bluuebunny/crossref_metadata_2025 huggingface dataset:
Vibrio choleraeRbmB is an α−1,4-polysaccharide lyase with biofilm-dispersal activity against Vibrio Polysaccharide (VPS)
Authors: Weerasekera Ranjuna , Moreau Alexis , Huang Xin , Nam Kee-Myoung , Hinbest Alex , Huynh Yun , Liu Xinyu , Ashwood Christopher , Pepi Lauren E. , Paulson Eric , Cegelski Lynette , Yan Jing , Olson Rich
Published: August 2024

Many pathogenic bacteria form biofilms as a protective measure against environmental and host hazards. The underlying structure of the biofilm matrix consists of secreted macromolecules, usually including exopolysaccharides. To escape the biofilm, bacteria may produce a number of matrix-degrading enzymes, including glycosidic enzymes that digest exopolysaccharide scaffolds. The human pathogenVibrio choleraeassembles and secretes an exopolysaccharide called VPS (Vibriopolysaccharide) which is essential in most cases for the formation of biofilms and consists of a repeating tetrasaccharide unit. Previous studies have indicated that a secreted glycosidase called RbmB is involved inVibrio choleraebiofilm dispersal, although the mechanism by which this occurs is not understood. To approach the question of RbmB function, we recombinantly expressed and purified RbmB and tested its activity against purified VPS. Using a fluorescence-based biochemical assay, we show that RbmB specifically cleaves VPSin vitrounder physiological conditions. Analysis of the cleavage products using mass spectrometry, solid-state NMR, and solution NMR indicates that RbmB cleaves VPS at a specific site (at the α−1,4 linkage between D-galactose and a modified L-guluronic acid) into a mixture of tetramers and octamers. We demonstrate that the product of the cleavage contains a double bond in the modified-guluronic acid ring, strongly suggesting that RbmB is cleaving using a glycoside lyase mechanism. Finally, we show that recombinant RbmB fromVibrio choleraeand the related aquatic speciesVibrio coralliilyticusare both able to disperse livingVibrio choleraebiofilms. Our results support the role of RbmB as a polysaccharide lyase involved in biofilm dispersal as well as an additional glycolytic enzyme to add to the toolbox of potential therapeutic antibacterial enzymes.

Author summary

Biofilms are protective sheaths produced by many bacteria that play important roles in survival in the environment and in hosts during infection. Understanding how biofilms form and disperse is essential in the fight against harmful bacterial pathogens.Vibrio choleraeis a historically significant human pathogen that forms biofilms made of a polysaccharide called VPS and secreted accessory proteins. Within theV. choleraebiofilm gene cluster is a gene encoding a protein called RbmB, which is known to play a role in biofilm dispersal. Using a combination of biochemical and analytical tools, we show that RbmB indeed cleaves VPS into 4- and 8-monosaccharide fragments at a unique site and demonstrate that it falls into the family of polysaccharide lyase enzymes (as opposed to the more common hydrolases). Furthermore, recombinant RbmB disperses livingV. choleraebiofilms further indicating that it may play a role in VPS processing or degradation.
Comparison of retinol binding protein 1 with cone specific G-protein as putative effector molecules in cryptochrome signalling
Authors: Yee Chad , Bartölke Rabea , Görtemaker Katharina , Schmidt Jessica , Leberecht Bo , Mouritsen Henrik , Koch Karl-Wilhelm
Published: August 2024

Vision and magnetoreception in navigating songbirds are strongly connected as recent findings link a light dependent radical-pair mechanism in cryptochrome proteins to signalling pathways in cone photoreceptor cells. A previous yeast-two-hybrid screening approach identified six putative candidate proteins showing binding to cryptochrome type 4a. So far, only the interaction of the cone specific G-protein transducin α-subunit was investigated in more detail. In the present study, we compare the binding features of the G-protein α-subunit with those of another candidate from the yeast-two-hybrid screen, cellular retinol binding protein. Purified recombinant European robin retinol binding protein bound retinol with high affinity, displaying an EC50of less than 5 nM, thereby demonstrating its functional state. We applied surface plasmon resonance and a Förster resonance transfer analysis to test for interactions between retinol binding protein and cryptochrome 4a. In the absence of retinol, we observed no robust binding events, which contrasts the strong interaction we observed between cryptochrome 4a and the G-protein α-subunit. We conclude that retinol binding protein is unlikely to be involved in the primary magnetosensory signalling cascade.
Vascular FLRT2 regulates venous-mediated angiogenic expansion and CNS barriergenesis
Authors: Llaó-Cid C. , Peguera B. , Kobialka P. , Decker L. , Vogenstahl J. , Alivodej N. , Srivastava S. , Jin J. , Kirchmaier B. C. , Milla C. , Schlierbach H. , Schänzer A. , Acker T. , Segarra M. , Acker-Palmer A.
Published: August 2024

Veins have emerged as the origin of all other endothelial cell subtypes needed to expand vascular networks during developmental and pathological neoangiogenesis. Here, we uncover the significant role of the angioneurin Fibronectin Leucine Rich Transmembrane protein (FLRT) 2 in central nervous system (CNS) vascular development in the mouse. Early postnatal FLRT2 deletion reveals specific defects in retinal veins, impacting endothelial cell proliferation, sprouting and polarity that result in reduced tip cells at the vascular front. FLRT2 interacts with VE-cadherin and together with the endocytic adaptor protein Numb contribute to the modulation of adherens junction morphology in both retina and cerebral cortexin vivo. Utilizing expansion microscopy, we visualize the altered dynamic distribution of VE-cadherin in tissue of FLRT2 endothelial mutants. Additionally, FLRT2 in cortical vessels regulates the crosstalk between adherens and tight junctions, influencing blood-brain barrier development. Our findings position FLRT2 as a vein-specific crucial regulator of CNS vascular development.
Solving the SLoSS debate: Scale-dependent effects of habitat fragmentation on biodiversity loss
Authors: de Jager Monique , Pos Edwin T.
Published: August 2024

Should what is left of nature be contained in a Single Large or Several Small (SLoSS) areas? This question of what would minimize the impact severity of habitat destruction on biodiversity loss is much debated, mainly because studies generally focus on different spatial and temporal scales. Using a semi-spatially explicit, (near-)neutral, individual-based model, we investigate the effects of fragmentation on biodiversity loss at two spatial (landscape-versus subcommunity level) and two temporal scales (static versus dynamic effects). Our results show that the role of spatial configuration of habitat destruction depends on when and at what scale we measure biodiversity loss. When considering the more realistic assumption that species differ in dispersal capacity, differences between spatial configurations are likely to be amplified. Our results indicate that the spatial configuration of habitat loss needs to be considered when evaluating the risks of further habitat destruction.
Mitigation of chytrid infection on tadpoles with the antimicrobial metabolites ofXenorhabdus szentirmaii
Authors: Ujszegi János , Boros Zsófia , Harmos Krisztián , Magos Gábor , Tóth Ábris , Vörös Judit , Kásler Andrea
Published: August 2024

Survival of amphibian assemblages is threatened by many factors. Among them, chytridiomycosis, the disease caused by the chytrid fungusBatrachochytrium dendrobatidis(Bd) has great importance, also threatening the populations of the yellow-bellied toad (Bombina variegata), which has a scattered, isolated distribution in Hungary. Treatment with secondary metabolites of the entomopathogenic bacterium,Xenorhabdus szentirmaiiis a promising method in the mitigation of chytridiomycosis, as recently demonstrated. To assess whether it may also be effective for lowering infection intensities inB. variegatatadpoles, we extracted cell-free culture media (CFCM) from liquid cultures ofX. szentirmaiiand tested their antifungal efficacy at a dilution of 0.1 % (v/v), while also measuring possible short-term malign effects on tadpoles experimentally infected with Bd or sham infection. According to our results, CFCM treatment alone did not compromise tadpoles’ survival probability, nor reduced the body mass and developmental speed of the individuals. At the same time, the treatment reduced the intensity and prevalence of Bd infection, but this effect was affected by the population of origin. The antimicrobial metabolites produced byX. szentirmaiimay therefore be suitable for the safe mitigation of chytridiomycosis inB. variegatatadpoles, but further studies are needed, aiming to monitor and increase the efficacy of this method.
High nutritional conditions influence feeding plasticity inPristionchus pacificusand render worms non-predatory
Authors: Piskobulu Veysi , Athanasouli Marina , Witte Hanh , Feldhaus Christian , Streit Adrian , Sommer Ralf J.
Published: August 2024

Developmental plasticity, the ability of a genotype to produce different phenotypes in response to environmental conditions, has been subject to intense studies in the last four decades. The self-fertilizing nematodePristionchus pacificushas been developed as a genetic model system for studying developmental plasticity due to its mouth-form polyphenism that results in alternative feeding strategies with a facultative predatory and a non-predatory mouth form. Many studies linked molecular aspects of the regulation of mouth-form polyphenism with investigations of its evolutionary and ecological significance. Also, several environmental factors influencingP. pacificusfeeding structure expression were identified including temperature, culture condition and population density. However, the nutritional plasticity of the mouth form has never been properly investigated although polyphenisms are known to be influenced by changes in nutritional conditions. For instance, studies in eusocial insects and scarab beetles have provided significant mechanistic insights into the nutritional regulation of polyphenisms but also other forms of plasticity. Here, we study the influence of nutrition on mouth-form polyphenism inP. pacificusthrough experiments with monosaccharide and fatty acid supplementation. We show that in particular glucose supplementation renders worms non-predatory. Subsequent transcriptomic and mutant analyses indicate thatde novofatty acid synthesis and peroxisomal beta-oxidation pathways play an important role in the mediation of this plastic response. Finally, the analysis of fitness consequences through fecundity counts suggests that non-predatory animals have an advantage over predatory animals grown in the glucose-supplemented condition.

Research highlights

This study represents the first systematic attempt to investigate the influence of nutrition on mouth-form polyphenism in the genetic model organismPristionchus pacificus. Through glucose and oleic acid supplementation we show that high nutritional conditions influence feeding plasticity and render worms non-predatory. Mutant analysis indicates a role ofde novofatty acid synthesis and peroxisomal beta-oxidation pathways for these responses.
Antibiotics Change the Growth Rate Heterogeneity and Morphology of Bacteria
Authors: Kals Morten , Kals Emma , Kotar Jurij , Donald Allen , Mancini Leonardo , Cicuta Pietro
Published: August 2024

A better understanding of the system-level effects of antibiotics is necessary to fight the rise of antibiotic resistance. Utilising the Multipad Agarose Plate (MAP), we monitor the growth rate and cell morphology of three clinically relevant species (E.coli, S.aureusandP.aeruginosa) after exposure to 11 different concentrations of 13 antibiotics (for a total of 24 microbe-antibiotic combinations). As the drug dose approaches the MIC and regardless of the mode of action, our results show a consistent increase in growth rate heterogeneity. Remarkably, drugs that affect protein synthesis consistently show the opposite trend, reducing heterogeneity. We hypothesize that growth rate heterogeneity under antibiotic treatment might therefore depend on the functional distance of the target from ribosomal activity, which is key in determining growth rate. Low heterogeneity is desirable from a clinical perspective, as the opposite is often associated to persistence and antibiotic survival. For all of the antibiotics and species tested, we also find a striking and non-trivial correlation between morphological alterations and growth inhibition. This observation allows us to introduce a new morphological parameter, MOR50, that enables the estimation of minimum inhibitory concentration (MIC) for antibiotic susceptibility testing (AST) with a single snapshot after 2.5 hours of incubation. In addition to introducing a novel, resource-efficient, rapid AST method, our findings shed new light on the effects of antibiotic perturbations on bacteria at the system level that might inform treatment design.
Exosomes can modulate the early hyperexcitability in cortical neurons with ASD-associatedShank3mutation
Authors: Choudhary Ashwani , Rosh Idan , Hussein Yara , Shemen Aviram , Rike Wote Amelo , Zinger Assaf , Offen Daniel , Stern Shani
Published: August 2024

Shank3, a scaffolding protein, is critical for synaptic structure and function, particularly for the formation and maintenance of dendritic spines.Shank3mutations are strongly implicated in autism spectrum disorder (ASD) and related neuropsychiatric conditions such as Phelan-McDermid Syndrome (PMS) also known as the 22q13.3 deletion syndrome. Previous work has recognized early hyperexcitability in cortical neurons derived from ASD patients with various gene mutations as a potential common endophenotype. In this study, we examined the effects of exosomes extracted from several cell types on the neurophysiological properties of cortical neurons derived fromShank3(c.3679insG mutation) induced pluripotent stem cells (iPSCs). First, we sought to understand the implications of exosome-based intercellular communication on the neurophysiology ofShank3mutant and control neurons by switching their respective exosomes. We found that while control neuron-derived exosomes do not change the neurophysiology ofShank3neurons, theShank3neuron-derived exosomes transfer the early hyperexcitability and other ASD-related phenotypes to control neurons. Next, we also explored the therapeutic potential of mesenchymal stem cells (MSC) and iPSC-derived exosomes from healthy donors in theShank3cortical neurons. We demonstrate that both MSC and iPSC-derived exosomes rescue the early hyperexcitability and accelerated maturation ofShank3neurons. Proteomic analysis of exosomes derived fromShank3mutant and control neurons, as well as from exosomes derived from MSCs and iPSCs, revealed distinct protein cargoes that may cause changes in the neurophysiological properties of the recipient neurons. Our results hence provide novel insights into the pathophysiology of ASD emphasizing the importance of exosomes in intercellular communication and their potential to influence intrinsic and network properties of neurons. Moreover, our findings support the need for further exploration of exosome-based interventions as potential therapeutics for treating neurodevelopmental disorders.
Allogenic platelet-rich plasma and platelet-rich plasma extracellular vesicles alter the proteome of tenocytes in an in vitro equine model of tendon inflammation: A pilot study
Authors: Clarke Emily J , Jensen Anders , Gillen Alexandra M , Bardell David , Senior Mark , Anderson James R , Peffers Mandy J
Published: August 2024

Background

Tendon injuries are common in horses, often resulting in a high risk of reinjury. Hemoderivative therapeutics including platelet-rich plasma (PRP) show promise but outcomes vary due to inconsistent composition. PRP is rich in soluble growth factors and extracellular vesicles (EVs), the latter facilitate cell-to-cell communication by delivering biologically active cargo. This pilot study profiled the proteome of PRP and PRP-derived EVs and examined their effects on an equine tendon inflammatory modelin vitro.

Methods

Plasma was isolated via double centrifugation and PRP produced using a commercial filtration kit. EVs were isolated from PRP and plasma using differential ultracentrifugation and characterised with the Exoview Tetraspanin assay. Equine tenocytes were stimulated with interleukin 1β and tumor necrosis factor α, then treated with PRP or PRP-derived EVs. Proteomic analysis was conducted on cell lysates, PRP and PRP-EVs using data-dependent acquisition liquid chromatography-tandem mass spectrometry and the data analyzed using multivariate and univariate approaches.

Results

PRP contained 575 quantifiable proteins and PRP-derived EVs 209 proteins. When compared to plasma and plasma derived EVs respectively, PRP and PRP-EVs were enriched in proteins associated with cellular waste disposal and inhibition of lipid metabolism. Experimental factors (inflammatory stimulation and/or treatments) significantly affected the abundance of 18 proteins as expressed in equine tenocytes including col1a1 (col1a1) and sequestosome 1, associated with collagen metabolism and nuclear factor kappa B signaling.

Discussion

The findings from this study suggest PRP-derived EVs influence inflammatory tenocytes and may be crucial to the efficacy of PRP.
Is variation in female aggressiveness across Drosophila species associated with reproductive potential?
Authors: Bath Eleanor , Gleason Jennifer M
Published: August 2024

Aggression is a key determinant of fitness in many species, mediating access to mates, food, and breeding sites. Variation in intrasexual aggression across species is likely driven by variation in resource availability and distribution. While males primarily compete over access to mates, females are likely to compete over resources to maximize offspring quantity and/or quality, such as food or breeding sites. To date, however, most studies have focused on male aggression and we know little about drivers of female aggression across species. To investigate potential reproductive drivers of female aggression, we tested the relationship between three reproductive traits and aggression in eight Drosophila species. Using machine learning classifiers developed for D. melanogaster, we quantified aggressive behaviours displayed in the presence of yeast for mated and unmated females. We found that female aggression was correlated with ovariole number across species, suggesting that females that lay more eggs are more aggressive. A need for resources for egg production or oviposition sites may therefore be drivers of female aggression, though other potential hypotheses are discussed.
Uncovering novel functions of the enigmatic, abundant and activeAnaerolineaein a salt marsh ecosystem
Authors: Payne Paige E. , Knobbe Loren N. , Chanton Patricia , Zaugg Julian , Mortazavi Behzad , Mason Olivia U.
Published: August 2024

Anaerolineae, particularly uncultured representatives, are one of the most abundant microbial groups in coastal salt marshes, dominating the belowground rhizosphere, where over half of plant biomass production occurs. However, this class generally remains poorly understood, particularly in a salt marsh context. Here, novelAnaerolineaemetagenome assembled genomes (MAGs) were generated from the salt marsh rhizosphere representingAnaerolineales,Promineifilales,JAAYZQ01, B4-G1, JAFGEY01, UCB3, andCaldilinealesorders. Metagenome and metatranscriptome reads were mapped to annotated MAGs, revealing nearly allAnaerolineaeencoded and transcribed genes required for oxidation of simple sugars to complex carbon compounds, fermentation, and carbon fixation. Further, the majority ofAnaerolineaeexpressed genes involved in anaerobic and aerobic respiration and secondary metabolite production. The data revealed that the belowground salt marshAnaerolineaein the rhizosphere are important players in carbon cycling, including degradation of simple carbon compounds to more recalcitrant plant material, such as cellulose, using a diversity of electron acceptors and represent an unexplored reservoir of novel secondary metabolites.

Importance

Given that coastal salt marshes are recognized as biogeochemical hotspots, it is fundamentally important to understand the functional role of the microbiome in this ecosystem. In particular,Anaerolineaeare abundant members of the salt marsh rhizosphere and have been identified as core microbes, suggesting they play a particularly important functional role. Yet, little is known about the metabolic pathways encoded and expressed in this abundant salt marsh clade. Using an ‘omics based approach we determined thatAnaerolineaeare capable of oxidizing a range of carbon compounds, including simple sugars to complex carbon compounds, while also encoding fermentation and carbon fixation. Surprisingly,Anaerolineaeencoded and transcribed genes involved in aerobic respiration, which was unexpected given the reduced nature of the salt marsh rhizosphere. Finally, the majority ofAnaerolineaeappear to be involved in secondary metabolite production, suggesting that this group represents an unexplored reservoir of novel and important secondary metabolites.
A Bioinert Hydrogel Framework for Precision 3D Cell Cultures: Advancing Automated High-Content and High-Throughput Drug Screening
Authors: Jeon Hyunsu , Zanon Tiago Thomaz Migliati , Carpenter James , Ilias Aliciana , Colón Yamil , Wang Yichun
Published: August 2024

Enhanced drug testing efficiency has driven the prominence of high-content (HC) and high-throughput (HT) screening (HCHTS) in drug discovery and development. However, traditional HCHTS in well-plates often lack complexity ofin vivoconditions. 3D cell cultures, like cellular spheroids/organoids, offer a promising alternative by replicatingin vivoconditions and improving the reliability of drug responses. Integrating spheroids/organoids into HCHTS requires strategies to ensure uniform formation, systemic function, and compatibility with analysis techniques. This study introduces an easy-to-fabricate, low-cost, safe, and scalable approach to create a bioinert hydrogel-based inverted colloidal crystal (BhiCC) framework for uniform and high-yield spheroid cultivation. Highly uniform alginate microgels were fabricated and assembled into a colloidal crystal template with controllable contact area, creating engineered void spaces and interconnecting channels within agarose-based BhiCC through the template degradation by alginate lyase and buffer. This results in a multi-layered iCC domain, enabling the generation ofin-vitro3D culture models with over 1,000 spheroids per well in a 96-well plate. The unique hexagonal-close-packed (HCP) geometry of iCC structure enables HCHTS through conventional plate reader analysis and fluorescent microscopy assisted by house-developed automated data processing algorithm. This advancement offers promising applications in tissue engineering, disease modeling, and drug development in biomedical research.
Cell type-specific impact of aging and Alzheimer disease on hippocampal CA1 perforant path input
Authors: Santoro Bina , Srinivas Kalyan V. , Reyes Isabel , Tian Chengju , Masurkar Arjun V.
Published: August 2024

The perforant path (PP) carries direct inputs from entorhinal cortex to CA1 pyramidal neurons (PNs), with an impact dependent on PN position across transverse (CA1a–CA1c) and radial (superficial/deep) axes. It remains unclear how aging and Alzheimer disease (AD) affect PP input, despite its critical role in memory and early AD. Applyingex vivorecordings and two-photon microscopy in slices from mice up to 30 months old, we interrogated PP responses across PN subpopulations and compared them to Schaffer collateral and intrinsic excitability changes. We found that aging uniquely impacts PP excitatory responses, abolishing transverse and radial differences via a mechanism independent of presynaptic and membrane excitability change. This is amplified in aged 3xTg-AD mice, with further weakening of PP inputs to CA1a superficial PNs associated with distal dendritic spine loss. This demonstrates a unique feature of aging-related circuit dysfunction, with mechanistic implications related to memory impairment and synaptic vulnerability.
Morphological Profiling Dataset of EU-OPENSCREEN Bioactive Compounds Over Multiple Imaging Sites and Cell Lines
Authors: Wolff Christopher , Neuenschwander Martin , Beese Carsten Jörn , Sitani Divya , Ramos Maria C. , Srovnalova Alzbeta , Varela María José , Polishchuk Pavel , Skopelitou Katholiki E. , Škuta Ctibor , Stechmann Bahne , Brea José , Clausen Mads Hartvig , Dzubak Petr , Fernández-Godino Rosario , Genilloud Olga , Hajduch Marian , Loza María Isabel , Lehmann Martin , von Kries Jens Peter , Sun Han , Schmied Christopher
Published: August 2024

Morphological profiling with the Cell Painting assay has emerged as a promising method in drug discovery research. The assay captures morphological changes across various cellular compartments enabling the rapid identification of the effect of compounds. We present a comprehensive morphological profiling dataset using the carefully curated and well-annotated EU-OPENSCREEN Bioactive Compound Set.

Our profiling dataset was generated across multiple imaging sites with high-throughput confocal microscopes using the Hep G2 as well as the U2 OS cell line. We employed an extensive assay optimization process to achieve high data quality across the different imaging sites. An analysis of the four replicates validates the robustness of the generated data. We compare morphological features of the different cell lines and map the profiles to activity, toxicity, and basic compound targets to further describe the dataset as well as to demonstrate the potential of this dataset to be used for mechanism of action exploration.
Circuit firing homeostasis following synaptic perturbation ensures robust behavior
Authors: Hoagland Adam , Newman Zachary Louis , Cai Zerong , Isacoff Ehud Y.
Published: August 2024

Homeostatic regulation of excitability and synaptic transmission ensures stable neural circuit output under changing conditions. We find that pre- or postsynaptic weakening of motor neuron (MN) to muscle glutamatergic transmission inDrosophilalarva has little impact on locomotion, suggesting non-synaptic compensatory mechanisms.In vivoimaging of MN to muscle synaptic transmission and MN activity both show that synaptic weakeningincreasesactivity in tonic type Ib MNs, but not in the phasic type Is MN that innervate the same muscles. Additionally, an inhibitory class of pre-MNs that innervates type Ib—but not Is—MNsdecreasesactivity. Our experiments suggest that weakening of MN evoked synaptic release onto the muscle is compensated for by an increase in MN firing due to a combined cell-autonomous increase in excitability and decreased inhibitory central drive. Selectivity for type Ib MNs may serve to restore tonic drive while absence of firing adjustment in the convergent Is MN can maintain the contraction wave dynamics needed for locomotion.
Diseased skin dermal proteomic profiles reflect shared extracellular matrix dysregulation patterns
Authors: Martins Luís , Malta Mariana D. , Chaves Sara , Osório Hugo , Guttmann-Gruber Christina , Kocher Thomas , Marques Alexandra P.
Published: August 2024

Extracellular matrix (ECM) plays a major role in the maintenance of skin homeostasis and modifications in its structure are commonly linked with skin diseases of different origins. Recent evidence shows that epidermal fibroblasts can be important regulators of epidermal pathology. However, despite recent advances, the intricate mechanisms responsible for the ECM defects in a wide range of skin pathologies are still evasive.

In this work we used Dystrophic Epidermolysis Bullosa, Pemphigus vulgaris and Squamous Cell Carcinoma, as the models for epidermal diseases of distinct etiology, in order to explore potential shared alterations in diseased dermal fibroblasts.

Our proteome analysis revealed that differentially expressed proteins in all diseases are commonly enriched in processes related to supramolecular fiber organization, complex of collagen trimers and actomyosin, however with opposite patterns. Nevertheless, Collagen XII is significantly downregulated in all diseases. Additionally, an algorithmic pipeline predicts that MAPKs and CDKs are major regulators of dermal proteome alterations across all diseases.

Altogether, our results highlight a possible shared mechanism where downregulation of Collagen XII mediates ECM organization disruption leading to diverse disease phenotypes.
Prenatal glyphosate exposure disrupts the gut-brain axis across several generations in mice
Authors: Barnett J.A. , Josephson J.K. , Haskey N. , Hart M.M. , Soma K.K. , Bandy M.L. , McComb C.J. , Verdugo A. , Ghosh S. , Letef C. , Copp A. , Gibon J. , Ye J. , Giebelhaus R.T. , Murch S.J. , Jung M.M. , Gibson D.L.
Published: August 2024

Glyphosate, a widely used herbicide in North America, has become prevalent in the food supply due to preharvest applications, raising concerns about potential health impacts. This study investigated the effects of prenatal glyphosate exposure on the gut bacteriome, colitis, metabolic health, and behavior across generations in mice. In healthy mice, glyphosate decreased goblet cell numbers and mucin-2 expression in the colon and dysregulated cytokines in F1 and F2 progeny at levels below the EPA acceptable daily limit. Glyphosate also disrupted metabolism, including impaired glucose tolerance, increased insulin resistance and reduced serum GLP-1 levels. Moreover, prenatal glyphosate exposure induced behavioral deficits, including reduced locomotor activity and impaired working memory, which are associated with alterations in the gut microbiome composition and key gut-brain axis mediators. These data underscore the potential risks associated with glyphosate exposure, highlighting the need for further research and regulatory consideration.
LncRNA-536 and RNA Binding Protein RBM25 Interactions in Pulmonary Arterial Hypertension
Authors: Mahajan Aatish , Kumar Ashok , Chen Ling , Dhillon Navneet K.
Published: August 2024

OBJECTIVE

Hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the essential features of the maladaptive inward remodeling of the pulmonary arteries in pulmonary arterial hypertension (PAH). In this study, we define the mechanistic association between long-noncoding RNA: ENST00000495536 (Lnc-536) and anti-proliferative HOXB13 in mediating smooth muscle hyperplasia.

METHODS

Antisense oligonucleotide-based GapmeRs or plasmid overexpressing lnc-536 were used to evaluate the role of lnc-536 in mediating hyperproliferation of PDGF-treated or idiopathic PAH (IPAH) PASMCs. Further, we pulled down lnc536 to identify the proteins directly interacting with lnc536. The in-vivo role of lnc-536 was determined in Sugen-hypoxia and HIV-transgenic pulmonary hypertensive rats.

RESULTS

Increased levels of lnc-536 in PDGF-treated or IPAH PASMCs promote hyperproliferative phenotype by downregulating the HOXB13 expression. Knockdown of lnc-536in-vivoprevented increased RVSP, Fulton Index, and pulmonary vascular remodeling in Sugen-Hypoxia rats. The lncRNA-536 pull-down assay demonstrated the interactions of RNA binding protein: RBM25 with SFPQ, a transcriptional regulator that has a binding motif on HOXB13 exon Further, The RNA-IP experiment using the SFPQ antibody showed direct interaction of RBM25 with SFPQ and knockdown of RBM25 resulted in increased interactions of SFPQ and HOXB13 mRNA while attenuating PASMC proliferation. Finally, we examined the role of lnc-536 and HOXB13 axis in the PASMCs exposed to the dual hit of HIV and a stimulant: cocaine as well.

CONCLUSION

lnc-536 acts as a decoy for RBM25, which in turn sequesters SFPQ, leading to the decrease in HOXB13 expression and hyperproliferation of smooth muscle cells associated with PAH development.
An automated microfluidic platform for toxicity testing based onCaenorhabditis elegans
Authors: Wu Jiaying , Xi Jing , Zhu Zhouhai , Zhao Wei , Peng Qiyuan , Liu Chunbo , Wan Ziqian , Cao Yiyi , Chen Xiang , Luan Yang
Published: August 2024

Humans are frequently exposed to a multitude of chemicals daily, necessitating efficient methods for rapidly assessing toxicity and potential health risks. Microfluidics has shown promise as an intelligent tool for rapid compound testing, owing to its flexibility in integrating with automated devices. The article introduces an automated microfluidic platform, based onCaenorhabditis elegans (C. elegans), designed for chemical toxicity testing. This platform consists of three modules – worm culture, monitoring, and image analysis – which enable automated worm culturing, drug delivery, periodic monitoring, and automated phenotypic analysis. Researchers have designed a bridged microfluidic chip that permits worms to move freely during experiments and established an economical monitoring module for long-term tracking and periodic imaging. Furthermore, they have developed an automated image analysis algorithm to automatically determine worm bending frequency. The platform was subsequently utilized for long-term toxicological assessments of the organophosphate pesticide and environmental pollutants. Results indicated that the platform can effectively evaluate the general and developmental impacts of chemicals. The automated microfluidic worm analysis platform holds significant potential for applications in drug safety assessmentand drug screening research, contributing to human health and industry advancement.
Effects of Improved Partner Notification on the Transmission of HIV and N. Gonorrhoea Among Men Who Have Sex With Men: A Modelling Study
Authors: Reitsema Maarten , Wallinga Jacco , van Benthem Birgit , Op de Coul Eline , Sighem Ard van , Schim van der Loeff Maarten , Xiridou Maria
Published: August 2024

Men who have sex with men (MSM) are disproportionally affected by HIV in the Netherlands. Partner Notification (PN) is an important element of controlling the transmission of sexually transmitted infections (STIs) and HIV. We investigated the effects of improving PN on the transmission of HIV and N. gonorrhoeae (NG) among MSM in the Netherlands.

We developed an agent-based model that describes the transmission of HIV and NG among MSM. In the baseline scenario 14.3% and 29.8% of casual and steady partners of the index case get notified and tested for HIV/STI after three weeks (percentage notified and tested, PNT). We examined the following scenarios: 1) Increase PNT to 41% for both partner types; 2) Decrease the time between index and the partners tested to one week; 3) Combine scenario 1 and 2. Effects are expressed as cumulative change from the baseline simulation over 15 years.

Increasing PNT could lead to a decrease in gonorrhea cases of 45% (IQR: 39.9 – 49.9%), with an increase in number of HIV/STI tests of 4.4% (IQR: 1.6 – 7.3%), but no change in HIV infections (−5.4%; IQR: -21 – 7.9%). Decreasing time between tests could lead to a change in new NG infections of -14.2% (IQR: -17.2 – -10%), no change in HIV infections (8.2%; IQR: - 1.3 – 20%) or in number of HIV/STI tests performed (−0.4%; IQR: - 1.5 – 0.6%). Scenario 3 led to a change in NG infections of -56.8% (IQR: - 63.8 – - 47.4%), no change in HIV infections (11.5%; IQR: -11.1 – 33.9%) or in number of HIV/STI tests (− 0.5%; IQR: - 4.9 – 4.3%).

Increasing the percentage of sexual partners notified and tested for HIV/STI may have only a small effect on HIV, but could reduce the number of new NG infections substantially. However, it could lead to an increase in the number of HIV/STI tests performed.

Key messages

What is already known on this topic: Notifying recent sexual partners of people diagnosed with HIV or other sexually transmitted infections (STI) can promote timely testing and early treatment, thereby reducing further transmission of STIs

What this study adds: We quantify the effects of improving partner notification on the transmission of two STIs simultaneously.

How this study might affect research, practice or policy: In our scenarios, increasing the percentage of partners who get notified and tested had a bigger impact than decreasing the time between testing the index and his partners.
Modulation of antigen delivery and lymph node activation in non-human primates by saponin adjuvant SMNP
Authors: Yousefpour Parisa , J. Zhang Yiming , Maiorino Laura , Melo Mariane B. , Arainga Ramirez Mariluz A. , Kumarapperuma Sidath C. , Xiao Peng , Silva Murillo , Li Na , Michaels Katarzyna K. , Georgeson Erik , Eskandarzadeh Saman , Kubitz Michael , Groschel Bettina , Qureshi Kashif , Fontenot Jane , Hangartner Lars , Nedellec Rebecca , Love J. Christopher , Burton Dennis R. , Schief William R. , Villinger Francois J. , Irvine Darrell J.
Published: August 2024

Saponin-based vaccine adjuvants are potent in preclinical animal models and humans, but their mechanisms of action remain poorly understood. Here, using a stabilized HIV envelope trimer immunogen, we carried out studies in non-human primates (NHPs) comparing the most common clinical adjuvant alum with Saponin/MPLA Nanoparticles (SMNP), a novel ISCOMs-like adjuvant. SMNP elicited substantially stronger humoral immune responses than alum, including 7-fold higher peak antigen-specific germinal center B cell responses, 18-fold higher autologous neutralizing antibody titers, and higher levels of antigen-specific plasma and memory B cells. PET-CT imaging in live NHPs showed that, unlike alum, SMNP promoted rapid antigen accumulation in both proximal and distal lymph nodes (LNs). SMNP also induced strong type I interferon transcriptional signatures, expansion of innate immune cells, and increased antigen presenting cell activation in LNs. These findings indicate that SMNP promotes multiple facets of the early immune response relevant for enhanced immunity to vaccination.
High-throughput Image-based Clustering of CAR-T/Tumor Cocultures for Rapid and Facile Hit Identification
Authors: Xu Zhi , Liu Xueqi , Madden-Hennessey Kirby , Urbani Jordan , Nikkhoi Shahryar Khoshtinat , Ramasubramanian Anusuya , Venugopal Kartika G. , Zhao Qi , Smith Eric L. , Fu Yun
Published: August 2024

Abstract

Chimeric antigen receptor T cell is important because of its potential to treat various diseases. As deep learning continues to advance, using unsupervised methods to classify medical images has become a significant focus because collecting high-quality labeled data for medical images is labor-intensive and time-consuming. Beyond the need for accurate labeling, there is a desire to explore the underlying characteristics of the data, even when labels may be ambiguous or uncertain. To address these challenges, we present a novel approach that combines image clustering with an insightful explanation of how these clusters are formed. Our method employs a U-net combined with a clustering algorithm to segment the dataset into different groups. After clustering, we use various techniques to interpret and elucidate the results. Moreover, our paper introduces a unique dataset focused on cell data, specifically highlighting the developmental patterns of cancer cells and T cells under various experimental conditions. This dataset offers a rich source of information and presents a complex challenge for image classification due to the diversity of conditions and cell behaviors involved. Our study thoroughly compares different architectural models on this new dataset, demonstrating the superior performance of our proposed architecture. Through experimental analysis and ablation studies, we provide substantial evidence of the benefits offered by our architecture, not only in terms of accuracy but also in its ability to reveal deeper insights into the data. This work advances the field of image classification and opens new possibilities for understanding complex biological processes through computer vision.
Global Scientific Trends in Organoids from 2004 to 2023: A Data-Driven Bibliometric and Visualized Analysis
Authors: Zhao Min , Kuang Liangju , Guo Haoxin , Cao Xindan , Dai Junshi , Wang Yupeng , Wang Zhongqing , Peng Cheng
Published: August 2024

To conduct a bibliometric analysis of organoids to describe international research trends and visualize current research directions. This cross-sectional bibliometric analysis examined the development of organoid research from 2004 to 2023. The current study used VOS-viewer to assess and analyze 13,174 documents. Literature data were collected on a specific date (Feb 19, 2024) and downloaded in plain text from Web of Science Core Collection. In this paper, 13,174 organoid papers were retrieved from Web of Science Core Collection. There were only 114 organoid studies in 2004, and from 2015 onward, the number of annual publications on this topic began to proliferate, reaching 10,023 from 2019 to 2023, accounting for as much as 76.1% of the total number of published papers. The United States proudly leads the way in both the volume of articles published and the number of citations garnered, standing tall as the undisputed frontrunner. Among the illustrious institutions, Harvard University and the University of Washington are among the most prolific. Hans Clevers has worked with 121 prolific authors and has the most publications. With the use of organoids in cancer modeling, drug screening, and regenerative medicine, organoid technology has attracted much attention in medicine, and the significant increase in the number of published papers and citations signifies the expanding influence and global collaboration in the field of organoid research. This study contributes to our understanding of current trends and potential future advances in the field of organoid research by identifying five distinct clusters in the field.
Electronic and magnetic phase diagram of
Sr2FeO4
at high pressure: A synchrotron Mössbauer study
Authors: Adler Peter , Medvedev Sergey A. , Mu Qingge , Bessas Dimitrios , Chumakov Aleksandr , Yaroslavtsev Sergey , Jansen Martin , Felser Claudia
Published: August 2024

Transition metal (TM) oxides with high oxidation state TM ions exhibit a variety of unconventional electronic and magnetic states owing to electron correlations effects combined with highly covalent TM–O bonding. Here, we have studied the pressure dependence of electronic state and magnetism of the K2NiF4-type iron(IV) oxide Sr2FeO4 up to 89 GPa by temperature and magnetic field dependent energy-domain synchrotron Mössbauer spectroscopy and derived a (P,T) magnetic phase diagram. Considering also previous resistance studies [Rozenberg , ] several magnetic and electronic regimes with increasing pressure can be identified. Near 7 GPa, the insulating cycloidal antiferromagnetic low-P state is transformed into a semiconducting ferromagnetic state and the magnetic ordering temperature Tm increases from 55 K at ambient pressure to about 100 K at 13 GPa. Between 18 and about 50 GPa the system is ferromagnetic and metallic (FMM) with a strong rise of Tm to above room temperature (RT). Contrary to a recent theoretical study [Kazemi-Moridani , ], the FMM state is attributed to a high-spin t2g3eg1 electronic state with itinerant eg coupled to more localized t2g electrons. Between 50 and 89 GPa a doublet with large quadrupole splitting in the RT Mössbauer spectra indicates a partial high-spin to low-spin (t2g4) transition leading to a decrease in Tm again. The general features of the (P,T) phase diagram of Sr2FeO4 are comparable to those of other simple and A-site ordered iron(IV) perovskite-related oxides with the peculiarity that Sr2FeO4 adopts an insulating state without charge disproportionation of Fe4+ in the low-P region. The high-pressure behavior of Sr2FeO4 and other iron(IV) oxides may be relevant for exploring the role of Hund's physics in multiorbital systems and contributing to the understanding of the electronic situation in unconventional superconductors such as La3Ni2O7 and Sr2RuO4.

Published by the American Physical Society
2024
Mixed higher-order topology, and nodal and nodeless flat band topological phases in a superconducting multiorbital model
Authors: Arouca Rodrigo , Nag Tanay , Black-Schaffer Annica M.
Published: August 2024

We investigate the topological phases that appear in an orbital version of the Benalcazar-Bernevig-Hughes (BBH) model in the presence of conventional spin-singlet s-wave superconductivity and with the possibility of tuning an in-plane magnetic field. We chart out the phase diagram by considering different boundary conditions, with the topology of the individual phases further examined by considering both the Wannier and entanglement spectra, as well as the Majorana polarization. For weak to moderate values of magnetic field and superconducting pairing amplitude, we find a second-order topological superconductor phase with eight zero-energy corner modes. Further increasing field or pairing, half of the corner states can be turned into zero-energy edge-localized modes, thus forming what we name hybrid-order phase. Then, we find two different putative first-order topological phases, a nodal and a nodeless phase, both with zero-energy flat bands localized along mirror-symmetric open edges. For the nodal phase, the flat bands are, as expected, localized between the nodes in reciprocal space, while in the nodeless phase, the zero-energy boundary flat band instead spans the whole Brillouin zone and appears disjoint from the fully gapped bulk spectrum. As a consequence, this model present several unexpected phases with unusual surface states that can be tuned via an external magnetic field.

Published by the American Physical Society
2024
Gauge-equivariant pooling layers for preconditioners in lattice QCD
Authors: Lehner C. , Wettig T.
Published: August 2024

We demonstrate that gauge-equivariant pooling and unpooling layers can perform as well as traditional restriction and prolongation layers in multigrid preconditioner models for lattice QCD. These layers introduce a gauge degree of freedom on the coarse grid, allowing for the use of explicitly gauge-equivariant layers on the coarse grid. We investigate the construction of coarse-grid gauge fields and study their efficiency in the preconditioner model. We show that a combined multigrid neural network using a Galerkin construction for the coarse-grid gauge field eliminates critical slowing down.

Published by the American Physical Society
2024
Nambu-Goldstone modes in magnetized
T2n
extra dimensions
Authors: Hirose Takuya , Otsuka Hajime , Tsumura Koji , Uchida Yoshiki
Published: August 2024

We consider a U(1) gauge theory on M4×T4 with background magnetic fluxes. We show that a theory including arbitrary fluxes can always be studied in a theory involving only diagonal fluxes by appropriate coordinate transformations. It is found that the number of independent magnetic fluxes is equal to the rank of the classical value of the field strength matrix, rank⟨F⟩. The number of massless zero modes induced from extra components of higher-dimensional gauge field (Wilson-line scalar field) is also determined by rank⟨F⟩. We explicitly confirm that the quantum corrections due to the matter fermion to the squared mass of the Wilson-line scalar field cancel out at the one-loop level. For this purpose, we derive the fermion mass spectrum on M4×T4 with arbitrary fluxes. By taking the flux diagonal basis, creation and annihilation operators for Kaluza-Klein quantum numbers are defined appropriately. Our results are easily generalized to the case of M4×T2n(n≥3).

Published by the American Physical Society
2024