bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACTBackgroundCorrectly 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 MethodsThe 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.ResultsRlapsRisk 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.ConclusionsOur 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

ABSTRACTTwo 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

AbstractStable 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 HighlightsModern 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.ORSignificance StatementThe 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

AbstractBacteria 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

AbstractAlthough 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 StatementGreat 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

ABSTRACTWetland 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

AbstractLanthipeptides 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

SUMMARYiRhoms 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

ABSTRACTVimentin 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

AbstractAtherosclerotic 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

AbstractBackgroundTo 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.MethodsThe 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.FindingsGenetically 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).InterpretationRepurposing several drugs with well-established safety and low costs for LS prevention in clinical practice may contribute to healthier brain aging.FundingThis study was supported by National Natural Science Foundation of China (grant numbers 8210051863).