bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating the undetected burden of infections and the likelihood of strain persistence of drug-resistantNeisseria gonorrhoeae
Authors: Oliveira Roster Kirstin I. , Rönn Minttu M. , Elder Heather , Gift Thomas L. , Roosevelt Kathleen A. , Salomon Joshua A. , Hsu Katherine K. , Grad Yonatan H. 
Published: August 2024

AbstractAntimicrobial resistance (AMR) is a serious public health threat.Neisseria gonorrhoeaehas developed resistance to all antibiotics recommended for treatment and reports of reduced susceptibility to ceftriaxone, the last-line treatment, are increasing. Since many asymptomatic infections remain undiagnosed and most diagnosed infections do not undergo antibiotic susceptibility testing, surveillance systems may underestimate the number of ceftriaxone non-susceptible infections. There is an urgent need for better interpretation and use of surveillance data to estimate the prevalence of resistance. In this modeling study, we simulated the spread of a new strain of ceftriaxone non-susceptible gonorrhea in a population of men who have sex with men as well as heterosexual men and women. We compared scenarios with varying strain characteristics and surveillance capacity. For each scenario, we estimated (i) the number of undetected infections by the time the non-susceptible strain was discovered and (ii) the likelihood of strain persistence in the absence of newly reported cases. Upon detection of one ceftriaxone non-susceptible isolate, the undetected disease burden was an estimated 5.4 infections with substantial uncertainty (0-18 infections, 95% uncertainty interval). In the absence of additional reports of ceftriaxone non-susceptible infections over the subsequent 180 days, the estimate declined to 2.5 infections with a narrower uncertainty interval (0-10 infections). The likelihood of ongoing transmission also declined from 66% (26-86%) at first detection to 2% (0-10%) after 180 days. Enhanced monitoring of the magnitude and trends of AMR is a key priority to reduce the burden of resistance and extend the useful lifespan of last-line antibiotics.
Integrating a host transcriptomic biomarker with a large language model for diagnosis of lower respiratory tract infection
Authors: Van Phan Hoang , Spottiswoode Natasha , Lydon Emily C. , Chu Victoria T. , Cuesta Adolfo , Kazberouk Alexander D. , Richmond Natalie L. , Calfee Carolyn S. , Langelier Charles R. 
Published: August 2024

AbstractLower respiratory tract infections (LRTIs) are a leading cause of mortality worldwide. Despite this, diagnosing LRTI remains challenging, particularly in the intensive care unit, where non-infectious respiratory conditions can present with similar features. Here, we tested a new method for LRTI diagnosis that combines the transcriptomic biomarkerFABP4with assessment of text from the electronic medical record (EMR) using the large language model Generative Pre-trained Transformer 4 (GPT-4). We evaluated this methodology in a prospective cohort of critically ill adults with acute respiratory failure, in which we measured pulmonaryFABP4expression and identified patients with LRTI or non-infectious conditions using retrospective adjudication. A diagnostic classifier combiningFABP4and GPT-4 achieved an area under the receiver operator curve (AUC) of 0.92 ± 0.06 by five-fold cross validation (CV), outperforming classifiers based onFABP4expression alone (AUC 0.83) or GPT-4 alone (AUC 0.84). At the Youden’s index within each CV fold, the combined classifier achieved a mean sensitivity of 92% ± 7%, specificity of 90% ± 17% and accuracy of 91% +/- 8%. Taken together, our findings suggest that combining a host transcriptional biomarker with interpretation of EMR data using artificial intelligence is a promising new approach to infectious disease diagnosis.
Blood DNA methylation levels of the oxytocin promoter predict conversion from mild cognitive impairment to dementia in females within a clinical cohort of cognitive complaints
Authors: Koulousakis Philippos , Reijnders Rick , Ramakers Inez , Verhey Frans , Vanmierlo Tim , van den Hove Daniël L.A. , Riemens Renzo J.M. 
Published: August 2024

AbstractRecent studies have highlighted the role of oxytocin (OXT) in Alzheimer’s disease (AD) dementia and demonstrated its potential as a therapeutic target to reverse cognitive impairment and mitigate AD pathology. Epigenetic dysregulation ofOXThas been identified in brain tissue from AD patients, and DNA methylation levels of the exact same locus in the blood of healthy aged individuals have shown predictive biomarker value for conversion to AD. Building on these insights, we investigated the DNA methylation status of theOXTpromoter in blood in a prospective cohort of consecutive patients from the BioBank Alzheimer Center Limburg (BBACL). This cohort included males and females suffering from subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia. Our findings revealed that DNA methylation levels of theOXTpromoter at baseline predict the conversion from MCI to dementia in female participants. In addition to discovering differences in theOXTpromoter related to sex, we also observed alterations associated with aging, alcohol consumption, and smoking. Overall, our findings underscore the implications ofOXTand its DNA methylation changes in blood within the context of dementia.
Promising effects of duck vaccination against highly pathogenic avian influenza, France 2023-24
Authors: Guinat Claire , Fourtune Lisa , Lambert Sébastien , Martin Eva , Gerbier Guillaume , Jimenez Pellicer Andrea , Guérin Jean-Luc , Vergne Timothée 
Published: August 2024

AbstractThe ongoing panzootic of highly pathogenic avian influenza (HPAI) H5 clade 2.3.4.4b has caused widespread poultry mortality and raised concerns about zoonotic pandemics and wildlife conservation. France recently adopted a preventive vaccination strategy, vaccinating domestic ducks with inactivated and mRNA vaccines. This study evaluates the impact of this campaign on reducing HPAI H5 outbreaks. Using predictive modelling based on previous outbreak data, the expected number of outbreaks in 2023-24 without vaccination was significantly higher than the observed cases, indicating a 95.9% reduction attributable to vaccination. These findings suggest that vaccination effectively mitigated the HPAI H5 outbreak in France.
Structural and kinetic insights into tRNA promoter engagement by yeast general transcription factor TFIIIC
Authors: Seifert-Dávila Wolfram , Chaban Anastasiia , Baudin Florence , Girbig Mathias , Hauptmann Luis , Hoffmann Thomas , Duss Olivier , Eustermann Sebastian , Müller Christoph W. 
Published: August 2024

AbstractTranscription of tRNA genes by RNA polymerase III requires the general transcription factor IIIC (TFIIIC), which recognizes intragenic A-box and B-box DNA motifs of type II gene promoters. However, the underlying mechanism has remained elusive, in part due to missing structural information for A-box recognition. In this study, we use single-particle cryo-EM and single-molecule FRET (smFRET) to reveal structural and real-time kinetic insights into how the 520 kDa yeast TFIIIC complex engages A- and B-box DNA motifs in the context of a tRNA gene promoter. Cryo-EM structures of τA and τB subcomplexes bound to the A- and B-box were obtained at 3.7 and 2.5 Å resolution, respectively, while cryo-EM single particle mapping determined the specific distance and relative orientation of the τA and τB subcomplexes revealing a fully engaged state of TFIIIC. smFRET experiments show that overall recruitment and residence times of TFIIIC on a tRNA gene are primarily governed by B-box recognition, while footprinting experiments suggest a key role of τA and the A-box in TFIIIB and Pol III recruitment following TFIIIC recognition of type II promoters.
Decapping activators Edc3 and Scd6 act redundantly with Dhh1 in post-transcriptional repression of starvation-induced pathways
Authors: Kumar Rakesh , Zhang Fan , Niphadkar Shreyas , Onu Chisom , Vijjamarri Anil Kumar , Greenberg Miriam L. , Laxman Sunil , Hinnebusch Alan G. 
Published: August 2024

ABSTRACTDegradation of many yeast mRNAs involves decapping by the Dcp1:Dcp2 complex. Previous studies on decapping activators Edc3 and Scd6 suggested their limited roles in mRNA decay. RNA-seq analysis of mutants lacking one or both proteins revealed that Scd6 and Edc3 have largely redundant activities in targeting numerous mRNAs for degradation that are masked in the single mutants. These transcripts also are frequently targeted by decapping activators Dhh1 and Pat1, and the collective evidence suggests that Scd6/Edc3 act interchangeably to recruit Dhh1 to Dcp2. Ribosome profiling shows that redundancy between Scd6 and Edc3 and their functional interactions with Dhh1 and Pat1 extend to translational repression of particular transcripts, including a cohort of poorly translated mRNAs displaying interdependent regulation by all four factors. Scd6/Edc3 also participate with Dhh1/Pat1 in post-transcriptional repression of proteins required for respiration and catabolism of alternative carbon sources, which are normally expressed only in limiting glucose. Simultaneously eliminating Scd6/Edc3 increases mitochondrial membrane potential and elevates metabolites of the tricarboxylic acid and glyoxylate cycles typically observed only during growth in low glucose. Thus, Scd6/Edc3 act redundantly, in parallel with Dhh1 and in cooperation with Pat1, to adjust gene expression to nutrient availability by controlling mRNA decapping and decay.
The transaminase-ω-amidase pathway is a redox switch in glutamine metabolism that generates α-ketoglutarate
Authors: Herrle Niklas , Malacarne Pedro F. , Warwick Timothy , Cabrera-Orefice Alfredo , Chen Yiheng , Gheisari Maedeh , Chatterjee Souradeep , Leisegang Matthias S. , Sarakpi Tamim , Wionski Sarah , Lopez Melina , Koch Ina , Keßler Marcus , Klein Sabine , Uschner Frank Erhard , Trebicka Jonel , Brunst Steffen , Proschak Ewgenij , Günther Stefan , Rosas-Lemus Mónica , Baumgarten Nina , Klatt Stephan , Speer Thimoteus , Wittig Ilka , Schulz Marcel H. , Richards J. Brent , Gilsbach Ralf , Denton Travis T. , Fleming Ingrid , Hannibal Luciana , Brandes Ralf P. , Rezende Flávia 
Published: August 2024

SummaryOxidative stress is caused by short-lived molecules and metabolic changes belong to the fastest cellular responses. Here we studied how the endothelial cell metabolome reacts to acute oxidative challenges (menadione or H2O2) to identify redox-sensitive metabolic enzymes. H2O2selectively increased α-ketoglutaramate (αKGM), a largely uncharacterized metabolite produced by glutamine transamination and a yet unrecognized intermediate of endothelial glutamine catabolism. The enzyme nitrilase-like 2 ω-amidase (NIT2) converts αKGM to α-ketoglutarate (αKG). Reversible oxidation of specific cysteine in NIT2 by H2O2inhibited its catalytic activity. Furthermore, a variant in theNIT2gene that decreases its expression is associated with high plasma αKGM level in humans. Endothelial-specific knockout mice of NIT2 exhibited increased levels of αKGM and impaired angiogenesis. Knockout of NIT2 impaired endothelial cell proliferation and sprouting and induced senescence. In conclusion, we show that the glutamine transaminase-ω-amidase pathway is a metabolic switch in which NIT2 is the redox-sensitive enzyme. The pathway is modulated in humans and functionally important for endothelial glutamine metabolism.
Renal outcomes of combination therapy with sodium-glucose cotransporter 2 inhibitors plus renin-angiotensin system blockers in patients with type 2 diabetes mellitus: A population-based cohort study
Authors: Tsai Ming-Hsien , Chen Ming-chih , Huang Yen-Chun , Chang Wei-Shan , Hsiao Kai-Yuan , Liou Hung-Hsiang , Fang Yu-Wei 
Published: August 2024

AbstractBackgroundSodium-glucose cotransporter 2 inhibitors (SGLT2i) can benefit patients with type 2 diabetes mellitus by reducing hazardous renal outcomes. This study aimed to evaluate whether the combination of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and conventional renin-angiotensin system blockers (RASB) provides a synergistic effect on renal outcomes in patients with type 2 diabetes mellitus, compared to the combination of RASB and dipeptidyl peptidase 4 inhibitors (DPP4i).MethodsThis is a retrospective cohort study. The study utilized data from the Taiwan National Health Insurance Research Database (NHIRD), including patients with type 2 diabetes mellitus enrolled between January 1, 2016, and December 31, 2016. Participants were divided into two groups: the case group (n = 3,622) receiving RASB plus SGLT2i and the comparison group (n = 3,622) receiving RASB plus DPP4i. The groups were matched 1:1 based on gender, age, and Charlson comorbidity index. Additionally, TriNetX was used for external validation.ResultsPrior to matching, unadjusted hazard ratios (HRs) showed significant differences favoring the SGLT2i group for chronic kidney disease (CKD) (HR: 0.66; 95% CI, 0.58–0.74), advanced kidney failure (HR: 0.64; 95% CI, 0.44–0.93), and initiation of long-term dialysis (HR: 0.61; 95% CI, 0.38–0.97). These differences remained significant post-matching: CKD (HR: 0.74; 95% CI, 0.65–0.84), advanced kidney failure (HR: 0.62; 95% CI, 0.42–0.92), and commencement of long-term dialysis (HR: 0.53; 95% CI, 0.32–0.87). The renal benefits of the combination therapy were consistently observed in the TriNetX dataset.LimitationsNHIRD lacks key clinical factors (e.g., physical features, lab data), potential baseline disparities due to retrospective design, and limited generalizability beyond Taiwanese patients, despite TriNexT validation.ConclusionsIn patients with type 2 diabetes mellitus, combination therapy with SGLT2i and RASB yielded better renal outcomes.
SF3B1-mutant mis-splicing ofUBA1confers a targetable therapeutic vulnerability through UBA1 inhibition
Authors: Thier Jonas , Hofmann Sophia , Kirchhof Katharina M , Todisco Gabriele , Mortera-Blanco Teresa , Barbosa Indira , Björklund Ann-Charlotte , Deslauriers André G , Papaemmanuil Elli , Papapetrou Eirini P , Hellström-Lindberg Eva , Moura Pedro L , Lundin Vanessa 
Published: August 2024

AbstractSF3B1mutation-driven myelodysplastic syndromes (MDS-SF3B1) arise due to somatic mutation in the splicing factorSF3B1gene.SF3B1mutations induce RNA mis-splicing and loss of expression of critical genes for erythropoiesis, leading to erythroid dysplasia and ultimately refractory anemia. The development of precision medicine approaches for MDS-SF3B1is hampered by the complexity of the mis-splicing landscape and its evaluation in disease-accurate model systems. To identify novel RNA mis-splicing events, isogenicSF3B1K700EandSF3B1WTiPSC lines from an MDS-SF3B1patient were differentiated into hematopoietic cellsin vitroand subjected to unsupervised splicing event analysis using full-length RNA sequencing data. This revealedSF3B1K700E-specific mis-splicing of ubiquitin-like modifier activating enzyme 1 (UBA1) transcripts, which encode the essential E1 protein at the apex of the ubiquitination cascade.UBA1mis-splicing (UBA1ms) preservedUBA1msmRNA but not protein expression. Consequently,UBA1msdiminished the pool of functional UBA1, sensitizingSF3B1K700Ecell lines to the small-molecule UBA1 inhibitor TAK-243. Finally, analysis of CD34+RNA sequencing data from an MDS patient cohort confirmed unique and ubiquitousUBA1msin MDS-SF3B1patients, without detection in other splicing factor-mutated MDS patients, or in healthy individuals. TAK-243 selectively targeted MDS-SF3B1primary CD34+cells and reduced mutant cell number in colony-forming unit studies. In contrast, normal hematopoietic progenitor cells were unaffected. Altogether, we here defineUBA1msas a novel therapeutic vulnerability inSF3B1-mutant cells, introducing UBA1 inhibition as a potential avenue for future MDS-SF3B1treatments.
Gain-of-function study reveals the pleiotropic roles of serine protease HtrA inBorrelia burgdorferi
Authors: Zhang Kai , Sze Ching Wooen , Zhao Hang , Liu Jun , Li Chunhao 
Published: August 2024

ABSTRACTHigh-temperature requirement protease A (HtrA) is a family of serine proteases degrading misfolded and damaged proteins that are toxic to bacteria. The Lyme disease agentBorrelia burgdorferiencodes a single HtrA (BbHtrA). Previous studies have shown that BbHtrA is a key virulence determinant ofB. burgdorferias a deletion mutant ofhtrA(ΔhtrA) fails to establish infection in mice. However, previous complementation could only restore protein expression but not infectivity in mice. In this report, we first identify the native promoter of BbHtrA which allows us to construct a fully complementedΔhtrAstrain. Follow up promoter activity analysis reveals that BbHtrA is likely dually regulated by the house keeping sigma factor RpoD and the alternative sigma factor RpoS. TheΔhtrAmutant exhibits growth defect upon entering the mid-log to stationary phase especially at high temperatures. Microscopic analysis further demonstrates that the absence ofhtrAinduces extensive cell death. Additionally, theΔhtrAmutant has defects in cell locomotion as the expression of several key chemotaxis proteins are significantly downregulated. Cryo-electron tomography imaging ofhtrAmutant further reveals that deletion ofhtrAdisrupts flagellar homeostasis. The failure ofΔhtrAto establish an infection in mice is likely due to repressed expression of BosR and RpoS at the transcriptional level which ultimately causes dysregulation of the RpoS-induced virulence factors. Collectively, we conclude that the expression ofhtrAis finely tuned which is critical for its pleiotropic roles in the regulation of motility, stress response, and virulence gene expression inB. burgdorferi.IMPORTANCELyme borreliosis is the most commonly reported vector-borne illnesses in the United States, which is caused byBorrelia burgdorferi.As the enzootic pathogen alternates between the tick vector and mammalian hosts, adaptation to drastically different growth milieu is imperative to its survival. Hence, robust alteration of gene expression and proper quality control on protein synthesis and turnover are pivotal for its fitness. The family of HtrA serine proteases is mainly responsible for the maintenance of protein homeostasis particularly under stressful conditions. The significance of this report is to decode how BbHtrA contributes to the fitness ofB. burgdorferi. BbHtrA is essential for mammalian host infection but little is known about its regulatory mechanism as well as its contribution to the virulence ofB. burgdorferi. By deciphering the regulatory elements involved in the expression of BbHtrA, we are one step closer to comprehending its significance in the pathophysiology ofB. burgdorferi.
The influence of sleep disruption on learning and memory in fish
Authors: Sowersby W. , Kobayahsi T. , Awata S. , Sogawa S. , Kohda M. 
Published: August 2024

ABSTRACTSleep is ubiquitous across animal taxa. Strong evolutionary pressures have conserved sleep over the evolutionary history of animals, yet our understanding of the functions of sleep still largely derives from mammals and select laboratory models. Sleep is considered to play an important role in mental processes, including learning and memory consolidation, but how widespread this relationship occurs across taxa remains unclear. Here, we test the impact of sleep disruption on the ability of the cleaner fish(Labroides dimidiatus)to both learn and then remember a novel cognitive task. We found a significant negative relationship between sleep disruption and the ability to learn a food reward choice system. Specifically, we found that fish in a disturbed sleep treatment took significantly longer and made more incorrect decisions when finding the food reward, compared to individuals in a non-disturbed/normal sleep treatment. In contrast, the differences between the two treatment groups were non-significant when fish where tasked with remembering the food reward several days later. Our results demonstrate a negative impact of sleep disruption on performance in a cognitive challenging task and that the effects were strongest when fish were first exposed to the challenge. Importantly, we show that the association between sleep and mental processes, such as learning, may be widespread across vertebrate taxa and potentially have an early origin in the evolutionary history of animals.
Effect of Wearing Glasses for Prevention of SARS-CoV-2 on Visits to Health Care Providers - Additional Results from a Randomized Controlled Trial
Authors: Elgersma Ingeborg Hess , Elstrøm Petter , Hemkens Lars G. , Helleve Arnfinn , Kacelnik Oliver , Fretheim Atle 
Published: August 2024

AbstractWe previously published results of a pragmatic randomized trial with 3717 participants in Norway that assessed the effect of wearing glasses on the risk of being infected with SARS-CoV-2 and other respiratory infections. Here we present unpublished findings on pre-specified secondary endpoints relying on routinely collected data from Norwegian health registries: Visits to health care providers for any cause (within 21 days), for respiratory symptoms (day 3-28), and for injuries (within 21 days).1469 participants (39.5%) visited a health care provider for any cause at least once. There was no statistically significant difference between groups, with 39.9.% of participants wearing glasses versus 39.1% in the control group received primary or specialist care (absolute risk difference 0.76%; 95% CI, -2.4% to 3.9%; relative risk 1.02; 95% CI, 0.94 to 1.10).Similarly, there was no statistically significant difference in visits due to respiratory symptoms (326 participants; 9.1% versus 8.4%; absolute risk difference 0.71%; 95% CI, -1.1% to 2.5%; relative risk 1.08; 95% CI, 0.88 to 1.33).There were 3 participants having visited primary or specialist care and having an injury registered in a registry for injuries, the difference between groups not statistically significant. The difference between participants in the proportion of visits for injury related diagnoses was nominally statistically significant (1.3% versus 0.7%; absolute risk difference 0.7%; 95% CI, 0.01% to 1.3%; relative risk 1.94; 95% CI, 1.01 to 3.89).The study underscores the potential of utilizing registry-based outcomes for randomized evaluations of public health measures for infection control.