bluuebunny/crossref_metadata_2025 huggingface dataset:
Postdeployment Respiratory Syndrome in Soldiers With Chronic Exertional Dyspnea
Authors: Gutor Sergey S. , Richmond Bradley W. , Du Rui-Hong , Wu Pingsheng , Sandler Kim L. , MacKinnon Grant , Brittain Evan L. , Lee Jae Woo , Ware Lorraine B. , Loyd James E. , Johnson Joyce E. , Miller Robert F. , Newman John H. , Rennard Stephen I. , Blackwell Timothy S. , Polosukhin Vasiliy V.
Published: June 2021

After deployment to Southwest Asia, some soldiers develop persistent respiratory symptoms, including exercise intolerance and exertional dyspnea. We identified 50 soldiers with a history of deployment to Southwest Asia who presented with unexplained dyspnea and underwent an unrevealing clinical evaluation followed by surgical lung biopsy. Lung tissue specimens from 17 age-matched, nonsmoking subjects were used as controls. Quantitative histomorphometry was performed for evaluation of inflammation and pathologic remodeling of small airways, pulmonary vasculature, alveolar tissue and visceral pleura. Compared with control subjects, lung biopsies from affected soldiers revealed a variety of pathologic changes involving their distal lungs, particularly related to bronchovascular bundles. Bronchioles from soldiers had increased thickness of the lamina propria, smooth muscle hypertrophy, and increased collagen content. In adjacent arteries, smooth muscle hypertrophy and adventitial thickening resulted in increased wall-to-lumen ratio in affected soldiers. Infiltration of CD4 and CD8 T lymphocytes was noted within airway walls, along with increased formation of lymphoid follicles. In alveolar parenchyma, collagen and elastin content were increased and capillary density was reduced in interalveolar septa from soldiers compared to control subjects. In addition, pleural involvement with inflammation and/or fibrosis was present in the majority (92%) of soldiers. Clinical follow-up of 29 soldiers (ranging from 1 to 15 y) showed persistence of exertional dyspnea in all individuals and a decline in total lung capacity. Susceptible soldiers develop a postdeployment respiratory syndrome that includes exertional dyspnea and complex pathologic changes affecting small airways, pulmonary vasculature, alveolar tissue, and visceral pleura.
Plasma microRNAs are associated with domain-specific cognitive function in people with HIV
Authors: Massanett Aparicio Julissa , Xu Yanxun , Li Yuliang , Colantuoni Carlo , Dastgheyb Raha , Williams Dionna W. , Asahchop Eugene L. , McMillian Jacqueline M. , Power Christopher , Fujiwara Esther , Gill M. John , Rubin Leah H.
Published: June 2021

Objective:

Cognitive impairment remains common in people with HIV (PWH) on antiretroviral therapy (ART). The clinical presentation and severity are highly variable in PWH suggesting that the pathophysiological mechanisms of cognitive complications are likely complex and multifactorial. MicroRNA (miRNA) expression changes may be linked to cognition as they are gene regulators involved in immune and stress responses as well as the development, plasticity, and differentiation of neurons. We examined plasma miRNA expression changes in relation to domain-specific and global cognitive function in PWH.

Design:

Cross-sectional observational study.

Methods:

Thirty-three PWH receiving care at the Southern Alberta Clinic, Canada completed neuropsychological (NP) testing and blood draw. Plasma miRNA extraction was followed by array hybridization. Random forest analysis was used to identify the top 10 miRNAs upregulated and downregulated in relation to cognition.

Results:

Few miRNAs were identified across cognitive domains; however, when evident a miRNA was only associated with two or three domains. Notably, miR-127–3p was related to learning/memory and miR-485–5p to motor function, miRNAs previously identified in CSF or plasma in Alzheimer's and Parkinson's, respectively. Using miRNET 2.0, a software-platform for understanding the biological relevance of the miRNA-targets (genes) relating to cognition through a network-based approach, we identified genes involved in signaling, cell cycle, and transcription relating to executive function, learning/memory, and language.

Conclusion:

Findings support the idea that evaluating miRNA expression (or any molecular measure) in the context of global NP function might exclude miRNAs that could be important contributors to the domain-specific mechanisms leading to the variable neuropsychiatric outcomes seen in PWH.
Can We Predict Incorrect PrEP Use in High HIV Risk Situations Among Men Who Have Sex With Men? An Analysis of Be-PrEP-ared, the Belgian PrEP Demonstration Study
Authors: Vuylsteke Bea , Reyniers Thijs , Nöstlinger Christiana , Smekens Tom , Kenyon Chris , Laga Marie
Published: June 2021

Background:

Pre-exposure prophylaxis (PrEP) efficacy for HIV prevention is highly correlated with the degree of adherence. The objective of this analysis was to identify PrEP users who did not correctly take their dose in high HIV exposure situations and to explore potential predictors of this behavior.

Methods:

Study participants completed a personal Web‐based diary during their entire follow-up, providing daily information on pill intake and sexual activity. They also completed a sociobehavioral questionnaire. The association between the number of unprotected high HIV exposure sex days (as a measure for suboptimal adherence) and potential predicting factors was examined using a logistic regression, followed by a negative binomial regression model. We also constructed a risk index score for predicting poor adherence.

Results:

A total of 40.8% of participants did not correctly use PrEP in at least one situation of high HIV exposure during follow-up. Not having a HIV-negative steady partner, reporting more than 10 occasional or more than 10 anonymous partners, using chemsex drugs, receiving money for sex, and a history of more than one sexually transmitted infection were significantly associated with unprotected high HIV exposure sex. The risk index score yielded a poor discriminative power (area under the curve 0.62 and 0.64).

Conclusions:

We observed a high proportion of suboptimal adherence. Even if none of the participants acquired HIV during the study, tailored adherence support is needed to specific men who have sex with men such as those taking chemsex drugs and those engaging in paid sex.
Update on cytomegalovirus in transplant recipients: new agents, prophylaxis, and cell-mediated immunity
Authors: Manuel Oriol , Avery Robin K.
Published: June 2021

Purpose of review

This review is an overview of recent advances in diagnostics, therapies, and prevention strategies for cytomegalovirus (CMV), focusing on solid-organ transplant and hematopoietic stem cell transplant recipients.

Recent findings

A randomized trial of prophylaxis vs preemptive therapy in donor-seropositive, recipient-seronegative liver transplant recipients found significantly less CMV disease in the preemptive group. Maribavir has shown promise for the treatment of resistant/refractory CMV and for uncomplicated CMV DNAemia. A post hoc mortality analysis, as well as emerging reports of real-world and off-label use, have expanded the spectrum of clinical experience with letermovir. The first interventional trials using CMV cell-mediated immune assays have been published and showed promising results for delineating antiviral strategies. New data from additional interventional trials are expected soon.

The past 1–2 years have seen major developments in the area of CMV management in transplant recipients. Expanding diagnostic and therapeutic capabilities provide a foundation for optimizing strategies in the future, to reduce morbidity and mortality from CMV.
Different Appearances of 3 Malignancies in 68Ga-PSMA-11 Versus 18F-FDG PET/CT
Authors: Weitzer Friedrich , Nazerani-Hooshmand Tina , Aigner Reingard Maria , Pernthaler Birgit
Published: June 2021

Prostate-specific membrane antigen (PSMA) overexpression has been described in various malignancies. Hereby we present a case of a 69-year-old man simultaneously diagnosed with prostate cancer, esophageal adenocarcinoma, and HCC (hepatocellular carcinoma). 18F-FDG PET/CT showed pathological uptake in the esophageal adenocarcinoma and the primary prostate tumor, whereas 68Ga-PSMA-11 PET/CT performed for staging of the histopathologically confirmed prostate cancer revealed the primary tumor and significant uptake in the HCC. This finding is remarkable because the high physiological liver uptake of 68Ga-PSMA-11 may hamper the detection of small lesions.
Out-of-Hospital Cardiac Arrest Bystander Defibrillator Search Time and Experience With and Without Directional Assistance: A Randomized Simulation Trial in a Community Setting
Authors: Johnson Anna M. , Cunningham Christopher J. , Zégre-Hemsey Jessica K. , Grewe Mary E. , DeBarmore Bailey M. , Wong Eugenia , Omofoye Fola , Rosamond Wayne D.
Published: June 2021

Introduction

Probability of survival after out-of-hospital cardiac arrest (OHCA) doubles when a bystander initiates cardiopulmonary resuscitation and uses an automated external defibrillator (AED) rapidly. National, state, and community efforts have increased placement of AEDs in public spaces; however, bystander AED use remains less than 2% in the United States. Little is known about the effect of giving bystanders directional assistance to the closest public access AED.

Methods

We conducted 35 OHCA simulations using a life-sized manikin with participants aged 18 through 65 years who searched for public access AEDs in 5 zones on a university campus. Zones varied by challenges to pedestrian AED acquisition and number of fixed AEDs. Participants completed 2 searches—first unassisted and then with verbal direction to the closest AED—and we compared AED delivery times. We conducted pretest and posttest surveys.

Results

In all 5 zones, the median time from simulated OHCA onset to AED delivery was lower when the bystander received directional assistance. Time savings (minutes:seconds) varied by zone, ranging from a median of 0:53 (P = 0.14) to 3:42 (P = 0.02). Only 3 participants immediately located the closest AED without directional assistance; more than half reported difficulty locating an AED.

Conclusions

These findings may inform strategies to ensure that AEDs are consistently marked and placed in visible, accessible locations. Continued emphasis on developing strategies to improve lay bystanders' ability to locate and use AEDs may improve AED retrieval times and OHCA outcomes.
Correlation of Donor-derived Cell-free DNA With Histology and Molecular Diagnoses of Kidney Transplant Biopsies
Authors: Gupta Gaurav , Moinuddin Irfan , Kamal Layla , King Anne L. , Winstead Ryan , Demehin Moses , Kang Le , Kimball Pamela , Levy Marlon , Bhati Chandra , Massey H. Davis , Kumar Dhiren , Halloran Philip F.
Published: June 2021

Background.

Circulating donor-derived cell-free DNA (cfDNA), a minimally invasive diagnostic tool for kidney transplant rejection, was validated using traditional histology. The molecular microscope diagnostic system (MMDx) tissue gene expression platform may provide increased precision to traditional histology.

Methods.

In this single-center prospective study of 208 biopsies (median = 5.8 mo) posttransplant, we report on the calibration of cfDNA with simultaneous biopsy assessments using MMDx and histology by area under the curve (AUC) analyses for optimal criterion, as well as for, previously published cfDNA cutoffs ≤ 0.21% to “rule-out” rejection and ≥1% to “rule-in” rejection.

Results.

There were significant discrepancies between histology and MMDx, with MMDx identifying more antibody-mediated rejection (65; 31%) than histology (43; 21%); the opposite was true for T cell–mediated rejection [TCMR; histology: 27 (13%) versus MMDx: 13 (6%)]. Most of the TCMR discrepancies were seen for histologic borderline/1A TCMR. AUC for cfDNA and prediction of rejection were slightly better with MMDx (AUC = 0.80; 95% CI: 0.74-0.86) versus histology (AUC = 0.75; 95% CI: 0.69-0.81). A cfDNA ≤ 0.21% had similar sensitivity (~91%) to “rule-out” rejection by histology and MMDx. Specificity was slightly higher with MMDx (92%) compared with histology (85%) to “rule-in” rejection using cfDNA criterion ≥1%. Strong positive quantitative correlations were observed between cfDNA scores and molecular acute kidney injury for both “rejection” and “nonrejection” biopsies.

Conclusions.

Molecular diagnostics using tissue gene expression and blood-based donor-derived cell-free DNA may add precision to some cases of traditional histology. The positive correlation of cfDNA with molecular acute kidney injury suggests a dose-dependent association with tissue injury irrespective of rejection characteristics.
Quantitative evaluation of brain volumes in drug-free major depressive disorder using MRI-Cloud method
Authors: Avnioglu Seda , Velioglu Halil Aziz , Cankaya Seyda , Yulug Burak
Published: June 2021

Background

Quantitative analysis of the high-resolution T1-weighted images provides useful markers to measure anatomical changes during brain degeneration related to major depressive disorder (MDD). However, there are controversial findings regarding these volume alterations in MDD indicating even to increased volumes in some specific regions in MDD patients.

Methods

This study is a case-controlled study including 23 depression patients and 15 healthy subject person and 20–38 years of age, who have been treated at the Neurology and Psychiatry Department here. We compared specific anatomic regions between drug-free MDD patients and control group through MRI-Cloud, which is a novel brain imaging method that enables to analyze multiple brain regions simultaneously.

Results

We have found that frontal, temporal, and parietal hemispheric volumes and middle frontal gyrus, inferior frontal gyrus, superior parietal gyrus, cingulum-hippocampus, lateral fronto-orbital gyrus, superior temporal gyrus, superior temporal white matter, middle temporal gyrus subanatomic regions were significantly reduced bilaterally in MDD patients compared to the control group, while striatum, amygdala, putamen, and nucleus accumbens bilaterally increased in MDD group compared to the control group suggesting that besides the heterogeneity among studies, also comorbid factors such as anxiety and different personal traits could be responsible for these discrepant results.

Conclusion

Our study gives a strong message that depression is associated with altered structural brain volumes, especially, in drug-free and first-episode MDD patients who present with similar duration and severity of depression while the role of demographic and comorbid risk factors should not be neglected.
Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants
Authors: Aragam Krishna G , Jiang Tao , Goel Anuj , Kanoni Stavroula , Wolford Brooke N , Weeks Elle M , Wang Minxian , Hindy George , Zhou Wei , Grace Christopher , Roselli Carolina , Marston Nicholas A , Kamanu Frederick K , Surakka Ida , Muñoz Venegas Loreto , Sherliker Paul , Koyama Satoshi , Ishigaki Kazuyoshi , O Åsvold Bjørn , Brown Michael R , Brumpton Ben , de Vries Paul S , Giannakopoulou Olga , Giardoglou Panagiota , Gudbjartsson Daniel F , Güldener Ulrich , Haider Syed M. Ijlal , Helgadottir Anna , Ibrahim Maysson , Kastrati Adnan , Kessler Thorsten , Li Ling , Ma Lijiang , Meitinger Thomas , Mucha Sören , Munz Matthias , Murgia Federico , Nielsen Jonas B , Nöthen Markus M , Pang Shichao , Reinberger Tobias , Thorleifsson Gudmar , von Scheidt Moritz , Ulirsch Jacob K ,   EPIC-CVD Consortium, Japan Biobank , Arnar David O , Atri Deepak S , P Burtt Noël , Costanzo Maria C , Flannick Jason , Gupta Rajat M , Ito Kaoru , Jang Dong-Keun , Kamatani Yoichiro , Khera Amit V , Komuro Issei , Kullo Iftikhar J , Lotta Luca A , Nelson Christopher P , Roberts Robert , Thorgeirsson Gudmundur , Thorsteinsdottir Unnur , Webb Thomas R , Baras Aris , Björkegren Johan LM , Boerwinkle Eric , Dedoussis George , Holm Hilma , Hveem Kristian , Melander Olle , Morrison Alanna C , Orho-Melander Marju , Rallidis Loukianos S , Ruusalepp Arno , Sabatine Marc S , Stefansson Kari , Zalloua Pierre , Ellinor Patrick T , Farrall Martin , Danesh John , Ruff Christian T , Finucane Hilary K , Hopewell Jemma C , Clarke Robert , Erdmann Jeanette , Samani Nilesh J , Schunkert Heribert , Watkins Hugh , Willer Cristen J , Deloukas Panos , Kathiresan Sekar , Butterworth Adam S
Published: June 2021

Rapid progress of the discovery of genetic loci associated with common, complex diseases has outpaced the elucidation of mechanisms pertinent to disease pathogenesis. To address relevant barriers for coronary artery disease (CAD), we combined genetic discovery analyses with downstream characterization of likely causal variants, genes, and biological pathways. Specifically, we conducted a genome-wide association study (GWAS) comprising 181,522 cases of CAD among 1,165,690 participants. We detected 241 associations, including 54 associations and 30 loci not previously linked to CAD. Next, we prioritized likely causal variants using functionally-informed fine-mapping, yielding 42 associations with fewer than five variants in the 95% credible set. Combining eight complementary predictors, we prioritized 185 candidate causal genes, including 94 genes supported by three or more predictors. Similarity-based clustering underscored a role for early developmental processes, cell cycle signaling, and vascular proliferation in the pathogenesis of CAD. Our analysis identifies and systematically characterizes risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.
Vaccine effectiveness of the BNT162b2 mRNA COVID-19 vaccine against RT-PCR confirmed SARS-CoV-2 infections, hospitalisations and mortality in prioritised risk groups
Authors: Emborg Hanne-Dorthe , Valentiner-Branth Palle , Schelde Astrid Blicher , Nielsen Katrine Finderup , Gram Mie Agermose , Moustsen-Helms Ida Rask , Chaine Manon , Seidelin Ulla Holten , Nielsen Jens
Published: June 2021

Objective

To estimate in a real life setting, the vaccine effectiveness of the BNT162b2 mRNA vaccine against confirmed SARS-CoV-2 infection, hospital admission, and death among five priority groups for vaccination

Design

Cohort study

Setting

Roll-out of the BNT162b2 mRNA vaccine in Denmark

Participants

864,096 individuals who were first inline to receive the BNT162b2 mRNA vaccine: 46,101 long-term care facility (LTCF) residents, 61,805 individuals 65 years and older living at home but requiring practical help and personal care (65PHC), 98,533 individuals ≥85 years of age (+85), 425,799 health-care workers (HCWs), and 231,858 individuals with comorbidities that predispose for severe COVID-19 disease (SCD).

Intervention

vaccination with BNT162b2 mRNA vaccine

Main outcome measures

RT-PCR confirmed SARS-CoV-2 infections, COVID-19 related admissions within 14 days after a confirmed SARS-CoV-2 infection, all-cause admission, COVID-19 related death within 30 days after confirmed SARS-CoV-2 infection, and all-cause death.

Results

Beyond 7 days after the second dose, the VE against SARS-CoV-2 infection in all groups ranged from 53-86%. In 65PHC, HCW and SCD, we observed a substantial reduction in risk of infection 0-7 days after the second dose ranging from 46-71%. The VE against COVID-19 related admissions ranged from 75-87% in all groups except +85 and HCWs where no events occurred. For COVID-19 related deaths, a significant VE was observed in LTCF residents (VE of 89%) and 65PHC (VE of 97%), whereas no events were observed in the three remaining groups. VE against all-cause death ranged from 26-73% in all groups except HCW where an insignificant VE was estimated. For all-cause admission, the VE ranged from 37-50% in all groups except in SCD where a negative VE was observed.

Conclusion

In a real-life setting and more than 7 days after the second dose of BNT162b2 mRNA was administered to the most vulnerable individuals, the vaccine was associated with a reduction of SARS-CoV-2 infection (53-86%) and COVID-19 related admissions (≥75%) or deaths (≥89%).
Irradiation of UVC LED at 277 nm inactivates coronaviruses by photodegradation of spike protein
Authors: Ong Qunxiang , Ronnie Teo J. W. , Cruz Joshua Dela , Wee Elijah , Wee Winson , Han Weiping
Published: June 2021

To interrupt SARS-CoV-2 transmission chains, Ultraviolet-C (UVC) irradiation has emerged as a potential disinfection tool to aid in blocking the spread of coronaviruses. While conventional 254-nm UVC mercury lamps have been used for disinfection purposes, other UVC wavelengths have emerged as attractive alternatives but a direct comparison of these tools is lacking with the inherent mechanistic properties unclear. Our results using human coronaviruses, hCoV-229E and hCoV-OC43, have indicated that 277-nm UVC LED is most effective in viral inactivation, followed by 222-nm far UVC and 254-nm UVC mercury lamp. While UVC mercury lamp is more effective in degrading viral genomic content compared to 277-nm UVC LED, the latter results in a pronounced photo-degradation of spike proteins which potentially contributed to the higher efficacy of coronavirus inactivation. Hence, inactivation of coronaviruses by 277-nm UVC LED irradiation constitutes a more promising method for disinfection.
Systematic comparison of experimental assays and analytical pipelines for identification of active enhancers genome-wide
Authors: Yao Li , Liang Jin , Ozer Abdullah , Leung Alden King-Yung ,   ENCODE Consortium, Lis John T. , Yu Haiyuan
Published: June 2021

Mounting evidence supports the idea that transcriptional patterns serve as more specific identifiers of active enhancers than histone marks1,2; however, the optimal strategy to identify active enhancers both experimentally and computationally has not been determined. In this study, we compared 13 genome-wide RNA sequencing assays in K562 cells and showed that the nuclear run-on followed by cap-selection assay (namely, GRO/PRO-cap) has significant advantages in eRNA detection and active enhancer identification. We also introduced a new analytical tool, Peak Identifier for Nascent-Transcript Sequencing (PINTS), to identify active promoters and enhancers genome-wide and pinpoint the precise location of the 5’ transcription start sites (TSSs) within these regulatory elements. Finally, we compiled a comprehensive enhancer candidate compendium based on the detected eRNA TSSs available in 120 cell and tissue types. To facilitate the exploration and prioritization of these enhancer candidates, we also built a user-friendly web server (https://pints.yulab.org) for the compendium with various additional genomic and epigenomic annotations. With the knowledge of the best available assays and pipelines, this large-scale annotation of candidate enhancers will pave the road for selection and characterization of their functions in a time-, labor-, and cost-effective manner in the future.
3D-Scaffold: Deep Learning Framework to Generate 3D Coordinates of Drug-like Molecules with Desired Scaffolds
Authors: Joshi Rajendra P. , Gebauer Niklas W. A. , Bontha Mridula , Khazaieli Mercedeh , James Rhema M. , Brown Ben , Kumar Neeraj
Published: June 2021

The prerequisite of therapeutic drug design is to identify novel molecules with desired biophysical and biochemical properties. Deep generative models have demonstrated their ability to find such molecules by exploring a huge chemical space efficiently. An effective way to obtain molecules with desired target properties is the preservation of critical scaffolds in the generation process. To this end, we propose a domain aware generative framework called 3D-Scaffold that takes 3D coordinates of the desired scaffold as an input and generates 3D coordinates of novel therapeutic candidates as an output while always preserving the desired scaffolds in generated structures. We show that our framework generates predominantly valid, unique, novel, and experimentally synthesizable molecules that have drug-like properties similar to the molecules in the training set. Using domain specific datasets, we generate covalent and non-covalent antiviral inhibitors. To measure the success of our framework in generating therapeutic candidates, generated structures were subjected to high throughput virtual screening via docking simulations, which shows favorable interaction against SARS-CoV-2 main protease and non-structural protein endoribonuclease (NSP15) targets. Most importantly, our model performs well with relatively small volumes of training data and generalizes to new scaffolds, making it applicable to other domains.
Nuclear depletion of RNA binding protein ELAVL3 (HuC) in sporadic and familial amyotrophic lateral sclerosis
Authors: Diaz-Garcia Sandra , Ko Vivian I. , Vazquez-Sanchez Sonia , Chia Ruth , Arogundade Olubankole Aladesuyi , Rodriguez Maria J , Cleveland Don , Traynor Bryan J. , Ravits John
Published: June 2021

Amyotrophic lateral sclerosis is a progressive fatal neurodegenerative disease caused by loss of motor neurons and characterized neuropathologically in almost all cases by nuclear depletion and cytoplasmic aggregation of TDP-43, a nuclear RNA binding protein (RBP). We identified ELAVL3 as one of the most downregulated genes in our transcriptome profiles of laser captured microdissection of motor neurons from sporadic ALS nervous systems and the top dysregulated RBPs. Neuropathological characterizations showed ELAVL3 nuclear depletion in a great percentage of remnant motor neurons, sometimes accompanied by cytoplasmic accumulations. These abnormalities were common in sporadic cases with and without intermediate expansions in ATXN2 and familial cases carrying mutations in C9orf72 and SOD1. Depletion of ELAVL3 occurred at both the RNA and protein levels and a short protein isoform was identified but it is not related to a TDP-43-dependent cryptic exon in intron 3. Strikingly, ELAVL3 abnormalities were more frequent than TDP-43 abnormalities and occurred in motor neurons still with normal nuclear TDP-43 present, but all neurons with abnormal TDP-43 also had abnormal ELAVL3. In a neuron-like cell culture model using SH-SY5Y cells, ELAVL3 mislocalization occurred weeks before TDP-43 abnormalities were seen. We interrogated genetic databases but did not identify association of ELAVL3 genetic structure associated with ALS. Taken together, these findings suggest that ELAVL3 is an important RBP in ALS pathogenesis acquired early and the neuropathological data suggest it is involved by loss of function rather than cytoplasmic toxicity.
An automated platform for structural analysis of membrane proteins through serial crystallography
Authors: Healey Robert D. , Basu Shibom , Humm Anne-Sophie , Leyrat Cedric , Cong Xiaojing , Golebiowski Jérome , Dupeux Florine , Pica Andrea , Granier Sébastien , Márquez José Antonio
Published: June 2021

Membrane proteins are central to many pathophysiological processes yet remain very difficult to analyze at a structural level. Moreover, high-throughput structure-based drug discovery has not yet been exploited for membrane proteins due to lack of automation. Here, we present a facile and versatile platform for in meso membrane protein crystallization, enabling rapid atomic structure determination at both cryogenic and room temperature and in a single support. We apply this approach to two human integral membrane proteins, which allowed us to capture different conformational states of intramembrane enzyme-product complexes and analyze the structural dynamics of the ADIPOR2 integral membrane protein. Finally, we demonstrate an automated pipeline combining high-throughput microcrystal soaking, automated laser-based harvesting and serial crystallography enabling screening of small molecule libraries with membrane protein crystals grown in meso. This approach brings badly needed automation for this important class of drug targets and enables high-throughput structure-based ligand discovery with membrane proteins.

Highlights

A fully automated, online workflow enables rapid determination of membrane protein structures by serial X-ray crystallography (SSX).

High resolution room temperature and cryogenic structures of ADIPOR2 provide insights into the dynamic nature of receptor:ligand interactions.

A web-based application allows remote user-guided experimental design and execution.

An automated SSX-based ligand discovery pipeline for integral membrane proteins is introduced.
Cryo-EM structures reveal how ATP and DNA binding in MutS coordinate the sequential steps of DNA mismatch repair
Authors: Borsellini Alessandro , Kunetsky Vladislav , Friedhoff Peter , Lamers Meindert H.
Published: June 2021

DNA mismatch repair detects and removes mismatches from DNA reducing the error rate of DNA replication a 100-1000 fold. The MutS protein is one of the key players that scans for mismatches and coordinates the repair cascade. During this, MutS undergoes multiple conformational changes that initiate the subsequent steps, in response to ATP binding, hydrolysis, and release. How ATP induces the different conformations in MutS is not well understood. Here we present four cryo-EM structures of Escherichia coli MutS at sequential stages of the ATP hydrolysis cycle. These structures reveal how ATP binding and hydrolysis induces a closing and opening of the MutS dimer, respectively. Additional biophysical analysis furthermore explains how DNA binding modulates the ATPase cycle by preventing hydrolysis during scanning and mismatch binding, while preventing ADP release in the sliding clamp state. Nucleotide release is achieved when MutS encounters single stranded DNA that is produced during the removal of the daughter strand. This way, the combination of the ATP binding and hydrolysis and its modulation by DNA enable MutS to adopt different conformations needed to coordinate the sequential steps of the mismatch repair cascade.
Early and late evoked brain responses differentially reflect feature encoding and perception in the flash-lag illusion
Authors: Keil Julian , Senkowski Daniel , Moran James K.
Published: June 2021

In the flash-lag illusion (FLI), the position of a flash presented ahead of a moving bar is mislocalized, so the flash appears to lag the bar. Currently it is not clear whether this effect is due to early perceptual-related neural processes such as motion extrapolation or reentrant processing, or due to later feedback processing relating to postdiction, i.e. retroactively altered perception. We presented 17 participants with the FLI paradigm while recording EEG. A central flash occurred either 51ms (“early”) or 16ms (“late”) before the bar moving from left to right reached the screen center. Participants judged whether the flash appeared to the right (“no flash lag illusion”) or to the left (“flash-lag illusion”) of the bar. Using single-trial linear modelling, we examined the influence of timing (“early” vs. “late”) and perception (“illusion” vs. “no illusion”) on flash-evoked brain responses, and estimated the cortical sources underlying the FLI. Perception of the FLI was associated with a late window (368-452ms) in the ERP, with larger deflections for illusion than no illusion trials, localized to the left fusiform gyrus. An earlier frontal and occipital component (200-276ms) differentiated time-locked early vs. late stimulus presentation. Our results suggest a postdiction-related reconstruction of ambiguous sensory stimulation involving late processes in the occipito-temporal cortex, previously associated with temporal integration phenomena. This indicates that perception of the FLI relies on an interplay between ongoing stimulus encoding of the moving bar and feedback processing of the flash, which takes place at later integration stages.

Highlights

Flash-lag illusion relates primarily to late evoked brain potentials (>300ms)

Illusion vs. no-illusion trials showed difference in fusiform gyrus

Flash-lag illusion could involve postdiction-driven integration of ongoing stimuli
Binding patterns of RNA binding proteins to repeat-derived RNA sequences reveal putative functional RNA elements
Authors: Onoguchi Masahiro , Zeng Chao , Matsumaru Ayako , Hamada Michiaki
Published: June 2021

Recent reports have revealed that repeat-derived sequences embedded in introns or long noncoding RNAs (lncRNAs) are targets of RNA binding proteins (RBPs) and contribute to biological processes such as RNA splicing or transcriptional regulation. These findings suggest that repeat-derived RNAs are important as scaffolds of RBPs and functional elements. However, the overall functional sequences of the repeat-derived RNAs are not fully understood. Here, we show the putative functional repeat-derived RNAs by analyzing the binding patterns of RBPs based on ENCODE eCLIP data. We mapped all eCLIP reads to repeat sequences and observed that 10.75 % and 7.04 % of reads on average were enriched (at least 2-fold over control) in the repeats in K562 and HepG2 cells, respectively. Using these data, we predicted functional RNA elements on the sense and antisense strands of long interspersed element 1 (LINE1) sequences. Furthermore, we found several new sets of RBPs on fragments derived from other transposable element (TE) families. Some of these fragments show specific and stable secondary structures and are found to be inserted into the introns of genes or lncRNAs. These results suggest that the repeat-derived RNA sequences are strong candidates for the functional RNA elements of endogenous noncoding RNAs.
Association between quinolone use in food animals and gonococcal resistance to ciprofloxacin: an ecological study
Authors: Gonzalez Natalia , Abdellati Said , Manoharan-Basil Sheeba , Kenyon Chris
Published: June 2021

Background

Concentrations of fluoroquinolones up to 200-fold lower than the MIC have been shown to be able to select for antimicrobial resistance in E. coli and Salmonella spp. (the minimum selection concentration – MSC). We aimed to i) establish what the ciprofloxacin MSC is for Neisseria gonorrhoeae and ii) Assess at a country level if the prevalence of gonococcal ciprofloxacin resistance is associated with the concentration of quinolones used in food animal production (an important determinant of long-term low dose ciprofloxacin exposures in humans).

Methods

i). To assess if sub-inhibitory ciprofloxacin concentrations could select for de novo generated resistant mutants, susceptible WHO-P was serially passaged at 1, 1/10, 1/100 and 1/1000 of the ciprofloxacin MIC of WHO-P (0.004mg/L) on GC agar plates. ii) Spearman’s correlation was used to assess the association between the prevalence of ciprofloxacin resistance in N. gonorrhoeae and the two independent variables – quinolone use for animals and quinolone consumption by humans.

Results

Ciprofloxacin concentrations as low as 1/1000 of the MIC of WHO-P were able to select for ciprofloxacin resistance. The prevalence of ciprofloxacin resistance in N. gonorrhoeae was positively associated with quinolone use for food animals (ρ=0.47; P=0.004; N=34).

Conclusion

Further individual level research is required to assess if low doses of ciprofloxacin from ingested foodstuffs are able to select for ciprofloxacin resistance in N. gonorrhoeae and other species.
Integrated design of fault-tolerant control for flight control systems using observer and fuzzy logic
Authors: Unal Gulay
Published: June 2021

Purpose

Fault detection, isolation and reconfiguration of the flight control system is an important problem to obtain healthy flight. This paper aims to propose an integrated approach for aircraft fault-tolerant control.

Design/methodology/approach

The integrated structure includes a Kalman filter to obtain without noise, a full order observer for sensor fault detection, a GOS (generalized observer scheme) for sensor fault isolation and a fuzzy controller to reconfigure of the healthy sensor. This combination is simulated using the state space model of a lateral flight control system in case of disturbance and under sensor fault scenario.

Findings

Using a dedicated observer scheme, the detection and time of sensor fault are correct, but the sensor fault isolation is evaluated incorrectly while the faulty sensor is isolated correctly using GOS. The simulation results show that the suggested approach works affectively for sensor faults with disturbance.

Originality/value

This paper proposes an integrated approach for aircraft fault-tolerant control. Under this framework, three units are designed, one is Kalman filter for filtering and the other is GOS for sensor fault isolation and another is fuzzy logic for reconfiguration. An integrated approach is sensitive to faults that have disturbances. The simulation results show the proposed integrated approach can be used for any linear system.
International higher education brand alliance: the role of brand fit and world-mindedness
Authors: Kim Kyung-Min , Nobi Benjamin , Lee Sangwon , Milewicz Chad
Published: June 2021

Purpose

This research investigates three major research questions. First, how does brand alliance type, defined by a partner's location and brand quality, affect consumers' emotional value perceptions of higher education brand alliances for dual-degree programs? Second, does perceived brand fit mediate the relationship between brand alliance type and emotional value perceptions? Third, do individual differences in world-mindedness moderate the influence of brand alliance type on emotional value perceptions?

Design/methodology/approach

In total, two experiments are performed. Experiment one examines the effect of brand alliance type, at varying combinations of partner brand quality and partner location (domestic or foreign), on consumers' emotional value perceptions. Experiment two examines the moderating role of world-mindedness in the relationship between brand alliance type and consumers' emotional value perceptions.

Findings

Results provide evidence that consumers' perception of brand fit mediates the relationship between brand alliance type and consumers' emotional value perceptions of the alliance. Results also indicate that world-mindedness moderates the relationship between brand alliance type and emotional value perceptions.

Originality/value

This research extends the previous literature on higher education dual-degree brand alliances and introduces world-mindedness as an important consumer-based characteristic to consider in this line of research. It answers calls for more research on higher education branding and calls for research into the potential mediating role and importance of brand fit. It provides several theoretical and managerial implications relevant to the higher education brand alliances, particularly in dual-degree programs.
Speed of internationalization and firm performance: the moderating role of potential slack and knowledge assets
Authors: Zhang Banruo , Li Zijie , Li Xiaomeng , Liu Ziqi
Published: June 2021

Purpose

The speed of internationalization is an important research topic in the process of internationalization. This paper aims to answer two questions: first, what is the relationship between the speed of internationalization of Chinese multinational firms and their performance? Second, how do potential slack and knowledge assets of firms affect this relationship?

Design/methodology/approach

The authors choose Chinese A-share listed manufacturing firms from 2009–2018 as the research sample and use the fixed-effect regression model to test the proposed hypotheses.

Findings

Firstly, there is an inverted U-shaped relationship between the speed of internationalization and firm performance (SI-P). Secondly, the potential slack and knowledge assets of firms moderate the inverted U-shaped relationship. Firms with a higher level of potential slack or knowledge assets have a flatter inverted U-shaped relationship between SI-P.

Originality/value

First, the authors develop and extend Penrose’s theory of firm growth to the research topic of speed of internationalization. Second, this paper incorporates the time dimension into the research on the internationalization process and locates the research context in emerging market firms (EMFs). This is a step forward in clarifying the complex relationship of SI-P. Third, the authors show that the SI-P relationship of EMFs is inverted U-shaped and integrate previous studies, which argue that rapid internationalization positively or negatively affects firm performance. Fourth, starting from inside the firm, the authors provide more contextual factors for better understanding and analysis of the SI-P relationship.
Assessing the expected current and future competencies of quantity surveyors in the Malaysian built environment
Authors: Yap Jeffrey Boon Hui , Skitmore Martin , Lim Yi Wen , Loo Siaw-Chuing , Gray Jason
Published: June 2021

Purpose

Quantity surveying is a profession that blends engineering, construction and economics. To be competent is to have the ability to apply the set of related knowledge, skills and abilities to perform a task effectively. This paper examines the competency requirements for quantity surveyors (QSs) in the face of changing and increasing client needs.

Design/methodology/approach

Based on a detailed meta-analysis of the literature, 12 basic/core and 16 evolving competencies are identified. Primary data were gathered through a field survey involving practicing QSs from client, consultant and contractor organisations, and university students undertaking QS programmes in Malaysia. The data obtained were analysed using both descriptive and inferential statistical tools.

Findings

The significance of the basic/core and evolving competencies are presented. Overall, the most important contemporary skills are cost planning, valuation of works, measurement/quantification and contract documentation. The evolved roles require expertise in communication and negotiation, ethics and professional conduct and value management. The analysis of variance (ANOVA) indicates there are misaligned expectations of the proficiency levels needed to provide contemporary and future services between practitioners in client/consultant organisations, contractors and new generation students.

Originality/value

The findings provide guidance on the education, training and practice of quantity surveying to deal with emerging challenges in the dynamic built environments in Malaysia and beyond.
Skilled immigrant women's career trajectories during the COVID-19 pandemic in Canada
Authors: Nardon Luciara , Hari Amrita , Zhang Hui , Hoselton Liam P.S. , Kuzhabekova Aliya
Published: June 2021

Purpose

Despite immigrant-receiving countries' need for skilled professionals to meet labour demands, research suggests that many skilled migrants undergo deskilling, downward career mobility, underemployment, unemployment and talent waste, finding themselves in low-skilled occupations that are not commensurate to their education and experience. Skilled immigrant women face additional gendered disadvantages, including a disproportionate domestic burden, interrupted careers and gender segmentation in occupations and organizations. This study explores how the ongoing COVID-19 pandemic impacted skilled newcomer women's labour market outcomes and work experiences.

Design/methodology/approach

The authors draw on 50 in-depth questionnaires with skilled women to elaborate on their work experiences during the ongoing COVID-19 pandemic.

Findings

The pandemic pushed skilled immigrant women towards unemployment, lower-skilled or less stable employment. Most study participants had their career trajectory delayed, interrupted or reversed due to layoffs, decreased job opportunities and increased domestic burden. The pandemic's gendered nature and the reliance on work-from-home arrangements and online job search heightened immigrant women's challenges due to limited social support and increased family responsibilities.

Originality/value

This paper adds to the conversation of increased integration challenges under pandemic conditions by contextualizing the pre-pandemic literature on immigrant work integration to the pandemic environment. Also, this paper contributes a better understanding of the gender dynamics informing the COVID-19 socio-economic climate.
The impact of corporate governance and IFRS on the relationship between financial reporting quality and investment efficiency in a continental accounting system
Authors: Houcine Asma , Zitouni Mouna , Srairi Samir
Published: June 2021

Purpose

The purpose of this paper is to investigate whether Financial Reporting Quality (FRQ), Corporate Governance and IFRS affect investment efficiency of French listed companies.

Design/methodology/approach

Based on a sample of 125 French firms listed on the CAC All Tradable index between 2008 and 2017, the study uses Feasible Generalized Least Squares (FGLS) regressions to examine the relationship between FRQ and firms' investment efficiency.

Findings

The findings show that FRQ plays a role in reducing overinvestment and does not affect underinvestment, suggesting that in a code-law country, informal and personal relationships tend to replace the role of financial reports in mitigating information asymmetry. The results also reveal that the relationship between FRQ and investment efficiency increases with better corporate governance and with the implementation of IFRS. However, the results provide no evidence between incentives to minimize profits for tax purposes and firms' underinvestment and continues to be negative for overinvesting companies that have more incentives to manage their earnings for tax purposes.

Research limitations/implications

Our study has some limitations. First, we only examine listed firms, so the results cannot be generalized to unlisted companies that represent the vast majority of French economic activity. Second, this research does not distinguish between government companies and private companies. The two types of companies have different governance mechanisms, financial reporting, disclosure environment and concentration of ownership.

Practical implications

This study suggests that in a code-law country with weak investor protection, FRQ acts as a governance mechanism by mitigating asymmetric information and improving firms' investment decisions.

Originality/value

The relationship between FRQ and investment efficiency has been widely examined for companies in “common law” countries. This study extends the scarce evidence of this relation to companies in a code-law country. It also builds on previous research by introducing new factors never discussed before that could change this relationship, namely corporate governance, IFRS implementation and tax purposes.
My choices are better than yours! Gender differences in narcissistic start-up entrepreneurs
Authors: Leonelli Simona
Published: June 2021

Purpose

The paper explores the role of narcissism on entrepreneurs' decisions in terms of organizational choices, discussing gender differences. The aim relies in the influence that entrepreneurs' personality, capabilities and cognitive orientation have in the creation and management of start-ups.

Design/methodology/approach

Analyzing an Italian sample of 207 entrepreneurs and using Analysis of variance (ANOVA) and generalized linear model methods, the hypotheses were tested to understand whether and how narcissism affects Research and development (R&D) expenditure, patent ownership and the presence of a specialized team in organizations led by women and men entrepreneurs.

Findings

Differences in the management and organizational choices of narcissistic women entrepreneurs compared to their men counterparts emerged. First, results show that women entrepreneurs are less narcissistic than men. Second, gender is shown to moderate the effect of narcissism on the choice of having a qualified team in a start-up. Third, narcissistic women entrepreneurs were found to engage less in risk-taking activities, such as R&D expenditure, and to patent their ideas more than their male counterparts.

Originality/value

The study expands the existing literature by applying a gendered lens to entrepreneurs' narcissism to investigate whether they behave and manage their start-ups differently.