bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating the incidence of antimicrobial resistant Neisseria gonorrhoeae in the United States among men and women aged 15-39 years, 2008-2019
Authors: Pondo Tracy , Nielsen Karen E. , Schmerer Matthew W. , Spicknall Ian H. , Pollock Emily D. , Kreisel Kristen M. ,   Antimicrobial-Resistant Neisseria gonorrhoeae Working Group
Published: December 2024

Background
The Gonococcal Isolate Surveillance Project (GISP) was established to monitor antimicrobial resistance (AR) in N. gonorrhoeae in the United States. Isolates collected in GISP undergo antimicrobial susceptibility testing allowing for estimates of resistance, based on exceeding minimum inhibitory concentrations (MICs), to be calculated.

Methods
We estimated the annual number and proportion of gonococcal infections with antibiotic resistance or elevated MICs (AR/eMICs) against six antibiotics for men and women aged 15 to 39 years in the US using male urethral specimens collected in GISP during 2008–2019. Although GISP only measured MICs for male gonococcal infections, this study estimated AR/eMICs in women using data from men with female sex partners. GISP data were weighted against national gonorrhea case report data based on four variables (age group, year of report, US Census region, and race/Hispanic ethnicity) to estimate annual, national proportions of gonococcal infections with AR/eMICs. These weighted proportions were then multiplied by national estimates of incident gonococcal infections to calculate the number of incident gonococcal infections with AR/eMICs nationally.

Results
Women had a higher estimated number of cases with AR/eMICs compared with men (440,900 vs. 387,200 in 2019) although the estimated percentage of gonococcal infections with AR/eMICs was lower in women (50.7% vs. 54.4% in 2019). Elevated MICs to ceftriaxone remained below 1% throughout the study period.

Conclusions
Our analysis indicates that there are more women with AR/eMICs gonorrhea than men. Although the proportion of cases that are resistant to any one antimicrobial is increasing, eMICs to ceftriaxone remains low.
Trends in Demographic Characteristics and Risk Factors among Individuals with Syphilis in Colorado from 2011-2020
Authors: Bianchini Monica L. , Rowan Sarah E. , Frost Holly M. , Valuck Robert , McQueen R. Brett , Anderson Heather D. 
Published: December 2024

Abstract:

Background
Identify opportunities to improve syphilis screening by describing changes in patient characteristics and risk factors among individuals with syphilis and by comparing cases with and without an indication for syphilis screening.

Methods
This retrospective cohort study used Colorado public health surveillance data to identify 8,326 syphilis diagnoses from 2011-2020. Demographics, clinical characteristics, and risk factors were compared across 2-year groups and between individuals with and without an indication for screening. Indications for screening were based on national guidelines and included men who have sex with men, persons living with HIV, pregnant individuals, those who test positive for chlamydia, gonorrhea, or HIV, and partners of those who test positive for syphilis.

Results
Across study years, there was a 234% increase in the proportion of syphilis cases that were females (5.3% to 17.7%; p < .01), a 78% increase in the proportion of cases living in rural areas (3.6% to 6.4%; p < .01), and a 15% increase in the proportion of cases among non-White individuals (47.9% to 54.9%; p < .01). The proportion of patients that had a guideline-recommended indication for screening decreased from 88% in 2011-2012 to 59% in 2019-2020 (p < .01). Females represented 5.5% of cases with an indication for screening and 29.8% of cases without an indication for screening (p < .01).

Conclusions
Syphilis cases increased annually from 2011-2020 yet the proportion of cases detected under current screening recommendations decreased. These findings reveal opportunities to expand syphilis screening.
Covalent inhibitors of the RAS binding domain of PI3Kα impair tumor growth driven by RAS and HER2
Authors: Klebba Joseph E. , Roy Nilotpal , Bernard Steffen M. , Grabow Stephanie , Hoffman Melissa A. , Miao Hui , Tamiya Junko , Wang Jinwei , Berry Cynthia , Esparza-Oros Antonio , Lin Richard , Liu Yongsheng , Pariollaud Marie , Parker Holly , Mochalkin Igor , Rana Sareena , Snead Aaron N. , Walton Eric J. , Wyrick Taylor E. , Aitichson Erick , Bedke Karl , Brannon Jacyln C. , Chick Joel M. , Hee Kenneth , Horning Benjamin D. , Ismail Mohamed , Lamb Kelsey N. , Lin Wei , Metzger Justine , Pastuszka Martha K. , Pollock Jonathan , Sigler John J. , Tomaschko Mona , Tran Eileen , Kinsella Todd M. , Molina-Arcas Miriam , Simon Gabriel M. , Weinstein David S. , Downward Julian , Patricelli Matthew P. 
Published: December 2024

AbstractGenetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3K’s role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of PI3K p110α and block the ability of RAS to activate PI3K activity. These inhibitors have a profound impact on the growth of RAS mutant and also HER2 over-expressing tumors, particularly when combined with other inhibitors of the RAS/MAPK pathway, without causing hyperglycemia.
Loss of olfaction reduces caterpillar performance and increases susceptibility to a natural enemy
Authors: Wang Qi , Jia Yufei , Smid Hans M. , Weldegergis Berhane T. , Greenberg Liana O. , Jongsma Maarten , Dicke Marcel , Haverkamp Alexander 
Published: December 2024

AbstractInsect herbivores such as caterpillars, are under strong selection pressure from natural enemies, especially parasitoid wasps. Although the role of olfaction in host-plant seeking has been investigated in great detail in parasitoids and adult lepidopteran, the caterpillar olfactory system and its significance in tri-trophic interactions remains poorly understood. In this study, we investigated the olfactory system ofPieris brassicaecaterpillars and the importance of olfactory information in the interactions among this herbivore, its host-plantBrassica oleraceaand its primary natural enemyCotesia glomerata. To examine the role of olfaction, we utilized CRISPR/Cas9 to knock out the odorant receptor co-receptor (Orco). This knockout (KO) impaired olfactory detection and primary processing in the brain.OrcoKO caterpillars exhibited reduced weight and lost preference for their optimal food plant. Interestingly, the KO caterpillars also experienced reduced weight when challenged by the parasitoidC. glomeratawhose ovipositor had been removed, and the mortality of the KO caterpillars under the attack of unmanipulated parasitoids increased. We then investigated the behavior ofP. brassicaecaterpillars in response to volatiles from plants attacked by conspecific caterpillars and volatiles from plants on which the caterpillars were themselves attacked byC. glomerata. After analyzing the volatile compounds involved in these interactions, we concluded that olfactory information enables caterpillars to locate suitable food sources more efficiently as well as selecting enemy-free spaces. Our results reveal the crucial role of olfaction in caterpillar feeding and natural enemy avoidance, highlighting the significance of chemoreceptor genes in shaping ecological interactions.
From Weak Interactions to Strong Affinity: Deciphering the Streptavidin-Biotin Interaction through NMR and Computational Analysis
Authors: Ptaszek Aleksandra L. , Kratzwald Sarah , Sagan Filip , Migotti Mario , Sánchez-Murcia Pedro A. , Konrat Robert , Platzer Gerald 
Published: December 2024

AbstractUnderstanding weak interactions in protein-ligand complexes is essential for advancing drug design. Here, we combine experimental and quantum mechanical approaches to study the streptavidin-biotin complex, one of the strongest known protein-ligand binders. Using a monomeric streptavidin mutant, we analyze1H NMR chemical shift perturbations (CSPs) of biotin upon binding, identifying unprecedented upfield shifts of up to -3.2 ppm. Quantum chemical calculations attribute these shifts primarily to aromatic ring currents, with additional contributions from charge transfer effects linked to weak interactions. The agreement between experimental and computed chemical shifts validated the X-ray structure as a reliable basis for detailed computational analyses. Energy decomposition analysis reveals that electrostatics dominate the biotin-streptavidin interaction, complemented by significant orbital and dispersion contributions. Notably, weak non-covalent interactions—such as CH· · · S, CH· · ·π, and CH· · · HC contacts—driven by London dispersion forces, contribute ∼44% to the complex’s stability.
Common and rare genetic variation intersects with ancestry to influence human skin and plasma carotenoid concentrations
Authors: Han Yixing , Mwesigwa Savannah , Wu Qiang , Laska Melissa N. , Jilcott Pitts Stephanie B. , Moran Nancy E. , Hanchard Neil A. 
Published: December 2024

ABSTRACTCarotenoids are dietary bioactive compounds with health effects that are biomarkers of fruit and vegetable intake. Here, we examine genetic associations with plasma and skin carotenoid concentrations in two rigorously phenotyped human cohorts (n=317). Analysis of genome-wide SNPs revealed heritability to vary by genetic ancestry (h²=0.08–0.44) with ten SNPs at four loci reaching genome-wide significance (P<5E-08) in multivariate models, including atRAPGEF1(rs3765544, P=8.86E-10, beta=0.75) with α-carotene, and nearIGSF11(rs80316816, P=6.25E-10, beta=0.74), with cryptoxanthin; these were replicated in the second cohort (n=110). Multiple SNPs nearIGSF11demonstrated genotype-dependent dietary effects on plasma cryptoxanthin. Deep sequencing of 35 candidate genes revealed associations between thePKD1L2-BCO1locus and plasma β-carotene (Padj=0.04, beta=-1.3 to -0.3), and rare, ancestry-restricted, damaging variants inCETP(rs2303790) andAPOA1(rs756535387) in individuals with high skin carotenoids. Our findings implicate novel loci in carotenoid disposition and indicate the importance of including cohorts of diverse genetic ancestry.
Neural Ordinary Differential Equations Inspired Parameterization of Kinetic Models
Authors: van Lent Paul , Bunkova Olga , Planken Lèon , Schmitz Joep , Abeel Thomas 
Published: December 2024

AbstractMotivationMetabolic kinetic models are widely used to model biological systems. Despite their widespread use, it remains challenging to parameterize these Ordinary Differential Equations (ODE) for large scale kinetic models. Recent work on neural ODEs has shown the potential for modeling time-series data using neural networks, and many methodological developments in this field can similarly be applied to kinetic models.ResultsWe have implemented a simulation and training framework for Systems Biology Markup Language (SBML) models using JAX/Diffrax, which we namedjaxkineticmodel. JAX allows for automatic differentiation and just-in-time compilation capabilities to speed up the parameterization of kinetic models. We show the robust capabilities of training kinetic models using this framework on a large collection of SBML models with different degrees of prior information on parameter initialization. Finally, we showcase the training framework implementation on a complex model of glycolysis. These results show that our framework can be used to fit large metabolic kinetic models efficiently and provides a strong platform for modeling biological systems.ImplementationImplementation ofjaxkineticmodelis available as a Python package athttps://github.com/AbeelLab/jaxkineticmodel.Author summaryUnderstanding how metabolism works from a systems perspective is important for many biotechnological applications. Metabolic kinetic models help in achieving understanding, but there construction and parametrization has proven to be complex, especially for larger metabolic networks. Recent success in the field of neural ordinary differential equations in combination with other mathematical/computational techniques may help in tackling this issue for training kinetic models. We have implemented a Python package namedjaxkineticmodelthat can be used to build, simulate and train kinetic models, as well as compatibility with the Systems Biology Markup Language. This framework allows for efficient training of kinetic models on time-series concentration data using a neural ordinary differential equation inspired approach. We show the convergence properties on a large collection of SBML models, as well as experimental data. This shows a robust training process for models with hundreds of parameters, indicating that it can be used for large-scale kinetic model training.
Food-entrainment of circadian timekeeping in the dorsal vagal complex
Authors: Chrobok Lukasz , Muir Charlotte , Kaur Tanya Chonkria , Veneri Iliana , Hitrec Timna , Ambler Michael , Pickering Anthony Edward , Piggins Hugh David 
Published: December 2024

AbstractThe dorsal vagal complex (DVC) is a multi-component brainstem satiety centre which has gained attention as a key target of anti-obesity pharmacotherapies. Our recent studies revealed its circadian timekeeping properties, with molecular and electrophysiological 24h rhythms persisting independently of the primary hypothalamic clock. However, the factors entraining these brainstem oscillators, and the downstream transcriptional targets of the DVC molecular clock remain unclear. Here, using fluorescentin situhybridisation, we demonstrate core clock gene expression in inhibitory and excitatory neuronal populations of the DVC, as well as in its output cholinergic vagal neurons. We further reveal that the molecular clock is associated with rhythmic expression of numerous neurotransmitter receptor genes in the DVCin vivo, with the phase of both clock and clock-controlled gene expression tightly regulated by meal timing. These findings uncover food-entrained circadian rhythms in the DVC and have important implications for clinical studies targeting brainstem satiety mechanisms.
Lipids modulate open probability of RyR1 under cryo-EM conditions
Authors: Li Chenyao , Efremov Rouslan G. 
Published: December 2024

AbstractRyanodine receptors (RyRs) are intracellular tetrameric ion channels responsible for Ca2+release from the sarcoplasmic and endoplasmic reticulum. Among the three known mammalian RyR isoforms, RyR1 is critical for muscle contraction and has been studied most extensively. The cytoplasm-exposed multidomain fragment of RyRs integrates multiple cellular signals that regulate channel gating and small deviations from the physiological open probability of RyRs leads to life-threatening diseases. While cryo-EM has been instrumental in revealing near-atomic details of RyR gating mechanisms, the open probability of RyR1 under cryo-EM conditions is notably lower than that observed in electrophysiological studies, complicating structural investigations of RyR1 gating modulation. Here, we present a cryo-EM study examining the open probability of RyR1 solubilized in CHAPS with varying lipid concentrations. We found that increasing lipid concentration from 0.001% to 0.05% raised the RyR1 open probability from 16 to 84%; however, RyR1 reconstituted into lipid nanodiscs remained closed. We modelled 72 lipid molecules in the map reconstructed at the highest lipid concentration. These findings demonstrate critical role of lipids in modulating RyR1 gating under cryo-EM conditions and suggest optimal lipid-mimetics for structural studies of RyR1 gating modulation.
Disruptions in Primary Visual Cortex Physiology and Function in a Mouse Model of Timothy Syndrome
Authors: Craddock Rosie , Tigaret Cezar M. , Sengpiel Frank 
Published: December 2024

AbstractTimothy syndrome (TS) is a rare genetic disorder caused by mutations in theCACNA1Cgene which encodes the L-type calcium channel α-1 CaV1.2 subunit. While it is expressed throughout the body the most serious symptoms are cardiac and neurological. Classical TS1 and TS2 mutations cause prolonged action potentials (APs) in cardiomyocytes and in induced neurons derived from pluripotent stem cells taken from TS patients, but effects of TS mutations on neuronal function in vivo are not fully understood. TS is frequently associated with autistic traits, which in turn have been linked to altered sensory processing. Using the TS2-neo mouse model we analysed effects of the TS2 mutation on the visual system. We observed a widening of APs of pyramidal cells in ex vivo patch-clamp recordings and an increase in the density of parvalbumin positive (PV+) cells in the primary visual cortex. Neurons recorded extracellularly in vivo were less likely to respond to visual stimuli of low spatial frequency, but more likely to respond to visual stimuli of mid-to-high spatial frequency, compared to WT mice. These results point to a basic processing abnormality in the visual cortex of TS2-neo mice.
A continuation of the assembly of a G-quadruplex repair complex by the FANCJ DNA helicase
Authors: Campbell Laura , Lowran Kaitlin , Cismas Emma , Wu Colin G. 
Published: December 2024

AbstractNucleic acid sequences that are rich in guanines can form G-quadruplex (G4) structures, which can impede DNA replication or repair. The FANCJ helicase plays a role in maintaining genomic stability by facilitating DNA replication through regions of DNA that form G4 structures. This activity has been associated with an AKKQ motif in FANCJ and it is thought that this motif retains the ability to also target 8-oxoguanine-modified G4 (8oxoG4) structures. We hypothesize that the molecular recognition of FANCJ AKKQ to 8oxoG4s is dependent upon the position of DNA damage, sequence composition, and substrate stability. We previously demonstrated that reducing the loop length between guanine tetrads increased the affinity of FANCJ AKKQ when 8-oxoguanines (8oxoGs) were located at the first and fifth positions of the G4 structure. In this work, we use fluorescence spectroscopy to measure the affinities of a FANCJ AKKQ peptide for G4s formed by (GGGT)4, (GGGTT)4, and (TTAGGG)4. G4 conformations and thermal stability were determined via circular dichroism spectroscopy. We substituted 8oxoGs at the first (8oxo1), third (8oxo3), and fifth (8oxo5) positions of each G4 sequence and found that the most destabilized structures were (GGGT)48oxo1, (GGGTT)48oxo1, and (TTAGGG)48oxo5 in KCl. The most destabilized structures in NaCl were (GGGT)48oxo1, (GGGTT)48oxo5, and (TTAGGG)48oxo5. The binding affinities of FANCJ AKKQ differed for the distinct damage positions for (GGGT)4in KCl and for (TTAGGG)4in NaCl. These findings suggest that FANCJ AKKQ targets G4s and 8oxoG4s in a manner dependent upon sequence composition and damage position.
Spanning spatial scales with functional imaging in the human brain; initial experiences at 10.5 Tesla
Authors: Vizioli Luca , Moeller Steen , Dowdle Logan , Grant Andrea , Sadeghi-Tarakameh Alireza , Eryaman Yigitcan , Lagore R Russel L. , Auerbach Edward , Adriany Gregor , Knudsen Lasse , Martino Federico De , Faes Lonike , Yacoub Essa , Uğurbil Kamil 
Published: December 2024

ABSTRACTOne of the most important new frontiers in the effort to improve the spatial resolution and accuracy of imaging of human brain activity is the recent development of greater than 10 Tesla magnetic fields. Here we present initial results for 10.5 Tesla Blood Oxygenation Level Dependent (BOLD) based functional brain imaging (fMRI) of the human brain acquired with previously unavailable or difficult to attain spatial resolutions and functional contrast. We present data obtained with nominal isotropic resolutions ranging from 0.65 to 0.35 mm for partial brain coverage for stimulus evoked responses, and 0.75 mm for whole brain coverage to capture the spontaneous fluctuations that are the source of functional connectivity measures. The increasingly higher nominal resolutions (i.e. smaller voxel volumes and dimensions) employed in image acquisition were shown to correspond to real gains in resolution using image reconstruction methods developed to minimize blurring. Existence of supralinear gains in stimulus-evoked percent signal change and major improvements in statistical significance were evident relative to 7 Tesla, the most advanced commercially available ultrahigh magnetic field platform currently employed in human brain studies. These results were feasible due to gains in intrinsic signal-to-noise ratio, BOLD contrast, and image acceleration provided by the uniquely high magnetic field of 10.5 Tesla, and the use of novel high channel count arrays to capture these gains. The results provide a preview of the potential that will be available in the new era of greater than 10 Tesla human functional imaging, particularly for mesoscale functional organizations and connectivity.
Incorporating histone H2B variants into chromatin modifies chromatin accessibility to induce epithelial-to-mesenchymal transition in breast cancer
Authors: Dhahri Hejer , Lau Kin H. , Saintilnord Wesley N. , Lopes Elisson , Damico Hannah N. , Palma Flavio R. , Melters Daniël P. , Chandler Darrell P. , Dalal Yamini , Licht Jonathan D. , Bonini Marcello G. , Fondufe-Mittendorf Yvonne 
Published: December 2024

AbstractHistones scaffold genomic DNA and regulate access to the transcriptional machinery. However, naturally occurring histone variants can alter histone-DNA interactions, DNA and histone modifications, and the chromatin interactome. Hence, alterations in histone variant deposition can disrupt chromatin, and are increasingly recognized as a way to trigger various disease, including cancer. While significant attention has been placed on the biochemical and functional roles of H2A, H3, and H4 histone variants, the variants of H2B remain largely understudied. Here, we show that H2B variants are dysregulated in breast cancer and that certain variants are associated with specific breast cancer subtypes.HIST1H2BOoverexpression (in particular) is more common in Asian, African American/Black, and young female populations and is associated with a worse prognosis.In vitrostudies show that H2B1O compacts nucleosome structure. Incorporating H2B1O into chromatin activates pro-inflammatory and oncogenic pathways, induces the epithelial-to-mesenchymal transition (EMT), and generates resistance to first-line chemotherapeutic agents. Thus, H2B1O acts much like an onco-histone, with H2B variant expression being a prognostic biomarker for breast cancer and a potential new target for drug therapies to enhance treatment efficacy.Graphical Abstract