bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preferences and Acceptability for Long-Acting PrEP Agents Among Pregnant and Postpartum Women with Experience Using Daily Oral PrEP in South Africa and Kenya
Authors: Wara Nafisa J. , Mvududu Rufaro , Marwa Mary M. , Gómez Laurén , Mashele Nyiko , Orrell Catherine , Moucheraud Corrina , Kinuthia John , John-Stewart Grace , Myer Landon , Hoffman Risa , Pintye Jillian , Davey Dvora L. Joseph 
Published: October 2022

AbstractIntroductionLong-acting pre-exposure prophylaxis (PrEP) options could overcome some barriers to oral PrEP persistence during pregnancy and postpartum. We evaluated long-acting PrEP preferences among oral PrEP-experienced pregnant and postpartum women in South Africa and Kenya, two countries with high coverage of oral PrEP and with pending regulatory approvals for long-acting injectable cabotegravir and the dapivirine vaginal ring (approved in South Africa, under review in Kenya).MethodsFrom September 2021 to February 2022, we surveyed pregnant and postpartum women enrolled in oral PrEP studies in South Africa and Kenya. We evaluated oral PrEP attitudes and preferences for existing and future long-acting PrEP methods.ResultsWe surveyed 190 women in South Africa (67% postpartum; median age 27 years [IQR 22-32]) and 204 women in Kenya (79% postpartum; median age 29 years [IQR 25-33]). 75% of participants reported oral PrEP use within the last 30 days. Overall, 49% of participants reported negative oral PrEP attributes, including side effects (21% South Africa, 30% Kenya) and pill burden (20% South Africa, 25% Kenya). Preferred PrEP attributes included long-acting method, effectiveness, safety while pregnant and breastfeeding, and free medication. Most participants (75%, South Africa and Kenya) preferred a potential long-acting injectable over oral PrEP, most frequently for longer duration of effectiveness in South Africa (87% South Africa, 42% Kenya) versus discretion in Kenya (5% South Africa, 49% Kenya). 87% of participants preferred oral PrEP over a potential long-acting vaginal ring, mostly due to concern about possible discomfort with vaginal insertion (82% South Africa, 48% Kenya). Significant predictors of long-acting PrEP preference included past use of injectable contraceptive (aOR 2.48, 95% CI: 1.34, 4.57), disliking at least one oral PrEP attribute (aOR 1.72, 95% CI: 1.05, 2.80), and preferring infrequent PrEP use (aOR 1.58, 95% CI: 0.94, 2.65).ConclusionsOral PrEP-experienced pregnant and postpartum women expressed a theoretical preference for long-acting injectable PrEP over other modalities, demonstrating potential acceptability among a key population who must be at the forefront of injectable PrEP rollout. Reasons for PrEP preferences differed by country, emphasizing the importance of increasing context-specific options and choice of PrEP modalities for pregnant and postpartum women.
Large effect loci have a prominent role in Darwin’s finch evolution
Authors: Enbody Erik D. , Sendell-Price Ashley T. , Sprehn C. Grace , Rubin Carl-Johan , Visscher Peter M. , Grant B. Rosemary , Grant Peter R. , Andersson Leif 
Published: October 2022

AbstractA fundamental goal in evolutionary biology is to understand the genetic architecture of adaptive traits and its evolutionary relevance. Using whole-genome data of 3,958 Darwin’s finches on the Galápagos Island of Daphne Major we identify six loci of large effect that explain 46% of the variation in beak size ofGeospiza fortis, a key ecological trait. Allele frequency changes across 30 years at these loci affected beak morphology in two ways. An abrupt change in beak size occurred inGeospiza fortisas a result of natural selection associated with a drought, and a more gradual change occurred inG. scandensas a result of introgressive hybridization. This study demonstrates how large effect loci are a major contributor to the genetic architecture of rapid diversification during adaptive radiations.One Sentence SummaryAllele frequency change at six loci of large effect causes evolutionary change in key ecological traits.
Cortical tracking of continuous speech under bimodal divided attention
Authors: Xie Zilong , Brodbeck Christian , Chandrasekaran Bharath 
Published: October 2022

AbstractSpeech processing often occurs amidst competing inputs from other modalities, e.g., listening to the radio while driving. We examined the extent to whichdividingattention between auditory and visual modalities (bimodal divided attention) impacts neural processing of natural continuous speech from acoustic to linguistic levels of representation. We recorded electroencephalographic (EEG) responses when human participants performed a challenging primary visual task, imposing low or high cognitive load while listening to audiobook stories as a secondary task. The two dual-task conditions were contrasted with an auditory single-task condition in which participants attended to stories while ignoring visual stimuli. Behaviorally, the high load dual-task condition was associated with lower speech comprehension accuracy relative to the other two conditions. We fitted multivariate temporal response function encoding models to predict EEG responses from acoustic and linguistic speech features at different representation levels, including auditory spectrograms and information-theoretic models of sublexical-, word-form-, and sentence-level representations. Neural tracking of most acoustic and linguistic features remained unchanged with increasing dual-task load, despite unambiguous behavioral and neural evidence of the high load dual-task condition being more demanding. Compared to the auditory single-task condition, dual-task conditions selectively reduced neural tracking of only some acoustic and linguistic features, mainly at latencies >200 ms, while earlier latencies were surprisingly unaffected. These findings indicate that behavioral effects of bimodal divided attention on continuous speech processing occur not due to impaired early sensory representations but likely at later cognitive processing stages. Crossmodal attention-related mechanisms may not be uniform across different speech processing levels.
Clustering laminar cytoarchitecture: in vivo parcellation based on cortical granularity
Authors: Shamir Ittai , Assaf Yaniv , Shamir Ron 
Published: October 2022

AbstractThe laminar microstructure of the cerebral cortex is considered a unique anatomical mark of the development, function, connectivity, and even various pathologies of the brain. In recent years, multiple neuroimaging studies have utilized magnetic resonance imaging (MRI) relaxometry to visualize and explore this intricate microstructure. By successfully delineating the cortical laminar components, the applicability of T1 relaxometry has been expanded beyond solely a direct measure of myeline content. However, validating its applicability as a measure of cortical cytoarchitecture demands analyzing the complex resulting laminar datasets. In this study, we adapt and implement an algorithm for clustering cell omics profiles to cluster these complex microstructural cortical datasets. The resulting clusters correspond with an established atlas of cytoarchitectonic features, providing robust validation of T1 imaging as a tool for exploring cortical laminar composition. Lastly, we demonstrate the applicability of this framework in the exploration of the cytoarchitectonic features behind various unique skillsets.
An expanded proteomic survey of the human parasiteLeishmania majorfocusing on changes in null mutants of the Golgi GDP-Mannose/Fucose/ArabinopyranosetransporterLPG2or the mitochondrial fucosyltransferaseFUT1
Authors: Polanco Gloria , Scott Nichollas E. , Lye Lon F. , Beverley Stephen M. 
Published: October 2022

ABSTRACTThe trypanosomatid protozoan parasiteLeishmaniahas a significant impact on human health globally. Understanding the pathways associated with virulence within this significant pathogen is critical for identifying novel vaccination and chemotherapy targets. Within this study we leverage an ultradeep proteomic approach to improve our understanding of two virulence associated genes inLeishmania, encoding the Golgi Mannose/Arabinopyranose/Fucose nucleotide-sugar transporterLPG2, and the mitochondrial fucosyltransferaseFUT1. Using deep peptide fractionation followed by complementary fragmentation approaches with higher energy collisional dissociation (HCD) and Electron-transfer dissociation (ETD) allowed the identification of over 6500 proteins, nearly doubling the experimentally knownLeishmania majorproteome. This deep proteomic analysis revealed significant quantitative differences in bothΔlpg2-andΔfut1smutants withFUT1-dependent changes linked to marked alterations within mitochondrial associated proteins whileLPG2-dependent changes impacted many pathways including the secretory pathway. While the FUT1 enzyme has been shown to fucosylate peptidesin vitro, no evidence for protein fucosylation was identified within our ultradeep analysis nor did we observe fucosylated glycans withinLeishmaniaglycopeptides isolated using HILIC enrichment. Combined this work provides a critical resource for the community on the observableLeishmaniaproteome as well as highlights phenotypic changes associated withLPG2orFUT1ablation which may guide the development of future therapeutics.ImportanceLeishmaniais a widespread trypanosomatid protozoan parasite of humans with ∼12 million cases ranging from mild to fatal, and hundreds of millions asymptomatically infected. This work advances knowledge of the experimental proteome by nearly 2 fold, to more than 6500 proteins a great resource to investigators seeking to decode how this parasite is transmitted and causes disease, and new targets for therapeutic intervention. The ultradeep proteomics approach identified potential proteins underlying the ‘persistence without pathology’ phenotype of deletion mutants of the Golgi nucleotide transporter LPG2, showing many alterations and several candidates. Studies of a rare deletion mutant of the mitochondrial fucosyltransferase FUT1 revealed changes underlying its strong mitochondrial dysfunction, but did not reveal examples of fucosylation of either peptides or N-glycans. This suggests this vital protein’s elusive target(s) may be more complex than the methods used could detect, or may not be a protein, perhaps another glycoconjugate or glycolipid.
Computational and experimental analyses of alanine racemase suggest new avenues for developing allosteric small-molecule antibiotics
Authors: Van Wieren Arie , Durant Jacob D , Majumdar Sudipta 
Published: October 2022

AbstractGiven the ever-present threat of antibacterial resistance, there is an urgent need to identify new antibacterial drugs and targets. One such target is alanine racemase (Alr), an enzyme required for bacterial cell-wall biosynthesis. Alr is an attractive drug target because it is essential for bacterial survival but is absent in humans. Here, we investigate the Alr fromM. tuberculosis(MT), the pathogen responsible for human tuberculosis, as a model Alr enzyme. MT-Alr functions exclusively as an obligate homodimer formed by two identical monomers. Both monomers contribute to the overall composition of their active sites. Therefore, disrupting the dimer interface could inhibit MT-Alr activity. Using computational methods, we identified seven interfacial residues predicted to be responsible for MT-Alr dimerization. Mutating one of the seven residues, Lys261, to alanine resulted in a completely inactive enzyme. Further investigation suggested a potential drug-binding site near Lys261 that might be useful for allosteric drug discovery.SummaryThe bacterial protein alanine racemase (Alr) converts L-alanine to D-alanine, a critical component of the bacterial cell wall. Cycloserine, a known antibiotic, inhibits Alr by binding to the same pocket that alanine binds. Several human proteins have similar pockets, so cycloserine has severe side effects. We identified additional Alr pockets and discovered that altering one of them abolishes Alr activity. Molecules that bind this pocket may similarly impact Alr activity, helping to address the ongoing antibiotic resistance crisis.
Quantifying quantify 64 drugs, illicit substances, and D- and L- isomers in human oral fluid with liquid-liquid extraction
Authors: Robbins Brian , Carpenter Rob E. , Long Mary , Perry Jacob 
Published: October 2022

ABSTRACTAlthough human oral fluid has become more routine for quantitative drug detection in pain management, detecting a large scope of medications and substances is costly and technically challenging for laboratories. This paper presents a quantitative assay for 64 pain medications, illicit substances, and drug metabolites in human oral fluid. The novelty of this assay is that it was developed on an older model AB SCIEX 4000 instrument and renders obscure the need for more technical and expensive laboratory equipment. This method includes addition of internal standard and a 2-step liquid-liquid extraction and dry-down step to concentrate and clean the samples. The samples were suspended in 50% MeOH in water and separation and detection was accomplished using triple quadrupole mass spectrometry (LC-MS/MS). Separation was achieved using reverse-phase liquid chromatography with detection by LC-MS/MS. A second injection was done in negative mode to determine THC-COOH concentration as an indicator of THC. An aliquot of the (already) extracted samples was analyzed for D- and L- isomers of amphetamine and methamphetamine using a chiral column. The standard curve spanned from 5 to 2000 ng/mL for most of the analytes (1 to 2000 ng/mL for fentanyl and THC-COOH) and up to 1000 ng/mL for 13 analytes. Pregabalin and gabapentin ranged from 25 to 2000 ng/mL. The result is a low-cost method for the sensitive detection of a wide-ranging oral fluid menu for pain management. This assay has a high sensitivity, and good precision and accuracy for all analytes with an older model mass spectrometer.
Molecular mechanism of tRNA binding by theEscherichia coliN7 guanosine methyltransferase TrmB
Authors: Schultz Sarah K. , Meadows Kieran , Kothe Ute 
Published: October 2022

AbstractAmong the large and diverse collection of tRNA modifications, 7-methylguanosine is frequently found in the tRNA variable loop at position 46. This modification is introduced by the TrmB enzyme, which is conserved in bacteria and eukaryotes. Complementing the report of various phenotypes for different organisms lacking TrmB homologs, we report here hydrogen peroxide sensitivity for theEscherichia coli ΔtrmBknockout strain. To gain insight into the molecular mechanism of tRNA binding byE. coliTrmB in real-time, we developed a new assay based on introducing a 4-thiouridine modification at position 8 ofin vitrotranscribed tRNAPheenabling us to fluorescently labelled this unmodified tRNA. Using rapid kinetic stopped-flow measurements with this fluorescent tRNA, we examined the interaction of wild-type and single substitution variants of TrmB with tRNA. Our results reveal the role of SAM for rapid and stable tRNA binding, the rate-limiting nature of m7G46 catalysis for tRNA release, and the importance of residues R26, T127 and R155 across the entire surface of TrmB for tRNA binding.
Routing States Transition During Oscillatory Bursts and Attentional Selection
Authors: Boroujeni Kianoush Banaie , Womelsdorf Thilo 
Published: October 2022

AbstractNeural information routing relies on spatiotemporal activity dynamics across interconnected brain areas. However, it remains unclear how routing states emerge at fast spiking timescales and interact with the slower activity dynamics of larger networks during cognitive processes.Here, we show that localized neural spiking events generate long-range directional routing states with spiking activity in distant brain areas that dynamically switch or amplify during oscillatory bursts, selective attention, and decision-making. Computational modeling and neural recordings from lateral prefrontal cortex (LPFC), anterior cingulate cortex (ACC), and striatum of nonhuman primates revealed that cross-areal, directional routing states arise within ∼20 ms around spikes of single neurons. On average, LPFC spikes led activity in the ACC and striatum by few milliseconds. The routing state was amplified during LPFC beta bursts between the LPFC and striatum and switched direction during ACC theta/alpha bursts between ACC and LPFC. Selective attention amplified the lead of these theta/alpha-specific lead-ensembles in the ACC, while decision-making amplified the lead of ACC and LPFC spiking output over the striatum. Notably, the fast lead/lag relationships of cross-areal neuronal ensembles that were modulated by attention states or decision-making predicted firing rate dynamics of their neurons during those functional states at slower timescales. Overall, our findings demonstrate directional routing of spiking activity across nonhuman primate frontal and striatal areas, as well as the functional and network states that modulate the direction and magnitude of these interactions.SummaryFast spatio-temporal dynamics of brain activity subserves the routing of information across distant regions and is integral to flexible cognition, decision-making, and selective attention. This study demonstrates that routing dynamics emerge as 20 ms brief lead and lag relationships of spiking activities across distant brain areas. The direction and magnitude of the lead and lag relationships systematically switched during frequency-specific oscillatory bursts and when attention shifts to visual cues.
Whole Human-Brain Mapping of Single Cortical Neurons for Profiling Morphological Diversity and Stereotypy
Authors: Han Xiaofeng , Guo Shuxia , Ji Nan , Li Tian , Liu Jian , Ye Xiangqiao , Wang Yi , Yun Zhixi , Xiong Feng , Rong Jing , Liu Di , Ma Hui , Wang Yujin , Huang Yue , Zhang Peng , Wu Wenhao , Ding Liya , Hawrylycz Michael , Lein Ed , Ascoli Giorgio A. , Xie Wei , Liu Lijuan , Zhang Liwei , Peng Hanchuan 
Published: October 2022

AbstractQuantification of individual cells’ morphology and their distribution at the whole brain scale is essential to understand the structure and diversity of cell types. Despite recent technological advances, especially single cell labeling and whole brain imaging, for many prevailing animal models, it is exceedingly challenging to reuse similar technologies to study human brains. Here we propose Adaptive Cell Tomography (ACTomography), a low-cost, high-throughput, high-efficacy tomography approach, based on adaptive targeting of individual cells suitable for human-brain scale modeling of single neurons to characterize their 3-D structures, statistical distributions, and extensible for other cellular features. Specifically, we established a platform to inject dyes into cortical neurons in surgical tissues of 18 patients with brain tumors or other conditions and 1 donated fresh postmortem brain. We collected 3-D images of 1746 cortical neurons, of which 852 neurons were subsequentially reconstructed to quantify their local dendritic morphology, and mapped to standard atlases both computationally and semantically. In our data, human neurons are more diverse across brain regions than by subject age or gender. The strong stereotypy within cohorts of brain regions allows generating a statistical tensor-field of neuron morphology to characterize 3-D anatomical modularity of a human brain.
Improving the sensitivity of in vivo CRISPR off-target detection with DISCOVER-Seq+
Authors: Zou Roger S. , Liu Yang , Gaido Oscar E. Reyes , Konig Maximilian F. , Mog Brian J. , Shen Leo L. , Aviles-Vazquez Franklin , Marin-Gonzalez Alberto , Ha Taekjip 
Published: October 2022

ABSTRACTDiscovery of off-target CRISPR-Cas genome editing activity in patient-derived cells and animal models is crucial for therapeutic applications, but currently exhibits low sensitivity. We demonstrate that inhibition of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) accumulates repair protein MRE11 at CRISPR-targeted sites, enabling high-sensitivity mapping of off-target sites to positions of MRE11 binding using chromatin immunoprecipitation sequencing (ChIP-seq). This technique, termed DISCOVER-Seq+, discovered up to 5-fold more CRISPR off-target sites in immortalized cell lines, primary human cells, and mice compared to previous methods. We demonstrated applicability to ex vivo knock-in of a cancer-directed transgenic T-cell receptor in primary human T cells and in vivo adenovirus knock-out of cardiovascular risk genePCSK9in mice. DISCOVER-Seq+ is the most sensitive method to-date for discovering off-target genome editing in vivo.
G-PROTEIN COUPLED RECEPTOR 19 (GPR19) KNOCKOUT MICE DISPLAY SEX-DEPENDENT METABOLIC DYSFUNCTION
Authors: Mushala Bellina A.S. , Xie Bingxian , Sipula Ian J. , Stoner Michael W. , Thapa Dharendra , Manning Janet R. , Bugga Paramesha , Vandevender Amber M. , Jurczak Michael J. , Scott Iain 
Published: October 2022

ABSTRACTG-protein coupled receptors (GPCRs) mediate signal transduction from the cellular surface to intracellular metabolic pathways. While the function of many GPCRs has been delineated previously, a significant number require further characterization to elucidate their cellular function. G-protein coupled receptor 19 (GPR19) is a poorly characterized class A GPCR which has been implicated in the regulation of circadian rhythm, tumor metastasis, and mitochondrial homeostasis. In this report, we use a novel knockout (KO) mouse model to examine the role of GPR19 in whole-body metabolic regulation. We show that loss of GPR19 promotes increased energy expenditure and decreased activity in both male and female mice. However, only male GPR19 KO mice display glucose intolerance in response to a high fat diet (HFD). Loss of GPR19 expression in male mice, but not female mice, resulted in diet-induced hepatomegaly, which was associated with decreased expression of key fatty acid oxidation genes in male GPR19 KO livers. Overall, our data suggest that loss of GPR19 impacts whole-body energy metabolism in diet-induced obese mice in a sex-dependent manner.