bluuebunny/crossref_metadata_2025 huggingface dataset:
Treadmilling and dynamic protrusions in fire ant rafts
Authors: Wagner Robert J. , Such Kristen , Hobbs Ethan , Vernerey Franck J.
Published: June 2021

Fire ants (
Solenopsis invicta
) are exemplary for their formation of cohered, buoyant and dynamic structures composed entirely of their own bodies when exposed to flooded environments. Here, we observe tether-like protrusions that emerge from aggregated fire ant rafts when docked to stationary, vertical rods. Ant rafts comprise a floating, structural network of interconnected ants on which a layer of freely active ants walk. We show here that sustained shape evolution is permitted by the competing mechanisms of perpetual raft contraction aided by the transition of bulk structural ants to the free active layer and outward raft expansion owing to the deposition of free ants into the structural network at the edges, culminating in global treadmilling. Furthermore, we see that protrusions emerge as a result of asymmetries in the edge deposition rate of free ants. Employing both experimental characterization and a model for self-propelled particles in strong confinement, we interpret that these asymmetries are likely to occur stochastically owing to wall accumulation effects and directional motion of active ants when strongly confined by the protrusions' relatively narrow boundaries. Together, these effects may realize the cooperative, yet spontaneous formation of protrusions that fire ants sometimes use for functional exploration and to escape flooded environments.
Determination of the membrane topology of PORCN, an O-acyl transferase that modifies Wnt signalling proteins
Authors: Galli Lisa M. , Anderson Marc O. , Gabriel Fraley J. , Sanchez Luis , Bueno Raymund , Hernandez David N. , Maddox Eva U. , Lingappa Vishwanath R. , Burrus Laura W.
Published: June 2021

Wnt gradients elicit distinct cellular responses, such as proliferation, specification, differentiation and survival in a dose-dependent manner. Porcupine (PORCN), a membrane-bound O-acyl transferase (MBOAT) that resides in the endoplasmic reticulum, catalyses the addition of monounsaturated palmitate to Wnt proteins and is required for Wnt gradient formation and signalling. In humans, PORCN mutations are causal for focal dermal hypoplasia (FDH), an X-linked dominant syndrome characterized by defects in mesodermal and endodermal tissues. PORCN is also an emerging target for cancer therapeutics. Despite the importance of this enzyme, its structure remains poorly understood. Recently, the crystal structure of DltB, an MBOAT family member from bacteria, was solved. In this report, we use experimental data along with homology modelling to DltB to determine the membrane topology of PORCN. Our studies reveal that PORCN has 11 membrane domains, comprising nine transmembrane spanning domains and two reentrant domains. The N-terminus is oriented towards the lumen while the C-terminus is oriented towards the cytosol. Like DltB, PORCN has a funnel-like structure that is encapsulated by multiple membrane-spanning helices. This new model for PORCN topology allows us to map residues that are important for biological activity (and implicated in FDH) onto its three-dimensional structure.
Therapeutic potential of astaxanthin and superoxide dismutase in Alzheimer's disease
Authors: Balendra Vyshnavy , Singh Sandeep Kumar
Published: June 2021

Oxidative stress, the imbalance of the antioxidant system, results in an accumulation of neurotoxic proteins in Alzheimer's disease (AD). The antioxidant system is composed of exogenous and endogenous antioxidants to maintain homeostasis. Superoxide dismutase (SOD) is an endogenous enzymatic antioxidant that converts superoxide ions to hydrogen peroxide in cells. SOD supplementation in mice prevented cognitive decline in stress-induced cells by reducing lipid peroxidation and maintaining neurogenesis in the hippocampus. Furthermore, SOD decreased expression of BACE1 while reducing plaque burden in the brain. Additionally, Astaxanthin (AST), a potent exogenous carotenoid, scavenges superoxide anion radicals. Mice treated with AST showed slower memory decline and decreased depositions of amyloid-beta (Aβ) and tau protein. Currently, the neuroprotective potential of these supplements has only been examined separately in studies. However, a single antioxidant cannot sufficiently resist oxidative damage to the brain, therefore, a combinatory approach is proposed as a relevant therapy for ameliorating pathological changes in AD.
The role of lipid droplets in microbial pathogenesis
Authors: Brink Jacobus T. R. , Fourie Ruan , Sebolai Olihile , Albertyn Jacobus , Pohl Carolina H.
Published: June 2021

The nonpolar lipids present in cells are mainly triacylglycerols and steryl esters. When cells are provided with an abundance of nutrients, these storage lipids accumulate. As large quantities of nonpolar lipids cannot be integrated into membranes, they are isolated from the cytosolic environment in lipid droplets. As specialized, inducible cytoplasmic organelles, lipid droplets have functions beyond the regulation of lipid metabolism, in cell signalling and activation, membrane trafficking and control of inflammatory mediator synthesis and secretion. Pathogens, including fungi, viruses, parasites, or intracellular bacteria can induce and may benefit from lipid droplets in infected cells. Here we review biogenesis of lipid droplets as well as the role of lipid droplets in the pathogenesis of selected viruses, bacteria, protists and yeasts.
Multiple evolutionary origins reflect the importance of sialic acid transporters in the colonization potential of bacterial pathogens and commensals
Authors: Severi Emmanuele , Rudden Michelle , Bell Andrew , Palmer Tracy , Juge Nathalie , Thomas Gavin H.
Published: June 2021

Located at the tip of cell surface glycoconjugates, sialic acids are at the forefront of host–microbe interactions and, being easily liberated by sialidase enzymes, are used as metabolites by numerous bacteria, particularly by pathogens and commensals living on or near diverse mucosal surfaces. These bacteria rely on specific transporters for the acquisition of host-derived sialic acids. Here, we present the first comprehensive genomic and phylogenetic analysis of bacterial sialic acid transporters, leading to the identification of multiple new families and subfamilies. Our phylogenetic analysis suggests that sialic acid-specific transport has evolved independently at least eight times during the evolution of bacteria, from within four of the major families/superfamilies of bacterial transporters, and we propose a robust classification scheme to bring together a myriad of different nomenclatures that exist to date. The new transporters discovered occur in diverse bacteria, including

Spirochaetes

,

Bacteroidetes

,

Planctomycetes

and

Verrucomicrobia

, many of which are species that have not been previously recognized to have sialometabolic capacities. Two subfamilies of transporters stand out in being fused to the sialic acid mutarotase enzyme, NanM, and these transporter fusions are enriched in bacteria present in gut microbial communities. Our analysis supports the increasing experimental evidence that competition for host-derived sialic acid is a key phenotype for successful colonization of complex mucosal microbiomes, such that a strong evolutionary selection has occurred for the emergence of sialic acid specificity within existing transporter architectures.
Sequencing SARS-CoV-2 Genomes from Saliva
Authors: Alpert Tara , Vogels Chantal B.F. , Breban Mallery I. , Petrone Mary E. ,   Yale IMPACT Research Team, Wyllie Anne L. , Grubaugh Nathan D. , Fauver Joseph R.
Published: June 2021

Genomic sequencing is crucial to understanding the epidemiology and evolution of SARS-CoV-2. Often, genomic studies rely on remnant diagnostic material, typically nasopharyngeal swabs, as input into whole genome SARS-CoV-2 next-generation sequencing pipelines. Saliva has proven to be a safe and stable specimen for the detection of SARS-CoV-2 RNA via traditional diagnostic assays, however saliva is not commonly used for SARS-CoV-2 sequencing. Using the ARTIC Network amplicon-generation approach with sequencing on the Oxford Nanopore MinION, we demonstrate that sequencing SARS-CoV-2 from saliva produces genomes comparable to those from nasopharyngeal swabs, and that RNA extraction is necessary to generate complete genomes from saliva. In this study, we show that saliva is a useful specimen type for genomic studies of SARS-CoV-2.
Japanese Project for Telepsychiatry Evaluation during COVID-19: Treatment Comparison Trial (J-PROTECT): Rationale, design, and methodology
Authors: Kishimoto Taishiro , Kinoshita Shotaro , Bun Shogyoku , Sato Yasunori , Kitazawa Momoko , Kikuchi Toshiaki , Sado Mitsuhiro , Takamiya Akihiro , Mimura Masaru , Nakamae Takashi , Abe Yoshinari , Kanazawa Tetsufumi , Kawabata Yasuo , Tomita Hiroaki , Abe Koichi , Hishimoto Akitoyo , Asami Takeshi , Suda Akira , Watanabe Yoshinori , Amagai Toru , Sakuma Kei , Kida Hisashi , Funayama Michitaka , Kimura Hiroshi , Sato Aiko , Fujiwara Shuichiro , Nagao Kiichiro , Sugiyama Naoya , Takamiya Maki , Kodama Hideyuki , Azekawa Takaharu
Published: June 2021

Introduction

The COVID-19 pandemic has had a profound impact on the mental health of people around the world. Anxiety related to infection, stress and stigma caused by the forced changes in daily life have reportedly increased the incidence and symptoms of depression, anxiety disorder and obsessive-compulsive disorder. Under such circumstances, telepsychiatry is gaining importance and attracting a great deal of attention. However, few large pragmatic clinical trials on the use of telepsychiatry targeting multiple psychiatric disorders have been conducted to date.

Methods

The targeted study cohort will consist of adults (>18 years) who meet the DSM-5 diagnostic criteria for either (1) depressive disorders, (2) anxiety disorders, or (3) obsessive-compulsive and related disorders. Patients will be assigned in a 1:1 ratio to either a “telepsychiatry group” (at least 50% of visits to be conducted using telemedicine, with at least one face-to-face treatment [FTF] every six months) or an “FTF group” (all visits to be conducted FTF, with no telemedicine). Both groups will receive the usual treatment covered by public medical insurance. The study will utilize a master protocol design in that there will be primary and secondary outcomes for the entire group regardless of diagnosis, as well as the outcomes for each individual disorder group.

Discussion

This study will be a non-inferiority trial to test that the treatment effect of telepsychiatry is not inferior to that of FTF alone. This study will provide useful insights into the effect of the COVID-19 pandemic on the practice of psychiatry.

Trial Registration

jRCT1030210037, Japan Registry of Clinical Trials (jRCT)
Age-dependent inequalities in HIV/STI burden and care receipt among men and transgender persons who have sex with men in Nairobi
Authors: Smith Adrian D , Fearon Elizabeth , Kabuti Rhoda , Irungu Erastus , Kungu Mary , Babu Hellen , Nyabuto Chrispo , Muthoga Peter , Weatherburn Peter , Bourne Adam , Kimani Joshua
Published: June 2021

Background

Gay, bisexual and other men who have sex with men (GBMSM) and transgender persons (TP) bear high burdens of HIV and other sexually transmitted infections (STIs) in sub-Saharan Africa, yet evidence of HIV care coverage for these groups is sparse from the region despite prevailing stigma and discrimination towards these groups.

Methods

618 GBMSM/TP were recruited in Nairobi between May to December 2017 using respondent-driven sampling. Participants reported recent sexual behaviour, HIV testing and care receipt, and symptoms of STIs. Participants tested for HIV using Kenyan testing algorithms and GeneXpert methods, syphilis, viral hepatitis and ano-genital gonorrhoea and chlamydia. We assessed associations with HIV status and detectable HIV viral load using multivariable robust Poisson regression models.

Findings

26.4% (286/618) were HIV positive of whom 76.5% were status aware, 65.3% were on ART, and 47.4% were virally suppressed (<50 copies/ml). Participants 18-22 years old were less likely to be status aware, be receiving ART or to have achieved viral suppression. Mean log viral load was 3.14 log higher in 18-22 year olds compared to older participants. Bacterial STIs were frequently detected at both urethral and rectal sites and a majority of infections at both sites were asymptomatic by self-report (rectal 82.2%, urethral 90.8%).

Interpretation

Engagement in the HIV diagnosis and care cascade among GBMSM/TP in Kenya is markedly better than in most sub-Saharan African countries. However it falls short of achievements among the general population in the country and cascades achieved in GBMSM in high income settings. Young men and transgender persons who have sex with men are least well served by the current configuration of adult key population services, and programmes should identify and address the sexual, social and developmental needs of adolescent and young key populations
The effect of D-cycloserine on brain processing of breathlessness over pulmonary rehabilitation - an experimental medicine study
Authors: Finnegan Sarah L. , Harrison Olivia K. , Booth Sara , Dennis Andrea , Ezra Martyn , Harmer Catherine J. , Herigstad Mari , Guillaume Bryan , Nichols Thomas E. , Rahman Najib M. , Reinecke Andrea , Renaud Olivier , Pattinson Kyle T.S.
Published: June 2021

Background

Pulmonary rehabilitation is the best treatment for chronic breathlessness in COPD but there remains an unmet need to improve efficacy. Pulmonary rehabilitation has strong parallels with exposure-based cognitive behavioural therapies (CBT), both clinically and in terms of brain activity patterns. The partial NMDA-receptor agonist, D-cycloserine has shown promising results in enhancing efficacy of CBT, thus we hypothesised that it would similarly augment the effects of pulmonary rehabilitation in the brain. Positive findings would support further development in phase 3 clinical trials.

Methods

72 participants with mild-to-moderate COPD were recruited to a double-blind pre-registered (ID: NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250mg D-cycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences between D-cycloserine and placebo in brain activity in the anterior insula, posterior insula, anterior cingulate cortices, amygdala and hippocampus following completion of pulmonary rehabilitation. Secondary outcomes included the same measures at an intermediate time point and voxel-wise difference across wider brain regions.

Results

No difference between D-cycloserine and placebo groups was observed across the primary or secondary outcome measures. Questionnaire and measures of respiratory function showed no group difference.

Conclusions

This is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power. Although increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial of D-cycloserine would not be worthwhile.

Key Messages

What is the key question?

Does the partial NMDA-receptor agonist, D-cycloserine, augment the effects of pulmonary rehabilitation on breathlessness related brain activity?

What is the bottom line?

Rigorous trial methodology and validated surrogate end-points revealed no effect of D-cycloserine on breathlessness related brain activity across pulmonary rehabilitation.

Why read on?

This study highlights both the value of functional magnetic resonance imaging in “de-risking” expensive clinical trials and provides detailed investigation of brain-targeted points for pharmacological treatments of breathlessness.
Using deep learning to predict age from liver and pancreas magnetic resonance images allows the identification of genetic and non-genetic factors associated with abdominal aging
Authors: Le Goallec Alan , Diai Samuel , Collin Sasha , Prost Jean-Baptiste , Vincent Théo , Patel Chirag J.
Published: June 2021

With age, abdominal organs and tissue undergo important changes. For example, liver volume declines, fatty replacement increases in the pancreas, and patients become more vulnerable to age-related diseases such as non-alcoholic fatty liver disease, alcoholic liver disease, hepatitis, fibrosis, cirrhosis, type two diabetes, cancer, gallstones and inflammatory pancreatic disease. Detecting early abdominal aging and identifying factors associated with this phenotype could help delay the onset of such diseases. In the following, we built the first abdominal age predictor by training convolutional neural networks to predict age from 45,552 liver magnetic resonance images [MRIs] and 36,784 pancreas MRIs (R-Squared=73.3±0.6; root mean squared error=3.70±0.03). Attention maps show that the prediction is driven not only by liver and pancreas anatomical features, but also by surrounding organs and tissue. We defined accelerated abdominal aging as the difference between abdominal age and chronological age, a phenotype which we found to be partially heritable (h_g2=26.3±1.9%). Accelerated abdominal aging is associated with seven single nucleotide polymorphisms in six genes (e.g PNPT1, involved in RNA metabolic processes). Similarly, it is associated with biomarkers (e.g body impedance), clinical phenotypes (e.g chest pain), diseases (e.g hypertension), environmental (e.g smoking) and socioeconomic (e.g education) variables, suggesting potential therapeutic and lifestyle interventions to slow abdominal aging. Our predictor could be used to assess the efficacy or emerging rejuvenating therapies on the abdomen.
Assessment of COVID-19 vaccine hesitancy among Zimbabweans: A rapid national survey
Authors: Mundagowa Paddington T. , Tozivepi Samantha N. , Chiyaka Edward T. , Mukora-Mutseyekwa Fadzai , Makurumidze Richard
Published: June 2021

Background

To minimise the devastating effects of the coronavirus disease 2019 (COVID-19) pandemic, scientists hastily developed a vaccine. However, the scale-up of the vaccine is likely to be hindered by the widespread social media misinformation. We, therefore, conducted a study to assess the COVID-19 vaccine hesitancy among Zimbabweans.

Methods

We conducted a descriptive online cross-sectional survey using a self-administered questionnaire among adults. The questionnaire assessed willingness to be vaccinated; socio-demographic characteristics, individual attitudes and perceptions, effectiveness, and safety of the vaccine. Multivariable logistic regression analysis was utilized to examine the independent factors associated with vaccine uptake.

Results

We analysed data for 1168 participants, age range of 19-89 years with the majority being females (57.5%). Half (49.9%) of the participants reported that they would accept the COVID-19 vaccine. The majority were uncertain about the effectiveness of the vaccine (76.0%) and its safety (55.0%). About half lacked trust in the government’s ability to ensure the availability of an effective vaccine and 61.0% mentioned that they would seek advice from a healthcare worker to vaccinate. Age 55 years and above [vs 18-25 years - Adjusted Odds Ratio (AOR): 2.04, 95% Confidence Interval (CI): 1.07-3.87], chronic disease [vs no chronic disease - AOR: 1.72, 95%CI: 1.32-2.25], males [vs females - AOR: 1.84, 95%CI: 1.44-2.36] and being a healthcare worker [vs not being a health worker – AOR: 1.73, 95%CI: 1.34-2.24] were associated with increased likelihood to vaccinate. History of COVID-19 infection [vs no history - AOR: 0.45, 95%CI: 0.25-0.81) and rural residence [vs urban - AOR: 0.64, 95%CI: 0.40-1.01] were associated with reduced likelihood to vaccinate.

Conclusion

We found half of the participants willing to vaccinate against COVID-19. The majority lacked trust in the government and were uncertain about vaccine effectiveness and safety. The policymakers should consider targeting geographical and demographic groups which were unlikely to vaccinate with vaccine information, education, and communication to improve uptake.
Improvement of behavioural pattern and alpha-synuclein levels in autism spectrum disorder after consumption of a beta-glucan food supplement in a randomized, parallel-group pilot clinical study
Authors: Raghavan Kadalraja , Dedeepiya Vidyasagar Devaprasad , Ikewaki Nobunao , Sonoda Tohru , Iwasaki Masaru , Preethy Senthilkumar , Abraham Samuel JK
Published: June 2021

Background

Autism spectrum disorders (ASDs) are a wide range of behavioural disabilities for which there are no definite interventional modalities available. Remedial therapies remain the only option but with varying outcomes. We have evaluated the childhood autism rating scale (CARS) and alpha-synuclein levels in this parallel-group, multiple-arm pilot clinical study after supplementation with a biological response modifier beta-glucan food supplement (Nichi Glucan).

Methods

Six subjects with ASD (n = 6) Gr. 1 underwent conventional treatment comprising remedial behavioural therapies and L-carnosine 500 mg per day, and 12 subjects (n = 12) Gr. 2 underwent supplementation with the Nichi Glucan 0.5 g twice daily along with the conventional treatment.

Results

There was a significant decrease in the CARS score in all of the children of the Nichi Glucan Gr.2 compared to the control (p-value = 0.034517). Plasma levels of alpha-synuclein were significantly higher in Gr. 2 (Nichi Glucan) than in the control group Gr. 1 (p-value = 0.091701).

Conclusion

Improvement of the behavioural pattern CARS score and a correlating alpha-synuclein level, followed by a safe beta-glucan food supplement, warrants further research on other parameters, such as gut-microbiota evaluation, and relevant neuronal biomarkers which is likely to cast light on novel solutions.
Exploration and analysis of molecularly annotated, 3D models of breast cancer at single-cell resolution using virtual reality
Authors: Bressan Dario , Mulvey Claire M. , Qosaj Fatime , Becker Robert , Grimaldi Flaminia , Coffey Suvi , Vogl Sara Lisa , Kuett Laura , Catena Raul , Dariush Ali , Gonzalez-Fernandez Carlos , Gonzalez-Solares Eduardo A. , Sa’d Mohammad Al , Yoldaş Aybüke Küpcü , Whitmarsh Tristan , Falciatori Ilaria , Watson Spencer S. ,   CRUK IMAXT Grand Challenge Team, Joyce Johanna A. , Walton Nicholas , Bodenmiller Bernd , Harris Owen , Hannon Gregory J.
Published: June 2021

A set of increasingly powerful approaches are enabling spatially resolved measurements of growing numbers of molecular features in biological samples. While important insights can be derived from the two-dimensional data that many of these technologies generate, it is clear that extending these approaches into the third and fourth dimensions will magnify their impact. Realizing biological insights from datasets where thousands to millions of cells are annotated with tens to hundreds of parameters in space will require the development of new computational and visualization strategies. Here, we describe Theia, a virtual reality-based platform, which enables exploration and analysis of either volumetric or segmented, molecularly-annotated, three-dimensional datasets, with the option to extend the analysis to time-series data. We also describe our pipeline for generating annotated 3D models of breast cancer and supply several datasets to enable users to explore the utility of Theia for understanding cancer biology in three dimensions.
Anoikis resistance in mammary epithelial cells is mediated by semaphorin 7a Semaphorin-7A and anoikis resistance
Authors: Rutherford Taylor R. , Elder Alan M , Lyons Traci R.
Published: June 2021

Semaphorin-7a (SEMA7A), best known as a neuroimmune molecule, plays a diverse role in many cellular processes and pathologies. Here, we show that SEMA7A promotes anoikis resistance in cultured mammary epithelial cells through integrins and activation of pro-survival kinase AKT, which led us to investigate a role for SEMA7A during postpartum mammary gland involution—a normal developmental process where cells die by anoikis. Our results reveal that SEMA7A is expressed on live mammary epithelial cells during involution, that SEMA7A expression is primarily observed in α6-integrin expressing cells, and that luminal progenitor cells, specifically, are decreased in mammary glands of SEMA7A−/− mice during involution. We further identify a SEMA7A-α6/β1-integrin dependent mechanism of mammosphere formation and chemoresistance in mammary epithelial cells and suggest that this mechanism is relevant for recurrence in breast cancer patients.
Predicting protein-membrane interfaces of peripheral membrane proteins using ensemble machine learning
Authors: Chatzigoulas Alexios , Cournia Zoe
Published: June 2021

Abnormal protein-membrane attachment is involved in deregulated cellular pathways and in disease. Therefore, the possibility to modulate protein-membrane interactions represents a new promising therapeutic strategy for peripheral membrane proteins that have been considered so far undruggable. A major obstacle in this drug design strategy is that the membrane binding domains of peripheral membrane proteins are usually not known. The development of fast and efficient algorithms predicting the protein-membrane interface would shed light into the accessibility of membrane-protein interfaces by drug-like molecules. Herein, we describe an ensemble machine learning methodology and algorithm for predicting membrane-penetrating amino acids. We utilize available experimental data in the literature for training 21 machine learning classifiers and a voting classifier. Evaluation of the ensemble classifier accuracy produced a macro-averaged F1score = 0.92 and an MCC = 0.84 for predicting correctly membrane-penetrating amino acids on unknown proteins of an independent test set. The python code for predicting protein-membrane interfaces of peripheral membrane proteins is available athttps://github.com/zoecournia/DREAMM.
OpenNeuro: An open resource for sharing of neuroimaging data
Authors: Markiewicz Christopher J. , Gorgolewski Krzysztof J. , Feingold Franklin , Blair Ross , Halchenko Yaroslav O. , Miller Eric , Hardcastle Nell , Wexler Joe , Esteban Oscar , Goncalves Mathias , Jwa Anita , Poldrack Russell A.
Published: June 2021

The sharing of research data is essential to ensure reproducibility and maximize the impact of public investments in scientific research. Here we describe OpenNeuro, a BRAIN Initiative data archive that provides the ability to openly share data from a broad range of brain imaging data types following the FAIR principles for data sharing. We highlight the importance of the Brain Imaging Data Structure (BIDS) standard for enabling effective curation, sharing, and reuse of data. The archive presently shares more than 600 datasets including data from more than 20,000 participants, comprising multiple species and measurement modalities and a broad range of phenotypes. The impact of the shared data is evident in a growing number of published reuses, currently totalling more than 150 publications. We conclude by describing plans for future development and integration with other ongoing open science efforts.
Reactivities of the Front Pocket N-Cap Cysteines in Human Kinases
Authors: Liu Ruibin , Zhan Shaoqi , Che Ye , Shen Jana
Published: June 2021

Discovery of targeted covalent inhibitors directed at nucleophilic cysteines is attracting enormous interest. The front pocket (FP) N-cap cysteine has been the most popular site of covalent modification in kinases. Curiously, a long-standing hypothesis associates the N-cap position with cysteine hyper-reactivity; however, traditional computational methods suggest that the FP N-cap cysteines in all human kinases are predominantly unreactive at physiological pH. Here we applied a newly developed GPU-accelerated continuous constant pH molecular dynamics (CpHMD) tool to test the N-cap hypothesis and elucidate the cysteine reactivities. Simulations showed that the N-cap cysteines in BTK/BMX/TEC/ITK/TXK, JAK3, and MKK7 sample the reactive thiolate form to varying degrees at physiological pH; however, those in BLK and EGFR/ERBB2/ERBB4 which contain an Asp at the N-cap+3 position adopt the unreactive thiol form. The latter argues in favor of the base-assisted thiol-Michael addition mechanisms as suggested by the quantum mechanical calculations and experimental structure-function studies of EGFR inhibitors. Analysis revealed that the reactive N-cap cysteines are stabilized by hydrogen bond as well as electrostatic interactions, and in their absence a N-cap cysteine is unreactive due to desolvation. To test a corollary of the N-cap hypothesis, we also examined the reactivities of the FP N-cap+2 cysteines in JNK1/JNK2/JNK3 and CASK. Additionally, our simulations predicted the reactive cysteine and lysine locations in all 15 kinases. Our findings offer a systematic understanding of cysteine reactivities in kinases and demonstrate the predictive power and physical insights CpHMD can provide to guide the rational design of targeted covalent inhibitors.
31,600-year-old human virus genomes support a Pleistocene origin for common childhood infections
Authors: Nielsen Sofie Holtsmark , van Dorp Lucy , Houldcroft Charlotte J. , Pedersen Anders G. , Allentoft Morten E. , Vinner Lasse , Margaryan Ashot , Pavlova Elena , Chasnyk Vyacheslav , Nikolskiy Pavel , Pitulko Vladimir , Pimenoff Ville N. , Balloux François , Sikora Martin
Published: June 2021

The origins of viral pathogens and the age of their association with humans remains largely elusive. To date, there is no direct evidence about the diversity of viral infections in early modern humans pre-dating the Holocene. We recovered two near-complete genomes (5.2X and 0.7X) of human adenovirus C (HAdV-C), as well as low-coverage genomes from four distinct species of human herpesvirus obtained from two 31,630-year-old milk teeth excavated at Yana, in northeastern Siberia. Phylogenetic analysis of the two HAdV-C genomes suggests an evolutionary origin around 700,000 years ago consistent with a common evolutionary history with hominin hosts. Our findings push back the earliest direct molecular evidence for human viral infections by ∼25,000 years, and demonstrate that viral species causing common childhood viral infections today have been in circulation in humans at least since the Pleistocene.
Directly interfacing brain and deep networks exposes non-hierarchical visual processing
Authors: Sexton Nicholas J. , Love Bradley C.
Published: June 2021

One reason the mammalian visual system is viewed as hierarchical, such that successive stages of processing contain ever higher-level information, is because of functional correspondences with deep convolutional neural networks (DCNNs). However, these correspondences between brain and model activity involve shared, not task-relevant, variance. We propose a stricter test of correspondence: If a DCNN layer corresponds to a brain region, then replacing model activity with brain activity should successfully drive the DCNN’s object recognition decision. Using this approach on three datasets, we found all regions along the ventral visual stream best corresponded with later model layers, indicating all stages of processing contained higher-level information about object category. Time course analyses suggest long-range recurrent connections transmit object class information from late to early visual areas.
Crystal structures of HER3 extracellular domain 4 in complex with the designed ankyrin-repeat protein D5
Authors: Radom Filip , Vonrhein Clemens , Mittl Peer R. E. , Plückthun Andreas
Published: June 2021

The members of the human epidermal growth factor receptor (HER) family are among the most intensely studied oncological targets. HER3 (ErbB3), which had long been neglected, has emerged as a key oncogene, regulating the activity of other receptors and being involved in progression and tumor escape in multiple types of cancer. Designed ankyrin-repeat proteins (DARPins) serve as antibody mimetics that have proven to be useful in the clinic, in diagnostics and in research. DARPins have previously been selected against EGFR (HER1), HER2 and HER4. In particular, their combination into bivalent binders that separate or lock receptors in their inactive conformation has proved to be a promising strategy for the design of potent anticancer therapeutics. Here, the selection of DARPins targeting extracellular domain 4 of HER3 (HER3d4) is described. One of the selected DARPins, D5, in complex with HER3d4 crystallized in two closely related crystal forms that diffracted to 2.3 and 2.0 Å resolution, respectively. The DARPin D5 epitope comprises HER3d4 residues 568–577. These residues also contribute to interactions within the tethered (inactive) and extended (active) conformations of the extracellular domain of HER3.
Evaluation of automated particle picking for cryogenic electron microscopy using high-precision transmission electron microscope simulation based on a multi-slice method
Authors: Ohashi Masataka , Hosokawa Fumio , Shinkawa Takao , Iwasaki Kenji
Published: June 2021

This work describes the GRIPS automated particle-picking software for cryogenic electron microscopy and the evaluation of this software using elbis, a high-precision transmission electron microscope (TEM) image simulator. The goal was to develop a method that can pick particles under a small defocus condition where the particles are not clearly visible or under a condition where the particles are exhibiting preferred orientation. The proposed method handles these issues by repeatedly performing three processes, namely extraction, two-dimensional classification and positioning, and by introducing mask processing to exclude areas with particles that have already been picked. TEM images for evaluation were generated with a high-precision TEM image simulator. TEM images containing both particles and amorphous ice were simulated by randomly placing O atoms in the specimen. The experimental results indicate that the proposed method can be used to pick particles correctly under a relatively small defocus condition. Moreover, the results show that the mask processing introduced in the proposed method is valid for particles exhibiting preferred orientation. It is further shown that the proposed method is applicable to data collected from real samples.
Attracting CEO directors: the case of Latin America
Authors: Rivas Jose Luis , Villamil-Diaz Jairo , Cannella Albert
Published: June 2021

Purpose

To understand if certain board traits can contribute to attract CEO directors

Design/methodology/approach

Panel data model with firm fixed effects of individual and firm level attributes from 450 public firms in Argentina, Brazil, Chile, Colombia, Mexico and Peru

Findings

Higher levels of masters abroad, board ties, government experience and foreign members are all negatively related to the appointment of CEO directors

Originality/value

The use of non-performance outcome variable such as CEO experience in the family led emergent environment of Latin America
Intrapreneurship in the digital era: driven by big data and human resource management?
Authors: Wan Wenhai , Liu Longjun
Published: June 2021

Purpose

This study aims to investigate whether big data enabling (BDE) and empowerment-focused human resource management (EHRM) can effectively promote employee intrapreneurship and their effects on platform enterprises’ innovation performance. The paper also examines the contexts under which employee intrapreneurship may affect business performance.

Design/methodology/approach

Data were collected from 155 platform enterprises in China in the form of questionnaires. Participants were mainly middle and senior managers with a comprehensive grasp of the enterprises’ information.

Findings

The results indicated that BDE, EHRM and their synergy positively influenced employee intrapreneurship, which could potentially extend to enterprise performance. Specifically, employee intrapreneurship played a partial mediating role between BDE, EHRM and performance, and a whole mediating role between synergy and performance. Finally, platform strategic flexibility played a positive moderating role between employee intrapreneurship and performance.

Practical implications

Platform enterprises should focus on the construction and utilization of big data and EHRM to stimulate organizational vitality. They also need to encourage employees to start businesses and build more flexible strategies to adapt to the dynamic economic environment.

Originality/value

This is an empirical study on the effect mechanism of big data and HRM on employee intrapreneurship and platform enterprises’ performance in China. The paper combined big data, HRM and employee intrapreneurship, which broke through the previous research on enterprise entrepreneurship and social entrepreneurship. The findings guide platform enterprises to stimulate organizational vitality and achieve better performance in the digital era.
Automatic sizing functions for unstructured mesh generation revisited
Authors: Liu Zhiwei , Chen Jianjun , Xia Yifan , Zheng Yao
Published: June 2021

Purpose

Sizing functions are crucial inputs for unstructured mesh generation since they determine the element distributions of resulting meshes to a large extent. Meanwhile, automating the procedure of creating a sizing function is a prerequisite to set up a fully automatic mesh generation pipeline. In this paper, an automatic algorithm is proposed to create a high-quality sizing function for an unstructured surface and volume mesh generation by using a triangular mesh as the background mesh.

Design/methodology/approach

A practically efficient and effective solution is developed by using local operators carefully to re-mesh the tessellation of the input Computer Aided Design (CAD) models. A nonlinear programming (NLP) problem has been formulated to limit the gradient of the sizing function, while in this study, the object function of this NLP is replaced by an analytical equation that predicts the number of elements. For the query of the sizing value, an improved algorithm is developed by using the axis-aligned bounding box (AABB) tree structure.

Findings

The local operations of re-meshing could effectively and efficiently resolve the banding issue caused by using the default tessellation of the model to define a sizing function. Experiments show that the solution of the revised NLP, in most cases, could provide a better solution at the lower cost of computational time. With the help of the AABB tree, the sizing function defined at a surface background mesh can be also used as the input of volume mesh generation.

Originality/value

Theoretical analysis reveals that the construction of the initial sizing function could be reduced to the solution of an optimization problem. The definitions of the banding elements and surface proximity are also given. Under the guidance of this theoretical analysis, re-meshing and ray-casting technologies are well-designed to initial the sizing function. Smoothing with the revised NLP and querying by the AABB tree, the paper provides an automatic method to get a high-quality sizing function for both surface and volume mesh generation.
Knowledge transfer in technological innovation clusters
Authors: Fioravanti Vania Lopes Simoes , Stocker Fabricio , Macau Flavio
Published: June 2021

Purpose

The aim of this research is to analyze the knowledge transfer process in technological innovation clusters. The problem of the study addresses how organizations can act in a network to enhance experiences and gains, particularly in the aspect of knowledge management.

Design/methodology/approach

The study is qualitative, applied through a case study, cross-sectional and multiple sources of evidence – semistructured interviews, nonparticipant observation and analysis of documents and secondary institutional data. The case analyzed was the Technology Park of São José dos Campos, in Brazil, involving private companies, governmental organizations, universities and research institutions.

Findings

The results reinforce the arguments that the transfer of knowledge is influenced by factors, facilitators or inhibitors such as: cooperation, relationship with institutions, workforce mobility and geographical proximity, influencing the competitiveness and performance of the organizations in the cluster.

Research limitations/implications

This study advances the knowledge management literature in network environments, especially in technological innovation clusters, systematizing and highlighting the facilitating and inhibiting dimensions of knowledge transfer.

Practical implications

The present work has a direct dialogue with the managers and actors involved in the governance of these organizational arrangements with regard to increasing the capacity for creation and the dissemination of knowledge among organizations, educational institutions, government and companies.

Originality/value

There is a presence of aspects indicating that knowledge goes beyond borders through dynamic and collaborative structures, reinforcing the premise that clusters must be perceived as an evolutionary system, whose result of interactions leads to a superior joint capacity.
User engagement and self-disclosure on Snapchat and Instagram: the mediating effects of social media addiction and fear of missing out
Authors: Sultan Abdullah J.
Published: June 2021

Purpose

The present research examines self-disclosure as a negative behavior arising from excessive engagement on social media as well as social media addiction and fear of missing out.

Design/methodology/approach

A convenience sample of 2,333 Snapchat and Instagram users in Kuwait collected using a snowball sampling procedure was utilized to validate the research model and test the proposed relationships using two-stage structural equation modeling.

Findings

A multigroup confirmatory factor analysis across Snapchat and Instagram users showed that the measurement invariance was statistically nonsignificant. In addition, path analysis confirmed both a significant direct relationship between user engagement and self-disclosure and indirect relationships through social media addiction and fear of missing out as mediators.

Practical implications

Ethicists and consumer protection agencies must increase public awareness about the danger of overdisclosure of personal information on social media. The desire to be popular like fashionistas and influencers has pushed some young users to expose themselves to the public at extreme levels. Serious steps must be taken to educate young users about the negative consequences of self-disclosure on social media and healthy ways to capitalize their social presence on social media.

Originality/value

This study focuses on Snapchat and Instagram as underexplored social media applications with excessive engagement and potentially negative consequences on society.
Entrepreneurial opportunity recognition: a bibliometric overview and clustering analysis
Authors: Mohammadi Navid , Heshmati Saeed
Published: June 2021

Purpose

Entrepreneurship is the driving force of countries for sustainable economic development. The importance of this issue is to the extent that in recent years, countries have made great efforts to develop their entrepreneurial ecosystem. But the starting point for entrepreneurship is when an opportunity is identified and the entrepreneur rises to use it. Accordingly, opportunity recognition will be the foundation of entrepreneurship and ultimately sustainable development. Given the importance of this topic, this paper attempts to provide a large picture of the studies conducted in this field.

Design/methodology/approach

Given the importance of this topic, this paper attempts to provide a large picture of the studies conducted in this field by reviewing 868 articles published on the Web of Science database in the field of opportunity recognition. Accordingly, using statistical descriptions of articles, analyzing the communication network among elements such as authors, countries, institutions, keyword analysis in articles and examining their trends over time, identifying the most important articles using co-citation analysis and finally this macroimage has been mapped, clustered and identified in leading articles in the last decade by co-citation clustering.

Findings

The results of the clustering show that the five main clusters of recent decades have included entrepreneurial characteristics and opportunity recognition, macroeconomic opportunity recognition cluster (community and impact on economic development of the country), opportunity recognition process cluster, opportunity recognition cluster in serial and intra-entrepreneurship and opportunity recognition cluster in new venture internationalization.

Originality/value

Using a bibliometric analysis and co-citation analysis in the field of opportunity recognition and making a big picture of studies in this field of study is a contribution that can be used for future studies and researchers and managers in this field.
Crab antics: the moral and political economy of greed accusations in the submerging Sundarbans delta of India
Authors: Mehtta Megnaa
Published: June 2021

The livelihood of crab collecting, practised for generations in the Sundarbans forest of India, has undergone a radical moral makeover in recent years. Largely landless crab fishers are now the subject of frequent public denunciations by local authorities for their supposed greed and reckless endangerment of the entire ecosystem. While greed and its related category of need emerge from a local moral ecology of the region, internationally funded conservation campaigns and recent disruptions in the global crab supply chain reveal how accusations are activated and the means through which they play out amidst pre‐existing village hierarchies. This article accounts for the political, economic, and moral shifts that underpin these accusations. In counterpoint, I present the defences of the accused, and explore crab collectors’ notions of a sufficient life and the rich moral distinctions they themselves make between greed (lobh), need (aubhav), desire (chahida), and habit (swabhav). I then step back to show the broader political contours that shape the discourse of ‘greedy’ crab collectors. I argue that both the conservation movement and allied state actors have distorted the material and moral resources intended to combat climate change and other environmental threats by scapegoating the politically disenfranchised: local fishers. Powerful stakeholders, as a result of their own political impotency, are deployed in a game of crab antics that fails to address the underlying environmental catastrophe while displacing the psychic burden of greed onto the poor.