bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered patterning of neural activity in a tauopathy mouse model
Authors: Hoffman C. , Cheng J. , Morales R. , Ji D. , Dabaghian Y. 
Published: March 2024

Alzheimer’s disease (AD) is a complex neurodegenerative condition that manifests at multiple levels and involves a spectrum of abnormalities ranging from the cellular to cognitive. Here, we investigate the impact of AD-related tau-pathology on hippocampal circuits in mice engaged in spatial navigation, and study changes of neuronal firing and dynamics of extracellular fields. While most studies are based on analyzing instantaneous or time-averaged characteristics of neuronal activity, we focus on intermediate timescales—spike trains and waveforms of oscillatory potentials, which we consider as single entities. We find that, in healthy mice, spike arrangements and wave patterns (series of crests or troughs) are coupled to the animal’s location, speed, and acceleration. In contrast, in tau-mice, neural activity is structurally disarrayed: brainwave cadence is detached from locomotion, spatial selectivity is lost, the spike flow is scrambled. Importantly, these alterations start early and accumulate with age, which exposes progressive disinvolvement the hippocampus circuit in spatial navigation. These features highlight qualitatively different neurodynamics than the ones provided by conventional analyses, and are more salient, thus revealing a new level of the hippocampal circuit disruptions.SignificanceWe expose differences in WT and tau brains, emerging at the circuit level, using a novel, morphological perspective on neural activity. This approach allows identifying qualitative changes in spiking patterns and in extracellular field oscillations, that are not discernible through traditional time-localized or time-averaged analyses. In particular, analyses of activity patterns facilitates detection of neurodegenerative deviations, conspicuously linking their effects to behavior and locomotion, thus opening a new venue for understanding how the architecture of neural activity shifts from normal to pathological.
Predicting Harmful Alcohol Use Prevalence in Sub-Saharan Africa between 2015 and 2019: Evidence from Population-based HIV Impact Assessment
Authors: Goma Mtumbi , Ng’ambi Wingston Felix , Zyambo Cosmas 
Published: March 2024

ABSTRACTIntroductionHarmful alcohol use is associated with significant risks to public health outcomes worldwide. Although data on harmful alcohol use have been collected by population-based HIV Impact Assessment (PHIA), there is a dearth of analysis on the effect of HIV/ART status on harmful alcohol use in the SSA countries with PHIA surveys. This study uses data from the national representative PHIA to predict the harmful alcohol use prevalence.MethodsA secondary analysis of the PHIA surveys: Namibia (n=27,382), Tanzania (n=1807), Zambia (n=2268), Zimbabwe (n=3418), Malawi (n=2098), Namibia (n=27,382), and Eswatini (n=2762). Using R version 4.2, the outcome variable and the descriptive variables were tested for association using chi square. Multivariable logistic regression analysis was used identify significant variables associated with harmful alcohol use. We employed to test and apply machine learning (ML) methods through Super Learner, Decision Tree, Random Forest (RF), Lasso Regression, Sample mean and Gradient boosting. Evaluation metrics methods specifically confusion matrix, accuracy, precision, recall, F1 score, and Area under the Receiver Operating Characteristics (AUROC) were used to evaluate the performance of predictive models. The cutoff point for statistically significant was P<0.05.ResultsOf the 12,460 persons, 15% used alcohol harmfully. Harmful alcohol use varied by countries and ranged from 8.7% in Malawi to 26.1% in Namibia (P<0.001). Females were less likely to use alcohol in a harmful way (AOR = 0.32, 95% CI: 0.29-0.35, P< 0.001). Compared to those HIV negative, persons that were with HIV-positive and on ART were less likely to use alcohol in a harmful way (AOR = 0.65, 95% CI: 0.57-0.73, P<0.001) however persons that were HIV-positive and not on ART were more likely to use alcohol in a harmful way (OR = 1.49, 95% CI: 1.32-1.69, P<0.001). Being married or formally married was protective to harmful use of alcohol. The best performing models were Lasso or Super Learner or Random Forest were the best performing models while gradient boosting models or sample mean did not perform well.ConclusionThe findings highlight concerning variations in harmful alcohol use prevalence across surveyed countries, with Namibia reporting the highest rate. Males, older individuals, those HIV positive and not yet on ART, and unmarried persons demonstrated a higher likelihood of engaging in harmful alcohol use. These findings collectively contribute to a comprehensive understanding of the multiple factors influencing harmful alcohol use within the surveyed populations, the importance of targeted interventions at country and individual levels.
Impact of Lactobacillus GG on weight loss in post-bariatric surgery patients: a randomized, double-blind clinical trial
Authors: Nasir Myra , Stone Samuel , Mahoney Ian , Chang Justin , Kim Julie , Shah Sajani , McDermott Laura A. , Sebastiani Paola , Tighiouart Hocine , Snydman David R. , Doron Shira 
Published: March 2024

AbstractIntroduction and ObjectivesThere is increasing evidence suggesting the impact of human gut microbiota on digestion and metabolism. It is hypothesized that the microbiome in obese subjects is more efficient than that in lean subjects in absorbing energy from food, thus predisposing to weight gain. A transformation in gut microbiota has been demonstrated in patients who have undergone bariatric surgery which has been positively associated with post-surgical weight loss. However, there is lack of studies investigating the impact of probiotics on weight loss in post-bariatric surgery patients. The objectives of our study were to investigate the impact of a probiotic, Lactobacillus GG (LGG), on weight loss and quality of life in patients who have undergone bariatric surgery.MethodsThe study was registered withClinicalTrials.govNCT01870544. Subjects were randomized to receive either LGG or placebo capsules. Percent total weight loss at their post-operative visits was calculated and differences between the two groups were tested using a t-test with unequal variances. The effect of LGG on Gastrointestinal Quality of Life Index (GIQLI) scores was estimated using a mixed model repeated measures model.ResultsThe mean rate of change in percent total weight loss at the ‘30-day’ post-operative visit for the placebo and treatment groups was 0.098 and 0.079 (p = 0.41), respectively, whereas that at the ‘90-day’ post-operative visit was 0.148 and 0.126 (p = 0.18), respectively. The difference in GIQLI scores on ‘30-day’ and ‘90-day’ visits were 0.5 (−7.1, 8.0), p=0.91 and 3.7 (−4.9, 12.3), p=0.42, respectively. LGG was recovered from the stools of 3 out of 5 subjects in the treatment group.ConclusionWe did not appreciate a significant difference in the mean rate of weight loss or GIQLI scores between the groups who received LGG versus placebo. This study demonstrated survival of lactobacillus during transit through the gastrointestinal tract.
Enteric glutamatergic interneurons regulate intestinal motility
Authors: Hamnett Ryan , Bendrick Jacqueline L. , Robertson Keiramarie , Zhao Eric Tianjiao , Kaltschmidt Julia A. 
Published: March 2024

AbstractThe enteric nervous system (ENS) controls digestion autonomously via a complex neural network within the gut wall. Enteric neurons expressing glutamate have been identified by transcriptomic studies as a distinct subpopulation, and glutamate can affect intestinal motility by modulating enteric neuron activity. However, the nature of glutamatergic neurons, their position within the ENS circuit, and their function in regulating gut motility are unknown.Here, we identify glutamatergic neurons as longitudinally projecting descending interneurons in the small intestine and colon, in addition to a novel class of circumferential neurons only in the colon. Both populations make synaptic contact with diverse neuronal subtypes, and signal with a variety of neurotransmitters and neuropeptides in addition to glutamate, including acetylcholine and enkephalin. Knocking out the glutamate transporter VGLUT2 from enkephalin neurons profoundly disrupts gastrointestinal transit, whileex vivooptogenetic stimulation of glutamatergic neurons initiates propulsive motility in the colon. This motility effect is reproduced when stimulating only the descending interneuron class, marked by Calb1 expression. Our results posit glutamatergic neurons as key interneurons that regulate intestinal motility.
Androgen receptor-negative prostate cancer is vulnerable to SWI/SNF-targeting degrader molecules
Authors: Thienger Phillip , Rubin Philip D. , Yao Xiaosai , Benjak Andrej , Shah Sagar R. , Leung Alden King-Yung , de Brot Simone , Naveed Alina , Shi Minyi , Tremblay Julien , Triscott Joanna , Cassanmagnago Giada , Bolis Marco , Mela Lia , Beltran Himisha , Chen Yu , Piscuoglio Salvatore , Yu Haiyuan , Ng Charlotte K Y , Yauch Robert L. , Rubin Mark A. 
Published: March 2024

AbstractThe switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex is frequently deregulated during progression to castration-resistant prostate cancer (CRPC). Proteolysis targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases offer a novel approach to interfere with androgen receptor (AR) signaling in AR-dependent CRPC (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI/SNF ATPase targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment of cell lines and organoid models reduced the viability of not only CRPC-AR but also WNT-signaling dependent AR-negative CRPC (CRPC-WNT), which accounts for about 10% of all clinical CRPC cases. In CRPC-WNT models, we discovered that SWI/SNF ATPase SMARCA4 depletion interfered with WNT signaling via the master transcriptional regulator TCF7L2 (TCF4). Functionally, TCF7L2 maintains proliferation via the MAPK signaling axis in this subtype of CRPC by forming a complex with β-Catenin and AP-1 transcription factor c-JUN. These data suggest a mechanistic rationale for MAPK inhibition or interventions that disrupt the formation of the pro-proliferative TCF7L2-β-Catenin-JUN complex in the CRPC-WNT subclass of advanced prostate cancer.
A molecular switch orchestrates the nuclear export of human messenger RNA
Authors: Hohmann Ulrich , Graf Max , Schellhaas Ulla , Pacheco-Fiallos Belén , Fin Laura , Riabov-Bassat Daria , Pühringer Thomas , Szalay Michael-Florian , Tirián László , Handler Dominik , Brennecke Julius , Plaschka Clemens 
Published: March 2024

ABSTRACTThe nuclear export of messenger RNA (mRNA) is a key step in eukaryotic gene expression (Köhler and Hurt, 2007). Despite recent insights into the packaging of newly transcribed mRNAs into ribonucleoprotein complexes (mRNPs) (Pacheco-Fiallos et al., 2023; Bonneau et al., 2023), the subsequent events that govern mRNA export are poorly understood. Here, we elucidate the molecular basis of human mRNA export licensing, which involves the remodeling of mRNP-bound transcription-export complexes (TREX), the formation of export-competent mRNPs, the docking of mRNPs at the nuclear pore complex (NPC), and the release of mRNPs at the NPC to initiate export. Our biochemical and structural data uncover the ATPase DDX39/UAP56 as a central molecular switch that directs mRNPs through the TREX and the NPC-anchored TREX-2 complexes using its ATPase and mRNA-binding cycle. Collectively, these findings establish a mechanistic framework for a general and conserved mRNA export pathway.
Multi-drug interaction target-controlled infusion from simultaneous optimization of pharmacometric models
Authors: Martinez-Vazquez Pablo , Abad-Torrent Ana 
Published: March 2024

AbstractBackgroundAccurately controlling drug delivery is crucial for safe anesthesia. Target-controlled infusion (TCI) systems use pharmacokinetic and pharmacodynamic (PK/PD) models to administer intravenous agents to reach target concentrations. However, TCI’s operation is restricted to a single-drug and a linear PK/PD model, not accounting for drug interactions. Dose-response interaction (DRI) models quantify such interactions by representing shared effects as a function of agents’ concentrations. For example, the co-administration of an analgesic and a hypnotic with TCI leads to an uncontrolled synergy.MethodsWe introduce a new administering methodology for multi-drug infusions, interaction target-controlled infusion (iTCI), that combines the PK/PD models of the co-administered drugs and their interactions into a single optimal non-linear dynamic control problem with terminal constraints.ResultsIncorporating DRI and PK/PD models allows novel administration procedures. Simulations of iTCI in different clinical scenarios under propofol and remifentanil co-administrations are presented. These show that: (1) iTCI requires lower administered volumes than TCI to reach simultaneously the same target concentrations. (2) It offers optimal interdependent administrations that address not only concentration targets but also effect targets. (3) iTCI comes with additional constraints on the administration, including controlled titrations along iso-effect conditions (isoboles) or (5) directly limiting plasma concentration levels. (6) Unlike TCI, iTCI can include different exerted effects (ke0) per drug, particularly relevant for opioids.ConclusionThe iTCI is a versatile multi-drug infusion paradigm where effects and interactions play a relevant role - providing better delivery profiles than current TCI while opening the door for using non-linear PK/PD descriptions in anesthesia.
A structured coalescent model reveals deep ancestral structure shared by all modern humans
Authors: Cousins Trevor , Scally Aylwyn , Durbin Richard 
Published: March 2024

1AbstractUnderstanding the series of admixture events and population size history leading to modern humans is central to human evolutionary genetics. Using a coalescence-based hidden Markov model, we present evidence for an extended period of structure in the history of all modern humans, in which two ancestral populations that diverged ∼1.5 million years ago came together in an admixture event ∼300 thousand years ago, in a ratio of ∼80:20 percent. Immediately after their divergence, we detect a strong bottleneck in the major ancestral population. We inferred regions of the present-day genome derived from each ancestral population, finding that material from the minority correlates strongly with distance to coding sequence, suggesting it was deleterious against the majority background. Moreover, we found a strong correlation between regions of majority ancestry and human-Neanderthal or human-Denisovan divergence, suggesting the majority population was also ancestral to those archaic humans.
A*PA2: up to 20 times faster exact global alignment
Authors: Groot Koerkamp Ragnar 
Published: March 2024

AbstractMethodsWe introduce A*PA2, an exact global pairwise aligner with respect to edit distance. The goal of A*PA2 is to unify the near-linear runtime of A*PA on similar sequences with the efficiency of dynamic programming (DP) based methods. Like Edlib, A*PA2 uses Ukkonen’s band doubling in combination with Myers’ bitpacking. A*PA2 1) extends this with SIMD (single instruction, multiple data), 2) uses large block sizes inspired by BlockAligner, 3) avoids recomputation of states where possible as suggested before by Fickett, 4) introduces a new optimistic technique for traceback based on diagonal transition, and 5) applies the heuristics developed in A*PA and improves them usingpre-pruning.ResultsThe average runtime of A*PA2 is 19×faster than the exact aligners BiWFA and Edlibon>500 kbp long ONT reads of a human genome having 6% divergence on average. On shorter ONT reads of 11% average divergence the speedup is 5.6×(avg. length 11 kbp) and 0.81×(avg. length 800 bp). On all tested datasets, A*PA2 is competitive with or faster than approximate methods.Availabilitygithub.com/RagnarGrootKoerkamp/astar-pairwise-alignerContactragnar.grootkoerkamp@inf.ethz.ch
TestingAnopheleslarvae and adults using standard bioassays reveals susceptibility to chlorfenapyr (pyrrole) while highlighting variability between species
Authors: Bouaka Calmes , Ambadiang Marilene , Ashu Fred , Fouet Caroline , Kamdem Colince 
Published: March 2024

AbstractA standard test is available for assessing the susceptibility of adultAnophelesmosquitoes to chlorfenapyr, a new active ingredient in insecticide-treated nets. However, for a new insecticide with a unique mode of action, testing both larvae and adults using different routes of exposure is crucial to a comprehensive evaluation of susceptibility and to identifying potential selection pressures that may drive resistance. We followed WHO guidelines to assess the lethal toxicity of chlorfenapyr and monitorAnophelessusceptibility. Based on the median lethal concentration (LC50), larvae of the pyrethroid-susceptible colonized strainAn. coluzziiNgousso were 16-fold more susceptible to chlorfenapyr than immature stages of another susceptible colony:An. gambiaeKisumu. Larval bioassays indicated 99.63 ± 0.2% mortality after 24 h at a discriminating concentration of 100 ng/ml inAnopheles gambiaeandAn. coluzziilarvae collected from seven locations in urban and rural areas of Yaoundé, Cameroon. By contrast, exposing emerging female adults from these populations to the recommended discriminating concentration (100 µg Active Ingredient (AI)/bottle) in bottle bioassays revealed variable mortality after 72 h, with values below the threshold of susceptibility (98%) in several tests.Anopheles coluzziilarvae and adults were fully susceptible, but mortality rates were slightly lower inAn. gambiaeadults compared to larvae (94 ± 1.5% vs 100%, Fisher’s exact test,p< 0.001). Piperonyl butoxide antagonized the activity of chlorphenapyr inAn. gambiaeadults. 100 ng/ml provides sufficient discriminative power for assessing the susceptibility ofAn. gambiaeandAn. coluzziilarvae to chlorfenapyr. TestingAn. gambiaeadults with 100 µg AI/bottle is likely to reveal inconsistent mortality values making it difficult to detect any emergence of resistance. Exploring different tests and accounting for variability between species are key to a reliable monitoring ofAnophelessusceptibility to chlorfenapyr.
Estimating Ejection Fraction from the 12 Lead ECG among Patients with Acute Heart Failure
Authors: Pokhrel Bhattarai Sunita , Dzikowicz Dillon J , Xue Ying , Block Robert , Tucker Rebecca G. , Bhandari Shilpa , Boulware Victoria E , Stone Breanne , Carey Mary G 
Published: March 2024

AbstractBackgroundIdentifying patients with low left ventricular ejection fraction (LVEF) in the emergency department using an electrocardiogram (ECG) may optimize acute heart failure (AHF) management. We aimed to assess the efficacy of 527 automated 12-lead ECG features for estimating LVEF among patients with AHF.MethodMedical records of patients >18 years old and AHF-related ICD codes, demographics, LVEF %, comorbidities, and medication were analyzed. Least Absolute Shrinkage and Selection Operator (LASSO) identified important ECG features and evaluated performance.ResultsAmong 851 patients, the mean age was 74 years (IQR:11), male 56% (n=478), and the median body mass index was 29 kg/m2(IQR:1.8). A total of 914 echocardiograms and ECGs were matched; the time between ECG-Echocardiogram was 9 hours (IQR of 9 hours);<30% LVEF (16.45%, n=140). Lasso demonstrated 42 ECG features important for estimating LVEF<30%. The predictive model of LVEF<30% demonstrated an area under the curve (AUC) of 0.86, a 95% confidence interval (CI) of 0.83 to 0.89, a specificity of 54% (50% to 57%), and a sensitivity of 91 (95% CI: 88% to 96%), accuracy 60% (95% CI:60 % to 63%) and, negative predictive value of 95%.ConclusionsAn explainable machine learning model with physiologically feasible predictors may be useful in screening patients with low LVEF in AHF.Clinical PerspectiveWhat is new?Among 527 ECG features, 42 were important in estimating<30% reduced left ventricular ejection fraction (LVEF), showing the model’s high diagnostic accuracy (AUC of 0.86).The model exhibits exceptional sensitivity (91%) in predicting<30% LVEFECG-derived metrics offer the potential for early detection of reduced LVEF, especially in settings with limited advanced diagnostic tools.What are the clinical implications?Enhanced diagnostic accuracy allows for the earlier detection of reduced LVEF through ECG analysis, which is critical in an environment where an echocardiogram is unavailable.ECG features enable patient risk stratification for reduced LVEF, facilitating targeted management and optimization of healthcare resources.The findings underscore the importance of integrating ECG features into AI-based diagnostic models for rapid, accurate LVEF estimation, supporting more informed clinical decisions and enabling effective remote patient monitoring.
Development of cell-free platforms for discovering, characterizing, and engineering post-translational modifications
Authors: Wong Derek A. , Shaver Zachary M. , Cabezas Maria D. , Daniel-Ivad Martin , Warfel Katherine F. , Prasanna Deepali V. , Sobol Sarah E. , Fernandez Regina , Nicol Robert , DeLisa Matthew P. , Balskus Emily P. , Karim Ashty S. , Jewett Michael C. 
Published: March 2024

AbstractPost-translational modifications (PTMs) are important for the stability and function of many therapeutic proteins and peptides. Current methods for studying and engineering PTM installing proteins often suffer from low-throughput experimental techniques. Here we describe a generalizable,in vitroworkflow coupling cell-free protein synthesis (CFPS) with AlphaLISA for the rapid expression and testing of PTM installing proteins. We apply our workflow to two representative classes of peptide and protein therapeutics: ribosomally synthesized and post-translationally modified peptides (RiPPs) and conjugate vaccines. First, we demonstrate how our workflow can be used to characterize the binding activity of RiPP recognition elements, an important first step in RiPP biosynthesis, and be integrated into a biodiscovery pipeline for computationally predicted RiPP products. Then, we adapt our workflow to study and engineer oligosaccharyltransferases (OSTs) involved in conjugate vaccine production, enabling the identification of mutant OSTs and sites within a carrier protein that enable high efficiency production of conjugate vaccines. In total, we expect that our workflow will accelerate design-build-test cycles for engineering PTMs.