Philip D. , Hughson Frederick M.
Published: July 2020

Fusion of intracellular trafficking vesicles is mediated by the assembly of solubleN-ethylmaleimide-sensitive fusion protein receptors (SNAREs) to form membrane-bridging complexes. Also required for SNARE-mediated membrane fusion are Sec1/Munc18-family (SM) proteins, SNARE chaperones that can function as templates to catalyze SNARE complex assembly. In the paradigmatic structure of an SM–SNARE complex, Munc18-1 bound to the Qa-SNARE syntaxin 1, the SNARE protein is trapped in an autoinhibited closed conformation that prevents it from entering into SNARE complexes. Here, we present the structure of a second SM–Qa-SNARE complex, Vps45–Tlg2. Strikingly, Vps45 holds Tlg2 in an open conformation, with its SNARE motif disengaged from its three-helical Habc domain and its linker region unfolded. The domain 3a helical hairpin of Vps45 is unfurled, exposing the presumptive R-SNARE binding site to allow template complex formation. Tlg2 has a pronounced tendency to self-associate via its SNARE motif, and we demonstrate that Vps45 can rescue Tlg2 oligomers into stoichiometric Vps45–Tlg2 complexes. Our findings demonstrate that SM proteins can engage Qa-SNAREs using at least two different modes, one in which the SNARE is closed and one in which it is open.
Task specialization across research careers
Authors: Robinson-Garcia Nicolas , Costas Rodrigo , Sugimoto Cassidy R. , Larivière Vincent , Nane Gabriela F.
Published: July 2020

Scientific careers are conceived as one unique pathway which scientists must follow to succeed. We report the diversity of profiles scientists exhibit based on their contributorship and look into biases in their career trajectory. We use Bayesian networks to train a prediction model based on a dataset of 70,694 publications from PLoS journals representing 347,136 distinct authors and their associated contribution statements. This model is used to predict the contributions of 222,925 authors in 6,236,239 publications, and apply a robust archetypal analysis to profile scientists by career stage. We divide scientific careers into four stages: junior, early-career, mid-career and late-career. Three scientific archetypes are found throughout the four career stages: leader, specialized, and supporting. All three archetypes are encountered for the early- and mid-career stages, whereas for junior and late-career stages only two archetypes are found. Scientists assigned to the leader and specialized archetypes tend to have longer careers than researchers who belong to the supporting archetype. There is consistent gender bias at all stages: the majority of male scientists belong to the leader archetype, while the larger proportion of women belong to the specialized archetype, especially for early and mid-career researchers.
Mitochondrial uncoupling protein 2 (UCP2), but not UCP3, is sensitive to oxygen concentration in cells
Authors: Hilse Karolina E. , Rupprecht Anne , Ford Kristopher , Andrukhova Olena , Erben Reinhold , Pohl Elena E.
Published: July 2020

One of the important hallmarks of cardiovascular disease is mitochondrial dysfunction, which results in abnormal energy metabolism and increased ROS production in cardiomyocytes. Members of the mitochondrial uncoupling protein family, UCP2 and UCP3, are thought to be beneficial by reducing ROS due to mild uncoupling. More recent hypotheses suggest the involvement of both proteins in cell metabolism by the transport of yet unknown substrates. The protein expression pattern under physiological and pathological conditions is an important clue for the evaluation of UCP2/UCP3 function, however, there is still no consensus about it. Previously, we demonstrated that only UCP3 is present in the adult murine heart under physiological conditions and correlated it with the predominant use of fatty acids for oxidation. In contrast, UCP2 was found only in very young (stem cell – like) cardiomyocytes, that rely mostly on glycolysis. Here, we employed three different models (ex vivo heart ischemia-reperfusion model, myocardial infarction model, and embryonic stem cell differentiation into cardiomyocytes under hypoxic conditions) to evaluate the abundance of both proteins under ischemia and hypoxia conditions. We found that (i) oxygen shortage or bursts did not influence UCP3 levels in the heart and ii) UCP2 was not present in healthy, ischemic, or re-perfused hearts. However, (iii) UCP2 was sensitive to the oxygen concentration in stem cells, in which UCP2 is normally expressed. These results further support the idea, that two highly homologous proteins – UCP2 and UCP3 – are abundant in different cells and tissues, and differently regulated under physiological and pathological conditions.
FtsZ treadmilling is essential for Z-ring condensation and septal constriction initiation inBacillus subtiliscell division
Authors: Whitley Kevin D. , Jukes Calum , Tregidgo Nicholas , Karinou Eleni , Almada Pedro , Henriques Ricardo , Dekker Cees , Holden Séamus
Published: July 2020

Despite the central role of division in bacterial physiology, how division proteins work together as a nanoscale machine to divide the cell remains poorly understood. Cell division by cell wall synthesis proteins is guided by the cytoskeleton protein FtsZ, which assembles at mid-cell as a dense Z-ring formed of treadmilling filaments1,2. However, although FtsZ treadmilling is essential for cell division, the function of FtsZ treadmilling remains unclear2–5. Here, we systematically resolve the function of FtsZ treadmilling across each stage of division in the Gram-positive model organismBacillus subtilisusing a novel combination of nanofabrication, advanced microscopy, and microfluidics to measure the division-protein dynamics in live cells with ultrahigh sensitivity. We find that FtsZ treadmilling has two essential functions: mediating condensation of diffuse FtsZ filaments into a dense Z-ring, and initiating constriction by guiding septal cell wall synthesis. After constriction initiation, FtsZ treadmilling has a dispensable function in accelerating septal constriction rate. Our results show that FtsZ treadmilling is critical for assembling and initiating the bacterial cell division machine.
A functional overlap between actively transcribed genes and chromatin boundary elements
Authors: Harrold Caroline L , Gosden Matthew E , Hanssen Lars L P , Stolper Rosa J , Downes Damien J , Telenius Jelena M. , Biggs Daniel , Preece Chris , Alghadban Samy , Sharpe Jacqueline A , Davies Benjamin , Sloane-Stanley Jacqueline A. , Kassouf Mira T , Hughes Jim R , Higgs Douglas R
Published: July 2020

Mammalian genomes are subdivided into large (50-2000 kb) regions of chromatin referred to as Topologically Associating Domains (TADs or sub-TADs). Chromatin within an individual TAD contacts itself more frequently than with regions in surrounding TADs thereby directing enhancer-promoter interactions. In many cases, the borders of TADs are defined by convergently orientated boundary elements associated with CCCTC-binding factor (CTCF), which stabilises the cohesin complex on chromatin and prevents its translocation. This delimits chromatin loop extrusion which is thought to underlie the formation of TADs. However, not all CTCF-bound sites act as boundaries and, importantly, not all TADs are flanked by convergent CTCF sites. Here, we examined the CTCF binding sites within a ∼70 kb sub-TAD containing the duplicated mouse α-like globin genes and their five enhancers (5’-R1-R2-R3-Rm-R4-α1-α2-3’). The 5’ border of this sub-TAD is defined by a pair of CTCF sites. Surprisingly, we show that deletion of the CTCF binding sites within and downstream of the α-globin locus leaves the sub-TAD largely intact. The predominant 3’ border of the sub-TAD is defined by a steep reduction in contacts: this corresponds to the transcribed α2-globin gene rather than the CTCF sites at the 3’-end of the sub-TAD. Of interest, the almost identical α1- and α2-globin genes interact differently with the enhancers, resulting in preferential expression of the proximal α1-globin gene which behaves as a partial boundary between the enhancers and the distal α2-globin gene. Together, these observations provide direct evidence that actively transcribed genes can behave as boundary elements.

Significance Statement

Mammalian genomes are complex, organised 3D structures, partitioned into Topologically Associating Domains (TADs): chromatin regions that preferentially self-interact. These chromatin interactions are thought to be driven by a mechanism that continuously extrudes chromatin loops, forming structures delimited by chromatin boundary elements and reflecting the activity of enhancers and promoters. Boundary elements bind architectural proteins such as CCCTC-binding factor (CTCF). Previously, an overlap between the functional roles of enhancers and promoters has been shown. However, whether there is overlap between enhancers/promoters and boundary elements is not known. Here, we show that actively transcribed genes can also behave as boundary elements, similar to CTCF boundaries. In both cases, multi-protein complexes bound to these regions may stall the process of chromatin loop extrusion.
eEF3 promotes late stages of tRNA translocation on the ribosome
Authors: Ranjan Namit , Pochopien Agnieszka A. , Wu Colin Chih-Chien , Beckert Bertrand , Blanchet Sandra , Green Rachel , Rodnina Marina V. , Wilson Daniel N.
Published: July 2020

In addition to the conserved translation elongation factors eEF1A and eEF2, fungi require a third essential elongation factor, eEF3. While eEF3 has been implicated in tRNA binding and release at the A and E sites, its exact mechanism of action is unclear. Here we show that eEF3 acts at the mRNA–tRNA translocation step by promoting the dissociation of the tRNA from the E site, but independent of aminoacyl-tRNA recruitment to the A site. Depletion of eEF3in vivoleads to a general slow-down in translation elongation due to accumulation of ribosomes with an occupied A site. Cryo-EM analysis ofex vivoeEF3-ribosome complexes shows that eEF3 facilitates late steps of translocation by favoring non-rotated ribosomal states as well as by opening the L1 stalk to release the E-site tRNA. Additionally, our analysis provides structural insights into novel translation elongation states, enabling presentation of a revised yeast translation elongation cycle.
Two neuronal peptides encoded from a single transcript regulate mitochondrial complex III inDrosophila
Authors: Bosch Justin A. , Ugur Berrak , Pichardo-Casas Israel , Rabasco Jorden , Escobedo Felipe , Zuo Zhongyuan , Brown Ben , Celniker Susan , Sinclair David A. , Bellen Hugo , Perrimon Norbert
Published: July 2020

Naturally produced peptides (<100 amino acids) are important regulators of physiology, development, and metabolism. Recent studies have predicted that thousands of peptides may be translated from transcripts containing small open reading frames (smORFs). Here, we describe two peptides inDrosophilaencoded by conserved smORFs, Sloth1 and Sloth2. These peptides are translated from the same bicistronic transcript and share sequence similarities, suggesting that they encode paralogs. Yet, Sloth1 and Sloth2 are not functionally redundant, and loss of either peptide causes animal lethality, reduced neuronal function, impaired mitochondrial function, and neurodegeneration. We provide evidence that Sloth1/2 are highly expressed in neurons, imported to mitochondria, and regulate mitochondrial complex III assembly. These results suggest that phenotypic analysis of smORF genes inDrosophilacan provide a wealth of information on the biological functions of this poorly characterized class of genes.
Connexin 46 and connexin 50 gap junction channel open stability and unitary conductance are shaped by structural and dynamic features of their N-terminal domains
Authors: Yue Benny , Haddad Bassam G. , Khan Umair , Chen Honghong , Atalla Mena , Zhang Ze , Zuckerman Daniel M. , Reichow Steve L. , Bai Donglin
Published: July 2020

The connexins form intercellular communication channels, known as gap junctions (GJs), that facilitate diverse physiological roles in vertebrate species, ranging from electrical coupling and long-range chemical signaling, to coordinating development and nutrient exchange. GJs formed by different connexins are expressed throughout the body and harbor unique channel properties that have not been fully defined mechanistically. Recent structural studies have implicated the amino-terminal (NT) domain as contributing to isoform-specific functional differences that exist between the lens connexins, Cx50 and Cx46. To better understand the structural and functional differences in the two closely related, yet functionally distinct GJs, we constructed models corresponding to CryoEM-based structures of the wildtype Cx50 and Cx46 GJs, NT domain swapped chimeras (Cx46-50NT and Cx50-46NT), and point variants at the 9thresidue (Cx46-R9N and Cx50-N9R) for comparative MD simulation and electrophysiology studies. All of these constructs formed functional GJ channels, except Cx46-50NT, which correlated with increased dynamical behavior (instability) of the NT domain observed by MD simulation. Single channel conductance (γj) also correlated well with free-energy landscapes predicted by MD, where γjof Cx46-R9N was increased from Cx46 and the γjs of Cx50-46NT and Cx50-N9R was decreased from Cx50, but to a surprisingly greater degree. Additionally, we observed significant effects on transjunctional voltage-dependent gating (Vj-gating) and open-state dwell times induced by the designed NT domain variants. Together, these studies indicate that the NT domains of Cx46 and Cx50 play an important role in defining channel properties related to open-state stability and single channel conductance.
An evolutionary approach to systematic discovery of novel deubiquitinases, applied to Legionella
Authors: Hermanns Thomas , Woiwode Ilka , Guerreiro Ricardo F. M. , Vogt Robert , Lammers Michael , Hofmann Kay
Published: July 2020

Deubiquitinating enzymes (DUBs) are important regulators of the posttranslational protein ubiquitination system. Mammalian genomes encode about hundred different DUBs, which can be grouped into seven different classes. Members of other DUB classes are found in pathogenic bacteria, which use them to target the host defense. By combining bioinformatical and experimental approaches, we address the question if the known DUB families have a common evolutionary ancestry and share conserved features that set them apart from other proteases. By systematically comparing family-specific Hidden-Markov-Models, we uncovered distant relationships between established DUBs and other cysteine protease families. Most DUB families share a conserved aromatic residue linked to the active site, which restricts the cleavage of substrates with sidechains at the S2 position, corresponding to Gly-75 in ubiquitin. By applying these criteria toLegionella pneumophilaORFs, we identified lpg1621 and lpg1148 as deubiquitinases, characterized their cleavage specificities, and confirmed the importance of the aromatic gatekeeper motif for substrate selection.
SARS-CoV-2 reactive T cells in uninfected individuals are likely expanded by beta-coronaviruses
Authors: Stervbo Ulrik , Rahmann Sven , Roch Toralf , Westhof Timm H. , Babel Nina
Published: July 2020

The current pandemic is caused by the SARS-CoV-2 virus and large progress in understanding the pathology of the virus has been made since its emergence in late 2019. Several reports indicate short lasting immunity against endemic coronaviruses, which contrasts repeated reports that biobanked venous blood contains SARS-CoV-2 reactive T cells even before the outbreak in Wuhan. This suggests there exists a preformed T cell memory in individuals not exposed to the pandemic virus. Given the similarity of SARS-CoV-2 to other members of the Coronaviridae family, the endemic coronaviruses appear likely candidates to generate this T cell memory. However, given the apparent poor immunological memory created by the endemic coronaviruses, other immunity against other common pathogens might offer an alternative explanation. Here, we utilize a combination of epitope prediction and similarity to common human pathogens to identify potential sources of the SARS-CoV-2 T cell memory. We find that no common human virus, other than beta-coronaviruses, can explain the pre-existing SARS-CoV-2 reactive T cells in uninfected individuals. Our study suggests OC43 and HKU1 are the most likely pathogens giving rise to SARS-CoV-2 preformed immunity.
Detection of complex genetic architecture using two-locus population differentiation: modeling epistasis
Authors: Huang Minjun , Graham Britney , Zhang Ge , Bartlett Jacquelaine , Moore Jason H. , Muglia Louis , Williams Scott M.
Published: July 2020

Recent advances in genetics have increased our understanding of epistasis as important in the genetics of complex phenotypes. However, current analytical methods often cannot detect epistasis, given the multiple testing burden. To address this, we extended our previous method, Evolutionary Triangulation (ET), that uses differences among populations in both disease prevalence and allele frequencies to filter SNPs from association studies to generate novel interaction models. We show that two-locus ET identified several co-evolving gene pairs, where both genes associate with the same disease, and that the number of such pairs is significantly greater than expected by chance. Traits found by two-locus ET included those related to pigmentation and schizophrenia. We then applied two-locus ET to the analysis of preterm birth (PTB) genetics. Using ET to filter SNPs at loci identified by genome-wide association studies (GWAS), we showed that ET derived PTB two-locus models are novel and were not seen when only the index SNPs were used to generate epistatic models. One gene pair,ADCY5andKCNAB1 5’, was identified as significantly interacting in a model of gestational age (pas low as 3 × 10−3). Notably, the same ET SNPs in these genes showed significant interactions in three of four cohorts analyzed. The robustness of this gene pair and others, demonstrated that the ET method can be used without prior biological hypotheses based on SNP function to select variants for epistasis testing that could not be identified otherwise. Two-locus ET clearly increased the ability to identify epistasis in complex traits.
Aedes aegyptivision-guided target recognition requires two redundant rhodopsins
Authors: Zhan Yinpeng , San Alberto Diego Alonso , Rusch Claire , Riffell Jeffrey A. , Montell Craig
Published: July 2020

Blood-feeding insects, such as the mosquito,Aedes(Ae.)aegypti, use multiple senses to seek out and bite humans [1, 2]. Upon exposure to CO2, the attention of female mosquitoes to potential human targets is greatly increased. Female mosquitoes use vision to assist them in honing in on hosts that may be up to 10 meters away [3–9]. Only after coming into close range do convective heat from skin and odors from volatile organic compounds come into play, allowing female mosquitoes to evaluate whether the object of interest might be a host [10, 11]. Here, using CRISPR/Cas9 we mutated the gene encoding Op1, which is the most abundant of the five rhodopsins expressed in the compound eyes ofAe. aegypti. Using a cage assay and a wind tunnel assay, we surprisingly found that elimination ofop1did not impair CO2-induced target seeking. We then mutatedop2, which encodes the rhodopsin most similar to Op1, and also found that there was no impact on this behavior. Rather, mutation of bothop1andop2was required to abolish vision-guided target recognition. In contrast to this defect, the double mutants still exhibited normal light attraction. By measuring the optomotor response, we found that the double mutants still recognized moving cues in their environment. In further support of the conclusion that the double mutant is not blind, we found that the animals retained an electrophysiological response to light, although it was diminished. This represents the first perturbation of vision in mosquitoes and indicates that hostseeking byAe. aegyptidepends on redundant rhodopsins.
A translational multiplex serology approach to profile the prevalence of anti-SARS-CoV-2 antibodies in home-sampled blood
Authors: Roxhed Niclas , Bendes Annika , Dale Matilda , Mattsson Cecilia , Hanke Leo , Dodig-Crnkovic Tea , Christian Murray , Meineke Birthe , Elsässer Simon , Andréll Juni , Havervall Sebastian , Thålin Charlotte , Eklund Carina , Dillner Joakim , Beck Olof , Thomas Cecilia E , McInerney Gerald , Hong Mun-Gwan , Murrell Ben , Fredolini Claudia , Schwenk Jochen M
Published: July 2020

The COVID-19 pandemic has posed a tremendous challenge for the global community. We established a translational approach combining home blood sampling by finger-pricking with multiplexed serology to assess the exposure to the SARS-CoV-2 virus in a general population. The developed procedure determines the immune response in multiplexed assays against several spike (S, here denoted SPK), receptor binding domain (RBD) and nucleocapsid (NCP) proteins in eluates from dried capillary blood. The seroprevalence was then determined in two study sets by mailing 1000 blood sampling kits to random households in urban Stockholm during early and late April 2020, respectively. After receiving 55% (1097/2000) of the cards back within three weeks, 80% (878/1097) were suitable for the analyses of IgG and IgM titers. The data revealed diverse pattern of immune response, thus seroprevalence was dependent on the antigen, immunoglobulin class, stringency to include different antigens, as well as the required analytical performance. Applying unsupervised dimensionality reduction to the combined IgG and IgM data, 4.4% (19/435; 95% CI: 2.4%-6.3%) and 6.3% (28/443; 95% CI: 4.1%-8.6%) of the samples clustered with convalescent controls. Using overlapping scores from at least two SPK antigens, prevalence rates reached 10.1% (44/435; 95% CI: 7.3%-12.9%) in study set 1 and 10.8% (48/443; 95% CI: 7.9%-13.7%). Measuring the immune response against several SARS-CoV-2 proteins in a multiplexed workflow can provide valuable insights about the serological diversity and improve the certainty of the classification. Combining such assays with home-sampling of blood presents a viable strategy for individual-level diagnostics and towards an unbiased assessment of the seroprevalence in a population and may serve to improve our understanding about the diversity of COVID-19 etiology.

One Sentence Summary

A multiplexed serology assay was developed to determine antibodies against SARS-CoV-2 proteins in home-sampled dried blood spots collected by finger pricking.
Social contact and inequalities in depression and loneliness among older adults: A mediation analysis of the English Longitudinal Study of Ageing
Authors: Green Michael J , Whitley Elise , Niedzwiedz Claire L , Shaw Richard J , Katikireddi S Vittal
Published: July 2020

Background

Social contact, including remote contact (by telephone, email, letter or text), could help reduce social inequalities in depression and loneliness among older adults.

Methods

Data were from the 8th wave of the English Longitudinal Study of Aging (2016/17), stratified by age (n=1,635 aged <65; n=4,123 aged 65+). Inverse probability weighting was used to estimate average effects of weekly in-person and remote social contact on depression (score of 3+ on 8-item CES-D scale) and two measures of loneliness (sometimes/often feels lonely vs hardly ever/never; and top quintile of UCLA loneliness scale vs all others). We also estimated controlled direct effects of education, partner status, and wealth on loneliness and depression under two scenarios: 1) universal infrequent (<weekly) in-person social contact; and 2) universal weekly remote social contact.

Results

Weekly in-person social contact was associated with reduced odds of depression and loneliness, but associations with remote social contact were weak. Lower education raised odds of depression and loneliness, but differences were attenuated with infrequent in-person contact. Respondents living alone experienced more depression and loneliness than those living with a partner, and less wealth was associated with more depression. With universal infrequent in-person contact, these differences narrowed among those aged under 65 but widened among those aged 65+. Universal weekly remote contact had little impact on inequalities.

Conclusions

Reduced in-person social contact may increase depression and loneliness among older adults, especially for those aged 65+ who live alone. Reliance on remote social contact seems unlikely to compensate for social inequalities.
Community vulnerability to epidemics in Nepal: A high-resolution spatial assessment amidst COVID-19 pandemic
Authors: Khanal Laxman , Paudel Binod Kumar , Acharya Bipin Kumar
Published: July 2020

The coronavirus disease 19 (COVID-19), the biggest health problem at present, doesn’t have uniform transmission and severity among the countries and communities therein. Knowledge of community vulnerability to the disease would facilitate interventions aimed at transmission control by the efficient deployment of available limited resources. Therefore, we assessed spatial variations and heterogeneity of disease vulnerability among the population in 753 municipal units of Nepal. We collected geospatial indicators representing the domain of socioeconomic inequalities, population dynamics, heterogeneity in accessibility and the information related to underlying health condition which potentially affect the severity of COVID-19 transmission. Those indicators were assembled to create three vulnerability indices using Geographic Information System (GIS); Social Vulnerability Index (SVI), Epidemiological Vulnerability Index (EVI) and a composite of the two- Social and Epidemiological Vulnerability Index (SEVI). The indicators were scaled to a common measurement scale and spatially overlaid via equally weighted arithmetic mean. The indices were classified into five level of risk and the municipal units and the population within vulnerabilities classes were quantified and visualized in the map. The index output indicated high vulnerability to epidemics in megacities like Kathmandu, Pokhara, Bharatpur, etc.; developing cities especially in the Province No 2; and, municipal units of Karnali and Sudoorpashchim provinces. Additionally, some other municipalities such as Dhulikhel, Beshishahar, Tansen etc. which have a higher prevalence of pulmonary and cardiovascular disorders are highly vulnerable. The SVI indicated that 174 municipal units and 41.5% population is highly vulnerable. The EVI identified 55 municipal units and 40.7% of the total population of the country highly vulnerable to COVID-19. The SEVI accounted that disease vulnerability is high in 105 municipal units and 40% population of Nepal. The vulnerability indices created are means for different tiers of the existing government in federal system of Nepal for prioritization and improved planning for disease intervention especially in highly vulnerable municipal units where the COVID-19 transmission could have high severity.
Resting heart rate as a biomarker for tracking change in cardiorespiratory fitness of UK adults: The Fenland Study
Authors: Gonzales Tomas I. , Jeon Justin Y. , Lindsay Timothy , Westgate Kate , Perez-Pozuelo Ignacio , Hollidge Stefanie , Wijndaele Katrien , Rennie Kirsten , Forouhi Nita , Griffin Simon , Wareham Nick , Brage Soren
Published: July 2020

Aims

Resting heart rate (RHR) is inversely associated with cardiorespiratory fitness (CRF) but few studies have investigated the nature of this relationship in large population samples. We examined the association between RHR and CRF in UK adults and explored factors that may influence this relationship.

Methods and Results

In a population-based sample of 5,143 men and 5,722 women (aged 29-65 years), mean (SD) RHR while seated, supine, and during sleep was 67.6 (9.8), 63.5 (8.9), and 56.9 (6.9) bpm, respectively. The age- and sex-adjusted association with CRF as assessed by submaximal treadmill testing was −0.26 (95%CI −0.27; −0.24), −0.31 (95%CI −0.33; −0.29), and −0.31 (95%CI −0.34; −0.29) ml O2 kg-1 beat-1. Sequential adjustment for objectively measured obesity and physical activity attenuated the RHR coefficient by 10% and 50%, respectively. In longitudinal analyses of 6,589 participants re-examined after 6 years, each 1 bpm increase in supine RHR was associated with 0.23 (95%CI 0.20; 0.25) ml O2 min-1 kg-1 decrease in CRF.

Conclusions

Across all measures, RHR is inversely associated with CRF; half of this association is explained by obesity and physical activity, suggesting CRF changes achieved through altered behaviour could be tracked through changes in RHR, a notion supported by longitudinal results. As well as its utility as a biomarker of CRF at population-level, serial measurements of RHR may facilitate personal goal setting/evaluation and remote patient monitoring.
Mass Screening for SARS-CoV-2 Infection among Residents and Staff in Twenty-eight Long-term Care Facilities in Fulton County, Georgia
Authors: Telford Carson , Onwubiko Udodirim , Holland David , Turner Kim , Prieto Juliana , Smith Sasha , Yoon Jane , Brown Wecheeta , Chamberlain Allison , Gandhi Neel , Khan Shamimul , Williams Steve , Khan Fazle , Shah Sarita
Published: July 2020

Mass screening for SARS-CoV-2 infection in long-term care facilities revealed significantly higher prevalence of infection in facilities that screened in response to a known infection compared to those that screened as a prevention measure. “Response” facilities had a SARS-CoV-2 prevalence of 28.9% while “preventive” facilities’ prevalence was 1.6% (p <0.001).
Phenoflow: A Microservice Architecture for Portable Workflow-based Phenotype Definitions
Authors: Chapman Martin , Rasmussen Luke V. , Pacheco Jennifer A. , Curcin Vasa
Published: July 2020

Phenotyping is an effective way to identify cohorts of patients with particular characteristics within a population. In order to enhance the portability of a phenotype definition across institutions, it is often defined abstractly, with implementers expected to realise the phenotype computationally before executing it against a dataset. However, unclear definitions, with little information about how best to implement the definition in practice, hinder this process. To address this issue, we propose a new multi-layer, workflow-based model for defining phenotypes, and a novel authoring architecture, Phenoflow, that supports the development of these structured definitions and their realisation as computable phenotypes. To evaluate our model, we determine its impact on the portability of both code-based (COVID-19) and logic-based (diabetes) definitions, in the context of key datasets, including 26,406 patients at North-western University. Our approach is shown to ensure the portability of phenotype definitions and thus contributes to the transparency of resulting studies.
Evaluating the effectiveness of the smartphone app, Drink Less, compared with the NHS alcohol advice webpage, for the reduction of alcohol consumption among hazardous and harmful adult drinkers in the UK at six-month follow-up: protocol for a randomised controlled trial
Authors: Garnett Claire , Oldham Melissa , Angus Colin , Beard Emma , Burton Robyn , Field Matt , Greaves Felix , Hickman Matthew , Kaner Eileen , Loebenberg Gemma , Michie Susan , Munafò Marcus , Pizzo Elena , Brown Jamie
Published: July 2020

Background and Aims

Digital interventions are effective for reducing alcohol consumption but evidence is limited regarding smartphone apps. Drink Less is a theory- and evidence-informed app to help people reduce their alcohol consumption that has been refined in terms of its content and design for usability across the socio-demographic spectrum. We aim to evaluate the effectiveness and cost-effectiveness of recommending Drink Less at reducing alcohol consumption compared with usual digital care.

Design

Two-arm individually randomised controlled trial.

Setting

Online trial in the UK.

Participants

Hazardous or harmful drinkers (Alcohol Use Disorders Identification Test score >=8) aged 18+, and want to drink less alcohol (n=5,562). Participants will be recruited from July 2020 to May 2022 using multiple strategies with a focus on remote digital methods.

Intervention and comparator

Participants will be randomised to receive either an email recommending that they use Drink Less (intervention) or view the NHS webpage on alcohol advice (comparator).

Measurements

The primary outcome is change in self-reported weekly alcohol consumption between baseline and 6-month follow-up. Secondary outcomes include the proportion of hazardous drinkers; alcohol-related problems and injury; health-related quality of life, and use of health services assessed at 6-month follow-up. Effectiveness will be examined with one-way ANCOVAs, adjusting for baseline alcohol consumption, and using an intention-to-treat approach. A mixed-methods process evaluation will assess engagement, acceptability and mechanism of action. Economic evaluations will be conducted using both a short- and longer-term time horizon.

Comments

This study will establish the effectiveness and cost-effectiveness of the Drink Less app at reducing alcohol consumption among hazardous and harmful adult drinkers and will be the first RCT of an alcohol reduction app for the general population in the UK. This study will inform the decision on whether it is worth investing resources in large-scale implementation.
Sensitive detection of SARS-CoV-2-specific-antibodies in dried blood spot samples
Authors: Morley Gabriella L. , Taylor Stephen , Jossi Sian , Perez-Toledo Marisol , Faustini Sian E. , Marcial-Juarez Edith , Shields Adrian M. , Goodall Margaret , Allen Joel D. , Watanabe Yasunori , Newby Maddy L. , Crispin Max , Drayson Mark T. , Cunningham Adam F. , Richter Alex G. , O’Shea Matthew K.
Published: July 2020

Importance

Population-wide serological testing is an essential component in understanding the COVID-19 pandemic. The logistical challenges of undertaking widespread serological testing could be eased through use of a reliable dried blood spot (DBS) sampling method.

Objective

To validate the use of dried blood spot sampling for the detection of SARS-CoV-2-specific antibodies.

Design, setting and participants

Eighty-seven matched DBS and serum samples were obtained from eighty individuals, including thirty-one who were previously PCR-positive for SARS-CoV-2. DBS eluates and sera were used in an ELISA to detect antibodies to the viral spike protein.

Results

Specific anti-SARS-Cov-2 spike glycoprotein antibodies were detectable in both serum and DBS eluate and there was a significant correlation between the antibody levels detected in matched samples (r = 0.96, p<0.0001). Using serum as the gold standard in the assay, matched DBS samples achieved a Cohen’s kappa coefficient of 0.975 (near-perfect agreement), a sensitivity of 98.1% and specificity of 100%, for detecting anti-spike glycoprotein antibodies.

Conclusions and relevance

Eluates from DBS samples are a reliable and reproducible source of antibodies to be used for the detection of SARS-CoV-2-specific antibodies. The use of DBS sampling could complement the use of venepuncture in the immunosurveillance of COVID-19 in both low and high income settings.