bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal blood microsampling and proteome monitoring facilitate timely intervention in experimental type 1 diabetes
Authors: Parajuli Anirudra , Bendes Annika , Byvald Fabian , Stone Virginia M. , Ringqvist Emma E. , Butrym Marta , Angelis Emmanouil , Kipper Sophie , Bauer Stefan , Roxhed Niclas , Schwenk Jochen M. , Flodström-Tullberg Malin 
Published: November 2024

ABSTRACTSymptoms of immune-mediated diseases (IMIDs) typically appear after irreversible tissue damage, making early interventions based on pre-symptomatic indicators crucial. Current efforts to identify molecular markers of early disease lack the resolution, convenience and cost efficiency required to prevent irreversible tissue damage. Analyzing frequently self-collected samples, such as dried blood spots (DBS), could enable the earlier detection of diseases, identify disease-predictive markers and facilitate tailored interventions. To test this, we regularly microsampled a mouse model infected with a type 1-diabetes (T1D)-associated virus. This longitudinal DBS sample collection was analyzed for 92 circulating proteins, revealing transient molecular changes in virus-infected animals that would have been missed with less frequent sampling. Machine learning predicted infection status after day 2 post-infection with >90% accuracy, enabling well-timed treatment of virus-infected animals and diabetes prevention. Our study demonstrates the utility of frequent blood microsampling to monitor disease during the pre-symptomatic phase, allowing for timely interventions.TeaserFrequent blood microsampling detects early biomarkers, enabling timely intervention in immune-mediated diseases
Mechanistic pathways of tick exposure risk in native and invaded plant communities
Authors: Hiatt Drew , Dillon Whalen W. , Gardner Allison , Cabrera Steven , Dietze Michael , Allan Brian F. , Flory S. Luke 
Published: November 2024

AbstractPlant invasions may alter vector abundance by several mechanistic pathways, including modifying microclimates that influence vector survival or changing habitats to influence host use. Here, we used a field experiment and observational data to evaluate multiple mechanistic pathways (tick survival and host abundance) by which plant invasions may alter vector-borne disease risk using the common disease vector lone star tick (Amblyomma americanum) and the widespread invasive cogongrass (Imperata cylindrica) in the southeastern USA. In the field experiment, ticks survived over 50% longer in areas dominated by the invasive plant compared to those with only native plant species. Invaded areas had lower temperatures and higher humidity that likely reduced tick desiccation. The observational study showed greater average tick abundance in native plant communities and no difference in wildlife host (white-tailed deer) activity between plant communities. There was also a positive relationship between tick abundance and white-tailed deer activity, but only in native areas. Together, these results suggest that more favorable microclimate conditions resulting in greater tick longevity is the dominant driver of tick abundance in invaded areas, while tick abundance in native-dominated areas is promoted, at least in part, by white-tailed deer activity. Our results demonstrate that plant invaders affect multiple, potentially off-setting mechanistic pathways contributing to tick exposure risk. The complexity of these relationships highlights the need for better understanding of how invasive species and other global change drivers influence abundance of disease vectors and, ultimately, disease transmission.
The impact of transplant location on the gut microbiome and resistome in patients undergoing hematopoietic stem cell transplantation at home versus in the hospital
Authors: Andermann T.M. , Zeng K. , Guirales-Medrano S. , Groth A. , Ramachandran B.C. , Sun S. , Sorgen A.A. , Hill L. , Bush A.T. , Liu H. , Jones C. , Roach J. , Conlon B.P. , Rao G. , Chao N.J. , Fodor A.A. , Sung A.D. 
Published: November 2024

ABSTRACTObjectivesHome-based hematopoietic stem cell transplantation (HCT) is a novel approach that has the potential to improve outcomes, however, the impact of transplant location on the gut microbiome remains uncharacterized. We hypothesized that patients randomized to undergo home HCT would have higher gut taxonomic diversity and lower antimicrobial resistance (AMR) gene abundance compared to those undergoing standard hospital HCT.MethodsWe identified 28 patients enrolled in Phase II randomized trials of home (n=16) v. hospital (n=12) HCT at Duke and performed shotgun metagenomic sequencing of stools to compare taxonomic and AMR gene composition between groups. We performed a secondary analysis of patients from each group transplanted at an outpatient infusion clinic with those who underwent standard inpatient HCT (“outpatient” v. “inpatient”).ResultsNo significant differences in duration of hospitalization were found in those randomized to home v. hospital HCT. Taxonomic and AMR gene α- and β-diversity were comparable. In contrast, secondary analyses demonstrated that patients from both home and hospital groups transplanted at an outpatient infusion clinic spent significantly less time in the hospital and demonstrated higher taxonomic α-diversity and differential β-diversity compared to standard inpatient HCT, although AMR gene α-diversity did not differ, and comparisons were confounded by both differences in transplant type and use of antibiotics.ConclusionsRandomization by transplant location did not impact the gut microbiota to the same extent as the duration of hospitalization, although secondary analyses were heavily confounded. Even when taxonomic differences were observed, AMR genes were similar between groups.
Using mathematical constraints to explain narrow ranges for allele-sharing dissimilarities
Authors: Liu Xiran , Ahsan Zarif , Rosenberg Noah A. 
Published: November 2024

AbstractAllele-sharing dissimilarity (ASD) statistics are measures of genetic differentiation for pairs of individuals or populations. Given the allele-frequency distributions of two populations—possibly the same population—the expected value of an ASD statistic is computed by evaluating the expectation of the pairwise dissimilarity between two individuals drawn at random, each from its associated allele-frequency distribution. For each of two ASD statistics, which we term 𝒟1and 𝒟2, we investigate the extent to which the expected ASD is constrained by allele frequencies in the two populations; in other words, how is the magnitude of the measure bounded as a function of the frequency of the most frequent allelic type? We first consider dissimilarity of a population with itself, obtaining bounds on expected ASD in terms of the frequency of the most frequent allelic type in the population. We then examine pairs of populations that might or might not possess the same most frequent allelic type. Across the unit interval for the frequency of the most frequent allelic type, the expected allele-sharing dissimilarity has a range that is more restricted than the r0, 1s interval. The mathematical constraints on expected ASD assist in explaining a pattern observed empirically in human populations, namely that when averaging across loci, allele-sharing dissimilarities between pairs of individuals often tend to vary only within a relatively narrow range.
The Accuracy of the Uganda National Tuberculosis and Leprosy Program algorithm and the World Health Organisation treatment decision algorithms for childhood tuberculosis: A retrospective analysis
Authors: Kitonsa Peter J , Kikaire Bernard , Wambi Peter , Nalutaaya Annet , Nakafeero Jascent , Nanyonga Gertrude , Kiconco Emma , Atwiine Deus , Castro Robert , Oumo Ernest A , Aanyu Hellen T , Mudiope Mary N , Mupere Ezekiel , Sekadde Moorine P , Mohanty Swomitra , Cattamanchi Adithya , Wobudeya Eric , Jaganath Devan 
Published: November 2024

ABSTRACTDiagnosing childhood pulmonary tuberculosis (TB) is a challenge, and this led the Uganda National Tuberculosis and Leprosy Program (NTLP) to develop a clinical treatment decision algorithm (TDA) for children. However, there is limited data on its accuracy and how it compares to new World Health Organization (WHO) TB TDAs for children. This study aimed to evaluate and compare the accuracy of the 2017 Uganda NTLP algorithm with the 2022 WHO TDAs for TB among children in Kampala, Uganda.We retrospectively assessed children <15 years old who underwent an evaluation for TB between November 2018 and November 2022. Children were classified as per National Institutes of Health (NIH) consensus definitions. We applied the 2017 Uganda NTLP and 2022 WHO algorithms (A with chest x-ray [CXR], B without CXR) to make a decision to treat for TB or not, and calculated accuracy in reference to Confirmed vs. Unlikely TB, as well as a microbiological and composite reference standard. We compared accuracy of the Uganda NTLP algorithm to the WHO TDAs among children <10 years old.A total of 699 children were included in this analysis with 64% (451/699) under 5 years, 53% (373/669) were male, 12% (85/699) were Xpert Ultra positive, 11% (74/669) were HIV positive and 6% had severe acute malnutrition (SAM). The Uganda NTLP algorithm had a sensitivity of 97.9% (95% CI: 96.4-99.4) and specificity of 25.9% (95% CI: 21.2-30.7). If CXR was considered unavailable, sensitivity was 97.9% (95% CI: 96.4-99.4) and specificity 28.1% (95% CI: 23.2-33.0). Accuracy remained similar among high-risk children. In comparison, WHO TDAs had similar sensitivity to the Uganda NTLP, but algorithm A was more specific (32.2%, 95% CI: 26.9-37.5) and algorithm B was less specific (15.4%, 95% CI: 11.3-19.5).Both the Uganda NTLP and WHO TDAs had high sensitivity but low specificity. The WHO TDAs had better specificity than the NTLP algorithm with CXR, and worse specificity without CXR. Further optimization of the algorithms is needed to improve specificity and reduce over-treatment of TB in children.
CellBinDB: A Large-Scale Multimodal Annotated Dataset for Cell Segmentation with Benchmarking of Universal Models
Authors: Shi Can , Fan Jinghong , Deng Zhonghan , Liu Huanlin , Kang Qiang , Li Yumei , Guo Jing , Wang Jingwen , Gong Jinjiang , Liao Sha , Chen Ao , Zhang Ying , Li Mei 
Published: November 2024

ABSTRACTIn recent years, cell segmentation techniques have played a critical role in the analysis of biological images, especially for quantitative studies. Deep learning-based cell segmentation models have demonstrated remarkable performance in segmenting cell and nucleus boundaries, however, they are typically tailored to specific modalities or require manual tuning of hyperparameters, limiting their generalizability to unseen data. Comprehensive datasets that support both the training of universal models and the evaluation of various segmentation techniques are essential for overcoming these limitations and promoting the development of more versatile cell segmentation solutions. Here, we present CellBinDB, a large-scale multimodal annotated dataset established for these purposes. CellBinDB contains more than 1,000 annotated images, each labeled to identify the boundaries of cells or nuclei, including 4’,6-Diamidino-2-Phenylindole (DAPI), Single-stranded DNA (ssDNA), Hematoxylin and Eosin (H&E), and Multiplex Immunofluorescence (mIF) staining, covering over 30 normal and diseased tissue types from human and mouse samples. Based on CellBinDB, we benchmarked seven state-of-the-art and widely used cell segmentation technologies/methods, and further analyzed the effects of four cell morphology indicators and image gradient on the segmentation results.
Strikingly different neurotransmitter release strategies in dopaminergic subclasses
Authors: Dorrego-Rivas Ana , Byrne Darren J. , Liu Yunyi , Cheah Menghon , Arslan Ceren , Lipovsek Marcela , Ford Marc C. , Grubb Matthew S. 
Published: November 2024

AbstractNeuronal function is intimately tied to axodendritic polarity. Neurotransmitter release, for example, is usually the role of the axon. There are widespread exceptions to this rule, however, including many mammalian neuronal types that can release neurotransmitter from their dendrites. In the mouse olfactory bulb, closely related subclasses of dopaminergic interneuron differ markedly in their polarity, with one subtype lacking an axon entirely. These axon-bearing and anaxonic dopaminergic subclasses have distinct developmental profiles and sensory responses, but how their fundamental polarity differences translate to functional outputs remains entirely unknown. Here, we provide anatomical evidence for distinct neurotransmitter release strategies among these closely related dopaminergic subtypes: anaxonic cells release from their dendrites, while axon-bearing neurons release exclusively from their intermittently myelinated axon. These structural differences are linked to a clear functional distinction: anaxonic, but not axon-bearing dopaminergic neurons are capable of self-inhibition. Our findings suggest that variations in polarity can produce striking distinctions in neuronal outputs, and that even closely related neuronal subclasses may play entirely separate roles in sensory information processing.
Integration of multi-modal measurements identifies critical mechanisms of tuberculosis drug action
Authors: Johnson William C. , Alivisatos Ares , Smith Trever C. , Van Nhi , Soni Vijay , Wallach Joshua B. , Clark Nicholas A. , Fitzgerald Timothy A. , Whiteley Joshua J. , Sokolov Artem , Ando D. Michael , Schnappinger Dirk , Rhee Kyu Y. , Aldridge Bree B. 
Published: November 2024

ABSTRACTTreatments for tuberculosis remain lengthy, motivating a search for new drugs with novel mechanisms of action. However, it remains challenging to elucidate the direct targets of a drug, and even more so, to determine which disrupted cellular processes lead to bacterial killing. We developed a computational tool, DECIPHAER (DEcoding Cross-modal Information of PHarmacologies via AutoEncodeRs), to select the important correlated transcriptional and morphological responses ofMycobacterium tuberculosisto drug treatments. By finding a reduced feature space from these measurements, DECIPHAER highlighted essential features of Mtb cellular damage such as phosphosugar stress and inhibition of translation and DNA replication. After training, DECIPHAER provides cell-death-relevant insight into single-modal datasets, enabling interrogation of drug treatment responses for which transcriptional data are unavailable. Using morphological data alone with DECIPHAER, we discovered that respiration inhibition by the poly-pharmacological drugs, SQ109 and BM212, can influence cell death more than their effects on the cell wall. This study demonstrates that DECIPHAER can extract the critical shared information from multi-modal measurements to identify cell death-relevant mechanisms of TB drugs.
Computer assisted multi-level optimization of malonyl-CoA availability inPseudomonas putida
Authors: Batianis Christos , van Rosmalen Rik P. , Moñino Fernandez Pedro , Asin-Garcia Enrique , Martin-Pascual Maria , Jeschek Markus , Weusthuis Ruud , Suarez-Diez Maria , Martins dos Santos Vitor A. P. 
Published: November 2024

ABSTRACTMalonyl-CoA is the major precursor for the biosynthesis of diverse industrially valuable products such as fatty acids/alcohols, flavonoids, and polyketides. However, its intracellular availability is limited in most microbial hosts, hampering the biological synthesis of such chemicals. To address this limitation, we present a multi-level optimization workflow using modern metabolic engineer-ing technologies to systematically increase the malonyl-CoA levels in Pseudomonas putida. The workflow involves the identification of gene downregulations, chassis selection, and optimization of the acetyl-CoA carboxylase complex through ribosome binding site engineering. Computa-tional tools and high-throughput screening with a malonyl-CoA biosensor enabled the rapid eval-uation of numerous genetic targets. Combining the most beneficial targets led to a 5.8-fold en-hancement in the production titer of the valuable polyketide phloroglucinol. This study demon-strates the effective integration of computational and genetic technologies for engineering P. putida, opening new avenues for the development of industrially relevant strains and the investi-gation of fundamental biological questions.
Piezo1 balances membrane tension and cortical contractility to stabilize intercellular junctions and maintain epithelial barrier integrity
Authors: Javed Ahsan , Stubb Aki , Villeneuve Clémentine , Peters Franziska , Rübsam Matthias , Niessen Carien M. , Biggs Leah C. , Wickström Sara A. 
Published: November 2024

AbstractFormation of a bi-directional skin barrier is essential for organismal survival and maintenance of tissue homeostasis. Barrier formation requires positioning of functional tight junctions (TJ) to the most suprabasal viable layer of the epidermis through a mechanical circuit that is driven by generation of high tension at adherens junctions. However, what allows the sensing of tension build-up at these adhesions and how this tension is balanced to match the requirements of tissue mechanical properties is unclear. Here we show that the mechanosensitive ion channel Piezo1 is essential for the maturation of intercellular junctions into functional, continuous adhesions. Deletion of Piezo1 results in an imbalance of cell contractility and membrane tension, leading to a delay in adhesion maturation. Consequently, the requirement for Piezo1 activity can be bypassed by lowering contractility or elevating membrane tension.In vivo, Piezo1 function in adhesion integrity becomes essential only in aged mice where alterations in tissue mechanics lead to impaired TJs and barrier dysfunction. Collectively these studies reveal an essential function of Piezo1 in the timely establishment and maintenance of cell-cell junctions in the context of a mechanically tensed epidermis.
G-quadruplex Structures in Dysregulated Long Non-Coding RNA of Ovarian Cancer and their Binding Interactions with Human Serum Albumin
Authors: Singh Deepshikha , Shukla Chinmayee , Datta Bhaskar 
Published: November 2024

AbstractOvarian carcinoma (OC) is a major cause of cancer-related mortality among women worldwide, with especially poor outcomes in resource-constrained regions. Long non-coding RNAs (lncRNAs) have emerged as critical players in OC progression, influencing drug resistance, metastasis, and other cellular processes. This study examines the potential of dysregulated lncRNAs in OC to form G-quadruplex (G4) structures. Using in silico predictions and experimental validation, we identified five lncRNAs ERLNC1, DLX6-AS1, LINC01127, FMNL1-DT, and LINP1 as candidates with a high propensity towards G4 formation. A combination of circular dichroism (CD) spectroscopy, Thioflavin T (ThT) fluorescence assay, Dot Blot assay, and reverse transcriptase stop assay, confirmed the ability of the lncRNAs to fold into stable G4 structures. Competitive DNA binding assays enabled the identification of essential G-tracts within each G4 motif highlighting the subtle differences in structure and stability of the different quadruplexes. Human serum albumin (HSA), a major circulatory protein, was found to interact with these G4-forming lncRNAs, albeit with different affinities and structural implications on the G4 motifs. This study provides the first detailed characterization of G4 structures in OC-dysregulated lncRNAs and elucidates their interactions with HSA. The G4 structures identified in these lncRNAs and their interaction with HSA can be of potential value for early OC diagnosis.Graphical Abstract
Protein-S-Nitrosylation of Human Cytomegalovirus pp65 Reduces its Ability to Undermine cGAS
Authors: Cox Justin B. , Nukui Masatoshi , Murphy Eain A. 
Published: November 2024

AbstractPost-translational modifications (PTMs) are key regulators of various processes important for cell survival. These modifications are critical for dealing with stress conditions such as those observed in disease states and during infections with various pathogens. We previously reported that during infection of primary dermal fibroblasts, multiple Human Cytomegalovirus (HCMV) encoded proteins were post-translationally modified by the addition of a nitric oxide group to cysteine residues, a modification called protein-S-nitrosylation. For example, tegument protein pp71 is nitrosylated, diminishing its ability to inhibit STING, a protein necessary for DNA virus immune response. Herin, we report that an additional HCMV tegument protein, pp65, responsible for the inhibition of cGAS, is also modified by protein-S-nitrosylation on two cysteine residues. Utilizing site-directed mutagenesis to generate recombinant viruses that encode a pp65 that cannot be protein-S-nitrosylated, we evaluated the impact of this PTM on viral replication and how the virus impacts the cGAS/STING pathway. We report that the nitrosylation of pp65 negatively impacts its ability to block cGAS enzymatic functions. pp65 protein-S-nitrosylation mutants demonstrated a decrease in cGAS/STING induced IRF3 and TBK1 phosphorylation. Additionally, we observe a reduction in IFN-β1 secretion in NuFF-1 cells expressing a nitrosylation-resistant pp65. We report that HCMV expressing a protein-S-nitrosylation deficient pp65 is resistant to the activation of cGAS in the infection of primary dermal fibroblasts. Our work suggests that nitrosylation of viral proteins may serve as a broadly neutralizing mechanism in HCMV infection.ImportancePost translational modifications (PTM) are utilized by host cells to limit an invading pathogen’s ability to establish a productive infection. A potent PTM called protein-S-nitrosylation has anti-bacterial and anti-viral properties. Increasing protein-S-nitrosylation with the addition of nitric oxide donor compounds, reduced HCMV replication in fibroblasts and epithelial cells1. We previously reported that protein-S-nitrosylation of HCMV pp71 limits its ability to inhibit STING. Herein, we report that the protein-S-nitrosylation of HCMV pp65 impacts it’s ability to limit cGAS activity, an additional protein important in regulating interferon response. Therapeutically, patients provided nitric oxide by inhalation reduced viral replication in COVID-19, influenza and even impacted bacterial growth within patients lungs2,3. It is thought an increase in free nitric oxide increases the frequency of nitrosylated proteins4. Understanding how protein-S-nitrosylation regulates a common DNA virus like HCMV will provide insights into the development of broadly neautralizing therapeutics in drug resistant viral infections.