bluuebunny/crossref_metadata_2025_split huggingface dataset:
From Big Data to the clinic: methodological and statistical enhancements to implement the UK Biobank imaging framework in a memory clinic
Authors: Gillis Grace , Bhalerao Gaurav , Blane Jasmine , Mitchell Robert , Pretorius Pieter M , McCracken Celeste , Nichols Thomas E , Smith Stephen M , Miller Karla L , Alfaro-Almagro Fidel , Raymont Vanessa , Martos Lola , Mackay Clare E , Griffanti Ludovica 
Published: August 2024

AbstractIntroductionThe analysis tools and statistical methods used in large neuroimaging research studies differ from those applied in clinical contexts, making it unclear whether these techniques can be translated to a memory clinic setting. The Oxford Brain Health Clinic (OBHC) was established in 2020 to bridge this gap between research studies and memory clinics.MethodsWe optimised the UK Biobank imaging framework for the memory clinic setting by integrating enhanced quality control (QC) processes (MRIQC, QUAD, and DSE decomposition) and supplementary dementia-informed analyses (lobar volumes, NBM volumes, WMH classification, PSMD, cortical diffusion MRI metrics, and tract volumes) into the analysis pipeline. We explored associations between resultant imaging-derived phenotypes (IDPs) and clinical phenotypes in the OBHC patient population (N=213), applying hierarchical FDR correction to account for multiple testing.Results14-24% of scans were flagged by automated QC tools, but upon visual inspection, only 0-2.4% of outputs were excluded. The pipeline successfully generated 5683 IDPs aligned with UK Biobank and 110 IDPs targeted towards dementia-related changes. We replicated established associations and found novel associations between brain metrics and age, cognition, and dementia-related diagnoses.ConclusionThe imaging protocol is feasible, acceptable, and yields high-quality data that is usable for both clinical and research purposes. We validated the use of this methodology in a real-world memory clinic population, which demonstrates the potential of this enhanced pipeline to bridge the gap between big data studies and clinical settings.Key PointsThe imaging methods, analysis techniques, and population characteristics in research studies often differ to those in traditional clinical settings.To bridge this gap, we optimised the UK Biobank imaging framework for memory clinic use by integrating enhanced quality control (QC) and supplementary analyses targeted towards dementia-related changes.We generated 5683 imaging-derived phenotypes (IDPs) aligned with UK Biobank and 110 supplementary dementia-informed IDPs that captured both established and novel associations between brain metrics and dementia-related clinical phenotypes, highlighting the value of integrating UK Biobank-aligned imaging and analyses in a real-world memory clinic population.
Clinical Advancement Forecasting
Authors: Czech Eric , Wojdyla Rafal , Himmelstein Daniel , Frank Daniel , Miller Nick , Milwid Jack , Kolom Adam , Hammerbacher Jeff 
Published: August 2024

AbstractChoosing which drug targets to pursue for a given disease is one of the most impactful decisions made in the global development of new medicines. This study examines the extent to which the outcomes of clinical trials can be predicted based on a small set of longitudinal (temporally labeled) evidence and properties of drug targets and diseases. We demonstrate a novel statistical learning framework for identifying the top 2% of target-disease pairs that are as much as 4-5x more likely to advance beyond phase 2 trials. This framework is 1.5-2x more effective than an Open Targets composite score based on the same set of evidence. It is also 2x more effective than a common measure for genetic support that has been observed previously, as well as in this study, to confer a 2x higher likelihood of success. Utilizing a subset of our biomedical evidence base, non-negative linear models resulting from this framework can produce simple weighting schemes across various types of human, animal, and cell model genomic, transcriptomic, proteomic, and clinical evidence to identify previously undeveloped target-disease pairs poised for clinical success. In this study we further explore: i) how longitudinal treatment of evidence relates to leakage and reverse causality in biomedical research and how temporalized evidence can mitigate common forms of potential biases and inflation ii) the relative impact of different types of features on our predictions; and iii) an analysis of the space of currently undeveloped, tractable targets predicted with these methods to have the highest likelihood of clinical success. To ease reproduction and deployment, no data is used outside of Open Targets and the described methods require no expert knowledge, and can support expansion of lines of evidence to further improve performance.
The cardiac output – cerebral blood flow relation is abnormal in most ME/CFS patients with a normal heart rate and blood pressure response during a tilt test
Authors: van Campen C. (Linda) M.C. , Verheugt Freek W.A. , Rowe Peter C. , Visser Frans C. 
Published: August 2024

AbstractIntroductionOrthostatic intolerance is highly prevalent in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and is caused by an abnormal reduction in cerebral blood flow (CBF). In healthy controls (HC) regulation of CBF is complex and involves multiple mechanisms including cardiac output (CO), cerebral perfusion pressure, PO2and PCO2, flow-metabolism coupling, and innervation of cerebral vessels. In ME/CFS multiple other mechanisms have also been identified.Aim of the studyWe previously found that both CBF and CO were reduced in ME/CFS patients during tilt testing, and we hypothesized that the relation between CBF and CO is abnormal and different from HC. In this retrospective study we analyzed this relation in a large group of patients. To compare the patient data with those of HC, we focused on patients with a normal heart rate (HR) and blood pressure (BP) response to upright tilt. Also, the influence of clinical data was analyzed.MethodsA total of 534 ME/CFS patients and 49 HC underwent tilt testing with measurements of HR, BP, CBF, and CO. In 46 (9%) patients CO and CBF changes were in the normal range of HC, and in 488 (91%) an abnormal CO and CBF reduction was found.Resultspatients with a CO and CBF reduction in the range of HC had less severe disease and were more likely to be male. In patients with an abnormal CO and CBF reduction the slope of the regression line of CO versus CBF reduction was almost 1. A multiple regression analysis of the latter group, including patients with PetCO2measurements (440/488: 90%) showed that the CO reduction for the major part predicted the CBF reduction, with a limited role for the PetCO2reduction and the tilt duration. Other data did not add to the model.ConclusionsTwo different patient groups with a normal HR and BP response during the tilt were identified: those with a CO and CBF in the normal range of HC and those with an abnormal CO and CBF reduction during the tilt (91% of patients). The former group had milder disease and included more men. In the largest group of patients there was an almost 1:1 relation between the CO and CBF reduction, suggesting absence of compensatory vasodilation in the cerebral vasculature. This may be an appropriate target for clinical and therapeutic interventions.
Sainsc: a computational tool for segmentation-free analysis ofin-situcapture
Authors: Müller-Bötticher Niklas , Tiesmeyer Sebastian , Eils Roland , Ishaque Naveed 
Published: August 2024

AbstractSpatially resolved transcriptomics has become the method of choice to characterise the complexity of biomedical tissue samples. Until recently, scientists have been restricted to profiling methods with high spatial resolution but for a limited set of genes or methods that can profile transcriptome-wide but at low spatial resolution. Through recent developments, there are now methods which offer subcellular spatial resolution and full transcriptome coverage. However, utilizing the high spatial and gene resolution of these new methods remains elusive due to several factors including low detection efficiency, high computational cost and difficulties in delineating cell borders. Here we present Sainsc (Segmentation-free analysis ofin-situcapture data), which combines a cell-segmentation free approach with efficient data processing of transcriptome-wide nanometer resolution spatial data. Sainsc can generate cell-type maps with accurate cell-type assignment at a subcellular level, together with corresponding maps of the assignment scores that facilitate the interpretation in the local confidence of cell-type assignment. We demonstrate its utility and accuracy across different tissues and profiling methods. Compared to other methods, Sainsc requires lower computational resources and has scalable performance, enabling interactive data exploration. Sainsc is compatible with common data analysis frameworks and is available as open-source software in multiple programming languages.
Modeling the transmission dynamics of African swine fever virus within commercial swine barns: Quantifying the contribution of multiple transmission pathways
Authors: Deka Aniruddha , Galvis Jason A , Fleming Christian , Safari Maryam , Yeh Chi-An , Machado Gustavo 
Published: August 2024

ABSTRACTTransmission of the African swine fever virus (ASFV) within commercial swine barns occurs through direct and indirect pathways. Identifying and quantifying the roles of ASFV dissemination within barns is crucial for the development of effective disease control strategies. We developed a stochastic transmission model to examine the ASFV dissemination dynamics through eight transmission routes within commercial swine barns. We consider seven transmission routes at three disease dynamics levels: within-pens, between-pens, and within-room transmission, along with the transfer of pigs between pens within the same room. We simulated ASFV spread within barns of various sizes and layouts from rooms with a median of 32 pens (IQR:28-40), where each pen housing a median of 34 pigs (IQR: 29-36). Our model enables the tracking of the viral load in each pen and the monitoring of the disease status at the pen level. Simulation results show that between-pen transmission pathways exhibited the highest contribution to ASFV spread, accounting for 71.4%, where within-pen and within-room pathways account for 20.1% and 8.5%, respectively. Among the direct transmission pathways, nose-to-nose contact between pens was the primary route of dissemination, comprising an average of 49%, while the fecal transmission between pens contributed 21%. On the other hand, aerosol transmission within pens had the lowest contribution, accounting for less than 1%. Furthermore, we show that the daily transfer of pigs between pens did not impact the spread of ASFV. The combination of passive surveillance of daily detection and active surveillance focused on mortality allowed the detection of ASFV within three Days, with peak detection occurring when mortality rates peaked. The model also allows us to pinpoint where the majority of infections and viral load are concentrated during the ASFV spread. This work significantly deepens our understanding of ASFV spread within commercial swine production farms in the U.S. and highlights the main transmission pathways that should be prioritized when implementing ASFV countermeasure actions at the room level.
Structural and functional characterization of SidF, a possible dual substrateAspergillus fumigatusN5-acetyl-N5-hydroxy-L-ornithine transacetylase
Authors: Poonsiri Thanalai , Demitri Nicola , Stransky Jan , Haas Hubertus , Cianci Michele , Benini Stefano 
Published: August 2024

AbstractSiderophore-mediated iron acquisition is essential for the virulence ofAspergillus fumigatus, a fungus causing life-threatening aspergillosis. Developing drugs targeting the siderophore biosynthetic pathway could help improve disease management. The transacetylases SidF and SidL generate intermediates for different siderophores inA. fumigatus.A. fumigatushas a yet unidentified transacetylase that complements SidL during iron deficiency in SidL-lacking mutants.We present the first X-ray structure of SidF, revealing a conserved two-domain architecture with tetrameric assembly. Importantly, the N-terminal domain contributes to protein solubility and oligomerization, while the C-terminal domain containing the GCN5-related N-acetyltransferase (GNAT) motif is crucial for the enzymatic activity and mediates oligomer formation. Notably, AlphaFold modelling demonstrated structural similarity between SidF and SidL. Enzymatic assays showed that SidF can utilize acetyl-CoA as a donor, previously thought to be a substrate of SidL but not SidF, and selectively uses N5-hydroxy-L-ornithine as an acceptor. Based on these findings, we propose SidF as the unknown transacetylase complementing SidL activity, highlighting its central role inA. fumigatussiderophore biosynthesis.This study elucidates the structure of SidF and reveals a novel role in siderophore biosynthesis. Investigation of this uncharacterized GNAT protein enhances our understanding of fungal virulence and holds promise for its potential application in developing antifungal therapies.
Weight loss-induced adipose macrophage memory improves localStaphylococcus aureusclearance in male mice
Authors: Bolden McArthur , Davis Xenia D , Sherwood Edward R , Bohannon Julia K , Caslin Heather L 
Published: August 2024

AbstractDifferent stimuli can induce innate immune memory to improve pathogen defense or worsen cardiometabolic disease. However, it is less clear if the same stimuli can induce both the protective and detrimental effects of innate immune memory. We previously showed that weight loss induces innate immune memory in adipose macrophages that correlates with worsened diabetes risk after weight regain. In this study, we investigated the effect of weight loss on macrophage cytokine production and overall survival in a mouse model of infection. Male C57Bl/6J mice were put on high-fat or low-fat diets over 18 weeks to induce weight gain or weight loss. Lean mice served as controls. All mice were then infected IV with 2.5×10^6 CFUStaphylococcus aureus. Tissues were collected from 10 mice/group at day 3 and the remaining animals were followed for survival. Weight gain mice had the highest blood neutrophils and the highest bacterial burden in the kidney. However, there was no significant difference in survival. The weight loss group had the highest plasma TNF-α and a significant reduction in bacterial burden in the adipose tissue that correlated with increased adipose macrophage cytokine production. Thus, weight loss-induced adipose macrophage memory may both improve localS.aureusclearance and worsen diabetes risk upon weight regain. Collectively, these findings support the notion that innate immune memory is an evolutionarily protective mechanism that also contributes to the development of cardiometabolic diseases.
Both T and B cells contribute to dysregulated activation and differentiation of CD4+T cells in Activated PI3K delta syndrome 1
Authors: Bier Julia , Lau Anthony , Jackson Katherine JL , Ruiz-Diaz Stephanie , Brink Robert , Tangye Stuart G , Deenick Elissa K 
Published: August 2024

AbstractActivated PI3K delta syndrome 1 (APDS1) is caused by a heterozygous germline gain-of-function (GOF) variants inPIK3CDwhich encodes the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K). APDS1 patients display a broad range of clinical manifestations and perturbations in cellular phenotype. One of the most striking features is the dysregulation of the T cell compartment characterised by an increase in memory T cells, including Tfh cells, and a concomitant decrease in naïve T cells. We have previously shown that many of these changes in T cell populations were T cell extrinsic and were also induced in WT T cells that developed in the presence of PI3K GOF cells. Here we dissected the drivers of dysregulated T cell activation using a mouse model of APDS1. This revealed PI3K GOF macrophages and DCs made little contribution to the aberrant T cell activation. Instead, the loss of naïve T cells was mostly driven extrinsically by PI3K GOF T cells, while the increase in Tfh cells was mediated by dysregulated PI3K GOF B cells. Surprisingly, despite previous reports of increased PI3K driving dysregulated inflammatory Tregs, we saw no evidence forPik3cdGOF Tregs acquiring an inflammatory phenotype and driving T cell activation. These studies provide new insights into the clinical phenotype of patients with APDS1 and new understanding of the role of PI3K in immune cells.
The Origins of Arginine “Magic”: Guanidinium Like-Charge Ion Pairing and Oligoarginine Aggregation in Water by NMR, Cryoelectron Microscopy, and Molecular Dynamics Simulations
Authors: Biriukov Denys , Osifová Zuzana , Hong Man Nguyen Thi , Mason Philip E. , Dračínský Martin , Jungwirth Pavel , Heyda Jan , Morandi Mattia I. , Vazdar Mario 
Published: August 2024

AbstractThe phenomenon of like-charge pairing of hydrated ions is a physical manifestation of the unique solvation properties of certain ion pairs in water. Water’s high dielectric constant and related ion screening capability significantly influence the interaction between like-charged ions, with the possibility to transform it – in some cases – from repulsion to attraction. Guanidinium cations (Gdm+) represent a quintessential example of such like-charge pairing due to their specific geometry and charge distribution. In this work, we present experimental quantification of Gdm+–Gdm+contact ion pairing in water utilizing nuclear magnetic resonance (NMR) spectroscopy experiments complemented by molecular dynamics (MD) simulations and density functional theory (DFT) calculations. The observed interaction is very weak — about –0.5 kJ·mol−1— which aligns with theoretical estimation from MD simulations. We also contrast the behavior of Gdm+with NH4+cations, which do no exhibit contact ion pairing in water. DFT calculations predict that the NMR chemical shift of Gdm+dimers is smaller than that of monomers, in agreement with NMR titration curves that display a non-linear Langmuir-like behavior. Additionally, we conducted cryo-electron microscopy experiments on oligoarginines R9, which (unlike nona-lysines K9) exhibit aggregation in water. This points again to like charge pairing of the guanidinium side chain groups, as corroborated also by molecular dynamics simulations of these peptides in water.
Deep-underground dark matter search with a COSINUS detector prototype
Authors: Angloher G. , Bharadwaj M. R. , Dafinei I. , Di Marco N. , Einfalt L. , Ferroni F. , Fichtinger S. , Filipponi A. , Frank T. , Friedl M. , Fuss A. , Ge Z. , Heikinheimo M. , Hughes M. N. , Huitu K. , Kellermann M. , Maji R. , Mancuso M. , Pagnanini L. , Petricca F. , Pirro S. , Pröbst F. , Profeta G. , Puiu A. , Reindl F. , Schäffner K. , Schieck J. , Schmiedmayer D. , Schwertner C. , Shera K. , Stahlberg M. , Stendahl A. , Stukel M. , Tresca C. , Wagner F. , Yue S. , Zema V. , Zhu Y. ,   COSINUS Collaboration
Published: August 2024

Sodium iodide (NaI)-based cryogenic scintillating calorimeters using quantum sensors for signal readout have shown promising first results toward a model-independent test of the annually modulating signal detected by the DAMA/LIBRA dark matter experiment. The COSINUS Collaboration has previously reported on the first above-ground measurements using a dual-channel readout of phonons and light based on transition edge sensors (TESs) that allows for particle discrimination on an event-by-event basis. In this article, we outline the first underground measurement of a NaI cryogenic calorimeter readout via the novel remoTES scheme. A 3.67 g NaI absorber with an improved silicon light detector design was operated at the Laboratori Nazionali del Gran Sasso, Italy. A significant improvement in the discrimination power of e−/γ events to nuclear recoils was observed with a fivefold improvement in the nuclear recoil baseline resolution, achieving σ=441  eV. Furthermore, we present a limit on the spin-independent dark matter nucleon elastic scattering cross section, achieving a sensitivity of O(pb) with an exposure of only 11.6 g d.

Published by the American Physical Society
2024
Digital information needs and information-seeking behaviour among legal practitioners at the Lahore High Court, Punjab, Pakistan
Authors: Junaid Samreen , Mairaj Muhammad Ijaz , Aslam Sanila 
Published: August 2024

Purpose
This study aims to investigate the digital information needs and seeking behaviour of legal practitioners practising at the Lahore High Court in the Punjab province of Pakistan.

Design/methodology/approach
This study adopts a quantitative approach based on an e-questionnaire survey to collect data from legal practitioners following a comprehensive census. Among the 9,933 registered legal practitioners, a random sample size of 370 respondents was determined, of whom 302 responded to the survey, resulting in a response rate of 81.6%.

Findings
Legal practitioners prefer the Pakistan Law Site and law journals as primary sources of information acquisition, with a distinct inclination towards digital formats over traditional print. These resources are primarily used for court case preparation, significantly enhancing the research capabilities of legal practitioners and ensuring they remain current in their field. However, several challenges were identified, including time constraints, limited access to digital resources and inadequate availability of legal resources in digital format. These challenges emphasize the critical need for enhancing the digital infrastructure of law libraries.

Research limitations/implications
The study calls for law libraries to adopt technological advancements and underscores the necessity of improving digital infrastructure to better serve the evolving information needs of legal practitioners.

Originality/value
This study underscores the preferred information sources and formats of legal practitioners for seeking information, their purpose for using law resources and the impact of digital media on their information-seeking behaviour. In addition, this study reveals the challenges they face in seeking them.