bluuebunny/crossref_metadata_2025 huggingface dataset:
The algorithm for proven and young (APY) from a different perspective
Authors: Nilforooshan Mohammad Ali
Published: November 2022

The inverse of the genomic relationship matrix (G-1) is used in genomic BLUP (GBLUP) and the single-step GBLUP. The rapidly growing number of genotypes is a constraint for invertingG. The APY algorithm efficiently resolves this issue. MatrixGhas a limited dimensionality. Dividing individuals into core and non-core,G-1is approximated via the inverse partition ofGfor core individuals. The quality of the approximation depends on the core size and composition. The APY algorithm conditions genomic breeding values of the non-core individuals to those of the core individuals, leading to a diagonal block ofG-1for non-core individuals (Mnn-1). Dividing observations into two groups (e.g., core and non-core, genotyped and non-genotyped,etc), any symmetric matrix can be expressed in APY and APY-inverse expressions, equal to the matrix itself and its inverse, respectively. The change ofGnntoMnn-1= diag(Gnn) makes APY an approximate. This change is projected to the other blocks ofG-1as well. The application of APY is extendable to the inversion of any large symmetric matrix with a limited dimensionality at a lower computational cost. Furthermore, APY may improve the numerical condition of the matrix or the equation system.
Bioschemas Training Profiles: A set of specifications for standardizing training information to facilitate the discovery of training programs and resources
Authors: Jael Castro Leyla , Palagi Patricia M. , Beard Niall , Attwood Teresa K. , Brazas Michelle D.
Published: November 2022

Stand-alone life science training events and e-learning solutions are amongst the most sought-after modes of training because they address both point-of-need learning and the limited timeframes available for ‘upskilling’. Yet, finding relevant life sciences training courses and materials is challenging because such resources are not marked up for Internet searches in a consistent way. This absence of mark-up standards to facilitate discovery, re-use and aggregation of training resources limits their usefulness and knowledge-translation potential. Through a joint effort between the Global Organisation for Bioinformatics Learning, Education and Training (GOBLET), the Bioschemas Training community and the ELIXIR FAIR Training Focus Group, a set of Bioschemas Training profiles has been developed, published and implemented for life sciences training courses and materials. Here, we describe our development approach and methods, which were based on the Bioschemas model, and present the results for the three Bioschemas Training profiles:TrainingMaterial, CourseandCourseInstance. Several implementation challenges were encountered, which we discuss alongside potential solutions. Over time, continued implementation of these Bioschemas Training profiles by training providers will obviate the barriers to skill development, facilitating both the discovery of relevant training events to meet individuals’ learning needs, and the discovery and re-use of training and instructional materials.
Inferring Spatially Resolved Transcriptomics Data from Whole Slide Images for the Assessment of Colorectal Tumor Metastasis: A Feasibility Study
Authors: Fatemi Michael , Feng Eric , Sharma Cyril , Azher Zarif , Goel Tarushii , Ramwala Ojas , Palisoul Scott , Barney Rachael , Perreard Laurent , Kolling Fred , Salas Lucas A. , Christensen Brock C. , Tsongalis Gregory , Vaickus Louis , Levy Joshua J.
Published: November 2022

Over 150,000 Americans are diagnosed with colorectal cancer (CRC) every year, and annually over 50,000 individuals will die from CRC, necessitating improvements in screening, prognostication, disease management, and therapeutic options. Tumor metastasis is the primary factor related to the risk of recurrence and mortality. Yet, screening for nodal and distant metastasis is costly, and invasive and incomplete resection may hamper adequate assessment. Signatures of the tumor-immune microenvironment (TIME) at the primary site can provide valuable insights into the aggressiveness of the tumor and the effectiveness of various treatment options. Spatially-resolved transcriptomics technologies offer an unprecedented characterization of TIME through high multiplexing, yet their scope is constrained by cost. Meanwhile, it has long been suspected that histological, cytological and macroarchitectural tissue characteristics correlate well with molecular information (e.g., gene expression). Thus, a method for predicting transcriptomics data through inference of RNA patterns from whole slide images (WSI) is a key step in studying metastasis at scale. In this work, we collected and preprocessed Visium spatial transcriptomics data (17,943 genes at up to 5,000 spots per patient sampled in a honeycomb pattern) from tissue across four stage-III matched colorectal cancer patients. We compare and prototype several convolutional, Transformer, and graph convolutional neural networks to predict spatial RNA patterns under the hypothesis that the transformer and graph-based approaches better capture relevant spatial tissue architecture. We further analyzed the model’s ability to recapitulate spatial autocorrelation statistics using SPARK and SpatialDE. Overall, results indicate that the transformer and graph-based approaches were unable to outperform the convolutional neural network architecture, though they exhibited optimal performance for relevant disease-associated genes. Initial findings suggest that different neural networks that operate on different scales are relevant for capturing distinct disease pathways (e.g., epithelial to mesenchymal transition). We add further evidence that deep learning models can accurately predict gene expression in whole slide images and comment on understudied factors which may increase its external applicability (e.g., tissue context). Our preliminary work will motivate further investigation of inference for molecular patterns from whole slide images as metastasis predictors and in other applications.
SARS-CoV-2 Spike Protein Induces Hemagglutination: Implications for COVID-19 Morbidities and Therapeutics and for Vaccine Adverse Effects
Authors: Boschi Celine , Scheim David E. , Bancod Audrey , Millitello Muriel , Bideau Marion Le , Colson Philippe , Fantini Jacques , Scola Bernard La
Published: November 2022

Experimental findings for SARS-CoV-2 related to the glycan biochemistry of coronaviruses indicate that attachments from spike protein to glycoconjugates on the surfaces of red blood cells (RBCs), other blood cells and endothelial cells are key to the infectivity and morbidity of COVID-19. To provide further insight into these glycan attachments and their potential clinical relevance, the classic hemagglutination (HA) assay was applied using spike protein from the Wuhan, Alpha, Delta and Omicron B.1.1.529 lineages of SARS-CoV-2 mixed with human RBCs. The electrostatic potential of the central region of spike protein from these four lineages was studied through molecular modeling simulations. Inhibition of spike protein-induced HA was tested using the macrocyclic lactone ivermectin (IVM), which is indicated to bind strongly to SARS-CoV-2 spike protein glycan sites. The results of these experiments were, first, that spike protein from these four lineages of SARS-CoV-2 induced HA. Omicron induced HA at a significantly lower threshold concentration of spike protein than for the three prior lineages and was much more electropositive on its central spike protein region. IVM blocked HA when added to RBCs prior to spike protein and reversed HA when added afterwards. These results validate and extend prior findings on the role of glycan bindings of viral spike protein in COVID-19. They furthermore suggest therapeutic options using competitive glycan-binding agents such as IVM and may help elucidate rare serious adverse effects (AEs) associated with COVID-19 mRNA vaccines which use spike protein as the generated antigen.
Population genomics, resistance, pathogenic potential, and mobile genetic elements of carbapenem-resistantKlebsiella pneumoniaecausing infections in Chile
Authors: Veloso Marcelo , Acosta Joaquín , Arros Patricio , Berríos-Pastén Camilo , Rojas Roberto , Varas Macarena , Allende Miguel L. , Chávez Francisco P. , Araya Pamela , Hormazábal Juan Carlos , Lagos Rosalba , Marcoleta Andrés E.
Published: November 2022

Multidrug and carbapenem-resistantK. pneumoniae(CR-Kp) are considered critical threats to global health and key traffickers of resistance genes to other pathogens. In Chile, although a sustained increase in CR-Kpinfections has been observed, few strains have been described at the genomic level, lacking molecular details of their resistance and virulence determinants and the mobile elements mediating their dissemination. In this work, we studied the antimicrobial resistance and performed a comparative genomics analysis of ten CR-Kpisolates from the Chilean surveillance of carbapenem-resistantEnterobacteriaceae. High resistance to most of the antibiotics tested was observed among the isolates, five ST25, three ST11, one ST45, and one ST505, which harbored a total of 44 plasmids, many of them predicted to be conjugative and carrying genes conferring resistance to a variety of antibiotic, metals, and disinfectants. Ten plasmids encoding either KPC-2, NDM-1, or NDM-7 carbapenemases were characterized, including novel plasmids with increased resistance gene load and a novel genetic environment forblaKPC-2gene. This corresponds to the first report of ST25 and ST45Kpproducing NDM-7 in South America, and of an ST505 CR-Kpworldwide, producing both NDM-7 and KPC-2. Moreover, we characterized a variety of genomic islands carrying virulence and fitness factors. These results provide baseline knowledge for the detailed understanding of molecular and genetic determinants behind antibiotic resistance and virulence ofK. pneumoniaein Chile and South America.
Tissue- and sex-specific DNA damage tracks aging in rodents and humans
Authors: Guilbaud Axel , Ghanegolmohammadi Farzan , Wang Yijun , Leng Jiapeng , Kreymerman Alexander , Varela Jacqueline Gamboa , Garbern Jessica , Elwell Hannah , Cao Fang , Ricci-Blair Elisabeth M. , Liang Cui , Balamkundu Seetharamsingh , Vidoudez Charles , DeMott Michael S. , Bedi Kenneth , Margulies Kenneth B. , Bennett David A. , Palmer Abraham A. , Barkley-Levenson Amanda , Lee Richard T. , Dedon Peter C.
Published: November 2022

DNA damage causes genomic instability underlying many human diseases. Traditional approaches to DNA damage analysis provide minimal insights into the spectrum of disease-driving DNA lesions and the mechanisms causing imbalances in damage formation and repair. Here we used untargeted mass spectrometry-based adductomics1to discover 114 putative DNA lesions and modifications consistently detected in humans and two independent analyses in rats, showing species-, tissue-, age-, and sex-biases. As evidence of methodologic rigor, 10 selected adductomic signals were structurally validated as epigenetic marks: 5-MdC, 5-HMdC, 5-FdC; DNA damage products:N2-CMdG, 1,N6ε-dA, 3,N4-εdC, M1dG,O6/N2-MdG, and 8-Oxo-dG; and established analytical artifacts: cyclobutane dimers of 2’-deoxycytosine. With steady-state levels of putative DNA adducts integrating multiple cell types in each tissue, there was strong age-dependent variation for many putative adducts, includingN2-CMdG, 5-HMdC, and 8-Oxo-dG in rats and 1,N6ε-dA in human heart, as well as sex biases for 67 putative adducts in rat tissues. These results demonstrate the potential of untargeted adductomic analysis for defining DNA adducts as disease determinants, assigning substrates to DNA repair pathways, discovering new metabolically-driven DNA lesions, and quantifying inter-individual variation in DNA damage and repair across populations.
Deep Learning Allows Assessment of Risk of Metastatic Relapse from Invasive Breast Cancer Histological Slides
Authors: Garberis I. , Gaury V. , Saillard C. , Drubay D. , Elgui K. , Schmauch B. , Jaeger A. , Herpin L. , Linhart J. , Sapateiro M. , Bernigole F. , Kamoun A. , Bendjebbar E. , de Lavergne A. , Dubois R. , Auffret M. , Guillou L. , Bousaid I. , Azoulay M. , Lemonnier J. , Sefta M. , Jacquet A. , Sarrazin A. , Reboud J-F , Brulport F. , Dachary J. , Pistilli B. , Delaloge S. , Courtiol P. , André F. , Aubert V. , Lacroix-Triki M.
Published: November 2022

Background

Correctly classifying early estrogen receptor-positive and HER2-negative (ER+/HER2) breast cancer (EBC) cases allows to propose an adapted adjuvant systemic treatment strategy. We developed a new AI-based tool to assess the risk of distant relapse at 5 years for ER+/HER2-EBC patients from pathological slides.

Patients and Methods

The discovery dataset (GrandTMA) included 1429 ER+/HER2-EBC patients, with long-term follow-up and an available hematoxylin-eosin and saffron (HES) whole slide image (WSI). A Deep Learning (DL) network was trained to predict metastasis free survival (MFS) at five years, based on the HES WSI only (termed RlapsRisk). A combined score was then built using RlapsRisk and well established prognostic factors. A threshold corresponding to a probability of MFS event of 5% at 5 years was applied to dichotomize patients into low or high-risk groups. The external validation, as well as assessment of the additional prognosis value of the DL model beyond standard clinico-pathologic factors were carried out on an independent, prospective cohort (CANTO,NCT01993498) including 889 HES WSI of ER+/HER2-EBC patients.

Results

RlapsRisk was an independent prognostic factor of MFS in multivariable analysis adjusted for established clinico-pathological factors (p<0.005 in GrandTMA and CANTO). Combining RlapsRisk score and the clinico-pathological factors improved the prognostic discrimination as compared to the clinico-pathological factors alone (increment of c-index in the validation set 0.80 versus 0.76, +0.04, p-value < 0.005). After dichotomization, the Combined Model showed a higher cumulative sensitivity on the entire population (0.76 vs 0.61) for an equal dynamic specificity (0.76) in comparison with the clinical score alone.

Conclusions

Our deep learning model developed on digitized HES slides provided additional prognostic information as compared to current clinico-pathological factors and has the potential of valuably informing the decision making process in the adjuvant setting when combined with current clinico-pathological factors.
Fc mediated pan-sarbecovirus protection after alphavirus vector vaccination
Authors: Adams Lily E. , Leist Sarah R. , Dinnon Kenneth H. , West Ande , Gully Kendra L. , Anderson Elizabeth J. , Loome Jennifer F. , Madden Emily A. , Powers John M. , Schäfer Alexandra , Sarkar Sanjay , Castillo Izabella N. , Maron Jenny S. , McNamara Ryan P. , Bertera Harry L. , Zweigert Mark R. , Higgins Jaclyn S. , Hampton Brea K. , Premkumar Lakshmanane , Alter Galit , Montgomery Stephanie A. , Baxter Victoria K. , Heise Mark T. , Baric Ralph S.
Published: November 2022

Two group 2B β-coronaviruses (sarbecoviruses) have caused regional and global epidemics in modern history. The mechanisms of cross protection driven by the sarbecovirus spike, a dominant immunogen, are less clear yet critically important for pan-sarbecovirus vaccine development. We evaluated the mechanisms of cross-sarbecovirus protective immunity using a panel of alphavirus-vectored vaccines covering bat to human strains. While vaccination did not prevent virus replication, it protected against lethal heterologous disease outcomes in both SARS-CoV-2 and clade 2 bat sarbecovirus HKU3-SRBD challenge models. The spike vaccines tested primarily elicited a highly S1-specific homologous neutralizing antibody response with no detectable cross-virus neutralization. We found non-neutralizing antibody functions that mediated cross protection in wild-type mice were mechanistically linked to FcgR4 and spike S2-binding antibodies. Protection was lost in FcR knockout mice, further supporting a model for non-neutralizing, protective antibodies. These data highlight the importance of FcR-mediated cross-protective immune responses in universal pan-sarbecovirus vaccine designs.
Unprecedented shift in Canadian High Arctic polar bear food web unsettles four millennia of stability
Authors: Routledge Jennifer , Sonne Christian , Letcher Robert J , Dietz Rune , Szpak Paul
Published: November 2022

Stable carbon (δ13C) and nitrogen (δ15N) isotope analysis was conducted on modern and archaeological polar bear bone collagen from the Canadian Arctic Archipelago to investigate potential changes in polar bear foraging ecology over four-millennia. Polar bearδ13C values showed a significant decline in the modern samples relative to all archaeological time-bins, indicating a disruption in the sources of production that support the food web, occurring after the Industrial Revolution. The trophic structure, indicated throughδ15N, remained unaltered throughout all time periods. The lowerδ13C observed in the modern samples indicates a change in the relative importance of pelagic (supported by open-water phytoplankton) over sympagic (supported by sea ice-associated algae) primary production. The consistency in polar bearδ13C through the late Holocene includes climatic shifts such as the Medieval Warm Period (MWP, A.D. 950-1250) and the early stages of the Little Ice Age (LIA, A.D. 1300-1850). These findings suggest that polar bears inhabit a food web that is more pelagic and less sympagic today than it was through the Late Holocene. We suggest that modern, anthropogenic warming has already affected food web structure in the Canadian Arctic Archipelago when modern data are contextualized with a deep time perspective.

Research Highlights

Modern polar bear bone collagenδ13C suggests recent decline in ice associated prey.

Archaeological polar bear bone collagen suggests food web stability for millennia.

No change in sea-ice association through the Medieval Warm Period and Little Ice Age.

Recent isotopic shifts are unusual relative to the stability of ancient samples.

Modern Arctic warming has isotopically observable impacts that past events did not.

OR

Significance Statement

The lack of behavioral plasticity of both polar bears and their principal prey, ringed seals, make these species particularly vulnerable to declining sea ice. While the Lancaster Sound food web has demonstrated stability through past climate fluctuations, the speed and magnitude of ongoing changes in the Arctic has had an observable effect on the source of primary production. Given that past climate fluctuations are referenced as an argument to minimize the importance of modern anthropogenic warming, it is important to take opportunities to position contemporary climate change relative to the archaeological record. Here we present a unique illustration of the effects of past and present warming on polar bear diet and the marine food web in the Canadian Arctic Archipelago.
Twitching cells use a chemoreceptor to detect bacterial competitors
Authors: Yarrington Kaitlin D. , Shendruk Tyler N. , Limoli Dominique H.
Published: November 2022

Bacteria live in cosmopolitan communities, where the ability to sense and respond to interspecies and environmental signals is critical for survival. We previously showed the pathogenPseudomonas aeruginosadetects secreted peptides from bacterial competitors and navigates interspecies signal gradients using pilus-based motility. Yet, it remained unknown whetherP. aeruginosautilizes a designated chemosensory system for this behavior. Here, we performed a comprehensive genetic analysis of a putative pilus chemosensory system to reveal behaviors of mutants that retain motility, but are blind to interspecies signals. The enzymes predicted to methylate (PilK) and demethylate (ChpB) the putative pilus chemoreceptor, PilJ, are necessary for cells to control the direction of migration. While these findings implicate PilJ as abona fidechemoreceptor, such function had yet to be experimentally defined, as PilJ is essential for motility. Thus, we constructed systematic genetic modifications of PilJ and found that without the predicted ligand binding domains or methylation sites cells lose the ability to detect competitor gradients, despite retaining pilus-mediated motility. Collectively, this work uncovers the chemosensory nature of PilJ, providing insight into chemotactic interactions necessary for bacterial survival in polymicrobial communities and revealing putative pathways where therapeutic intervention might disrupt bacterial communication.
Chemosensory afference in the tentacle nerve ofLymnaea stagnalis
Authors: Ucciferri Carmen C. , Wyeth Russell C.
Published: November 2022

Although the neural control of behavior has been extensively studied in gastropods, basic gaps remain in our understanding of how sensory stimuli are processed. In particular, there is only patchy evidence regarding the functional roles of sense organs and the extensive peripheral nervous system they contain. Our goal was to use extracellular electrophysiological recordings to confirm the chemosensory role of the tentacles in the great pond snail,Lymnaea stagnalis. Employing a special twin channel suction electrode to improve signal-to-noise ratio, we applied three food odours (derived from earthworm-based food pellets, algae-based pellets, and fresh lettuce) to a reduced preparation of the tentacle while recording neuronal activity in the tentacle nerve. Responses were assessed by comparing average spike frequencies produced in response to saline flow with and without odours. Confirming the omnivorous nature of this gastropod, we report strong neuronal responses to earthworm-based food odours and mild neuronal responses to algae-based food odours. There were no clear neuronal responses produced when lettuce food odour or control saline was applied to the tentacle. Overall, our results provide strong evidence for the chemosensory role of the tentacles inL. stagnalis. While it is unclear whether the differences in neuronal responses can be explained by differing sizes, numbers, or populations of neurons, these results are a useful foundation for further study of peripheral nervous system function in gastropods.

Summary Statement

Great pond snail tentacles send sensory signals to the brain in response to some (but not all) food odours.
Long-term fertilization modifies the composition of slow-growing oligotrophs more than fast-growing copiotrophs in a nutrient poor coastal plain wetland
Authors: Walker Allison , Stephens Daniya , Garcia Aied , Peralta Ariane L.
Published: November 2022

Wetland ecosystems are known for their carbon storage potential due to slow decomposition rates and high carbon fixation rates. However, nutrient addition from human activities affects this carbon storage capacity as the balance of fixed and respired carbon shifts due to plant and microbial communities. Ongoing atmospheric deposition of nutrients could be changing wetland plant-microbe interactions in ways that tip the balance from carbon storage to loss. Therefore, examining microbial community patterns in response to nutrient enrichment is important to understanding nutrient effects on carbon storage potential. In this study, we hypothesized that fertilization of a low nutrient ecosystem leads to increased organic carbon input from plant biomass into the soil and results in increased soil bacterial diversity and modifications to soil bacterial community composition. As such, increased soil nutrients and carbon resources provide more energy to support increased microbial growth rates, which can result in wetland carbon losses. To test this hypothesis, we used bacterial community-level and soil chemical data from the long-term wetland ecology experiment at East Carolina University’s West Research Campus (established in 2003). Specifically, we examined the extent that long-term effects of nutrient enrichment affect wetland microbial communities and plant biomass, which are factors that can affect carbon storage. We collected soil cores from fertilized and unfertilized test plots. We extracted genomic DNA from soil samples and conducted 16S rRNA targeted amplicon sequencing to characterize the bacterial community composition. In addition, we measured plant above and belowground biomass and soil carbon content. Results revealed an increase in aboveground plant biomass, soil carbon, and bacterial diversity. In contrast, belowground plant biomass and microbial biomass were similar in fertilized and unfertilized plots. To further examine bacterial community changes to nutrient enrichment, we compared the relative abundance of fast growing copiotrophic and slow growing oligotrophic bacteria of a subset of taxa putatively identified as belonging to either life history strategy. These taxa-level results revealed a decrease in oligotroph relative abundance and little to no change in copiotroph relative abundance of a subset of bacterial taxa. If there is a community-wide shift in the proportion of oligotroph to copiotroph life history strategies, this would have a negative impact on organic carbon storage since oligotrophic bacteria respire less carbon than copiotrophic bacteria over the same amount of time. Taken together, this study provided evidence that long-term nutrient enrichment influences wetland soils in ways that decrease their carbon storage potential of important carbon sinks.
Sequence Controlled Secondary Structure Determines Site-selectivity of Lanthipeptides
Authors: Mi Xuenan , Desormeaux Emily K. , Le Tung T. , van der Donk Wilfred A. , Shukla Diwakar
Published: November 2022

Lanthipeptides are ribosomally synthesized and post-translationally modified peptides that are generated from precursor peptides through a dehydration and cyclization process in the biosynthetic pathways. In contrast to most other lanthipeptide synthetases, ProcM, a class II lanthipeptide synthetase, demonstrates high substrate tolerance. It is enigmatic that a single enzyme can catalyze the cyclization process of a diverse range of substrates with high fidelity. Previous studies suggested that the site-selectivity of lanthionine formation is determined by substrate sequence rather than by the enzyme. However, exactly how substrate sequence contributes to site-selective lanthipeptide biosynthesis is not clear. In this study, we performed molecular dynamic simulations for ProcA3.3 core peptide variants to explore how the predicted solution structure of the substrate without enzyme correlates to final product formation. Our simulation results support a model in which the secondary structure of the core peptide controls the ring pattern of the final product. We also demonstrate that the dehydration step in the biosynthesis pathway does not influence the site-selectivity of ring formation. In addition, we performed simulation for the core peptides of ProcA1.1 and 2.8, which are well-suited candidates to investigate the connection between order of ring formation and solution structure. Simulation results indicate that in both cases, C-terminal ring formation is more likely which was supported by experimental results. Our findings indicate that the substrate sequence and its solution structure can be used to predict the site-selectivity and order of ring formation, and that secondary structure is a crucial factor influencing the site-selectivity. Taken together, these findings will facilitate our understanding of the lanthipeptide biosynthetic mechanism and accelerate bioengineering efforts for lanthipeptide-derived products.
Cleavage of the pseudoprotease iRhom2 by the signal peptidase complex reveals an ER-to-nucleus signalling pathway
Authors: Dulloo Iqbal , Tellier Michael , Levet Clémence , Chikh Anissa , Zhang Boyan , Webb Catherine M , Kelsell David P , Freeman Matthew
Published: November 2022

iRhoms are pseudoprotease members of the rhomboid-like superfamily and are cardinal regulators of inflammatory and growth factor signalling; they function primarily by recognising transmembrane domains of their clients. Here we report an unexpected, and mechanistically distinct, nuclear function of iRhoms. iRhom2 is a non-canonical substrate of the signal peptidase complex (SPC), the protease that removes signal peptides from secreted proteins. Cleavage of iRhom2 generates an N-terminal fragment that enters the nucleus and modifies the cellular transcriptome. We observed elevated nuclear iRhom2 in skin biopsies of patients with psoriasis and tylosis with oesophageal cancer (TOC); increased SPC-mediated iRhom2 cleavage in a psoriasis model; and overlapping transcriptional signatures between psoriasis and expression of the iRhom2 N-terminus. This work highlights the pathophysiological significance of this SPC-dependent ER-to-nucleus signalling pathway, and is the first example of a rhomboid-like protein that mediates protease-regulated nuclear signalling.
Extracellular vimentin is sufficient to promote cell attachment, spreading, and motility by a mechanism involving N-acetyl glucosamine-containing structures
Authors: Bucki Robert , Iwamoto Daniel V. , Shi Xuechen , Kerr Katherine E. , Byfield Fitzroy J. , Suprewicz Łukasz , Skłodowski Karol , Sutaria Julian , Misiak Paweł , Wilczewska Agnieszka , Ramachandran Sekar , Wolfe Aaron , Thanh Minh-Tri Ho , Whalen Eli , Patteson Alison E. , Janmey Paul A.
Published: November 2022

Vimentin intermediate filaments form part of the cytoskeleton of mesenchymal cells, but under pathological conditions often associated with inflammation, vimentin filaments depolymerize as the result of phosphorylation or citrullination, and vimentin oligomers are secreted or released into the extracellular environment. In the extracellular space, vimentin can bind surfaces of other cells and the extracellular matrix, and the interaction between extracellular vimentin and other cell types can trigger changes in cellular functions, such as activation of fibroblasts to a fibrotic phenotype. The mechanism by which extracellular vimentin binds external cell membranes and whether vimentin alone can act as an adhesive anchor for cells is largely uncharacterized. Here, we show that various cell types (normal and vimentin null fibroblasts, mesenchymal stem cells, A549 lung carcinoma cells) attach to and spread on polyacrylamide hydrogel substrates covalently linked to vimentin. Using traction force microscopy and spheroid expansion assays, we characterize how different cell types respond to extracellular vimentin. Cell attachment to and spreading on vimentin-coated surfaces is inhibited by hyaluronic acid (HA) degrading enzymes, HA synthase inhibitors, soluble heparin, or N-acetyl glucosamine, treatments that have little or no effect on the same cell types binding to collagen-coated hydrogels. These studies highlight the effectiveness of substrate-bound vimentin as a ligand for cells and suggest that carbohydrate structures, including the glycocalyx and glycosylated cell surface proteins that contain N-acetyl glucosamine, form a novel class of adhesion receptors for extracellular vimentin.
Trem2 Promotes Foamy Macrophage Lipid Uptake and Survival in Atherosclerosis
Authors: Patterson Michael T. , Firulyova Maria , Xu Yingzheng , Bishop Courtney , Zhu Alisha , Schrank Patricia R. , Ronayne Christine E. , Fredrickson Gavin , Kennedy Ainsley E. , Acharya Nisha , Revelo Xavier , Stromnes Ingunn , Bold Tyler D. , Zaitsev Konstantin , Williams Jesse W.
Published: November 2022

Atherosclerotic plaque formation is driven by the continued expansion of cholesterol loaded ‘foamy’ macrophages within the arterial intima. Foamy macrophages are primarily derived from newly recruited monocytes, but factors regulating monocyte specification toward foamy macrophage differentiation and prolonged survival in plaque remain poorly understood. We used trajectory analysis of integrated single cell RNA-seq data, along with a genome-wide CRISPR screening approach to identify Triggering Receptor Expressed on Myeloid Cells 2 (Trem2) as a candidate regulator for foamy macrophage specification. Loss of Trem2 led to a reduced ability of foamy macrophages to take up additional oxidized low density lipoprotein (LDL) cholesterol in vitro. Competitive chimera experiments showed that Trem2-deficient macrophages were less competent to form foamy macrophages when competed against Trem2-sufficient macrophages in vivo. In addition, myeloid specific conditional deletion of Trem2 resulted in a dramatic attenuation of plaque progression, even when targeted in established atherosclerotic lesions. This was independent of changes in circulating inflammatory cytokines, monocyte recruitment, or serum cholesterol levels, but due to a reduction in plaque macrophage proliferation and enhanced cell death. Mechanistically, we link Trem2-deficient macrophages with an inability for cells to sense cholesterol loading and failure to upregulate efflux molecules. Accumulation of cholesterol in the endoplasmic reticulum enhanced activation of the ER-stress response that increased susceptibility for cholesterol-toxicity and cell death in foamy Trem2-deficient macrophages. Overall, this study identifies Trem2 as a regulator of foamy macrophage differentiation, atherosclerotic plaque growth, and as a putative therapeutic target for future intervention studies.
Repurposing antihypertensive, lipid-lowering and antidiabetic drugs for lacunar stroke
Authors: Zhang Linjing , Xia Kailin , Yu Zhou , Fu Yu , Huang Tao , Fan Dongsheng
Published: November 2022

Background

To estimate the causal associations of modifiable risk factors with lacunar stroke (LS) and repurposing of common antihypertensive, lipid-lowering and antidiabetic drugs to prevent LS.

Methods

The effects of common antihypertensive, lipid-lowering and antidiabetic drugs on LS were estimated using a drug-target Mendelian randomization (MR) approach. LS data for the transethnic analysis were derived from meta-analyses comprising 7,338 cases and 254,798 controls.

Findings

Genetically predicted hypertension and type 2 diabetes significantly increased LS risk. Elevated triglyceride and apolipoprotein B levels caused a 14% increased LS risk, while elevated apolipoprotein A-I and high-density lipoprotein levels caused a 12% decreased risk. Elevated triglyceride levels remained significantly associated with a higher LS risk in multivariable MR analysis (OR, 1.21; 95% CI, 1.06-1.40, P =0.005). Drug-target MR demonstrated that genetic variants mimicking calcium channel blockers most stably prevented LS (OR, 0.75; 95% CI, 0.61-0.92, P =0.006). The genetic variants at or nearHMGCR(i.e., mimicking the effect of statins), NPC1L1 (mimicking the effects of ezetimibe) and APOC3 (mimicking antisense anti-apoC3 agents) were predicted to decrease LS incidence.

Genetically proxied GLP1R agonism showed a marginal effect on LS, while a genetically proxied improvement in overall glycemic control was associated with a reduced LS risk (OR, 0.94; 95% CI, 0.92–0.96;P=4.58×10−7).

Interpretation

Repurposing several drugs with well-established safety and low costs for LS prevention in clinical practice may contribute to healthier brain aging.

Funding

This study was supported by National Natural Science Foundation of China (grant numbers 8210051863).
Defective synaptic plasticity in a model of Coffin–Lowry syndrome is rescued by simultaneously targeting PKA and MAPK pathways
Authors: Liu Rong-Yu , Zhang Yili , Smolen Paul , Cleary Leonard J. , Byrne John H.
Published: November 2022

Empirical and computational methods were combined to examine whether individual or dual-drug treatments can restore the deficit in long-term synaptic facilitation (LTF) of theAplysiasensorimotor synapse observed in a cellular model of Coffin–Lowry syndrome (CLS). The model was produced by pharmacological inhibition of p90 ribosomal S6 kinase (RSK) activity. In this model, coapplication of an activator of the mitogen-activated protein kinase (MAPK) isoform ERK and an activator of protein kinase A (PKA) resulted in enhanced phosphorylation of RSK and enhanced LTF to a greater extent than either drug alone and also greater than their additive effects, which is termed synergism. The extent of synergism appeared to depend on another MAPK isoform, p38 MAPK. Inhibition of p38 MAPK facilitated serotonin (5-HT)-induced RSK phosphorylation, indicating that p38 MAPK inhibits activation of RSK. Inhibition of p38 MAPK combined with activation of PKA synergistically activated both ERK and RSK. Our results suggest that cellular models of disorders that affect synaptic plasticity and learning, such as CLS, may constitute a useful strategy to identify candidate drug combinations, and that combining computational models with empirical tests of model predictions can help explain synergism of drug combinations.
Female leadership in communication management in Spain: making a difference in a sexist culture
Authors: Zeler Ileana , Fuentes-Lara Cristina , Moreno Ángeles
Published: November 2022

Purpose

This paper aims to explore the position of women in the communication management sector in Spain from their own experiences. The study examines female communication and leadership styles, emphasising the cost of leadership in which they are leaders or led.

Design/methodology/approach

This study used a qualitative methodology based on in-depth interviews with 22 women actively working in top companies and agencies: female communication directors, female employees with a female leader and female employees with a male leader. Data were analysed through thematic analysis.

Findings

Results show mixed communication and leadership styles. In addition, the high level of self-demand of female communication managers stands out, making it challenging to achieve a work-life balance and the implementation of successful role models.

Social implications

Exploring the factors of female leadership remains necessary to understand and make their situation in various industries and positions visible. It also helps remove barriers to leadership, guide organisations in addressing gender discrimination issues and develop mechanisms for the internal promotion of female professionals.

Originality/value

To the best of authors' knowledge, this is the first study exploring the leadership and communication styles of women in the Spanish Public Relations (PR) and communication management industries. It also highlights the aspects influencing the cost of leadership.
Influence of big data analytical capability on new product performance – the effects of collaboration capability and team collaboration in high-tech firm
Authors: Chen Chi-hsiang
Published: November 2022

Purpose

As the application of artificial intelligence (AI) becomes more prevalent, many high-tech firms have employed AI applications to deal with emerging societal, technological and environmental challenges. Big data analytical capability (BDAC) has become increasingly important in the AI application processes. Drawing upon the resource-based view and the theory of planned behavior, this study aims to investigate how BDAC and collaboration affect new product performance (NPP). Practically, a harmonic working team is particularly important for creating management synergies, this empirical analysis demonstrates the importance of BDAC and collaboration for NPP.

Design/methodology/approach

This paper focuses on the performance of firms that applied AI in their operations. This study collected data from firms in Greater China, including China and Taiwan, as Greater China is currently the leading manufacturer of semiconductor, electronic and electric products for AI applications in the manufacturing process. Confirmatory factor analysis and structural equation modeling is employed for statistical analysis.

Findings

The analytical results indicate that BDAC positively relates to collaboration capability (CC) in AI applications but not to team collaboration (TC). CC positively correlates with TC, and both CC and TC positively correlate with NPP. Further, the mediating effect was examined using the Sobel t-test, which reveals that CC is a significant mediator in the influence of BDAC on NPP.

Practical implications

The strategic implementation of BDAC and collaboration can allow an enterprise to improve its NPP when driven by the external environment to use AI, which further enhances NPP. These processes indicate that AI and BDAC are both crucial for the success of a company’s collaboration and for effective management to improve NPP in the face of global competition.

Originality/value

This study introduces the concept of BDAC to explain the relationship between CC and TC, as they pertain to NPP. This study presented a discussion of the theoretical and practical implications of the research findings and could provide a framework for managing BDAC.
Examining the nonlinear relationships of corporate social responsibility, innovation and construction firm performance: the moderating role of construction firms' competitive position
Authors: Zheng Xian , Deng Jiawei , Song Xiangnan , Ye Meng , Luo Lan
Published: November 2022

Purpose

Corporate social responsibility (CSR) and innovation are the two main approaches firms utilize to promote sustainable development. However, as yet, scholars have reached no consensus regarding their precise impact on construction firm performance (CFP), hindering efforts to implement effective sustainable development strategies that improve CFP. In view that a simple linear relationship may not be sufficient to capture their precise pattern, this study aims to unveil the nonlinear impact of CSR and innovation on CFP, especially when construction firms take up a distinct competitive position.

Design/methodology/approach

This study first proposed four hypotheses to establish a new theoretical model by incorporating CSR, innovation, CFP and construction firms' competitive position (CFCP). Then the model was tested by using 292 annual observations collected from 75 construction firms in China. A multiple regression model analysis was carried out to analyze the survey data and validate the hypotheses.

Findings

The results reveal that both CSR and innovation have a U-shaped impact on the price-to-book ratio of a construction firm, a specific CFP measure. CFCP negatively moderates the U-shaped relationship between CSR and CFP, but positively moderates the U-shaped relationship between innovation and CFP.

Originality/value

This study goes beyond a simple linear view, instead of unveiling the nonlinear U-shaped effects of CSR and innovation on CFP that deepen the understanding of their complex relationships in the construction industry and makes construction firms aware that CSR and innovation can only improve performance if they reach a certain level. The moderating role of CFCP provides important implications for construction firms seeking to adopt appropriate competitive strategies related to social responsibility and innovation that both promote CFP and achieve sustainable development.
Examining the pathway linking workplace incivility and employee well-being: a study among frontline hotel employees in India
Authors: Kuriakose Vijay , Paul V. Maria Tresita , Bishwas Sumant Kumar
Published: November 2022

Purpose

This study aims to analyze the direct relationship between workplace incivility and employee well-being among frontline hotel employees. Anchoring on affective events theory, this study also analyzes the explanatory role of loneliness and the role of workplace social support as a boundary condition influencing the proposed relationships in the model.

Design/methodology/approach

Responses were collected from 243 frontline hotel employees using established scales in two-time points through survey method. The proposed hypotheses were analyzed using SPSS PROCESS macros.

Findings

The results confirmed the detrimental effect of incivility at work on employee well-being and the mediating role of loneliness at work. This. study has also demonstrated that workplace social support conditions the mediated effect of workplace incivility on employee well-being via loneliness.

Practical implications

This study has vital practical implications for mitigating the adverse effects of workplace incivility on employee well-being through loneliness at work by developing interventions that foster social support among employees. This study also provides directions to reduce workplace incivility and loneliness at work.

Originality/value

This study provides a unique understanding of the consequences of workplace incivility on employee well-being. To the best of the authors’ knowledge, this could be the first study that has established loneliness as a pathway linking workplace incivility and employee well-being. This study results have unique significance in the management of hospitality employees.
Nonlinear effects of employee engagement and satisfaction on turnover intention
Authors: Oh Haemoon , Jeong Miyoung , Shin Hyejo Hailey , Schweyer Allan
Published: November 2022

Purpose

This study aims to advance the understanding of the relationships between employee engagement (EE), satisfaction and turnover intention (TI) beyond their known linear functions by providing a set of significant empirical evidence on nonlinear functions including quadratic, cubic and interactive effects.

Design/methodology/approach

This study used four 2 × 2 between-subjects experiments sampling 640 hospitality sales professionals through online data collection methods. EE and employee satisfaction (ES) were examined in disaggregation into personal and organizational dimensions. Residual regression models controlling for age and gender as covariates were the main approaches for analyzing data for nonlinear effects.

Findings

Both EE and ES consistently have significant negative quadratic and positive cubic effects on employees’ TI. EE and ES have a negative interaction effect, that is, complementing each other, on TI such that the effect is more pronounced at higher levels than lower levels of EE and satisfaction.

Practical implications

Organizations need to understand some threshold phenomena that may exist in the widely believed linear effects of EE and satisfaction on TI. Doing so may help allocate resources more effectively for EE and satisfaction.

Originality/value

This study examined the nonlinear as well as interactive nature of the relationships between EE and TI and ES and TI to expand our understanding of these relationships beyond the known linearity and add new empirical evidence to the literature.