bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kinetic-model-guided engineering of multipleS. cerevisiaestrains improvesp-coumaric acid production
Authors: Narayanan Bharath , Jiang Wei , Wang Shengbao , Sáez-Sáez Javier , Weilandt Daniel , Barcon Maria Masid , Hesselberg-Thomsen Viktor , Borodina Irina , Hatzimanikatis Vassily , Miskovic Ljubisa 
Published: January 2025

AbstractThe use of kinetic models of metabolism in design-build-learn-test cycles is limited despite their potential to guide and accelerate the optimization of cell factories. This is primarily due to difficulties in constructing kinetic models capable of capturing the complexities of the fermentation conditions. Building on recent advances in kinetic-model-based strain design, we present the rational metabolic engineering of anS. cerevisiaestrain designed to overproducep-coumaric acid (p-CA), an aromatic amino acid with valuable nutritional and therapeutic applications. To this end, we built nine kinetic models of an already engineeredp-CA-producing strain by integrating different types of omics data and imposing physiological constraints pertinent to the strain. These nine models contained 297 mass balances involved in 303 reactions across four compartments and could reproduce the dynamic characteristics of the strain in batch fermentation simulations. We used constraint-based metabolic control analysis to generate combinatorial designs of 3 enzyme manipulations that could increase p-CA yield on glucose while ensuring that the resulting engineering strains did not deviate far from the reference phenotype. Among 39 unique designs, 10 proved robust across the phenotypic uncertainty of the models and could reliably increasep-CA yield in nonlinear simulations. We implemented these top 10 designs in a batch fermentation setting using a promoter-swapping strategy for down-regulations and plasmids for up-regulations. Eight out of the ten designs produced higherp-CA titers than the reference strain, with 19 – 32% increases at the end of fermentation. Importantly, these eight designs also maintained at least 90% of the growth of the reference strain; this indicates the importance of the phenotypic constraint. The high success rate of our in-silico designs in an experimental setting demonstrates the potential and utility of kinetic-model-based strain design. This work sets the foundation for accelerated design-build-test-learn cycles using large-scale kinetic models as a scaffold.
Refining Muscle Morphometry Through Machine Learning and Spatial Analysis
Authors: Ono Daisuke , Kawai Honami , Kuwahara Hiroya , Yokota Takanori 
Published: January 2025

AbstractAimsMuscle morphology provides important information in differentiating the disease aetiology, but its measurement remains challenging due to the lack of an efficient and objective method. This study aimed to quantitatively refine the morphological features of muscle fibres in neuromuscular diseases using machine learning.MethodsThis retrospective study analysed muscle biopsy specimens on hematoxylin and eosin-staining. A machine learning-based software was developed to segment muscle fibre contours and perform automated muscle morphometry and subsequent graph theory-based spatial analysis of atrophied fibre grouping. A decision tree-based framework, LightGBM, was trained to predict underlying aetiologies based on the morphometric and spatial variables.ResultsThe study included 100 muscle samples, including 20 normal muscles, 49 myopathies, and 19 neuropathies. The fine-tuned segmentation model, YOLOv8, achieved a mask average precision of 0.819. The muscle morphometry revealed the significance of fibre circularity. The mean circularity was higher in the myopathy group, and the SD of circularity was elevated in the neuropathy group. Although most cases were consistent with textbook findings, atypical presentations, such as dermatomyositis with angular atrophy and amyotrophic lateral sclerosis with round atrophy, were objectively documented. Spatial analysis quantified grouped atrophy, showing the potential to feature specific atrophy patterns. The LightGBM model successfully predicted the final clinical diagnosis of the myopathies and neuropathies with an accuracy of 0.852, which exceeded that of 0.808 by human annotation.ConclusionAutomated muscle morphometry and spatial analysis provided the quantification of muscle morphology and atrophy patterns, which will facilitate objective and efficient investigation of neuromuscular diseases.Key PointsThis study aimed to quantitatively refine the morphological features of muscle fibres in neuromuscular diseases using machine learning-based software.Automated muscle morphometry successfully characterised myopathies and neuropathies, presenting the utility of circularity for their differentiation.Spatial analysis based on graph theory proposed quantitative definitions for grouped atrophy and perifascicular atrophy, which showed the potential to feature the grouping patterns of atrophic fibres.This open-source tool will facilitate objective and efficient investigation of neuromuscular diseases.
Two-week supplementation ofBifidobacterium adolescentisiVS-1 reduces fecal urgency and diarrhea and enhances overall lactose tolerance in lactose maldigesters
Authors: Ramakrishnan Monica , Cross Tzu-Wen L. , Wilcox Anne K. , Organski Anna Clapp , Rhine Robin L. , Saiprasad Sindusha Mysore , Simpson Abigayle M. R. , Tancredi Daniel J. , Van Haute Mallory J. , Christensen Chloe M. , Lewis Zachery T. , Auchtung Thomas A. , Walter Jens , Hutkins Robert , Savaiano Dennis A. 
Published: January 2025

ABSTRACTProbiotic supplements containing high β-galactosidase-producing bacteria may aid in the management of lactose intolerance. We previously isolated a strain ofBifidobacterium adolescentis, iVS-1, from the fecal sample of a human donor after consumption of galactooligosaccharides (GOS), a prebiotic derived from lactose. Therefore, it was hypothesized that iVS-1 might reduce symptoms associated with lactose maldigestion. Compared to other probiotic strains, iVS-1 had high β-galactosidase activity and reduced gas formation by fecal communities during in vitro fermentations of lactose or milk. A randomized placebo-controlled clinical trial was then conducted with 21 lactose maldigesters, randomized to receive eitherB. adolescentisiVS-1 (n = 11) or placebo (n = 10) daily for two weeks. Compared to the two-week run-in period, iVS-1 abundance was higher at the end of the treatment period (p = 0.0005) and after the two week post-treatment period (p = 0.045). The iVS-1 group experienced less overall daily symptoms during the treatment period when compared to placebo (p = 0.032) and had significant improvement for fecal urgency (p = 0.033) and diarrhea (p = 0.006). The metabolism of lactose, reduction of gas, and improvement of multiple gastrointestinal symptoms suggestsB. adolescentisiVS-1 may be an effective treatment for lactose intolerance.Trial RegistrationThe trial is registered atClinicalTrials.gov(https://clinicaltrials.gov/study/NCT05668468).
Impact of Surgeon cadre, theatre location, and presence of intern healthcare professionals on decision-to-delivery interval in women undergoing emergency caesarean section in Northern Uganda: a historical cohort study
Authors: Ochola Henry , Omoro Ronnie , Buga Paul , Odong Emintone Ayella , Ocaya Oscar , Kajabwangu Rogers , Ochola Emmanuel , Atim Nelly , Akello Harriet , Acayo Judith Praiselyn , Ekwem Doris , Namuddu Jovia , Mukurasi Derrick , Lukyamuzi Enock , Onen Hudson , Lenia Maurine , Gimono Martha , Webb Emily , Campbell Oona , Komata Ronald , Okot Jerom , Ojara Sande 
Published: January 2025

AbstractIntroductionEmergency caesarean sections (CS) are crucial for preventing life-threatening complications. The Decision-to-Delivery Interval (DDI), the time between decision and actual delivery, impacts maternal and neonatal outcomes. While the World Health Organization recommends a DDI of < 30 minutes, achieving this in low-resource settings remains challenging. This study examines the impact of surgeon’s cadre, operating theatre location, and presence of intern healthcare professionals on DDI and whether these associations vary by CS indication.MethodsThis historical cohort study was conducted at St. Mary’s Hospital Lacor, a tertiary hospital in Northern Uganda, involving 760 women who underwent emergency CS between 6thSeptember 2022 and 1stJune 2024. We assessed the association of prolonged DDI (≥60 minutes) with surgeon cadre, operating theatre location, and intern presence using logistic regression, adjusting for key confounders and investigated interaction with the indication for emergency CS.ResultsThe median DDI was 51 minutes (IQR: 36-67), with 36.0% of cases classified as prolonged (≥ 60 minutes). Emergency CS performed by junior doctors had twice the odds of prolonged DDI compared to senior doctors (adjusted OR: 2.07; 95% CI: 1.38-3.10). Theatre location showed no effect on DDI (OR: 0.89; 95% CI: 0.61-1.28). The presence of interns was weakly associated, with slightly lower odds of prolonged DDI when interns were absent (OR: 0.71; 95% CI: 0.51-1.02). No significant variations were found based on the indication for emergency CS.ConclusionSurgeon’s cadre is a key factor in reducing prolonged DDI, highlighting the importance of training and supervision for junior doctors. While theatre location did not significantly impact DDI, improving theatre readiness and coordination remains essential. The weak association with intern presence suggests further investigation into their role in emergency CS. These findings highlight the importance of addressing system-level delays to improve timely emergency obstetric care in resource-limited settings.
DIYNAFLUOR: An Affordable DIY Plug-and-Play Nucleic Acid Fluorometer for eDNA Quantification in Resource Limited Settings
Authors: Anderson Will , Antaw Fiach , Kenny Sophie , Rupani Harshita , Khamis Ramlah , Constantin Nicolas , Kumar Vinay , Gemmell Anna , Bell Craig , Trau Matt , Korbie Darren 
Published: January 2025

AbstractNucleic Acid (NA) fluorometry is widely employed for quantifying environmental DNA (eDNA) samples and their downstream DNA sequencing libraries, owing to its sensitivity, accuracy, and speed. However, the high cost of NA fluorometers presents a barrier to eDNA sequencing in resource limited settings (RLSs). For instance, at ∼$1.5-3.3k USD, current NA fluorometers present a greater capital cost than ONT’s $1k USD portable MinION third-generation Nanopore sequencing platform. The collapse of international scientific device and consumable supply chains during the COVID-19 pandemic also highlighted the need for distributed manufacturing of molecular research tools to mitigate the impact of increased pricing to RLSs. To address these challenges, we have developed the “DIYNAFLUOR” (DIY Nucleic Acid FLUORometer), a portable, open-source, <$40 USD NA fluorometer, designed using readily available off-the-shelf components, simple 3D-printed parts, and plug-and-play, solder-free assembly. The DIYNAFLUOR was primarily designed to be compatible with the popular DNA-centric Qubit High Sensitivity (HS) and Broad Range (BR) assay kits. Notably, the DIYNAFLUOR demonstrated an ‘in-assay’ Limit of Detection with the Qubit HS kit of 0.0028 ng/μL, and an average absolute bias of 0.018 ng/μL across a 0–10 ng/μL working range using a 2-point linear calibration methodology. Device verification was performed by comparative measurements with a Qubit 4 fluorometer in a busy biotechnology laboratory, and build instructions were validated through assembly and qualification of three DIYNAFLUOR devices by researchers outside the primary design team. We also describe a custom “extreme”low-cost assay, <13¢ USD per-measurement, that uses SYBR Safe dye to quantify DNA across a working range of 0-0.5 ng/μL. This assay reports a lower sensitivity and accuracy than commercial kits but may be of use to RLSs in times of extreme resource constraints or as a teaching tool for STEM educators. To demonstrate its practical application for field-based eDNA analysis in RLSs, the DIYNAFLUOR was used to perform all quality control measurements throughout the preparation of a 16S and 18S metabarcoding library generated from eDNA extracted from Australian lake water, leading to the successful identification of Australian fauna via Nanopore sequencing. Finally, configurations of the DIYNAFLUOR for RNA and Protein quantification are briefly described.TOC
Spatial Phylogenetics with Continuous Data: an Application to California Bryophytes
Authors: Kling Matthew M. , González-Ramírez Ixchel S. , Carter Benjamin , Borokini Israel , Mishler Brent D. 
Published: January 2025

AbstractSpatial phylogenetics is premised on the idea that species are not discrete categorical entities but instead lie on a hierarchical evolutionary continuum that contains rich biological information valuable for quantifying spatial biodiversity patterns. Yet while spatial phylogenetic approaches use quantitative information to represent phylogenetic patterns, most have continued to rely on methods that discard valuable information about spatial patterns by converting continuous variables into binary categories. This includes representing geographic ranges using binary presence-absence data, classifying statistical significance into categories, and quantifying biogeographic gradients into discrete regions. In this paper we show how a full suite of spatial phylogenetic analyses, including analyses of alpha and beta diversity, neo- and paleo-endemism, biogeographic hypothesis testing, and spatial conservation prioritization, can be implemented with “smooth” methods that never remove information content by categorizing continuous data. Our analysis focuses on the bryophytes of California, an understudied group in a global plant biodiversity hotspot. Using a time-calibrated phylogeny and species distribution models for 548 species of mosses and liverworts, we profile the evolutionary diversity, compositional turnover, and conservation value of bryophyte communities across the state. Our results highlight important patterns in the diversity of this key plant group, while our methods can serve as a model for future studies seeking to maximize the information content of spatial phylogenetic analyses.
Hamsters with long Covid exhibits a neurodegenerative signature in the brainstem
Authors: Coleon Anthony , Larrous Florence , Kergoat Lauriane , Tichit Magali , Hardy David , Obadia Thomas , Kornobis Etienne , Bourhy Hervé , de Melo Guilherme Dias 
Published: January 2025

AbstractAfter infection with SARS-CoV-2, patients may present with one or more symptoms that appear or persist over time, including fatigue, respiratory, cardiovascular and neurological disorders. Neurological symptoms include anxiety, depression and impaired short-term memory. However, the exact underlying mechanisms of long Covid are not yet decrypted. Using the golden hamster as a model, we provide further evidence that SARS-CoV-2 is neuroinvasive and can persist in the central nervous system, as we found viral RNA and replicative virus in the brainstem after 80 days of infection. Infected hamsters presented a neurodegenerative signature in the brainstem, with overexpression of innate immunity genes, impacted dopaminergic and glutamatergic synapses, altered energy metabolism. Finally, the infected hamsters manifested persistent signs of depression and impaired short-term memory, as well as late-onset signs of anxiety, as a valuable model to study long Covid. Conclusively, we provide evidence that virus-related and neurodegenerative and immunometabolic mechanisms coexist in the brainstem of infected hamsters and contribute to the manifestation of neuropsychiatric and cognitive symptoms.HighlightsSARS-CoV-2 infects and persists in the brainstem of intranasally-inoculated hamstersPersistent neuropsychiatric and cognitive consequences are observed in SARS-CoV-2-infected hamstersThe brainstem present distinct transcriptome profiles in acute and in long CovidThe dopaminergic and glutamatergic systems are affected in long CovidThe SARS-CoV-2 infection affects the expression of genes related to neurodegenerative processes in acute and in long Covid
The anti-inflammatory activity of IgG requires the co-engagement of types I and II Fc receptors
Authors: Jones Andrew T. , Martynyuk Tetyana , Marino Alessandra E. , Bournazos Stylianos , Ravetch Jeffrey V. 
Published: January 2025

AbstractIntravenous immunoglobulin administered at high doses has been used for decades as an effective anti-inflammatory preparation to treat a wide array of autoimmune diseases. Studies in murine models have found this activity to be dependent on 1) sialylation of the N-linked glycan on the CH2 domain of IgG, 2) the type I IgG inhibitory Fc receptor FcγRIIB, and 3) the type II Fc receptor DC-SIGN. Here, we demonstrate that the ectodomain glycan on FcγRIIB interacts with the lectin domain of DC-SIGN to form a cell surface complex, thereby enabling the binding of sialylated IgG1. We have exploited this observation to Fc-engineer sialylated IgG1 to enhance its affinity for FcγRIIB and demonstrate that the resulting molecule is at least 100-fold more potent in reducing the inflammatory sequelae of antibody or T cell mediated autoimmune diseases, providing the basis for a new class of anti-inflammatory therapeutics.
GPCRchimeraDB: A database of chimeric G-Protein Coupled Receptors (GPCRs) to assist their design
Authors: Crauwels Charlotte , Díaz Adrián , Vranken Wim 
Published: January 2025

AbstractG-Protein Coupled Receptors (GPCRs) are membrane proteins implicated in numerous diseases that have been studied for decades. However, despite their significance, many GPCRs remain poorly characterized and untargeted by drugs. Chimeric GPCRs have emerged as valuable tools for elucidating GPCR function by facilitating the identification of signaling pathways, resolving structures, and discovering novel ligands of poorly understood GPCRs. Such chimeric GPCRs are obtained by merging a well-characterized and a less-well-characterized GPCR at the intracellular loops, leveraging knowledge transfer from the well-characterized GPCR. However, despite the 170 chimeric GPCRs engineered to date, the design process remains largely trial-and-error and lacks a standardized approach. To address this gap, we introduce GPCRchimeraDB (https://www.bio2byte.be/gpcrchimeradb/), the first comprehensive database dedicated to chimeric GPCRs. It catalogs 170 chimeric receptors, identified through extensive literature review, and includes 1,758 natural GPCRs, enabling connections between chimeras and their parent receptors while facilitating the exploration of novel parent combinations. Both chimeric and natural GPCR entries are extensively described at the sequence, structural, and biophysical level through a range of visualization tools, with annotations from resources like UniProt and GPCRdb and predictions from AlphaFold, ESMFold and b2btools. Additionally, GPCRchimeraDB offers a GPCR sequence aligner and a feature comparator to investigate differences between natural and chimeric receptors as well as guidelines to support the design of novel chimeras. GPCRchimeraDB is therefore a resource to facilitate and optimize the design of new chimeras, so helping to gain insights into poorly characterized receptors and contributing to advances in GPCR therapeutic development.Graphical Abstract
A modelling framework to estimate vector dispersal and disease spread in an important agricultural pathosystem
Authors: Preedy Katharine F. , Namara Louise Mc , Mostafiz Md Munir , Schughart Maximilian , Bramham Lawrence E. , Leybourne Daniel J. 
Published: January 2025

AbstractCereals are some of the most agriculturally important crops grown worldwide. Cereal aphids are small sap-feeding insects that infest cereals and vector devastating cereal pathogens, principally the yellow dwarf viruses, with severe infection reducing yields by 20−80%. Currently, farmers are advised to apply insecticide if a single cereal aphid is found within the crop. However, this is an oversimplification of the biology and ecology of the vector-virus system: Each aphid species can transmit a range of yellow dwarf virus species with variable efficiency, and intra-species diversity within a vector species (genotype) can influence this further. Accounting for this variation in decision-making processes has the potential to help with developing bespoke management options based on the composition of the local vector-virus population, and represents a novel avenue that could be explored to develop more sustainable management strategies. Here we describe a stage-structured model that can estimate vector dispersal and disease spread. We use data for the two main cereal aphid species and the two yellow dwarf virus species of greatest concern in Europe to examine how diversity at each level of the vector-virus system impacts disease spread. More broadly, our modelling framework represents a tool that can be used to explore vector-virus-host interactions in greater detail, and we use cereal systems as a case study. Our modelling scenarios highlight diversity at each scale as an important factor. We show that the two main vector species have contrasting dispersal patterns, and that this interacts with virus transmission efficacy to influence disease spread; genetic variation within a vector population is a key driver behind disease spread and disease risk; and for vector species that transmit multiple virus species, the specific vector-virus species combination is a key risk factor to consider.
Localized translation of cell junction mRNAs is required for epithelial cell polarity
Authors: Chin Ashley , Bergeman Jonathan , Communal Laudine , Boulais Jonathan , Mes-Masson Anne-Marie , Lécuyer Eric 
Published: January 2025

ABSTRACTEpithelial cells exhibit a highly polarized organization along their apico-basal axis, a feature that is critical to their function and frequently perturbed in cancer. One less explored process modulating epithelial cell polarity is the subcellular localization of mRNA molecules. In the present study, we report that several mRNAs encoding evolutionarily conserved epithelial polarity regulatory proteins, includingZo-1,AfdnandScrib, are localized to cell junction regions inDrosophilaepithelial tissues and human epithelial cells. Targeting of these mRNAs is coincident with the robust junctional distribution of their encoded proteins, and we demonstrate that they are locally translated at cell junction regions. To identify RNA binding proteins (RBPs) potentially implicated in junctional mRNA regulation, we performed systematic immuno-labeling with a collection of validated RBP antibodies, identifying a dozen RBPs with consistent junctional distribution patterns, several of which directly bind junctional transcripts. Strikingly, depletion of these RBP candidates, including MAGOH, a core component of the exon-junction complex (EJC), perturbed the junctional distribution and localized translation ofZo-1andScribmRNAs, as well as the junctional accumulation of their protein products. Functional disruption of MAGO, or its interaction partner Y14, inDrosophilafollicular epithelial cells perturbs the distribution of junctional transcripts and proteins. Finally, tissue microarray analysis of ovarian cancer tumor specimens revealed that expression of MAGOH and ZO-1 is positively correlated and that both proteins are potential biomarkers of good prognosis. Altogether, this work reveals that localized mRNA translation at cell junction regions is important for modulating epithelial cell polarity.HIGHLIGHTSCell junction mRNA targeting is conserved between tissues and speciesThese mRNAs undergo localized translation at areas of cell-cell contactA diversity of RBPs localize to cell junction regions and interact with junctional transcripts.Disruption of junctional RBPs impacts epithelial cell polarity and localized translationMAGOH and ZO-1 expression is correlated in ovarian tumor specimens and are potential biomarkers of good prognosis