bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends in Low-Value Cancer Care During the COVID-19 Pandemic
Authors: Parikh Ravi B. , Civelek Yasin , Ozluk Pelin , Drell Helayne A. , DeBono David , Fisch Michael J. , Sylwestrzak Gosia , Bekelman Justin E. , Schwartz Aaron L.
Published: September 2022

Background

Low-value services are common in cancer care. The onset of the COVID-19 pandemic caused a dramatic decrease in health care utilization, leading many to suspect that low-value cancer services may decrease.

Methods

In this retrospective cohort study, we used administrative claims from the HealthCore Integrated Research Environment, a repository of medical and pharmacy data from US health plans representing over 80 million members, to identify 204,581 patients diagnosed with breast, colorectal, and/or lung cancer between January 1, 2015, and March 31, 2021. We used linear probability models to investigate the relation between the onset of COVID-19 pandemic and 5 guideline-based metrics of low-value cancer care: 1) Positron Emission Tomography/Computed Tomography (PET/CT) instead of conventional CT imaging for initial staging; 2) conventional fractionation instead of hypofractionation for early-stage breast cancer; 3) non-guideline-based antiemetic use for minimal-, low-, or moderate-to-high-risk chemotherapies; 4) off-pathway systemic therapy; and 5) aggressive end-of-life care.

Results

Among 204,581 patients, the mean [SD] age was 63.1 [13.2], 68.1% were female, 83,593 (40.8%) had breast cancer, 56,373 (27.5%) had colon cancer, and 64,615 (31.5%) had lung cancer. Rates of low-value cancer services did not exhibit meaningful declines during the pandemic: PET/CT imaging, adjusted percentage point difference 1.87 (95% CI −0.13 to 3.87); conventional radiotherapy, adjusted percentage point difference 3.93 (95% CI 1.50 to 6.36); off-pathway systemic therapy, adjusted percentage point difference 0.82 (95% CI −0.62 to 2.25); non-guideline-based antiemetics, adjusted percentage point difference −3.62 (95% CI −4.97 to −2.27); aggressive end-of-life care, adjusted percentage point difference 2.71 (95% CI −0.59 to 6.02).

Discussion

Low-value cancer care remained prevalent through the pandemic. Policymakers should consider changes to payment and incentive design to turn the tide toward higher-value cancer care.
Leveraging deep-learning on raw spirograms to improve genetic understanding and risk scoring of COPD despite noisy labels
Authors: Cosentino Justin , Behsaz Babak , Alipanahi Babak , McCaw Zachary R. , Hill Davin , Schwantes-An Tae-Hwi , Lai Dongbing , Carroll Andrew , Hobbs Brian D. , Cho Michael H. , McLean Cory Y. , Hormozdiari Farhad
Published: September 2022

Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, is highly heritable. While COPD is clinically defined by applying thresholds to summary measures of lung function, a quantitative liability score has more power to identify new genetic signals. Here we train a deep convolutional neural network on noisy self-reported and ICD-based labels to predict COPD case/control status from high-dimensional raw spirograms and use the model predictions as a liability score. The machine-learning-based (ML-based) liability score accurately discriminates COPD cases and controls (AUROC = 0.82 ± 0.01) and COPD-related hospitalization (AUROC = 0.89 ± 0.01) without any domain-specific knowledge. Moreover, the ML-based liability score is associated with overall survival (Hazard ratio = 1.22 ± 0.01; P ≤ 2 × 10−16) and exacerbation events (R2 = 0.10 ± 0.01; P ≤ 4 × 10−101). A genome-wide association study on the ML-based liability score replicates existing COPD and lung function loci, but also identifies 67 new loci. Thirty-eight of these have supportive evidence in independent datasets, including a locus near LTBR. We demonstrate the biological plausibility of the novel variants through enrichment analyses, phenome-wide association studies, and generalizability of COPD prediction in multiple datasets. These results provide an example of the potential to improve genetic discovery of disease-relevant variants by training deep neural networks to predict noisy labels from high-dimensional raw data.
Style Transfer Generative Adversarial Networks to Harmonize Multi-Site MRI to a Single Reference Image to Avoid Over-Correction
Authors: Liu Mengting , Zhu Alyssa H. , Maiti Piyush , Thomopoulos Sophia I. , Gadewar Shruti , Chai Yaqiong , Kim Hosung , Jahanshad Neda ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: September 2022

Recent work within neuroimaging consortia have aimed to identify reproducible, and often subtle, brain signatures of psychiatric or neurological conditions. To allow for high-powered brain imaging analyses, it is often necessary to pool MR images that were acquired with different protocols across multiple scanners. Current retrospective harmonization techniques have shown promise in removing cross-site image variation. However, most statistical approaches may over-correct for technical, scanning-related, variation as they cannot distinguish between confounded image-acquisition based variability and cross-site population variability. Such statistical methods often require that datasets contain subjects or patient groups with similar clinical or demographic information to isolate the acquisition-based variability. To overcome this limitation, we consider cross-site MRI image harmonization as a style transfer problem rather than a domain transfer problem. Using a fully unsupervised deep-learning framework based on a generative adversarial network (GAN), we show that MR images can be harmonized by inserting the style information encoded from a single reference image, without knowing their site/scanner labelsa priori. We trained our model using data from five large-scale multi-site datasets with varied demographics. Results demonstrated that our style-encoding model can harmonize MR images, and match intensity profiles, without relying on traveling subjects. This model also avoids the need to control for clinical, diagnostic, or demographic information. We highlight the effectiveness of our method for clinical research by comparing extracted cortical and subcortical features, brain-age estimates, and case-control effect sizes before and after the harmonization. We showed that our harmonization removed the cross-site variances, while preserving the anatomical information and clinical meaningful patterns. We further demonstrated that with a diverse training set, our method successfully harmonized MR images collected from unseen scanners and protocols, suggesting a promising novel tool for ongoing collaborative studies. Source code is released inUSC-IGC/style_transfer_harmonization (github.com).
B/T cell crosstalk and aberrant inflammatory IgG exacerbate autoimmune intestinal inflammation
Authors: Gadjalova Iana , Heinze Julia M. , Goess Marie Christine , Hofmann Julian , Albers Julian J. , Spallek Ria , Blissenbach Birgit , Buck Annalisa , Weber Marie-Christin , Scherer Emely , Kampick Maximilian , Öllinger Rupert , Krut Oleg , Rad Roland , Steiger Katja , Winter Christof , Janssen Klaus-Peter , Neumann Philipp-Alexander , Geha Raif S. , Ruland Jürgen , Keppler Selina J.
Published: September 2022

Dysregulated B cell responses have been described in inflammatory-bowel disease (IBD) patients; however, the role of B cells in IBD pathology remained incompletely understood. We here described Wiskott-Aldrich Syndrome interacting protein deficient (Wipf1-/-) mice as novel mouse model of spontaneous, chronic colitis modelling human IBD. Concomitant with aberrant IgG production in colonic tissue of Wipf1-/- mice, we identified systemic, hypo-sialylated IgG as drivers of IL-1β production in monocytes. Pathological antibody production was promoted by the hyper-reactivity of Wipf1-/- B cells in response to LPS stimulation, resulting in efficient activation of the MAPK/Erk and mTOR/Akt/4E-BP1 pathways and heightened metabolic activity. In addition to abundant inflammatory IgG, we found that B cells directly promoted the production of pro-inflammatory cytokines by intestinal CD4+ T cells. B/T co-culture assays defined the co-stimulatory molecule CD86 as driver of IFN-γ and GM-CSF production by CD4+ T cells. CD86 expression was further enhanced by the presence of sCD40L, which was elevated in sera of Wipf1-/- mice. Similarly, colonic B cells of IBD patients expressed increased mRNA levels of CD86 correlating with enhanced levels of systemic sCD40L. Together, B cell-mediated pro-inflammatory cytokine secretion and B cell-derived inflammatory antibody production contributed to exacerbated pathogenesis during intestinal inflammation.

One Sentence Summary

B cells fuel intestinal inflammation
Inconsistencies between human and macaque lesion data can be resolved with a stimulus-computable model of the ventral visual stream
Authors: Bonnen Tyler , Eldridge Mark A.G.
Published: September 2022

Decades of neuroscientific research has sought to understand medial temporal lobe (MTL) involvement in perception. The field has historically relied on qualitative accounts of perceptual processing (e.g. descriptions of stimuli), in order to interpret evidence across subjects, experiments, and species. Here we use stimulus computable methods to formalize MTL-dependent visual behaviors. We draw from a series of experiments (Eldridge et al., 2018) administered to monkeys with bilateral lesions that include perirhinal cortex (PRC), an MTL structure implicated in visual object perception. These stimuli were designed to maximize a qualitative perceptual property (‘feature ambiguity’) considered relevant to PRC function. We formalize perceptual demands imposed by these stimuli using a computational proxy for the primate ventral visual stream (VVS). When presented with the same images administered to experimental subjects, this VVS model predicts both PRC-intact and -lesioned choice behaviors; a linear readout of the VVS should be sufficient for performance on these tasks. Given the absence of PRC-related deficits on these ‘ambiguous’ stimuli, we (Eldridge et al., 2018) originally concluded that PRC is not involved in perception. Here we (Bonnen & Eldridge) reevaluate this claim. By situating these data alongside computational results from multiple studies administered to humans with naturally occurring PRC lesions, this work offers the first formal, cross-species evaluation of MTL involvement in perception. In doing so, we contribute to a growing understanding of visual processing that depends on—and is independent of—the MTL.
Anchors for Time, Distance, and Magnitude in Virtual Movements
Authors: Gladhill Keri Anne , Robinson Eva Marie , Stanfield-Wiswall Candice , Bader Farah , Wiener Martin
Published: September 2022

In order to navigate through the environment, humans must be able to measure both the distance traveled in space, and the interval covered in time. Yet, how these two dimensions are computed and interact across neural systems remains unknown. One possibility is that subjects measure how far and how long they have traveled relative to a known reference point, or anchor. To measure this, we had human participants (n=24) perform a distance estimation task in a virtual environment in which they were cued to attend to either the spatial or temporal interval traveled, while responses were measured with multiband fMRI. We observed that both dimensions evoked similar frontoparietal networks, yet with a striking rostrocaudal dissociation between temporal and spatial estimation. Multivariate classifiers trained on each dimension were further able to predict the temporal or spatial interval traveled, with centers of activation within the supplementary motor area (SMA) and retrosplenial cortex (RSC) for time and space, respectively. Further, a cross-classification approach revealed the right supramarginal gyrus (SMG) and occipital place area (OPA) as regions capable of decoding the general magnitude of the traveled distance. Altogether, our findings suggest the brain uses separate systems for tracking spatial and temporal distances, which are combined together along with amodal estimates.
Practical guide to calculating impact of avidity in models of bispecific antibodies with two membrane-bound targets
Authors: Kareva Irina , Zutshi Anup , Rhoden John , Kabilan Senthil
Published: September 2022

Here we present details of the calculation necessary to estimate the impact of avidity in a mathematical model of a bispecific antibody with two membrane-bound targets. The calculation is used to reproduce the results reported in Rhoden et al. (2016) and implemented in Kareva et al. (2018). We reproduce the impact of difference in relative concentration of the two targets on projections of free and bound concentrations of both targets and the antibody and highlight the applicability of this approach for supporting model informed decision making particularly in the early stages of drug discovery and development.
ATF4 Dependent Increase in Mitochondrial-Endoplasmic Reticulum Tethering Following OPA1 Deletion in Skeletal Muscle
Authors: Hinton Antentor , Katti Prasanna , Mungai Margaret , Hall Duane D. , Koval Olha , Shao Jianqiang , Vue Zer , Lopez Edgar Garza , Rostami Rahmati , Neikirk Kit , Ponce Jessica , Streeter Jennifer , Schickling Brandon , Bacevac Serif , Grueter Chad , Marshall Andrea , Beasley Heather K. , Do Koo Young , Bodine Sue C. , Nava Nayeli G. Reyes , Quintana Anita M. , Song Long-Sheng , Grumbach Isabella , Pereira Renata O. , Glancy Brian , Abel E. Dale
Published: September 2022

Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein- and lipid-enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca2+, lipid, and other metabolites between these organelles. Defective MERCs are associated with cellular oxidative stress, neurodegenerative disease, and cardiac and skeletal muscle pathology via mechanisms that are poorly understood. We previously demonstrated that skeletal muscle-specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin-2, a known MERC protein. In the present study, we tested the hypothesis thatOpa1downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice andDrosophila, and in primary myotubes. Our results revealed that OPA1 deficiency induced tighter and more frequent MERCs in concert with a greater abundance of MERC proteins involved in calcium exchange. Additionally, loss of OPA1 increased the expression of activating transcription factor 4 (ATF4), an integrated stress response (ISR) pathway effector. ReducingAtf4expression prevented the OPA1-loss-induced tightening of MERC structures. OPA1 reduction was associated with decreased mitochondrial and sarcoplasmic reticulum, a specialized form of ER, calcium, which was reversed following ATF4 repression. These data suggest that mitochondrial stress, induced by OPA1 deficiency, regulates skeletal muscle MERC formation in an ATF4-dependent manner.
Imbalanced classification for protein subcellular localisation with multilabel oversampling
Authors: Rana Priyanka , Sowmya Arcot , Meijering Erik , Song Yang
Published: September 2022

Motivation

Subcellular localisation of human proteins is essential to comprehend their functions and roles in physiological processes, which in turn helps in diagnostic and prognostic studies of pathological conditions and impacts clinical decision making. Since proteins reside at multiple locations at the same time and few subcellular locations host far more proteins than other locations, the computational task for their subcellular localisation is to train a multilabel classifier while handling data imbalance. In imbalanced data, minority classes are underrepresented, thus leading to a heavy bias towards the majority classes and the degradation of predictive capability for the minority classes. Furthermore, data imbalance in multilabel settings is an even more complex problem due to the coexistence of majority and minority classes.

Results

Our studies reveal that based on the extent of concurrence of majority and minority classes, oversampling of minority samples through appropriate data augmentation techniques holds promising scope for boosting the classification performance for the minority classes. We measured the magnitude of data imbalance per class and the concurrence of majority and minority classes in the dataset. Based on the obtained values, we identified minority and medium classes, and a new oversampling method is proposed that includes nonlinear mixup, geometric and colour transformations for data augmentation and a sampling approach to prepare minibatches. Performance evaluation on the Human Protein Atlas Kaggle challenge dataset shows that the proposed method is capable of achieving better predictions for minority classes than existing methods.

Availability

Data used in this study is available at https://www.kaggle.com/competitions/human-protein-atlas-image-classification/data.

Contact

yang.song1@unsw.edu.au

Supplementary information

Supplementary data are available at Bioinformatics online.
Novel Small Molecular Compound AE-848 Showed Potent Inhibitory Activity Against Human Hepatoblastoma Cells
Authors: Wang Juandong , Zhou Qian , Sun Likun , Xu Yaqi , Jiang Yang , Liu Xiaoli , Li Shuo , Li Hui , Zheng Chengyun , Jie Guitao
Published: September 2022

Purpose

AE-848/33345007, is a novel small molecular compound that was independently synthesized by our laboratory. The aim of the current study was to investigate potential therapeutic effects of the small molecule compound AE-848 on human hepatoblastoma cells.

Methods

Human hepatoblastoma cell line HepG2 was cultured under different concentrations of AE-848. MTT assay was used to detect the inhibitory ability of AE-848 on the activity of this cell line, while flow cytometry was applied to quantify apoptosis. Western-blot technique was used to determine expression levels of signaling pathway-associated molecules. The antitumor in vivo activity of AE-848 against hepatoblastoma was evaluated using hepatoblastoma-bearing nude mice randomly divided into AE-848 (experimental) and saline (control) groups respectively. Changes in survival and tumor sizes were compared between these two groups.

Results

AE-848 significantly inhibited proliferation and induced apoptosis of HepG2 cells, and induced activation of PI3K/Akt/mTOR signaling pathways. More importantly, AE-848 administration significantly inhibited tumor growth and prolonged survival of hepatoblastoma-bearing mice.

Conclusion

AE-848 had a strong anti-hepatoblastoma activity both in vitro and in vivo, indicating the importance of developing AE-848 as a potential drug for hepatoblastoma treatment.
Immune Isoform Atlas: Landscape of alternative splicing in human immune cells
Authors: Inamo Jun , Suzuki Akari , Ueda Mahoko , Yamaguchi Kensuke , Nishida Hiroshi , Suzuki Katsuya , Kaneko Yuko , Takeuchi Tsutomu , Ishihama Yasushi , Yamamoto Kazuhiko , Kochi Yuta
Published: September 2022

Alternative splicing events are a major causal mechanism for complex traits, but they have been understudied due to the limitation of short-read sequencing. Here, we generated a comprehensive full-length isoform annotation of human immune cells, Immune Isoform Atlas, by long-read sequencing for 29 cell subsets. Our atlas contained a number of unannotated transcripts and isoforms such as a read-through transcript of TOMM40-APOE. We profiled functional characteristics of isoforms including encoded domains, inserted repetitive elements, and translational efficiency, and we showed that repetitive elements significantly explained the diversity of unannotated isoforms. Some of the isoforms are expressed in a cell-type specific manner, whose alternative 3’-UTRs usage contributed to their specificity. Further, we identified a number of disease-associated isoforms by isoform switch analysis and by integration of several quantitative trait loci analyses with genome-wide association study data. Our findings will promote the elucidation of the pathomechanism of diseases via alternative splicing.
A novel insertional allele ofCG18135gene is associated with severe mutant phenotypes inDrosophila melanogaster
Authors: Ratiu Attila Cristian , Ionascu Adrian , Ecovoiu Alexandru Al.
Published: September 2022

Drosophila melanogasterhas been at the forefront of genetic studies and biochemical modelling for over a century. Yet, the functions of many genes are still unknown mainly because no phenotypic data are available. Herein, we present first evidence data regarding the particular molecular and other quantifiable phenotypes, such as viability and anatomical anomalies, induced by a novelP{lacW}insertional mutant allele ofCG18135gene. So far, theCG18135functions have only been theorized based on electronic annotation and presumptive associations inferred upon high-throughput proteomics or RNA sequencing experiments. The descendants of individuals harboring theCG18135P{lacW}CG18135allele were scored in order to assess mutant embryos, larvae and pupae viability versus Canton Special. Our results revealed that the homozygousCG18135P{lacW}CG18135/CG18135P{lacW}CG18135genotype determines significant lethality both at the inception of larval stage and during pupal development. Few imago escapers that breach the puparium and even more rarely fully exit from it exhibit specific eye depigmentation, wing abnormal unfolding and strong locomotor impairment with apparent spasmodic legs movements. Their maximum lifespan is shorter than two days. When using the quantitative Real-Time PCR (qRT-PCR) method to confirm thatCG18135is indeed upregulated in males compared to females an unexpected gene upregulation was also detected in heterozygous mutants comparative to wild-type flies, probably because of regulatory perturbations induced byP{lacW}transposon. Our work provides the first phenotypic evidence for the essential role ofCG18135, a scenario in accordance with the putative role of this gene in the carbohydrate binding processes.
The dilution effects of healthy lifestyles on the risk of depression attributed to life-course disadvantages among Chinese middle-aged and older adults
Authors: Ren Ziyang , Du Yushan , Lian Xinyao , Zheng Xiaoying , Liu Jufen
Published: September 2022

Background

Life-course disadvantages and unhealthy lifestyles are well-known to independently induce depression, but their joint effects on depression and whether adopting healthy lifestyles can dilute the depressive risks attributed to life-course disadvantages remain unknown in China.

Methods

Data were from the China Health and Retirement Longitudinal Study. Life-course (childhood and adulthood) disadvantages were defined using 60 questions and were classified as mild, moderate, and severe by principal component analysis. Healthy lifestyles, including regular exercise, reasonable sleep, never smoking, and no heavy alcohol consumption, were classified as 0/1, 2, 3, and 4. Depression was assessed using CESD-10 with cutoff ≥10. Logistic regression was used to investigate the association of life-course disadvantages and lifestyles with depression and the dilution effects of healthy lifestyles on the depressive risks attributed to life-course disadvantages.

Results

Among 5724 participants included, sleep and smoking mediated 5.1% and 1.1% the effect of severe life-course disadvantages on depression while exercise mediated - 0.8%. Multiple (vs. 0/1) healthy lifestyles were associated with decreased depressive risks more significantly as the life-course disadvantages increased, with odds ratios (ORs) and 95% confidence intervals (CIs) of 0.44 (0.25-0.80) and 0.33 (0.21-0.53) for 4 healthy lifestyles in participants with mild and severe life-course disadvantages, respectively. Compared to participants with mild life-course disadvantages and 4 healthy lifestyles, those who with severe life-course disadvantages and less than one lifestyles were more than 10 times as significantly associated with depression. Finally, participants with mild/moderate life-course disadvantages but ≤2 healthy lifestyles (vs. severe but 4 lifestyles) were not associated with decreased depressive risks.

Conclusion

Adopting multiple healthy lifestyles can well-dilute the depressive risks attributed to life-course disadvantages in middle-aged and older Chinese, which is of great importance for reducing the depressive burden and the construction of healthy aging in China.
Interactions between metabolism and growth can determine the co-existence ofStaphylococcus aureusandPseudomonas aeruginosa
Authors: Pajon Camryn , Fortoul Marla C. , Diaz-Tang Gabriela , Meneses Estefania Marin , Mariah Taniya , Toscan Brandon , Marcelin Maili , Lopatkin Allison J. , Eldakar Omar Tonsi , Smith Robert P.
Published: September 2022

Most bacteria exist and interact within polymicrobial communities. These interactions produce unique compounds, increased virulence and augmented antibiotic resistance. One community associated with negative healthcare outcomes consists ofPseudomonas aeruginosaandStaphylococcus aureus. When co-cultured, virulence factors secreted byP. aeruginosareduce metabolism and growth inS. aureus. When grownin vitrothis allowsP. aeruginosato driveS. aureustowards extinction. However, when foundin vivo, both species can co-exist. Previous work has noted that this may due to altered gene expression or mutations. However, little is known about how the growth environment could influence co-existence of both species. Using a combination of mathematical modeling and experimentation, we show that changes to bacterial growth and metabolism caused by differences in the growth environment can determine final population composition. We found that changing the carbon source in growth medium affects the ratio of ATP to growth rate for both species, a metric we call absolute growth. We found that as a growth environment increases absolute growth for one species, that species will dominate the co-culture. This is due to interactions between growth, metabolism and metabolism altering virulence factors produced byP. aeruginosa. Finally, we show that the relationship between absolute growth and final population composition can be perturbed by altering the spatial structure in the community. Our results demonstrate that differences in growth environment can account for conflicting observations regarding the co-existence of these bacterial species in the literature, and may offer a novel mechanism to manipulate polymicrobial populations.
A Subtle Balance between Host Selection and Microbial Size Effect Mediates Plant Microbiome Assembly in Mulberry
Authors: He Jintao , Shen Xiaoqiang , Zhang Nan , Muhammad Abrar , Shao Yongqi
Published: September 2022

Breeding toward improved ecological plant–microbiome interactions requires improved knowledge of ecological processes/principles underlying microecological patterns, but these remain elusive. Here, we systematically investigated in-planta biogeographic patterns of plant-associated bacteriome and mycobiome along soil– plant and episphere–endosphere continuum in Morus alba. Microecological patterns in diversity, structure, co-occurrence network, species turnover, and assembly process were revealed and varying between bacteriome and mycobiome, possibly driven by multiple factors including host selection, community cohesion, and particularly size-dependent dispersal limitation. Based on these findings, we hypothesized that host selection historically recruits microbiotas, whereas microbial size affects the subsequent turnovers due to the limited dispersal of larger-size microbes. This hypothesis was supported by datasets from other plant species and confirmed by stochastic dispersal experiments showing that smaller-size microbes are more likely to escape/disperse from endosphere niches, contributing to fleeting niches occupied by larger-size microbes. These findings may open new avenues toward an improved understanding of the dynamics of plant microbiome assembly.
Cryo-EM-based structural insights into supramolecular assemblies of γ-Hemolysin from Staphylococcus aureus reveal the pore formation mechanism
Authors: Mishra Suman , Roy Anupam , Dutta Somnath
Published: September 2022

γ-hemolysin (γ-HL) is a hemolytic and leukotoxic bicomponent β-pore-forming toxin (β-PFT), a potent virulence factor from Staphylococcus aureus Newman strain. In this study, we performed single particle cryo-EM of γ-HL in a lipid environment. We observed clustering and square lattice packing of octameric HlgAB pores upon membrane bilayer, and an octahedral superassembly of octameric pore complexes, that we resolved at resolution 3.5 Å. Our atomic model further demonstrated the key residues involved in hydrophobic zipping between the rim domains of adjacent octameric pore complexes, thus providing first evidence of additional structural stability in PFTs upon membrane lysis. We also observed lipid densities at the octahedral and octameric interfaces, providing critical insights into the lipid-binding residues involved for both HlgA and HlgB components. Furthermore, the hitherto elusive N-terminal region of HlgA has also been resolved in our cryo-EM map and an overall mechanism of pore formation for bicomponent β-PFTs is proposed.
Systematically attenuating DNA targeting enables CRISPR-driven editing in bacteria
Authors: Collias Daphne , Vialetto Elena , Yu Jiaqi , Co Khoa , Almási Éva d.H. , Rüttiger Ann-Sophie , Achmedov Tatjana , Strowig Till , Beisel Chase L.
Published: September 2022

Bacterial genome editing commonly relies on chromosomal cleavage with Cas nucleases to counter-select against unedited cells. However, editing normally requires efficient recombination and high transformation efficiencies, which are unavailable in most strains. Here, we show that systematically attenuating DNA targeting activity enables RecA-mediated repair in different bacteria, allowing chromosomal cleavage to drive genome editing. Attenuation can be achieved by altering the format or expression strength of guide (g)RNAs; using nucleases with reduced cleavage activity; or engineering attenuated gRNAs (atgRNAs) with disruptive hairpins, perturbed nuclease scaffolds, non-canonical PAMs, or guide mismatches. These modifications greatly increase cell counts and even improve the efficiency of different types of edits for Cas9 and Cas12a in Escherichia coli and Klebsiella oxytoca. We further applied atgRNAs to restore ampicillin sensitivity in Klebsiella pneumoniae, establishing a new resistance marker for genetic studies. Attenuating DNA targeting thus offers a counterintuitive means to achieve CRISPR-driven editing across bacteria.
Biological and synthetic surfactant exposure increase anti-microbial gene occurrence in a freshwater mixed microbial biofilm environment
Authors: Gill Stephanie P. , Snelling William J. , Dooley James S.G. , Ternan Nigel G. , Banat Ibrahim M. , Arnscheidt Joerg , Hunter William R.
Published: September 2022

Aquatic habitats are particularly susceptible to chemical pollution from domestic, agricultural, and industrial sources. Antimicrobials are commonly used in medical and industrial environments to reduce harmful bacteria and biofilms. This has led to the rapid increase in the prevalence of antimicrobial resistant (AMR) genes. Alternate remedies to fight pathogenic bacteria and biofilms are in development including synthetic and biological surfactants such as sodium dodecyl sulphate (SDS) and rhamnolipids respectively. In the aquatic environment these surfactants are present as pollutants with potential to affect biofilm formation and AMR gene occurrence; however, there is limited research showing the actual environmental impact of such exposure. We tested the effects of rhamnolipid and SDS on natural aquatic biofilms in a freshwater stream in Northern Ireland. We grew biofilms on contaminant exposure substrata deployed within the stream over four weeks, and then carried out shotgun sequencing to determine microbial community composition, through 16s rRNA analyses (64,678 classifiable reads identified), and AMR gene occurrence (81 instances of AMR genes over 9 AMR gene classes) through a metagenomic analysis. There were no significant changes in community composition within all systems; however, biofilm exposed to rhamnolipid had a greater number of unique taxa as compared to our SDS treatments and controls. AMR gene prevalence was higher in surfactant-treated biofilms, with biofilm exposed to rhamnolipids having the highest presence of AMR genes and classes compared to the control or SDS treatments, in which genes encoding for rifampin resistance were detected. Our results suggest that the presence of rhamnolipid, and to a lesser extent SDS, encourages an increase in the prevalence of AMR genes in biofilms produced in mixed use water bodies.
Does ivermectin treatment for endemic hookworm infection alter the gut microbiota of endangered Australian sea lion pups?
Authors: Fulham Mariel , Power Michelle , Gray Rachael
Published: September 2022

The gut microbiota is essential for the development and maintenance of the hosts’ immune system, and disturbances can impact host health. This study aimed to determine if topical ivermectin treatment for endemic hookworm (Uncinaria sanguinis) infection in Australian sea lion (Neophoca cinerea) pups causes gut microbial changes. The gut microbiota was characterised for untreated (control) (n=23) and treated (n=23) pups sampled during the 2019 and 2020/21 breeding seasons at Seal Bay, Kangaroo Island. Samples were collected pre- and post-treatment on up to four occasions. The gut microbiota of both untreated (control) and treated pups was dominated by five bacterial phyla, Fusobacteria, Firmicutes, Proteobacteria, Actinobacteria and Bacteroides. There was a significant difference in alpha diversity between treatment groups in 2020/21 (p = 0.008), with greater diversity in treated pups. Modelling the impact of host factors on beta diversity revealed that pup ID accounted for most of the variation with pup ID, age and capture being the only significant contributors to microbial variation (p < 0.05). There were no statistically significant differences in microbial composition between treatment groups in both breeding seasons, indicating that ivermectin treatment did not alter microbial composition. To our knowledge, this is the first study to consider the impact of parasitic treatment on overall diversity and composition of the gut microbiota. Importantly, the lack of compositional changes in the gut microbiota with topical treatment support the utility of topical ivermectin as a safe and minimally invasive management strategy to enhance pup survival in this endangered species.

Importance

Disturbances to the gut microbiota in early life stages can have life-long impacts on host health. Australian sea lions are endangered and declining, and pups are endemically infected with hookworm (Uncinaria sanguinis) which contributes to pup mortality. Treatment with topical ivermectin has been shown to effectively eliminate hookworm infection and to improve pup health, but the impact on the gut microbiota was previously unknown, representing a key knowledge gap. The results from this study show that topical ivermectin treatment does not alter the gut microbiota of Australian sea lion pups, indicating that it is a safe and minimally invasive treatment that can aid in disease mitigation and conservation of this endangered species.
Gene amplifications cause high-level resistance against albicidin in Gram-negative bacteria
Authors: Saathoff Mareike , Kosol Simone , Semmler Torsten , Tedin Karsten , Dimos Nicole , Kupke Johannes , Seidel Maria , Ghazisaeedi Fereshteh , Wolf Silver A. , Kuropka Benno , Czyszczoń Wojciech , Ghilarov Dmitry , Grätz Stefan , Heddle Jonathan G. , Loll Bernhard , Süssmuth Roderich D. , Fulde Marcus
Published: September 2022

Antibiotic resistance is a continuously increasing concern for public health care. Understanding resistance mechanisms and their emergence is crucial for the development of new antibiotics and their effective use. Here, we report the discovery of a gene amplification-based mechanism that imparts an up to 1000-fold increase in resistance levels against the antibiotic albicidin. We show that this mechanism protects Salmonella Typhimurium and Escherichia coli by increasing the copy number of the GyrI-like transcription regulator STM3175 (YgiV) which binds albicidin. X-ray crystallography and molecular docking studies reveal a conserved binding motif that can interact with aromatic building blocks of albicidin. Phylogenetic studies suggest that this resistance mechanism is ubiquitous in Gram-negative bacteria and our experiments confirm that STM3175 homologs can convey resistance in pathogens such as Vibrio vulnificus and Pseudomonas aeruginosa.
O-Linked Sialoglycans Modulate the Proteolysis of SARS-CoV-2 Spike and Likely Contribute to the Mutational Trajectory in Variants of Concern
Authors: Gonzalez-Rodriguez Edgar , Zol-Hanlon Mia , Bineva-Todd Ganka , Marchesi Andrea , Skehel Mark , Mahoney Keira E. , Roustan Chloë , Borg Annabel , Di Vagno Lucia , Kjaer Svend , Wrobel Antoni G. , Benton Donald J. , Nawrath Philipp , Flitsch Sabine L. , Joshi Dhira , González-Ramírez Andrés Manuel , Wilkinson Katalin A. , Wilkinson Robert J. , Wall Emma C. , Hurtado-Guerrero Ramón , Malaker Stacy A. , Schumann Benjamin
Published: September 2022

The emergence of a polybasic cleavage motif for the protease furin in the SARS-CoV-2 spike protein has been established as a major factor for enhanced viral transmission in humans. The peptide region N-terminal to that motif is extensively mutated in major variants of concern including Alpha, Delta and Omicron. Besides furin, spike proteins from these variants appear to rely on other proteases for maturation, including TMPRSS2 that may share the same cleavage motif. Glycans found near the cleavage site have raised questions about proteolytic processing and the consequences of variant-borne mutations. Here, with a suite of chemical tools, we establish O-linked glycosylation as a major determinant of SARS-CoV-2 spike cleavage by the host proteases furin and TMPRSS2, and as a likely driving force for the emergence of common mutations in variants of concern. We provide direct evidence that the glycosyltransferase GalNAc-T1 primes glycosylation at Thr678 in the living cell, and this glycosylation event is suppressed by many, but not all variant mutations. A novel strategy for rapid bioorthogonal modification of Thr678-containing glycopeptides revealed that introduction of a negative charge completely abrogates furin activity. In a panel of synthetic glycopeptides containing elaborated O-glycans, we found that the sole incorporation of N-acetylgalactosamine did not substantially impact furin activity, but the presence of sialic acid in elaborated O-glycans reduced furin rate by up to 65%. Similarly, O-glycosylation with a sialylated trisaccharide had a negative impact on spike cleavage by TMPRSS2. With a chemistry-centered approach, we firmly establish O-glycosylation as a major determinant of spike maturation and propose that a disruption of O-GalNAc glycosylation is a substantial driving force for the evolution of variants of concern.

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Five factors affecting the on-body placement of wearable tactile safety promotion device for construction workers-on-foot
Authors: Yadav Neeraj , Sadeghi Neda , Kang Julian
Published: September 2022

Purpose

Tactile communication that relies on the human sense of touch replicated using vibration motors is increasingly being explored for seamless communication on construction jobsite. However, the technological efficacy cannot secure the users’ acceptability of the tactile communication devices. This study aims to assess the factors affecting the wearability of such a portable tactile device based on the responses from practicing professionals.

Design/methodology/approach

The investigation adapted a three-step phenomenological interviewing approach to seek feedback from construction personnel in Texas, the USA, regarding the viability of wearable tactile communication. The interviewees expressed various opinions about the on-body placement upon exposure to a portable tactile feedback prototype developed for this study, which was used to derive inferences regarding the factors affecting its on-field acceptability.

Findings

All the participants of the round-table study (11 out of 11) considered tactile feedback as a viable mode of communication on construction jobsite. Seven professionals supported the integration of a tactile device with the hard hat, whereas the rest preferred tactile eyeglasses. Weatherability, rechargeability, traceability, safety and social receptivity were identified as the major factors affecting the on-body placement of the wearable tactile communication device.

Originality/value

This paper presents a roadmap to gain construction industry opinion on the factors that can affect the on-body placement of a wearable tactile communication device. The five aforementioned factors impacting tactile communication acceptability were used to evaluate 10 potential on-body placements. The findings have implications for research and development of wearable tactile devices and the subsequent acceptability of such a device on the jobsite.
Natural-born peacemakers? Big five personality traits, gender, and interpersonal peacemaking
Authors: Zhang Xiaolei , Bollen Katalien , Peng Kaiping , Euwema Martin C.
Published: September 2022

Purpose

This study aims to investigate the relationship between personality, gender and interpersonal peacemaking. Peacemaking is considered as voluntary behavior of team members to help conflicting peers in an impartial way, to find an amicable solution. This study tests the relation between the Big Five personality dimensions, gender and five different components of interpersonal peacemaking (general involvement in peacemaking, multipartiality, focus of finding solutions, emotional support and the use of humor).

Design/methodology/approach

In total, 503 participants filled out a survey assessing their personality and peacemaking behavior at work. To test the hypotheses, this study conducted structural equation modeling in AMOS 22.0.

Findings

In line with expectations, openness, extraversion and agreeableness related positively to most peacemaking components, while conscientiousness and neuroticism related negatively to the use of humor and peacemakers’ multipartiality, respectively; comparing men and women, women engage more often in peacemaking in general and in emotional support, and use less humor than men. Results also showed that these gender differences are partially mediated by agreeableness being higher for women.

Originality/value

To the best of the authors’ knowledge, this is one of the first studies exploring the relationship between personality (Big Five), gender and different aspects of interpersonal peacemaking. Peacemaking is an important, however understudied, behavior in teams and part of OCB. The promotion of peacemaking contributes to team effectiveness.
College students are pro-environment but lack sustainability knowledge: a study at a mid-size Midwestern US university
Authors: Null Dawn Christina , Asirvatham Jebaraj
Published: September 2022

Purpose

The purpose of this study is to examine the differences in sustainability knowledge, behaviors and attitudes among college students and to estimate the influence of knowledge of sustainability on students’ sustainable behaviors.

Design/methodology/approach

A cross-sectional online survey was used to collect quantitative data on sustainability knowledge, behaviors and attitudes among 291 undergraduate college students at a mid-size Midwestern US university. This study used a structural equation model to answer the research questions.

Findings

In all, 291 students completed a sustainability attitudes and behaviors survey. The results of this study show sustainability knowledge is poor (average score 5.3/10). Statistical modeling indicates positive influence of economic attitudes on sustainable behaviors; however, ecology and social attitudes were not associated with sustainable behaviors. Furthermore, those with greater sustainable knowledge engaged in fewer sustainable behaviors.

Practical implications

Sustainability and/or wellness initiatives can provide education targeting actionable behaviors college students can make to reduce their carbon footprint, including washing clothes in cold water, limiting red meat consumption, recycling, reducing food waste and taking shorter showers. Sustainability initiatives such as organizing a recycling competition and coordinating volunteers for local clean-up days and events such as Earth Day celebrations offer opportunities for collaboration between campus departments and engagement and socialization among students, staff and faculty. The inclusion of sustainability in college curricula may increase students’ knowledge, develop critical thinking skills and self-efficacy related to sustainability and promote climate action.

Originality/value

First, this study adds to the literature in terms of the use of structural equation modeling. Second, this study’s results indicate a dissociation between positive sustainable attitudes as they relate to sustainable behaviors. Why is it that students think the environment is important yet do not place importance on sustainable behaviors? These issues are highly relevant and present opportunities for future research and interventions aimed at increasing sustainable behaviors.
Fake news detection on Twitter
Authors: Sharma Srishti , Saraswat Mala , Dubey Anil Kumar
Published: September 2022

Purpose

Owing to the increased accessibility of internet and related technologies, more and more individuals across the globe now turn to social media for their daily dose of news rather than traditional news outlets. With the global nature of social media and hardly any checks in place on posting of content, exponential increase in spread of fake news is easy. Businesses propagate fake news to improve their economic standing and influencing consumers and demand, and individuals spread fake news for personal gains like popularity and life goals. The content of fake news is diverse in terms of topics, styles and media platforms, and fake news attempts to distort truth with diverse linguistic styles while simultaneously mocking true news. All these factors together make fake news detection an arduous task. This work tried to check the spread of disinformation on Twitter.

Design/methodology/approach

This study carries out fake news detection using user characteristics and tweet textual content as features. For categorizing user characteristics, this study uses the XGBoost algorithm. To classify the tweet text, this study uses various natural language processing techniques to pre-process the tweets and then apply a hybrid convolutional neural network–recurrent neural network (CNN-RNN) and state-of-the-art Bidirectional Encoder Representations from Transformers (BERT) transformer.

Findings

This study uses a combination of machine learning and deep learning approaches for fake news detection, namely, XGBoost, hybrid CNN-RNN and BERT. The models have also been evaluated and compared with various baseline models to show that this approach effectively tackles this problem.

Originality/value

This study proposes a novel framework that exploits news content and social contexts to learn useful representations for predicting fake news. This model is based on a transformer architecture, which facilitates representation learning from fake news data and helps detect fake news easily. This study also carries out an investigative study on the relative importance of content and social context features for the task of detecting false news and whether absence of one of these categories of features hampers the effectiveness of the resultant system. This investigation can go a long way in aiding further research on the subject and for fake news detection in the presence of extremely noisy or unusable data.