bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anemia and tissue hypoxia are major determinants of malarial hypelactatemia
Authors: Georgiadou Athina , Yoon Chae Eun , Yu Huanghehui , Pearson William H. , Ueno Aika , Ebmeier Stefan , Larrouy-Maumus Gerald J. , Cunnington Aubrey J. 
Published: October 2024

AbstractHyperlactatemia, a key marker of severe malaria, is closely linked to increased mortality, though the exact mechanisms remain unclear. It may result from increased lactate production due to tissue hypoxia or reduced lactate clearance from organ dysfunction. This study usedPlasmodium yoelii17XL (Py17XL) murine model of severe malaria, which closely mimics hyperlactatemia seen in human cases, to investigate the contributions of severe anemia and infection-related organ dysfunction to hyperlactatemia. Non-infectious anemia models were also included for comparison. Anemia was found to elevate lactate in both malaria-infected and non-infectious models, but Py17XL infected mice showed higher lactate levels, indicating that anemia alone doesn’t fully explain hyperlactatemia. Evidence of tissue hypoxia, particularly in the liver, kidney, and gut, was seen with hypoxyprobe staining and upregulated hypoxia-inducible factor 1-alpha (HIF-1α), suggesting that hypoxia drives increased glycolysis and lactate production. Impaired lactate clearance may also play a role, as infected mice showed signs of liver and kidney dysfunction accompanied by reduced clearance of13C3-labeled sodium-L-Lactate. Whole blood transfusion combined with artesunate significantly improved lactate clearance compared to artesunate alone, underscoring the importance of addressing anemia in treatment. A link between intestinal damage and hyperlactatemia was suggested by correlations between trefoil factor 3 (TFF3), a marker of gut injury, and lactate levels in human samples. Our findings highlight the multifactorial origin of hyperlactatemia in malaria, driven primarily by anemia and tissue hypoxia, pointing to the need for therapies targeting both aspects to reduce mortality in severe cases.
Understanding disease-associated metabolic changes in human colon epithelial cells usingiColonEpithelium metabolic reconstruction
Authors: Jiang Boyu , Quinn-Bohmann Nick , Diener Christian , Nathan Vignesh Bose , Han-Hallett Yu , Reddivari Lavanya , Gibbons Sean M. , Baloni Priyanka 
Published: October 2024

AbstractThe colon epithelium plays a key role in the host-microbiome interactions, allowing uptake of various nutrients and driving important metabolic processes. To unravel detailed metabolic activities in the human colon epithelium, our present study focuses on the generation of the first cell-type specific genome-scale metabolic model (GEM) of human colonic epithelial cells, named iColonEpithelium. GEMs are powerful tools for exploring reactions and metabolites at systems level and predicting the flux distributions at steady state. Our cell-type-specific iColonEpithelium metabolic reconstruction captures genes specifically expressed in the human colonic epithelial cells. The iColonEpithelium is also capable of performing metabolic tasks specific to the cell type. A unique transport reaction compartment has been included to allow simulation of metabolic interactions with the gut microbiome. We used iColonEpithelium to identify metabolic signatures associated with inflammatory bowel disease. We integrated single-cell RNA sequencing data from Crohn’s Diseases (CD) and ulcerative colitis (UC) samples with the iColonEpithelium metabolic network to predict metabolic signatures of colonocytes between CD and UC compared to healthy samples. We identified reactions in nucleotide interconversion, fatty acid synthesis and tryptophan metabolism were differentially regulated in CD and UC conditions, which were in accordance with experimental results. The iColonEpithelium metabolic network can be used to identify mechanisms at the cellular level, and our network has the potential to be integrated with gut microbiome models to explore the metabolic interactions between host and gut microbiota under various conditions.Graphical Abstract
Smart Distributed Data Factory: Volunteer Computing Platform for Active Learning-Driven Molecular Data Acquisition
Authors: Ghukasyan Tsolak , Altunyan Vahagn , Bughdaryan Aram , Aghajanyan Tigran , Smbatyan Khachik , Papoian Garegin A. , Petrosyan Garik 
Published: October 2024

AbstractThis paper presents the Smart Distributed Data Factory (SDDF), an AI-driven distributed computing platform designed to address challenges in drug discovery by creating comprehensive datasets of molecular conformations and their properties. SDDF uses volunteer computing, leveraging the processing power of personal computers worldwide to accelerate quantum chemistry (DFT) calculations. To tackle the vast chemical space and limited high-quality data, SDDF employs an ensemble of machine learning models to predict molecular properties and selectively choose the most challenging data points for further DFT calculations. The platform also generates new molecular conformations using molecular dynamics with the forces derived from these models. SDDF makes several contributions: the volunteer computing platform for DFT calculations; an active learning framework for constructing a dataset of molecular conformations; a large public dataset of diverse ENAMINE molecules with calculated energies; an ensemble of state-of-the-art ML models for accurate energy prediction. The energy dataset was generated to validate the SDDF approach of reducing the need for extensive calculations. With its strict scaffold split, the dataset can be used for training and benchmarking energy models. By combining active learning, distributed computing, and quantum chemistry, SDDF offers a scalable, cost-effective solution for developing accurate molecular models and ultimately accelerating drug discovery.
Exploring new dimensions of immune cell biology inAnopheles gambiaethrough genetic immunophenotyping
Authors: Samantsidis George-Rafael , Smith Ryan C. 
Published: October 2024

AbstractMosquito immune cells, or hemocytes, are integral components of the innate immune responses that define vector competence. However, the lack of genetic resources has limited their characterization and our understanding of their functional roles in immune signaling. To overcome these challenges, we engineered transgenicAnopheles gambiaethat express fluorescent proteins under the control of candidate hemocyte promoters. Following the characterization of five transgenic constructs through gene expression and microscopy-based approaches, we examine mosquito immune cell populations by leveraging advanced spectral imaging flow cytometry. Our results comprehensively map the composition of mosquito hemocytes, classifying them into twelve distinct populations based on size, granularity, ploidy, phagocytic capacity, and the expression of PPO6, SPARC, and LRIM15 genetic markers. Together, our novel use of morphological properties and genetic markers provides increased resolution into our understanding of mosquito hemocytes, highlighting the complexity and plasticity of these immune cell populations, while providing the foundation for deeper investigations into their roles in immunity and pathogen transmission.
Distinct maternofetal immune signatures delineate preterm birth onset following urinary tract infection
Authors: Ottinger Samantha , Larson Addison B. , Mercado-Evans Vicki , Branthoover Holly , Zulk Jacob J. , Serchejian Camille , Mejia Marlyd E. , Hameed Zainab A. , Walde Ryan , Fleck Rachel C. , Shea Allyson E. , Patras Kathryn A. 
Published: October 2024

ABSTRACTPreterm birth is the leading cause of infant mortality resulting in over one million neonatal deaths annually. Maternal urinary tract infection (UTI) during pregnancy increases risk for preterm birth; however, biological processes mediating UTI-associated preterm birth are not well-described. We established a murine maternal UTI model in which challenge with uropathogenicE. coliresulted in preterm birth in about half of dams. Dams experiencing preterm birth displayed excessive bladder inflammation and altered uteroplacental T cell polarization compared to non-laboring infected dams, with no differences in bacterial burdens. Additional factors associated with preterm birth included higher proportions of male fetuses and lower maternal serum IL-10. Furthermore, exogenous maternal IL-10 treatment absolved UTI-associated preterm birth but contributed to fetal growth restriction in this model. Using urine samples from a cohort of human pregnancies with or without UTI, we correlated urinary cytokines with birth outcomes and urine culture status. These analyses yielded a non-invasive, highly predictive three-model system for evaluating preterm birth risk implicating cytokines IL-10, IL-15, IL-1β, and IL-1RA. Our unique bimodal murine model coupled with patient samples provides a platform to investigate immunological and microbial factors governing UTI-associated preterm birth, revealing novel therapeutic opportunities to predict or prevent preterm birth.
Antibody Profiles Elicited by Potent and Subpotent Whole Cell Pertussis Vaccines in Mice
Authors: Adewunmi Yetunde , Doering Jennifer , Kumar Prashant , Pablo Jozelyn V. , Teng Andy A. , Huynh Vu , Secrist Kathryn , Volkin David B. , Joshi Sangeeta B. , Campo Joseph J. , Mantis Nicholas J. 
Published: October 2024

ABSTRACTInactivated, whole cell pertussis (wP) vaccines remain at the frontline in the global fight against the resurgence of whooping cough, especially in low- and middle-income countries. However, the reliance on the intracerebral mouse potency test (ic-MPT or Kendrick assay) as the standard batch release assay is challenging for the production of commercial wP vaccines. The ic-MPT is technically challenging, labor intensive and, arguably, incongruous with modern animal welfare guidelines. Replacing the ic-MPT with a whole cellBordetella pertussisELISA, the so-called pertussis serology potency test (PSPT), has shown promise, but has been difficult to implement in practice. In this report, we tested the hypothesis that potent and subpotent wP vaccines have distinct serologic profiles in mice that could be developed as a substitute for the ic-MPT. We first established an accelerated decay (thermal stress) protocol in which wP, in the context of DTwP, was rendered>10-fold less effective than unstressed vaccine when evaluated in a mouse model ofB. pertussislung clearance following intranasal challenge. We then screened immune sera on a limitedB. pertussisTahoma I proteome array and identified >30 antigens whose antibody reactivity profiles increased, decreased or were unchanged as a function of wP potency. Interestingly, virtually all the “indicator” antigens identified are known virulence factors or reactive with human convalescent sera, thereby establishing a potential link between wP potency and pertussis infection and immunity. These results bode well for the development of a limitedB. pertussisantigen array as a stability-indicating surrogate potency assay for the ic-MPT.
Baicalein ameliorates experimental ulcerative colitis recurrency by downregulating neonatal Fc receptor via the NF-κB signaling pathway
Authors: Hu Haoyang , Lu Fuliang , Guan Xudong , Jiang Xuehua , Wen Chengming , Wang Ling 
Published: October 2024

AbstractUlcerative colitis (UC) is a chronic autoimmune disease (AID) that causes mild to moderate, unpredictable symptoms, including diarrhea and abdominal pain. Against neonatal Fc receptors (FcRn) has been proven a unique AID treatment strategy by decreasing the effects of pathogenic autoantibody. Our previous study revealed that FcRn inhibition is beneficial in UC treatment through reducing colonic neutrophil extracellular traps (NET) formation via accelerating serum anti-neutrophil cytoplasm antibodies (ANCA) clearance. In this study, we initially confirmed the specific impact of downregulating FcRn in preventing UC relapse by injecting rAAV, that carrying Fcgrt-shRNA, in mice. Next, we investigated the inhibition effects and regulation mechanisms of baicalein (BCL) on FcRn and assessed its capacity to withstand UC recurrence using NCM460 cells and dextran sodium sulfate-induced mice models by determining the expression of FcRn and its related transcription factors. We also measured colonic NET-associated protein (NAP) expression and serum concentrations of IgG, ANCA, TNF-α, IL-1β, and c-reactive protein (CRP). UC inflammation severity was determined using the disease activity index (DAI) and histopathological score (HS). BCL treatment remarkably decreased the mRNA and protein contents of FcRn, p50, and p65 but did not impact STAT1 expression and the phosphorylation of IκB and STAT1. Long-term BCL administration inhibited colonic FcRn expression and reduced serum ANCA levels, colonic NAPs expression, serum inflammation-related indexes (including TNF-α, IL-1β, and CRP), DAI, and HS scores in UC mice during inflammation relapse better than salazosulfapyridine. Our study indicates that BCL ameliorates UC recurrency by inhibiting FcRn expression via p50/p65 heterodimer-mediated NF-κB signaling.Chemical compoundsChemical compounds studied in this article were listed below:Baicalein (PubChem CID: 5281605); Salazosulfapyridine (PubChem CID: 5339).
Iron and redox sensing in plants: properties of the hemerythrin-like domains of Arabidopsis BRUTUS and BRUTUS-LIKE2 proteins
Authors: Pullin Jacob , Rodríguez-Celma Jorge , Franceschetti Marina , Mundy Julia E A , Svistunenko Dimitri A , Bradley Justin M , Le Brun Nick E , Balk Janneke 
Published: October 2024

ABSTRACTIron uptake in plants is negatively regulated by a unique subfamily of ubiquitin E3 ligases, exemplified byArabidopsis thalianaBRUTUS (BTS). These large proteins are comprised of an usual triple hemerythrin (Hr)-like domain at the N-terminus and a RING-type E3 ligase at the C-terminus. Physiological studies point to the highly conserved BTS proteins as the elusive iron sensors in plants, but biochemical evidence for this has been lacking. Here we characterize the redox properties and iron-binding dynamics of the Hr-like domain in both BTS and BTS-LIKE2 (BTSL2) and propose a model for their atypical mechanism of iron sensing. The recombinantly expressed BTS N-terminal domain contained three diiron centres, one in each Hr-like motif, whereas BTSL2 lacked the second diiron centre, which is positioned at the distal end according to protein models and SAXS data. The diiron centres of BTSL2 were reduced by dithionite and glutathione and could be re-oxidized upon exposure to O2and H2O2. In the reduced state, at least one of the irons of each diiron centre was labile and readily accessible to an Fe2+chelator. Addition of Fe2+to the hemi-apoprotein form and subsequent oxidation reconstituted the diiron centres, as monitored by circular dichroism spectroscopy. In the oxidized state, none of the Fe3+ions were labile. These data show that iron binding to BTS/L is dynamic, in support of their proposed iron-sensing function, but interestingly it is conditional on O2or oxidative stress. We speculate that the dual-sensing mode may be particularly important for photosynthetic organisms, for which labile diiron centres rather than other iron cofactors have been selected during evolution.
Adiponectin-receptor agonism prevents right ventricular tissue pathology in a mouse model of Duchenne muscular dystrophy
Authors: Gandhi Shivam , Delfinis Luca J. , Bhatt Parashar D. , Garibotti Madison C. , Bellissimo Catherine A. , Goli Amireza N. , Morris Brooke A. , Brahmbhatt Aditya N. , Yakobov-Shimonov Simona , Rahman Fasih A. , Quadrilatero Joe , Simpson Jeremy A. , Sweeney Gary , Abdul-Sater Ali A. , Backx Peter H. , Hsu Henry H. , Perry Christopher G.R. 
Published: October 2024

AbstractCardiac fibrosis during Duchenne muscular dystrophy (DMD) arises from cellular damage and inflammation and is associated with myofibre hypertrophy and metabolic dysfunction. However, the extent to which these relationships develop across all 4 cardiac chambers, particularly during early-stage disease, remains unknown. Here, we discovered that very young D2.mdxmice exhibit fibrosis exclusively in the right ventricle (RV) and left atrium. Concurrent cardiomyocyte hypertrophy and disorganization in the RV were related to a highly specific inflammatory signature of increased infiltrating pro-inflammatory macrophages (CD11b+CD45+CD64+F4/80+CCR2+), myofibre mitochondrial-linked apoptosis, and reduced carbohydrate and fat oxidation. This relationship did not occur in the left ventricle. Short-term daily administration of a peptidomimetic adiponectin receptor agonist, ALY688, completely prevented RV fibrosis, myofibre hypertrophy, infiltrating macrophages and mitochondrial stress as well as left atrial fibrosis. Our discoveries demonstrate early-stage cardiac tissue pathology occurs in a chamber-specific manner and is prevented by adiponectin receptor agonism, thereby opening a new direction for developing therapies that prevent tissue remodeling during DMD.TeaserHeterogeneous distribution of fibrosis, inflammation and metabolic dysfunction across the heart is prevented by adiponectin receptor agonism in a mouse model of Duchenne muscular dystrophy.
Integrating predictors of host condition into spatiotemporal multi-scale models of virus shedding
Authors: Kramer Andrew M , Faust Christina L , Castellanos Adrian A. , Fischhoff Ilya R , Peel Alison J. , Eby Peggy , Ruiz-Aravena Manuel , Borremans Benny , Plowright Raina K. , Han Barbara A 
Published: October 2024

ABSTRACTUnderstanding where and when pathogens occur in the environment has implications for reservoir population health and infection risk. In reservoir hosts, infection status and pathogen shedding are affected by processes interacting across different scales: from landscape features affecting host location and transmission to within-host processes affecting host immunity and infectiousness. While uncommonly done, simultaneously incorporating processes across multiple scales may improve pathogen shedding predictions. In Australia, the black flying fox (Pteropus alecto) is a natural host for the zoonotic Hendra virus, which is hypothesized to cause latent infections in bats. Re-activation and virus shedding may be triggered by poor host condition, leading to virus excretion through urine. Here, we developed a statistical modeling approach that combined data at multiple spatial and temporal scales to capture ecological and biological processes potentially affecting virus shedding. We parameterized these models using existing datasets and compared model performance to under-roost virus shedding data from 2011-2014 in 23 roosts across a 1200-km transect. Our approach enabled comparisons among multiple model structures to determine which variables at which scales are most influential for accurate predictions of virus shedding in space and time. We identified environmental predictors and temporal lags of these features that were important for determining where reservoirs are located and multiple independent proxies for reservoir condition. The best-performing multi-scale model delineated periods of low and high virus prevalence, reflecting observed shedding patterns from pooled under-roost samples. Incorporating regional indicators of food scarcity enhanced model accuracy while incorporating other stress indicators at local scales confounded this signal. This multiscale modeling approach enabled the combination of processes from different ecological scales and identified environmental variables influencing Hendra virus shedding, highlighting how integrating data across scales may improve risk forecasts for other pathogen systems.
Conflicts between the DNA replication and repair machineries promote cell death in Gram-positive bacteria
Authors: Gaimster Hannah , Stevens Daniel , Hubbard Julia , Mickiewicz Katarzyna , Murray Heath , Winterhalter Charles 
Published: October 2024

ABSTRACTCellular proliferation relies on successful coordination and completion of genome replication and segregation. To help achieve this, many bacteria utilise regulatory pathways that ensure DNA replication initiation only occurs once per cell cycle. When dysregulated, loss of DNA replication control can have severe consequences. InEscherichia coliit has been observed that hyper-initiation of DNA synthesis leads to pleiotropic genome instability and cell death. Therefore, targeting DNA replication initiation proteins to promote hyper-initiation may be an approach to generate novel antimicrobials. However, it is not clear whether DNA replication hyper-initiation generally inhibits bacterial proliferation, and if so, via which pathways. To address this question, we devised genetic systems to artificially induce hyper-initiation in the model organismBacillus subtilisand the pathogenStaphylococcus aureus. In both species, hyper-initiation elicited cellular degeneration culminating in growth inhibition by cell death. During this process inB. subtilis, temporal analyses revealed the early onset of the DNA damage response, followed by membrane depolarisation and cell lysis. This phenotype could be supressed by removing pathways that repair damaged DNA, suggesting that cell death is a consequence of conflicts between DNA replication and repair. InS. aureus,cells quickly accumulated striking morphological changes associated with rapid loss of chromosomal DNA and death via a lysis-independent pathway. Moreover, inducing hyper-initiation inS. aureuswas observed to decrease bacterial survival during infection of murine macrophages. Taken together, these results suggest that stimulating the initiation of bacterial DNA replication could be an alternative approach to inhibiting bacterial growth, particularly in combination with compounds that inhibit or poison DNA repair, akin to cancer therapies.
Filtering cells with high mitochondrial content removes viable metabolically altered malignant cell populations in cancer single-cell studies
Authors: Yates Josephine , Kraft Agnieszka , Boeva Valentina 
Published: October 2024

AbstractBackgroundSingle-cell transcriptomics has transformed our understanding of cellular diversity in biological systems. However, systematic noise, often introduced by low-quality cells, can obscure biological signals if not properly accounted for. Thus, one of the common quality control steps involves filtering out cells with a high percentage of mitochondrial RNA counts (pctMT), as high pctMT typically indicates cell death. Yet, commonly used filtering thresholds, primarily derived from studies on healthy tissues, may be overly stringent for malignant cells, which often naturally exhibit higher baseline mitochondrial gene expression. We analyzed public single-cell RNA-seq and spatial data to investigate if malignant cells with high pctMT are viable and functionally significant subpopulations.ResultsWe analyzed nine single-cell RNA-seq datasets from uveal melanoma, breast, lung, kidney, head and neck, prostate, and pancreatic cancers, including 439,507 cells from 151 patients. Malignant cells exhibited significantly higher pctMT than nonmalignant cells without a significant increase in dissociation-induced stress signature scores. Malignant cells with high pctMT showed metabolic dysregulation, including increased xenobiotic metabolism, which is implicated in cancer therapeutic response. Our analysis of pctMT in cancer cell lines uncovered associations with resistance and sensitivity to certain classes of drugs. Additionally, we observed a link between pctMT and malignant cell transcriptional heterogeneity as well as patient clinical features.ConclusionsThis study provides a detailed exploration of the functional characteristics of malignant cells with elevated pctMT, challenging current quality control practices in single-cell RNA-seq analyses of tumors. Our findings have the potential to improve data interpretation and refine the biological conclusions of future cancer studies.