bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of HLA class I homozygosity with unfavorable clinical outcomes in patients with non-small cell lung cancer treated with PD-1/PD-L1 inhibitor as first-line therapy
Authors: Lee Dongyup , Park Jonghanne , Choi Horyun , Gim Gahyun , Cho Sukjoo , Kim Leeseul , Oh Youjin , Kang Cyra Y , Kim Yeseul , Tan Dean , de Viveiros Pedro Antonio Hermida , Chae Young Kwang
Published: May 2021

Background

Homozygosity at HLA-I locus has been reported to be an unfavorable predictive biomarker of second-line or beyond immunotherapy in patients with different types of cancer. The linkage between HLA-I zygosity and survival in NSCLC patients treated with first-line immunotherapy with or without chemotherapy has not been reported.

Methods

Next generation sequencing with HLA genotyping was performed for patients with advanced NSCLC treated with immune checkpoint inhibitors with or without chemotherapy as first-line (N = 29). Progression free survival was compared between HLA-I homozygous (defined as homozygosity in at least one locus A, B, or C) and heterozygous patients. Kaplan-Meier curves were built, and log-rank test was used.

Results

Among 29 enrollees, 25 patients (86.2%) were HLA-I heterozygous and four patients (13.8%) were HLA-I homozygous. Treatment response was not available in five patients with HLA-I heterozygosity. Among 20 patients with HLA-I heterozygosity, five patients (20.0%) had partial response, 10 patients (50.0%) had stable disease, two patients (8.0%) had non-complete response/non-progressive disease, and three patients (12.0%) had progressive disease. Among four patients with HLA-I heterozygosity, one patient (25.0%) had partial response, one patient (25.0%) had stable disease, and two patients (50.0%) had progressive disease. The median progression free survival was not reached in heterozygous group and was 2.97 months in homozygous group (log-rank p = 0.68).

Conclusions

We observed a trend toward an inverse association between HLA-I homozygosity and survival outcomes in patients with NSCLC treated with first-line therapy containing immunotherapy. Further prospective studies to validate such a relationship are warranted.
Red Blood Cell-Conditioned Media from Non-Alcoholic Fatty Liver Disease Patients Contain Increased MCP1 and Induce TNF-α Release
Authors: Papadopoulos Charalampos , Mimidis Konstantinos , Papazoglou Dimitris , Kolios George , Tentes Ioannis , Anagnostopoulos Konstantinos
Published: May 2021

BACKGROUND

Non-Alcoholic Fatty Liver Disease (NAFLD) constitutes a global pandemic. An intricate network among cytokines and lipids possesses a central role in NAFLD pathogenesis. Red blood cells comprise an important source of both cytokines and signaling lipids and have an important role in the molecular crosstalk during immunometabolic deregulation. However, their role in NAFLD has not been investigated in deep.

METHODS

Conditioned media from erythrocytes derived from 10 NAFLD patients (4 men, 6 women, aged 57.875±15,16) and 10 healthy controls (4 men, 6 women, aged 39.3±15.55) were produced and used for the analysis of 9 cytokines (IFN-γ, TNF-α, CCL2, CCL5, IL-8, IL-1β, IL-12p40, IL-17, MIP-1β), 2 signaling lipids (Sphingosine 1-phosphate and Lysophosphatidic Acid), and cholesterol. Their effect on the cytokine profile released by RAW 264.7 macrophages was also studied.

RESULTS

Erythrocytes from patients with NAFLD augmented the levels of MCP1 in the growth medium in comparison to the erythrocytes derived from healthy controls (37±40 pg/ml vs 6.51±5.63). No statistically significant differences were found between patients and healthy controls with regard to S1P, LPA, cholesterol and 8 other cytokines. TNF-a release by RAW 264.7 cells was increased after incubation with patient-derived erythrocyte conditioned medium compared to medium without RAW 264.7 cells from either healthy of NAFLD subjects.

CONCLUSIONS

Erythrocytes could contribute to the liver infiltration by monocytes and to the activation of macrophages, partially due to release of CCL2, in the context of NAFLD.
Polygenic and environmental determinants of tics in the Avon Longitudinal Study of Parents and Children cohort
Authors: Abdulkadir Mohamed , Tischfield Jay A. , Heiman Gary A. , Hoekstra Pieter J. , Dietrich Andrea
Published: May 2021

BACKGROUND

Tourette syndrome (TS) is caused by multiple genetic and environmental factors. Yet, little is known about the interplay of these factors in the occurrence of tics in the general population.

METHODS

Using logistic regression, we investigated whether polygenic risk score (PRS) of TS and pregnancy-related environmental factors together enhance the explained variance of tic occurrence (as opposed to separate analysis) in the Avon Longitudinal Study of Parents and Children. We included a cumulative adverse pregnancy risk score, maternal anxiety and depression, and maternal smoking and alcohol use during pregnancy. We investigated possible independent (i.e. additive) genetic and environmental effects, gene-environment correlations (rGE), gene-environment interactions (G x E), and mediation effects in explaining tic presence.

RESULTS

Models that contained the PRS and the cumulative adverse pregnancy risk score, maternal anxiety, or maternal depression (but not maternal smoking and alcohol use) explained significantly more variance of tic presence compared to models including only the PRS, pointing to additive effects. Furthermore, we found that maternal anxiety, depression, and smoking were mediated by the cumulative adverse pregnancy risk score, and were thus all indirectly associated with tics through pregnancy complications. We did not find rGE or G x E.

CONCLUSIONS

We found evidence for both direct and indirect associations of environmental risk factors in relation to tics in the general population. Combining PRS and environmental risk factors improve our understanding of tics compared to considering these factors in isolation, suggesting both additive and mediation effects.
Cohort-based surveillance of SARS-CoV2 transmission mirrors infection rates at the population level: a one-year longitudinal study
Authors: Klein Christine , Borsche Max , Balck Alexander , Föh Bandik , Rahmöller Johann , Peters Elke , Knickmann Jan , Lane Miranda , Vollstedt Eva-Juliane , Elsner Susanne A. , Käding Nadja , Hauswaldt Susanne , Lange Tanja , Hundt Jennifer E. , Lehrian Selina , Giese Julia , Mischnik Alexander , Niemann Stefan , Maurer Florian , Homolka Susanne , Paulowski Laura , Kramer Jan , Twesten Christoph , Sina Christian , Gillessen-Kaesbach Gabriele , Busch Hauke , Ehlers Marc , Taube Stefan , Rupp Jan , Katalinic Alexander
Published: May 2021

Background

More than one year into the COVID-19 pandemic, important data gaps remain on longitudinal prevalence of SARS-CoV-2 infection at the population level and in defined risk groups, efficacy of specific lockdown measures, and on (cost-)effective surveillance.

Methods

The ELISA (LübeckLongitudinalInvestigation ofSARS-CoV-2 Infection) study invited adult inhabitants (n=∼300,000) from the Lübeck area (Northern Germany) and enrolled 3051 participants (∼1%); 1929 population-matched and 1645 with high-exposure based on profession. The one-year study period (03/2020-02/2021) spanned massive influx of tourism in the summer, rise of infection rates in the fall/winter 2020/2021, and two lockdowns. Participants were screened seven times for SARS-CoV-2 infection using PCR and antibody testing and monitored with an app-based questionnaire (n=∼91,000).

Results

Cohort (56% female; mean age: 45.6 years) retention was 75%-98%; 89 persons (3.5%) were antibody- and/or PCR-positive. Seropositivity was almost 2-fold higher in men and increased risk detected in several high-exposure groups (highest for nurses, followed by police, army, firemen, and students). In May 2020, 92% of the infections were missed by PCR testing; by February 2021, only 29% remained undiagnosed. “Contact to COVID-19-affected” was the most relevant risk factor. Other factors, such as frequent use of public transportation, shopping, close contacts at work, and extensive tourism in the summer did not impact infection rates.

Conclusions

We i) provide a model for effective, regional surveillance; ii) identify infection risk factors informing public health measures; iii) demonstrate that easing of lockdown measures appears safe at times of low prevalence in the presence of continuous monitoring.
Magnetofluidic platform for rapid multiplexed screening of SARS-CoV-2 variants and respiratory pathogens
Authors: Trick Alexander Y. , Chen Fan-En , Chen Liben , Lee Pei-Wei , Hasnain Alexander C. , Mostafa Heba H. , Carroll Karen C. , Wang Tza-Huei
Published: May 2021

The rise of highly transmissible SARS-CoV-2 variants brings new challenges and concerns with vaccine efficacy, diagnostic sensitivity, and public health responses in the fight to end the pandemic. Widespread detection of variant strains will be critical to inform policy decisions to mitigate further spread, and post-pandemic multiplexed screening of respiratory viruses will be necessary to properly manage patients presenting with similar respiratory symptoms. In this work, we have developed a portable, magnetofluidic cartridge platform for automated PCR testing in <30 min. Cartridges were designed for multiplexed detection of SARS-CoV-2 with either distinctive variant mutations or with Influenza A and B. The platform demonstrated a limit of detection down to 2 copies/µL SARS-CoV-2 RNA with successful identification of B.1.1.7 and B.1.351 variants. The multiplexed SARS-CoV-2/Flu assay was validated using archived clinical nasopharyngeal swab eluates (n = 116) with an overall sensitivity/specificity of 98.1%/95.2%, 85.7%/100%, 100%/98.2%, respectively, for SARS-CoV-2, Influenza A, and Influenza B. Further testing with saliva (n = 14) demonstrated successful detection of all SARS-CoV-2 positive samples with no false-positives.
Who should get vaccinated first? An effective network information-driven priority vaccination strategy
Authors: Liu Dong , Tse Chi Kong , Chan Rosa H. M. , Zhan Choujun
Published: May 2021

Approval of emergency use of the Novel Coronavirus Disease 2019 (COVID-19) vaccines in many countries has brought hope to ending the COVID-19 pandemic sooner. Considering the limited vaccine supply in the early stage of COVID-19 vaccination programs in most countries, a highly relevant question to ask is:who should get vaccinated first?In this article we propose a network information-driven vaccination strategy where a small number of people in a network (population) are categorized, according to a few key network properties, into priority groups. Using a network-based SEIR model for simulating the pandemic progression, the network information-driven vaccination strategy is compared with a random vaccination strategy. Results for both large-scale synthesized networks and real social networks have demonstrated that the network information-driven vaccination strategy can significantly reduce the cumulative number of infected individuals and lead to a more rapid containment of the pandemic. The results provide insight for policymakers in designing an effective early-stage vaccination plan.
CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes
Authors: Gupta Meghna , Azumaya Caleigh M. , Moritz Michelle , Pourmal Sergei , Diallo Amy , Merz Gregory E. , Jang Gwendolyn , Bouhaddou Mehdi , Fossati Andrea , Brilot Axel F. , Diwanji Devan , Hernandez Evelyn , Herrera Nadia , Kratochvil Huong T. , Lam Victor L. , Li Fei , Li Yang , Nguyen Henry C. , Nowotny Carlos , Owens Tristan W. , Peters Jessica K. , Rizo Alexandrea N. , Schulze-Gahmen Ursula , Smith Amber M. , Young Iris D. , Yu Zanlin , Asarnow Daniel , Billesbølle Christian , Campbell Melody G. , Chen Jen , Chen Kuei-Ho , Chio Un Seng , Dickinson Miles Sasha , Doan Loan , Jin Mingliang , Kim Kate , Li Junrui , Li Yen-Li , Linossi Edmond , Liu Yanxin , Lo Megan , Lopez Jocelyne , Lopez Kyle E. , Mancino Adamo , Moss Frank R. , Paul Michael D. , Pawar Komal Ishwar , Pelin Adrian , Pospiech Thomas H. , Puchades Cristina , Remesh Soumya Govinda , Safari Maliheh , Schaefer Kaitlin , Sun Ming , Tabios Mariano C , Thwin Aye C. , Titus Erron W. , Trenker Raphael , Tse Eric , Tsui Tsz Kin Martin , Wang Feng , Zhang Kaihua , Zhang Yang , Zhao Jianhua , Zhou Fengbo , Zhou Yuan , Zuliani-Alvarez Lorena ,   QCRG Structural Biology Consortium, Agard David A , Cheng Yifan , Fraser James S , Jura Natalia , Kortemme Tanja , Manglik Aashish , Southworth Daniel R. , Stroud Robert M , Swaney Danielle L , Krogan Nevan J , Frost Adam , Rosenberg Oren S , Verba Kliment A
Published: May 2021

The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIGYF2, an inhibitor of translation initiation and modulator of ribosome-associated quality control. Our work suggests a potential role of Nsp2 in linking viral transcription within the viral replication-transcription complexes (RTC) to the translation initiation of the viral message. Collectively, the structure reported here, combined with mutant interaction mapping, provides a foundation for functional studies of this evolutionary conserved coronavirus protein and may assist future drug design.
Analysis of the role of N-linked glycosylation in cell-surface expression, function and binding properties of SARS-CoV-2 receptor ACE2
Authors: Rowland Raymond , Brandariz-Nuñez Alberto
Published: May 2021

Human angiotensin I-converting enzyme 2 (hACE2) is a type-I transmembrane glycoprotein that serves as the major cell entry receptor for SARS-CoV and SARS-CoV-2. The viral spike (S) protein is required for attachment to ACE2 and subsequent virus-host cell membrane fusion. Previous work has demonstrated the presence of N-linked glycans in ACE2. N-glycosylation is implicated in many biological activities, including protein folding, protein activity, and cell surface expression of biomolecules. However, the contribution of N-glycosylation to ACE2 function is poorly understood. Here, we examined the role of N-glycosylation in the activity and localization of two species with different susceptibility to SARS-CoV-2 infection, porcine ACE2 (pACE2) and hACE2. The elimination of N-glycosylation by tunicamycin (TM) treatment or mutagenesis, showed that N-glycosylation is critical for the proper cell surface expression of ACE2 but not for its carboxiprotease activity. Furthermore, nonglycosylable ACE2 localized predominantly in the endoplasmic reticulum (ER) and not at the cell surface. Our data also revealed that binding of SARS-CoV and SARS-CoV-2 S protein to porcine or human ACE2 was not affected by deglycosylation of ACE2 or S proteins, suggesting that N-glycosylation plays no role in the interaction between SARS coronaviruses and the ACE2 receptor. Impairment of hACE2 N-glycosylation decreased cell to cell fusion mediated by SARS-CoV S protein but not SARS-CoV-2 S protein. Finally, we found that hACE2 N-glycosylation is required for an efficient viral entry of SARS-CoV/SARS-CoV-2 S pseudotyped viruses, which could be the result of low cell surface expression of the deglycosylated ACE2 receptor.

Importance

Elucidating the role of glycosylation in the virus-receptor interaction is important for the development of approaches that disrupt infection. In this study, we show that deglycosylation of both ACE2 and S had a minimal effect on the Spike-ACE2 interaction. In addition, we found that removal of N-glycans of ACE2 impaired its ability to support an efficient transduction of SARS-CoV and SARS-CoV-2 S pseudotyped viruses. Our data suggest that the role of deglycosylation of ACE2 on reducing infection is likely due to a reduced expression of the viral receptor on the cell surface. These findings offer insight into the glycan structure and function of ACE2, and potentially suggest that future antiviral therapies against coronaviruses and other coronavirus-related illnesses involving inhibition of ACE2 recruitment to the cell membrane could be developed.
The Effects of Stress Across the Lifespan on the Brain, Cognition and Mental Health: A UK Biobank study
Authors: McManus Elizabeth , Haroon Hamied , Duncan Niall W. , Elliott Rebecca , Muhlert Nils
Published: May 2021

Repeated overstimulation of the stress response system, caused by exposure to prolonged highly stressful experiences, is thought to affect brain structure, cognitive ability, and mental health. We tested the effects of highly stressful experiences during childhood and adulthood using data from the UK Biobank, a large-scale national health and biomedical study with over 500,000 participants. To do this, we defined four groups with high and low levels of childhood and adulthood stress. We then used T1- and diffusion-weighted MRI data to assess the macrostructure in grey matter and microstructure in white matter of limbic brain regions, commonly associated with the stress response. We also compared executive function and working memory between these groups. Our findings suggest that in females, higher levels of both childhood and adulthood stress were associated with reduced connectivity within the posterior thalamic radiation. High stress in both childhood and adulthood was associated with decreases in both executive function and working memory. Finally, stress across the lifespan was positively associated with the number of diagnosed mental health problems, with a stronger effect in females than in males. Together our findings demonstrate links between stress across the lifespan, brain structure and mental health outcomes that may differ between males and females. Our findings also suggest that exposure to highly stressful life events has a negative impact on cognitive abilities in later life regardless of sex.
COVID-19 in patients hospitalized and healthcare workers: what have changed after the first wave in a university hospital
Authors: Moreira Luiz Vinicius Leão , Barbosa Gabriela Rodrigues , de Souza Luna Luciano Kleber , Justo Alberto Fernando Oliveira , Chaves Ana Paula Cunha , Conte Danielle Dias , Carvalho Joseane Mayara Almeida , Perosa Ana Helena , Faico Filho Klinger Soares , Camargo Clarice Neves , Bellei Nancy
Published: May 2021

Objective

To assess the COVID-19 frequency rates in hospitalized patients (HP) and healthcare workers (HCW), viral load inference, and the impact of vaccination and variants of concern (VOC) during the first pandemic wave.

Methods

We evaluated the COVID-19 diagnostics at Hospital São Paulo, Brazil, from March 2020 to April 2021, in 10,202 samples (6,502 HP and 3,700 HCW) tested by RT-qPCR, inferring viral load by cycle threshold (Ct) values, and frequency rates.

Results

SARS-CoV-2 was detected in 31.27% of individuals (32.23% HP and 29.80% HCW). The mean age of HP positives was 57.26 ± 18.29 years (median = 59), with a mean Ct value of 25.55 ± 6.07. Neither age nor Ct values in both groups have significantly differed during the first and second waves or even since the predominance of VOC P.1 on March 2021.

Conclusions

The COVID-19 epidemic curves of HP and HCW accompanied the variations reported in São Paulo city, as well as the variation of hospitalization and occupancy of ICU beds. The VOC P.1 has no impact on the viral load, since its predominance in March 2021. The vaccination of HCW may have contributed to a decrease in the positivity rates, although more studies will provide a better understanding of the impact of immunization on the COVID-19 pandemic.
Occupational challenges of health care workers during the COVID-19 pandemic. A qualitative study
Authors: Jeleff Maren , Traugott Marianna , Jirovsky-Platter Elena , Jordakieva Galateja , Kutalek Ruth
Published: May 2021

Background

The COVID-19 pandemic has placed a significant burden on health care systems worldwide with health care workers (HCWs) delivering care under unprecedented conditions. This study deals with HCWs’ physical, mental, emotional and professional challenges of working during the COVID-19 pandemic and seeks to understand structural determinants of those challenges.

Methods

We carried out an exploratory qualitative study in public and private hospitals in Vienna, Austria. HCWs such as medical doctors, qualified nursing staff, nurse assistants, technical and cleaning staff in direct and indirect contact with COVID-19 patients were included. Collected data was analyzed using content analysis.

Findings

We conducted 30 semi-structured interviews in person and per phone from June 2020 to January 2021. Three overall themes resulted as relevant: challenges due to lack of preparedness, structural conditions, and physical and mental health of HCWs. Lack of preparedness included missing or delayed infection prevention and control (IPC) guidelines, shortages of personal protective equipment (PPE) combined with structural conditions such as staff shortages and overworked personnel. Physical and mental strains resulted from being overworked and working permanently on alert. Further, working in PPE, facing medical uncertainties and the critical conditions of patients were challenging factors. HCWs lacked recognition on multiple levels and dealt with social stigma and avoidance behavior of colleagues, especially in the beginning of the pandemic.

Interpretation

To mitigate HCWs’ occupational health risks and staff turnover, we propose the following context-specific recommendations: Required medical personnel in care of COVID-19 patients, especially nursing staff, should be carefully planned and increased to avert chronic work overload. Intensive training and education in palliative care, as well as in IPC for all HCWs is important. Providing supportive supervision is as essential as appropriate recognition by higher level management and the public.

Funding

This article has received funding from The Vienna Science and Technology Fund (WWTF) COVID-19 Rapid Response Funding 2020. The funders did not play a role in the decision to publish the article.
Biofilm self-patterning: mechanical forces drive a reorientation cascade
Authors: Nijjer Japinder , Li Changhao , Zhang Qiuting , Lu Haoran , Zhang Sulin , Yan Jing
Published: May 2021

In growing active matter systems, a large collection of engineered or living autonomous units metabolize free energy and create order at different length scales as they proliferate and migrate collectively. One such example is bacterial biofilms, which are surface-attached aggregates of bacterial cells embedded in an extracellular matrix. However, how bacterial growth coordinates with cell-surface interactions to create distinctive, long-range order in biofilms remains elusive. Here we report a collective cell reorientation cascade in growingVibrio choleraebiofilms, leading to a differentially ordered, spatiotemporally coupled core-rim structure reminiscent of a blooming aster. Cell verticalization in the core generates differential growth that drives radial alignment of the cells in the rim, while the radially aligned rim in turn generates compressive stresses that expand the verticalized core. Such self-patterning disappears in adhesion-less mutants but can be restored through opto-manipulation of growth. Agent-based simulations and two-phase active nematic modeling reveal the strong interdependence of the driving forces for the differential ordering. Our findings provide insight into the collective cell patterning in bacterial communities and engineering of phenotypes and functions of living active matter.
Implicit Laplacian of Enhanced Edge: An Unguided Algorithm for Accurate and Automated Quantitative Analysis of Cytoskeletal Images
Authors: Li Pai , Zhang Ze , Tong Yiying , Foda Bardees M. , Day Brad
Published: May 2021

The eukaryotic cytoskeleton plays essential roles in cell signaling and trafficking, which is broadly associated with immunity and diseases of human and plants. To date, most analyses aiming at defining the temporal and spatial dynamics of the cytoskeleton have relied on qualitative and quantitative analysis of fluorescence images to describe cytoskeletal function. While state-of-the-art, these approaches have limitations: the diverse shape and brightness of the cytoskeleton cause considerable inaccuracy in both human-driven and automated approaches, and the widely adopted image projection process (3D to 2D) leads to bias and information loss. Here, we describe the development and application of Implicit Laplacian of Enhanced Edge (ILEE), an unguided approach that uses a 2D/3D-compatible local thresholding algorithm for the quantitative evaluation of cytoskeletal status and organization at high performance. Using ILEE, we constructed a Python library to enable automated cytoskeletal image analysis, providing numerous biologically-interpretable indices measuring the density, bundling, severing, branching, and directionality of the cytoskeleton. The data presented herein demonstrate that ILEE resolves the defects of classic cytoskeleton analysis approaches, enables the measurement of novel cytoskeletal features, and yields quantitatively descriptive data with superior accuracy, stability, and robustness. We released the ILEE algorithm as an open-source library and further developed a Google Colab interface as a community resource.
Structural basis for cell-type specific evolution of viral fitness by SARS-CoV-2
Authors: Gupta Kapil , Toelzer Christine , Williamson Maia Kavanagh , Shoemark Deborah K. , Oliveira A. Sofia F. , Matthews David A. , Almuqrin Abdulaziz , Staufer Oskar , Yadav Sathish K.N. , Borucu Ufuk , Garzoni Frederic , Fitzgerald Daniel , Spatz Joachim , Mulholland Adrian J. , Davidson Andrew D. , Schaffitzel Christiane , Berger Imre
Published: May 2021

As the global burden of SARS-CoV-2 infections escalates, so does the evolution of viral variants which is of particular concern due to their potential for increased transmissibility and pathology. In addition to this entrenched variant diversity in circulation, RNA viruses can also display genetic diversity within single infected hosts with co-existing viral variants evolving differently in distinct cell types. The BriSΔ variant, originally identified as a viral subpopulation by passaging SARS-CoV-2 isolate hCoV-19/England/02/2020, comprises in the spike glycoprotein an eight amino-acid deletion encompassing the furin recognition motif and S1/S2 cleavage site. Here, we elucidate the structure, function and molecular dynamics of this variant spike providing mechanistic insight into how the deletion correlates to viral cell tropism, ACE2 receptor binding and infectivity of this SARS-CoV-2 variant. Moreover, our study reveals long-range allosteric communication between functional regions within the spike that differ in wild-type and deletion variant. Our results support a view of SARS-CoV-2 probing multiple evolutionary trajectories in distinct cell types within the same infected host.
Distinct interhemispheric connectivity at the level of the olfactory bulb emerges during Xenopus laevis metamorphosis
Authors: Weiss Lukas , Arias Paola Segoviano , Offner Thomas , Hawkins Sara Joy , Hassenklöver Thomas , Manzini Ivan
Published: May 2021

The olfactory system of anuran tadpoles requires substantial restructuring to adapt to the lifestyle of the adult frogs. Xenopus laevis tadpoles have a single main olfactory epithelium in the principal nasal cavity associated with aquatic olfaction. After metamorphosis, this epithelial surface is transformed into the adult air-nose and a new epithelium, the adult water-nose, is present in the middle cavity. Impacts of this massive remodeling on odor processing, behavior and network structure are still unexplored.

In the present study, we used neuronal tracings, calcium imaging and a behavioral assay to examine the functional connectivity between the epithelium and the main olfactory bulb during metamorphosis. In tadpoles, olfactory receptor neurons in the principal cavity epithelium project axons to glomeruli in the ventral main olfactory bulb. During metamorphosis, these projections are gradually replaced by receptor neuron axons emerging from the newly forming middle cavity epithelium. Despite this metamorphotic reorganization in the ventral bulb, two spatially and functionally segregated odor processing streams remain undisrupted. In line with this, metamorphotic rewiring does not alter behavioral responses to waterborne odorants. Contemporaneously, newly formed receptor neurons in the remodeling principal cavity epithelium project their axons to the dorsal part of the bulb. The emerging neuronal networks of the dorsal and ventral main olfactory bulb show substantial differences. Glomeruli around the midline of the dorsal bulb are innervated from the left and right nasal epithelia. In addition, postsynaptic projection neurons in the dorsal bulb predominantly have smaller tufts and connect to multiple glomeruli, while more than half of projection neurons in the ventral bulb have a single, bigger tuft.

Our results show that during the metamorphotic reconstruction of the olfactory network the ‘water system’ remains functional. Differences of the neuronal network of the dorsal and ventral olfactory bulb imply that a higher degree of odor integration takes place in the dorsal main olfactory bulb. This is likely connected with the processing of different odorants, airborne vs. waterborne, in these two parts of the olfactory bulb.
Gut microbiota features associated withClostridioides difficilecolonization in dairy calves
Authors: Redding Laurel E. , Berry Alexander S. , Indugu Nagaraju , Huang Elizabeth , Beiting Daniel P. , Pitta Dipti
Published: May 2021

Diarrheal disease, a major cause of morbidity and mortality in dairy calves, is strongly associated with the health and composition of the gut microbiome.Clostridioides difficileis an opportunistic pathogen that proliferates and can produce enterotoxins when the host experiences gut dysbiosis. However, even asymptomatic colonization withC. difficilecan be associated with differing degrees of microbiome disruption in a range of species, including people, swine, and dogs. Little is known about the interaction betweenC. difficileand the gut microbiome in dairy calves. In this study, we sought to define microbial features associated withC. difficilecolonization in pre-weaned dairy calves less than 2 weeks of age. We characterized the fecal microbiota of 80 calves from 23 different farms using 16S rRNA sequencing and compared the microbiota ofC. difficile-positive (n=24) andC. difficile-negative calves (n=56). Farm appeared to be the greatest source of variability in the gut microbiota. When controlling for calf age, diet, and farm location, there was no significant difference in Shannon alpha diversity (P= 0.50) or in weighted UniFrac beta diversity (P=0.19) betweenC. difficile-positive and –negative calves. However, there was a significant difference in beta diversity as assessed using Bray-Curtiss diversity (P=0.0077), andC. difficile-positive calves had significantly increased levels ofRuminococcus (gnavus group)(Adj. P=0.052), Lachnoclostridium(Adj. P=0.060), Butyricicoccus(Adj. P=0.060), andClostridium sensu stricto 2compared toC. difficile-negative calves. Additionally,C. difficile-positive calves had fewer microbial co-occurrences thanC. difficile–negative calves, indicating reduced bacterial synergies. Thus, whileC. difficilecolonization alone is not associated with dysbiosis and is therefore unlikely to result in an increased likelihood of diarrhea in dairy calves, it may be associated with a more disrupted microbiota.
The pitfalls of using Gaussian Process Regression for normative modeling
Authors: Xu Bohan , Kuplicki Rayus , Sen Sandip , Paulus Martin P.
Published: May 2021

Normative modeling, a group of methods used to quantify an individual’s deviation from some expected trajectory relative to observed variability around that trajectory, has been used to characterize subject heterogeneity. Gaussian Processes Regression includes an estimate of variable uncertainty across the input domain, which at face value makes it an attractive method to normalize the cohort heterogeneity where the deviation between predicted value and true observation is divided by the derived uncertainty directly from Gaussian Processes Regression. However, we show that the uncertainty directly from Gaussian Processes Regression is irrelevant to the cohort heterogeneity in general.
Termites have developed wider thermal limits to cope with environmental conditions in savannas
Authors: Woon Joel S. , Atkinson David , Adu-Bredu Stephen , Eggleton Paul , Parr Catherine L.
Published: May 2021

The most diverse and abundant family of termites, the Termitidae, evolved in warm, wet African tropical forests. Since then, they have colonised grassy biomes such as savannas. These environments have more extreme temperatures than tropical forests, and greater temporal fluctuations (both annually and diurnally) that are challenging for soft-bodied ectotherms. We propose that that a likely mechanism that facilitated the expansion from forest to savanna was the widening of physiological limits of savanna termite species in order to cope with more extreme environmental conditions. We sampled termites directly from mound structures across an environmental gradient in Ghana, and recorded the thermal tolerance of individual termites, both critical thermal maximum (CTmax) and critical thermal minimum (CTmin). We estimated colony thermal tolerance by taking an average of each tested individual, and modelled these data against several environmental factors (canopy cover above the mound, rainfall and temperature). We found that savanna termite species had significantly higher CTmaxvalues, and significantly lower CTminvalues, than forest species. In addition, areas with high canopy cover were significantly associated with low CTmaxvalues, and areas with higher average daily rainfall were significantly associated with higher CTminvalues. Our results suggest that the widening of thermal tolerances has occurred in savanna termite species, probably in response to the more extreme temperatures found in those environments.
Antimicrobial Effects of Ibuprofen Combined with Standard of Care Antimicrobials against Cystic Fibrosis Pathogens
Authors: Chen Qingquan , Ilanga Marleini , Simbassa Sabona B. , Chirra Bhagath , Shah Kush N. , Cannon Carolyn L.
Published: May 2021

Cystic Fibrosis (CF) is a common fatal genetic disease caused by mutations happened to cystic fibrosis transmembrane conductance regulator (CFTR) gene. Lungs of CF patients are often colonized or infected with microorganisms. Drug resistant bacterial infection has been problematic in cystic fibrosis patient. The chronic bacterial infections and concomitant airway inflammation could damage the lung and lead to respiratory failure. Several clinical trials have demonstrated that high-dose ibuprofen reduces the rate of pulmonary function decline in CF patients. This beneficial effect has been attributed to the anti-inflammatory properties of ibuprofen. Previously, we have confirmed that high-dose ibuprofen demonstrated antimicrobial activity against P. aeruginosa in in vitro and in vivo. However, no study has examined the antimicrobial effect of combining ibuprofen with standard-of-care (SoC) antimicrobials. Here, we evaluated possible synergistic activity of combinations of common nonsteroidal anti-inflammatory drugs (NSAIDs), namely, aspirin, naproxen, and ibuprofen, with commonly used antibiotics for CF patients. The drug combinations were screened against different CF clinical isolates. Drugs that demonstrated efficacy in the presence of ibuprofen were further verified synergistic effects between these antimicrobials and NSAIDs. Finally, the survival analysis of an P. aeruginosa murine infection model was used to demonstrate the efficacy of synergistic combination. Our results suggest that combinations of ibuprofen with commonly used antibiotics demonstrate synergistic antimicrobial activity against drug resistant, clinical bacterial strains in in vitro. The efficacy of combination ceftazidime and ibuprofen was demonstrated in in vivo.
PIP2-dependent coupling of voltage sensor and pore domains in Kv7.2
Authors: Pant Shashank , Zhang Jiaren , Kim Eung Chang , Lam Kin , Chung Hee Jung , Tajkhorshid Emad
Published: May 2021

Phosphatidylinositol-4,5-bisphosphate (PIP2) is a signaling lipid which regulates voltage-gated Kv7/KCNQ potassium channels. Altered PIP2 sensitivity of neuronal Kv7.2 channel is involved in KCNQ2 epileptic encephalopathy. However, the molecular action of PIP2 on Kv7.2 gating remains largely elusive. Here, we use molecular dynamics simulations and electrophysiology to characterize PIP2 binding sites in a human Kv7.2 channel. In the closed state, PIP2 localizes to the periphery of the voltage-sensing domain (VSD). In the open state, PIP2 binds to 4 distinct interfaces formed by the cytoplasmic ends of the VSD, the gate, intracellular helices A and B and their linkers. PIP2 binding induces bilayer-interacting conformation of helices A and B and the correlated motion of the VSD and the pore domain, whereas charge-neutralizing mutations block this coupling and reduce PIP2 sensitivity of Kv7.2 channels by disrupting PIP2 binding. These findings reveal the allosteric role of PIP2 in Kv7.2 channel activation.
Optimization of synthetic jet actuation by analytical modeling
Authors: Huber Max , Zienert Andreas , Weigel Perez , Schüller Martin , Berger Hans-Reinhard , Schuster Jörg , Otto Thomas
Published: May 2021

Purpose

The purpose of this paper is to analyze and optimize synthetic jet actuators (SJAs) by means of a literature-known one-dimensional analytical model.

Design/methodology/approach

The model was fit to a wide range of experimental data from in-house built SJAs with different dimensions. A comprehensive parameter study was performed to identify coupling between parameters of the model and to find optimal dimensions of SJAs.

Findings

The coupling of two important parameters, the diaphragm resonance frequency and the cavity volume, can be described by a power law. Optimal orifice length and diameter can be calculated from cavity height in good agreement with literature. A transient oscillation correction is required to get correct simulation outcomes.

Originality/value

Based on these findings, SJA devices can be optimized for maximum jet velocity and, therefore, high performance.
Updates in service standards in hotels: how COVID-19 changed operations
Authors: Chan Janelle , Gao Yixing (Lisa) , McGinley Sean
Published: May 2021

Purpose

The COVID-19 pandemic has tremendously affected the hospitality industry. With the experiences of severe acute respiratory syndrome in 2003 and commitments to ensure guests’ health and safety, many hotels in Asia have actively engaged in updating and implementing new service standards and measures. This study aims to investigate hotels’ service standard changes, processes of management decisions and preparations for the future.

Design/methodology/approach

Using grounded theory methodology, this research interviews 24 hotel managers from mainland China and Hong Kong. It examines the differences among hotels with different operation types, classifications and locations, and analyzes the service standards in physical and social services cape.

Findings

Building on the service marketing and crisis management literature, this research provides a synthesis that reflects how hotels have coped with the COVID-19 crisis. It depicts the service standard update process during the COVID-19.

Research limitations/implications

In line with the literature in disaster management, hotels experienced the outbreak, response and recovery phases of the crisis management procedure. However, given the severity and scope of the COVID-19 pandemic, undertaking particular processes is necessary at every procedure such as following local guidelines and updating local standard operating procedures (LSOPs). This research also expands the literature on the process of adopting new technology in hotels during crisis management.

Practical implications

The paper suggests that hotel managers should update and use well-thought-out standards on the bases of available scientific evidence. For example, hotels should use LSOPs according to the local situations. Hotels are also suggested to exert additional efforts and attention in service innovation, guest experience and enhancing hospitableness.

Originality/value

To the best of the authors’ knowledge, this paper is one of the first efforts to investigate the impact of COVID-19 on hotel operations. It offers empirical evidence from hotel operators who worked against the crisis during the pandemic and provides valuable theoretical contribution to the hospitality service literature as well as managerial implications for hotel operators globally.
Searching for a new perspective on institutional voids, networks and the internationalisation of SMEs in emerging economies: a systematic literature review
Authors: Dekel-Dachs Ofer , Najda-Janoszka Marta , Stokes Peter , Simba Amon , Tarba Shlomo
Published: May 2021

Purpose

This study, a systematic review, focuses on the internationalisation of small and medium-sized enterprises (SMEs) originating in developing countries. It critically analyses, evaluates and synthesises studies featuring formal and informal institutions, embedded in social and business networks, as a marketing solution for institutional voids. The review shows that current international marketing studies downplay the role of informal institutions in the internationalisation of SMEs. Thus, the authors set a new research agenda for advancing the institutional theory to account for the impact of informal institutions and networks on firm internationalisation.

Design/methodology/approach

This review followed five structured stages, including framing the research questions, identifying relevant studies, assessing their quality, summarising the evidence and interpreting the findings. Based on the systematic approach, 434 papers (374 from Web of Science, 60 from Scopus) were generated. Following that, the authors applied the qualitative inclusion/exclusion criteria, which yielded 63 papers. Their analysis involved three authors, with the fourth author focusing on ensuring quality in the analysis.

Findings

The study findings invite a different line of theorising market structures and processes focusing on the role of networks as an alternative to formal institutional systems. The outcome of our review suggests that there is scope for developing the institutional theory that account for the role of informal institutions and networks.

Originality/value

Based on the analysis, we call for new theorisation, in the international marketing literature, which accounts for informal networking amongst internationalising SMEs in the light of institutional voids. Thus, the authors promote novel participatory, bottom to top understanding of relationship between institutions and enterprises.
Contextual factors influencing talk in Australian residential aged care
Authors: Scerri Madalyn Anne , Presbury Rajka
Published: May 2021

Purpose

This paper offers an exploration of contextual factors that influence carer-to-resident talk in Australian residential aged care.

Design/methodology/approach

A qualitative exploratory multiple case study methodology and a theoretical framework of service language were applied to explore the perspectives of 21 registered nurses, assistants in nursing, leisure and lifestyle officers, general managers and care managers at three residential aged care homes in Australia.

Findings

The findings demonstrate contextual factors related to the care home environment, the carer and the relationship between carers and residents that impede or enable carer-to-resident talk in residential aged care. Multiple factors related to the care home environment were found to impede carer-to-resident talk, including time pressures, staffing levels, team culture and the prioritisation of tasks. Factors related to carers had potential to either impede or enable talk, including carers' awareness of the importance of communication, level of experience and individual characteristics, values and attitudes. A strong relationship between a carer and resident built on knowledge of individuals was a key enabling factor.

Originality/value

The paper advances an understanding of factors that influence talk and interaction in residential aged care in Australia from carers' and care home leaders' perspectives. The findings can be used to support verbal communication management strategies aligned with a person-centred care approach, including training and development of staff, cultural change interventions and a review of care delivery procedures.
Mobile learning acceptance and use in higher education during social distancing circumstances: an expansion and customization of UTAUT2
Authors: Sitar-Taut Dan-Andrei , Mican Daniel
Published: May 2021

Purpose

This paper investigates if the existing degree of students' acceptance and use of mobile or m-learning may face the online shift determined by SARS-CoV-2. Based on the extended unified theory of acceptance and use of technology (UTAUT2), a new comprehensive model, SD-UTAUT (social distancing-UTAUT), is developed to better understand relationships between the original constructs, plus personal innovativeness (PI) and information quality (IQ). It identifies the key factors affecting behavioral intention (BI) and use by examining the influence of revaluated hedonic motivation (HM) and learning value (LV) importance as mediators.

Design/methodology/approach

The paper opted for an exploratory study involving 311 learners, using partial least squares structural equation modeling (PLS-SEM).

Findings

SD-UTAUT can be a new m-learning model in higher education. It has high predictive power and confirmed 15 out of 16 hypotheses. The most powerful relationship is between performance expectancy (PE) and HM. IQ affected LV the most, since HM the behavioral use (BU). HM impacts the use behavior (UB) more than LV, but habit (HT) affects it the most.

Research limitations/implications

Because of the pandemic context, output may lack generalizability and reproducibility.

Practical implications

To improve usage, staff must provide better support, course creators emphasize the objectives and competencies and developers integrate innovation. The joy and pleasure of m-learning use may stimulate the LV through interesting and interactive content, like incorporating gamification.

Originality/value

The model set-up and circumstances are previously unseen. SD-UTAUT confirms ten new hypotheses and introduces the student's grade point average (GPA) as a moderator.

Peer review

The peer review history for this article is available at https://publons.com/publon/10.1108/OIR-01-2021-0017