bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence of supratentorial white matter injury prior to treatment in children with posterior fossa tumours using diffusion MRI
Authors: Drabek-Maunder Emily R. , Gains Jenny , Hargrave Darren R. , Mankad Kshitij , Aquilina Kristian , Dean Jamie A. , Nisbet Andrew , Clark Chris A. 
Published: December 2024

AbstractBackgroundPaediatric brain tumour survivors can have neurocognitive deficits that negatively impact their quality of life, but it is unclear if deficits are primarily caused by treatments, such as radiotherapy, or manifest earlier due to the tumour and related complications. The aim of this work is to characterise white matter injury caused by brain tumours, unrelated to treatment effects, and explore heterogeneity in these white matter abnormalities between individual patients.MethodsWe used diffusion tensor imaging (DTI) and Neurite Orientation Dispersion Diffusion Imaging (NODDI) to assess white matter injury in 8 posterior fossa tumour patients. A novel one-against-many approach was used by comparing an individual patient to 20 age- and sex-matched healthy controls to assess variability in white matter abnormalities between the posterior fossa tumour patients. White matter was analysed at presentation (prior to treatment), post-surgery (24-72 hours after surgery), and at follow-up (3-18 months after surgery).ResultsWe demonstrate white matter abnormalities in 5 posterior fossa tumour patients before treatment, likely related to tumour-induced hydrocephalus, which persisted after treatment. White matter changes were complex and patient-specific, and group-based comparisons with control sub-jects may fail to detect these individual abnormalities.ConclusionsIdentifying pre-treatment white matter injury in posterior fossa tumour patients highlights the importance of personalised assessment of brain microstructure, which should be considered in minimising neurocognitive deficits to improve patient quality of life.
EDEPS (Early Detection of ExtraPyramidal Symptoms): supervised machine learning models to detect antipsychotics-induced extrapyramidal hand tremor from a mobile device built-in sensors
Authors: Wysokiński Adam , Zwierzchowska-Kieszek Aleksandra 
Published: December 2024

AbstractIntroductionApproximately 30% of patients treated with antipsychotics develops extrapyramidal side effects, among which hand tremor is not only common, but also significantly impacting daily activities. No tool for remote assessment of hand tremor is available.Materials and methodsWe collected SAS and AIMS scores and digital recordings of health tremor from healthy and schizophrenia patients on antipsychotics. Next, we created and tested a supervised machine learning models for detecting and measuring severity of antipsychotics-induced hand tremor.ResultsWe present model details, accuracy measures (R2and RMSE for regressors; log loss, AUC, misclassification, rate, accuracy, sensitivity and specificity for classifiers) and analysis of hand tremor spectral analysis.ConclusionsOur model offers a satisfactory accuracy (0.95 to 1.0) and performance, even if only 10 second data is available. Result of the spectral analysis indicate that the dominating frequency of hand tremor in antipsychotics-induced EPS is approximately 5.0 Hz.
Non-Caloric Sweeteners combined with glucose affect hypothalamic glucose sensing-induced insulin secretion, food re-intake through neuronal cellular metabolism: Anin vivoandin vitroapproaches
Authors: Haydar J. , Fenech C. , Liénard F. , Abed B. , Grall S. , Briand Loïc , Walther G. , Leloup C. 
Published: December 2024

1ABSTRACTChanges in brain activity associated with deleterious metabolic effects of non-caloric sweeteners (NCS) have been demonstrated in humans, particularly when their intake is concomitant with that of glucose. Here, we have focused on hypothalamic glucose sensing in rats, detecting increases in circulating glucose levels and in turn triggering various physiological controls. The identification of sweet-taste receptors in the hypothalamus has suggested that they participate in glucosensing mechanism, but the existence of a dialogue between different pathways has never been studied. Here, we tested the acute effects of hypothalamic glucosensing combined with a NCS (sucralose or acesulfame potassium (aceK)), the latter binding only to sweet-taste receptors, without producing energy. Our working hypothesis was that the concomitance of two contradictory signals (energetic, sweet glucose vs. non-energetic, sweet NCS) could be responsible for deleterious physiological effects. After validation that sweet taste receptors and their signaling expressions were indeed present in the rat hypothalamus, insulin secretion induced by hypothalamic glucosensing (increased glucose level) in the presence of sucralose and aceK was examined. Insulin release was reduced compared to glucose alone, while the two NCS alone have no effect. Regarding the satiety-inducing effect of glucose, concomitant injection of each NCS with glucose produced the opposite effect to that observed with glucose alone, with food intake being increased, an effect also present with NCS injected alone. Using the GT1-7 hypothalamic cell line expressing sweet-taste receptors, we showed that the ATP concentration which normally increases with rising glucose levels was dose-dependently decreased in the presence of NCS, an effect which is inhibited in the presence of gurmarin, a specific inhibitor of sweet-taste receptors. The increase in ROS production in response to rising glucose levels was enhanced in the presence of NCS, an effect that was blocked in the presence of gurmarin. In both cases, NCS have an inhibitory effect on stimulated mitochondrial respiration. Taken together, these results suggest that NCS via sweet-taste receptors interfere with mitochondrial signaling and/or energy production during hypothalamic glucose sensing.
Maize inbreds show allelic variation for diel transcription patterns
Authors: Gage Joseph L. , Romay M. Cinta , Buckler Edward S. 
Published: December 2024

AbstractCircadian entrainment and external cues can cause gene transcript abundance to oscillate throughout the day, and these patterns of diel transcript oscillation vary across genes and plant species. Less is known about within-species allelic variation for diel patterns of transcript oscillation, or about how regulatory sequence variation influences diel transcription patterns. In this study, we evaluated diel transcript abundance for 24 diverse maize inbred lines. We observed extensive natural variation in diel transcription patterns, with two-fold variation in the number of genes that oscillate over the course of the day. A convolutional neural network trained to predict oscillation from promoter sequence identified sequences previously reported as binding motifs for known circadian clock genes in other plant systems. Genes showing diel transcription patterns that cosegregate with promoter sequence haplotypes are enriched for associations with photoperiod sensitivity and may have been indirect targets of selection as maize was adapted to longer day lengths at higher latitudes. These findings support the idea that cis-regulatory sequence variation influences patterns of gene expression, which in turn can have effects on phenotypic plasticity and local adaptation.
Variability of axon initial segment geometry and its impact on hippocampal pyramidal cell function
Authors: Stevens Nikolas Andreas , Achilles Maximilian , Monath Juri , Engelhardt Maren , Both Martin , Thome Christian 
Published: December 2024

ABSTRACTAction potentials, the primary information units of the nervous system, are usually generated at the axon initial segment (AIS). Changes in the length and position of the AIS are associated with alterations in neuronal excitability but there is only limited information about the baseline structural variability of the AIS. This work provides a comprehensive atlas of the diversity of proximal cell geometries across all anatomical axes of the murine hippocampus, encompassing dorsal-ventral, superficial-deep, and proximal-distal regions. We analyzed the morphology of 3,936 hippocampal pyramidal neurons in 12 animals of both sexes, focusing on AIS length, position, and their association with proximal cellular features such as the soma and dendritic geometries. Notably, neurons with axon-carrying dendrites were significantly more common in ventral compared to dorsal hippocampal areas, suggesting a functional adaptation to regional demands. Validation of this finding in human samples confirms the translational relevance of our murine model. We employed NEURON simulations to assess the functional implications of this variability. Here, variation in proximal geometry only minimally contributed to neuronal homeostasis, but instead increased heterogeneity of response patterns across neurons.
Disparate co-evolution and prevalence of sulfadoxine and pyrimethamine resistance alleles and haplotypes atdhfranddhpsgenes across Africa
Authors: White Nina F. D. , Whitton Georgia , Wasakul Varanya , Amenga-Etego Lucas , Dara Antoine , Andrianaranjaka Voahangy , Randrianarivelojosia Milijaona , Miotto Olivo , D’Alessandro Umberto , Djimdé Abdoulaye , Ariani Cristina V. , Pearson Richard D. , Amambua-Ngwa Alfred 
Published: December 2024

AbstractSulfadoxine-pyrimethamine (SP), despite the emergence and spread of mutations indhfranddhpsgenes associated with lower treatment efficacy, is still recommended alone or in combination by the WHO for preventive treatment in pregnant women, children and infants. Therefore, it is important to understand the evolution ofP. falciparum dhfranddhpsgenes. Here, we used a subset of the MalariaGEN Pf7 dataset to describe haplotype frequencies across 22 African countries, including changes over time in The Gambia, Mali, Ghana and Kenya. We show that the triple mutant ofdhfr,N51I/C59R/S108N, has remained the dominant haplotype across the continent with limited evidence of additional mutations. There is greater variation fordhps, with a total of 51 different haplotypes present. Thedhpsresistance mutation A437G has risen close to fixation across most of Africa, although at a lower frequency in the northwest malaria-endemic part of the continent (Gambia, Senegal and Mali). The A437G mutation is usually found together with K540E in East Africa, but K540E is still very rare in West Africa. Although samples from Madagascar have low genetic differentiation from samples from mainland East Africa at the whole genome level, we show thatdhpsK540E is highly differentiated between the two populations, being at very low frequency in Madagascar (4%). We used whole genome data to show that only 12 SNPs are more highly differentiated than K540E between Madagascar and East Africa, withaat1and a possible novel drug resistance locus approximately 20kb 3’ ofmdr1having even higher FST. We highlight the value of longitudinal sampling and whole genome sequence data for understanding the heterogeneity and ongoing changes in anti-malarial drug resistance genetic markers.
Intensive transmission in wild, migratory birds drove rapid geographic dissemination and repeated spillovers of H5N1 into agriculture in North America
Authors: Damodaran Lambodhar , Jaeger Anna , Moncla Louise H. 
Published: December 2024

AbstractSince late 2021, a panzootic of highly pathogenic H5N1 avian influenza virus has driven significant morbidity and mortality in wild birds, domestic poultry, and mammals. In North America, infections in novel avian and mammalian species suggest the potential for changing ecology and establishment of new animal reservoirs. Outbreaks among domestic birds have persisted despite aggressive culling, necessitating a re-examination of how these outbreaks were sparked and maintained. To recover how these viruses were introduced and disseminated in North America, we analyzed 1,818 Hemagglutinin (HA) gene sequences sampled from North American wild birds, domestic birds and mammals from November 2021-September 2023 using Bayesian phylodynamic approaches. Using HA, we infer that the North American panzootic was driven by ∼8 independent introductions into North America via the Atlantic and Pacific Flyways, followed by rapid dissemination westward via wild, migratory birds. Transmission was primarily driven by Anseriformes, shorebirds, and Galliformes, while species such as songbirds, raptors, and owls mostly acted as dead-end hosts. Unlike the epizootic of 2015, outbreaks in domestic birds were driven by ∼46-113 independent introductions from wild birds, with some onward transmission. Backyard birds were infected ∼10 days earlier on average than birds in commercial poultry production settings, suggesting that they could act as “early warning signals” for transmission upticks in a given area. Our findings support wild birds as an emerging reservoir for HPAI transmission in North America and suggest continuous surveillance of wild Anseriformes and shorebirds as crucial for outbreak inference. Future prevention of agricultural outbreaks may require investment in strategies that reduce transmission at the wild bird/agriculture interface, and investigation of backyard birds as putative early warning signs.
Different liposomal formulations of 5-Fluorouracil result in variations to gastrointestinal toxicities
Authors: Thorpe Daniel , Wang Wen , Milne Robert , Stringer Andrea 
Published: December 2024

Abstract5-Fluorouracil (5FU) treatment can induce severe mucositis, gastrointestinal toxicity. New formulations of 5-FU increase cancer cytotoxicity, such as neutral liposomes (NL), cationic liposomes (CL), and polyethylenimine copper (PEI-Cu) complexes. However, gastrointestinal toxicity for these new formulations remains unclear. We aim to determine if new formulations in 5FU reduce mucositis by reducing intestinal goblet cell and nerve integrity.Sprague Dawley rats were randomly assigned to groups: saline (n=6), 5FU (n=6 ), NL-5FU (n=5), CL-5FU (n=5), PEI-CU-5FU (n=6), NL-PEI-Cu-5FU (n=5) CL-PEI-Cu-5FU (n=5) (Formulations were equivalent to 10mg/kg 5FU in saline). Treatment was administered daily for 5 days. Rats where humanely killed 2 days after treatment. Haematoxylin and Eosin staining for histological change, Alcian Blue-PAS staining for mucin composition, and immunohistochemistry with S100 antibody for nerve integrity were performed. Statistical analysis using Kruskal-Wallis test with Dunns post-test and Mann Whitney U test d were performed. Effect size was determined using Cohen’s D test.In the jejunum, inflammatory infiltrate increased in PEI-Cu-5FU rats compared to 5-FU controls (p=0.0011). S100 positive nerve bundles increased in NL-5FU rats compared to saline control (p<0.05). S100 positive cells increased in CL-PEI-Cu-5FU rats compared to saline controls.PEI-Cu-5FU formulation was associated with increased inflammatory infiltrate potentially in response to damage in the jejunum. However, liposomal formulations increased S100 positive neural cells, which may offer protection through increased gastrointestinal motility and contraction. While these formulations of 5FU increase cancer cytotoxicity, the gastrointestinal toxicity remains similar. However, further close monitoring of 5FU formulations for gastrointestinal toxicity is warranted.
Recombinant Expression of Photo-crosslinkable 26S Proteasome Base Subcomplex
Authors: Restrepo Santiago Yori , Martin Andreas 
Published: December 2024

AbstractThe 26S proteasome complex is the hub for regulated protein degradation in the cell. It is composed of two biochemically distinct complexes: the 20S core particle with proteolytic active sites in an internal chamber and the 19S regulatory particle, consisting of a lid and base subcomplex. The base contains ubiquitin receptors and an AAA+ (ATPases associated with various cellular activities) motor that unfolds substrates prior to degradation. TheS. cerevisiaebase subcomplex can be expressed recombinantly inE. coliand reconstituted into functional 26S proteasomesin vitro, which allows the introduction of unnatural amino acids with novel functions or other mutations that may not be permissiblein vivo. Here, we present a method for the introduction of the photo-induced crosslinking amino acid p-benzoyl-L-phenylalanine into the proteasomal base subcomplex. This approach has exciting implications for the study of protein-protein interactions of this complex that mediates the degradation of an incredibly diverse protein pool.
An early-stage cost and implementation feasibility study of the administration of pro/synbiotics to infants 0-5 months in rural Kenya
Authors: McCallum Beth , Otiti Iwaret , Achieng Florence , Allen Stephen , Worral Eve 
Published: December 2024

AbstractBackgroundUndernutrition underlies approximately 45% of global deaths among children less than five years old, making it one of the most concerning global child health issues. ThePRObiotics andSYNbiotics in infants inKenya (PROSYNK) trial is assessing whether supervised doses of pro/synbiotics daily for the first 10 days and then weekly to age 6 months (total of 32 doses), has a positive impact on gut health and thereby growth and nutrition. This study is an early-stage cost and implementation feasibility study defining unit costs for the PROSYNK trial and estimating programmatic cost and feasibility of delivering the intervention to infants in rural Kenya.MethodsThis provider perspective costing study uses a combination of ingredients approach, activity-based costing and microcosting. First, an empirical cost analysis of the PROSYNK trial was conducted by review of trial documentation and time and motion observations. Next, semi-structured interviews with key informants informed a thematic analysis of implementation feasibility and the development of a theoretical programme structure which formed the basis for estimation of total economic programme costs.ResultsThe economic cost of delivering the full pro/synbiotics course under trial conditions was measured as $757.32 per participant. Experience gained during PROSYNK and discussions with key informants revealed that it was feasible for the Ministry of Health (MoH) to implement programmatic delivery of the pro/synbiotics, particularly through community-based delivery, without a cold chain and with pro/synbiotic administered directly into infant’s mouths. Incremental economic costs to the MoH of delivering the pro/synbiotic programmatically were estimated to be $9.15 per infant per full course under the base case scenario.ConclusionPro/synbiotic administration in early life may be feasible and bear similar costs to existing nutrition interventions. This study will provide policy makers and stakeholders with vital cost and feasibility information to inform effective programmatic implementation in Kenya and similar settings.
Structure-based Design of Chimeric Influenza Hemagglutinins to Elicit Cross-group Immunity
Authors: Castro Karla M. , Ayardulabi Reyhaneh , Wehrle Sarah , Cui Hongrui , Georgeon Sandrine , Schmidt Joseph , Xiao Shuhao , Seraj Nishat , Harshbarger Wayne , Mallett Corey P. , Vassilev Ventzislav , Saelens Xavier , Correia Bruno E. 
Published: December 2024

AbstractAntigenic variability among influenza virus strains poses a significant challenge to developing broadly protective, long-lasting vaccines. Current annual vaccines target specific strains, requiring accurate prediction for effective neutralization. Despite sequence diversity across phylogenetic groups, the hemagglutinin (HA) head domain’s structure remains highly conserved. Utilizing this conservation, we designed cross-group chimeric HAs that combine antigenic surfaces from distant strains. By structure-guided transplantation of receptor-binding site (RBS) residues, we displayed an H3 RBS on an H1 HA scaffold. These chimeric immunogens elicit cross-group polyclonal responses capable of neutralizing both base and distal strains. Additionally, the chimeras integrate heterotrimeric immunogens, enhancing modular vaccine design. This approach enables the inclusion of diverse strain segments to generate broad polyclonal responses. In the future, such modular immunogens may serve as tools for evaluating immunodominance and refining immunization strategies, offering potential to bridge and enhance immune responses in individuals with pre-existing immunity. This strategy holds promise for advancing universal influenza vaccine development.Graphical abstract: Overview of cross-group RBS transplantation approachPhylogenetically diverse HA strains can be incorporated into chimeric immunogens by RBS transplantation. The chimera are evaluated for cross-reactivity to subtype-specific antibodies and the ability to elicit neutralizing antibodies to multiple strains.
A low-cost FPGA-based approach for pile-up corrected high-speed in vivo FLIM imaging
Authors: Moros Felipe Velasquez , Amiet Dorian , Meister Rachel Megan , von Faber-Castell Alexandra , Wyss Matthias , Saab Aiman S. , Zbinden Paul , Weber Bruno , Ravotto Luca 
Published: December 2024

AbstractIntensity-based two-photon microscopy (2PM) is a cornerstone of biomedical research but lacks the ability to measure concentrations, a pivotal task for longitudinal studies and quantitative comparisons. Fluorescence Lifetime Imaging (FLIM) based on Time-Correlated Single Photon Counting (TCSPC) can overcome those limits but suffers from “pile-up” distortions at high photon count rates, severely limiting acquisition speed. We introduce the “laser period blind time” (LPBT) method to correct pile-up distortions in photon counting electronics, enabling reliable low-cost TCSPC-FLIM at high count rates. The correction was implemented on low-cost hardware based on a field programable gate array (FPGA) and validated using a combination of in silico simulations and in vitro, ex vivo and in vivo measurements. The LBPT approach achieves <3% error in lifetime measurements at count rates more than ten times higher than traditional limits, allowing robust FLIM imaging of sub-second metabolite dynamics with subcellular resolution. Our work enables high-precision, cost-effective FLIM imaging at rates comparable to commercial systems and at a fraction of the cost, facilitating the adoption of FLIM across all areas of research needing affordable, quantitative live imaging solutions.
Deep mutational scanning of rabies glycoprotein defines mutational constraint and antibody-escape mutations
Authors: Aditham Arjun K. , Radford Caelan E. , Carr Caleb R. , Jasti Naveen , King Neil P. , Bloom Jesse D. 
Published: December 2024

AbstractRabies virus causes nearly 60,000 human deaths annually. Antibodies that target the rabies glycoprotein (G) are being developed as post-exposure prophylactics, but mutations in G can render such antibodies ineffective. Here, we use pseudovirus deep mutational scanning to measure how all single amino-acid mutations to G affect cell entry and neutralization by a panel of antibodies. These measurements identify sites critical for rabies G’s function, and define constrained regions that are attractive epitopes for clinical antibodies, including at the apex and base of the protein. We provide complete maps of escape mutations for eight monoclonal antibodies, including some in clinical use or development. Escape mutations for most antibodies are present in some natural rabies strains. Overall, this work provides comprehensive information on the functional and antigenic effects of G mutations that can help inform development of stabilized vaccine antigens and antibodies that are resilient to rabies genetic variation.