bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep Learning Predicts Non-Normal Peptide FAIMS Mobility Distributions Directly from Sequence
Authors: McKetney Justin , Miller Ian J. , Hutton Alexandre , Sinitcyn Pavel , Coon Joshua J. , Meyer Jesse G.
Published: September 2024

Peptide ion mobility adds an extra dimension of separation to mass spectrometry-based proteomics. The ability to accurately predict peptide ion mobility would be useful to expedite assay development and to discriminate true answers in database search. There are methods to accurately predict peptide ion mobility through drift tube devices, but methods to predict mobility through high-field asymmetric waveform ion mobility (FAIMS) are underexplored. Here, we successfully model peptide ions’ FAIMS mobility using a multi-label multi-output classification scheme to account for non-normal transmission distributions. We trained two models from over 100,000 human peptide precursors: a random forest and a long-term short-term memory (LSTM) neural network. Both models had different strengths, and the ensemble average of model predictions produced higher F2 score than either model alone. Finally, we explore cases where the models make mistakes and demonstrate predictive performance of F2=0.66 (AUROC=0.928) on a new test dataset of nearly 40,000 differentE. colipeptide ions. The deep learning model is easily accessible viahttps://faims.xods.org.
Impact of anatomic variability and other vascular factors on lamina cribrosa hypoxia
Authors: Lu Yuankai , Hua Yi , Lee Po-Yi , Theophanous Andrew , Tahir Shaharoz , Tian Qi , Sigal Ian A.
Published: September 2024

Insufficient oxygenation in the lamina cribrosa (LC) may contribute to axonal damage and glaucomatous vision loss. To understand the range of susceptibilities to glaucoma, we aimed to identify key factors influencing LC oxygenation and examine if these factors vary with anatomical differences between eyes. We reconstructed 3D, eye-specific LC vessel networks from histological sections of four healthy monkey eyes. For each network, we generated 125 models varying vessel radius, oxygen consumption rate, and arteriole perfusion pressure. Using hemodynamic and oxygen supply modeling, we predicted blood flow distribution and tissue oxygenation in the LC. ANOVA assessed the significance of each parameter. Our results showed that vessel radius had the greatest influence on LC oxygenation, followed by anatomical variations. Arteriole perfusion pressure and oxygen consumption rate were the third and fourth most influential factors, respectively. The LC regions are well perfused under baseline conditions. These findings highlight the importance of vessel radius and anatomical variation in LC oxygenation, providing insights into LC physiology and pathology. Pathologies affecting vessel radius may increase the risk of LC hypoxia, and anatomical variations could influence susceptibility. Conversely, increased oxygen consumption rates had minimal effects, suggesting that higher metabolic demands, such as those needed to maintain intracellular transport despite elevated intraocular pressure, have limited impact on LC oxygenation.
An improved nanobody-based approach to capture and visualize specific interaction networks of binary protein complexes in living cells
Authors: Sleiman Nawal Hajj , Carnesecchi Julie , Jia Yunlong , Delolme Fréderic , Gilquin Laurent , Gouet Patrice , Merabet Samir
Published: September 2024

Protein interaction networks (or interactomes) are formed progressively, each interaction influencing the next one. Accordingly, a same protein will establish different interactomes depending on its first associated cofactor, thereby diversifying its function in the cell. In contrast to their central role, few methods exist to capture interactomes of dimeric protein complexes. Here, we tackle this issue by introducing an innovative method based on bimolecular fluorescence complementation and the specific binding of a nanobody fused to a proximity-dependent biotinylating enzyme. This method was applied to visualize and capture specific interactions of the cytoplasmic TAZ/14-3-3e and nuclear TAZ/TEAD2 complexes, which are major downstream effectors of the Hippo signaling pathway. Among other interactions, we identified SERPINB4 as a novel regulator of TAZ and 14-3-3e proliferative activity in mesenchymal stromal cells. Molecular dissections in living cells revealed the central role of a unique residue of TAZ for recruiting SERPINB4 specifically in the presence of 14-3-3e. Overall, our work demonstrates the importance of considering binary protein complexes for deciphering interactomes and establishes a novel sensitive method in this perspective.
Correlated and Anticorrelated Binocular Disparity Modulate GABA+ and Glutamate/glutamine Concentrations in the Human Visual Cortex
Authors: Matuszewski Jacek , Alvarez Ivan , Clarke William T. , Parker Andrew J. , Bridge Holly , Ip I. Betina
Published: September 2024

Binocular disparity is used for perception and action in three dimensions. Neurons in the primary visual cortex respond to binocular disparity in random dot patterns, even when the contrast is inverted between eyes (false depth cue). In contrast, neurons in the ventral stream largely cease to respond to false depth cues. This study evaluated whether GABAergic inhibition is involved in suppressing false depth cues in the human ventral visual cortex.

We compared GABAergic inhibition (GABA+) and glutamatergic excitation (Glx) during the viewing of correlated and anticorrelated binocular disparity in 18 participants using single voxel proton magnetic-resonance spectroscopy (MRS). Measurements were taken from the early visual cortex (EVC) and the lateral occipital cortex (LO). Three visual conditions were presented per voxel location: correlated binocular disparity; anticorrelated binocular disparity; or a blank grey screen with a fixation cross. To identify differences in neurochemistry, GABA+ or Glx levels were compared across viewing conditions.

In EVC, correlated disparity increased Glx over anticorrelated and rest conditions, also mirrored in the Glx/GABA+ ratio. In LO, anticorrelated disparity decreased GABA+ and increased Glx. Joint effects on GABA+ and Glx were summarised by the Glx/GABA+ ratio, which showed increased excitatory over inhibitory drive to anticorrelated disparity in LO. Glx during viewing of anticorrelation in LO was predictive of its object-selective BOLD-activity.

We provide evidence that early and ventral visual cortices change GABA+ and Glx concentrations during presentation of correlated and anticorrelated disparity, suggesting a contribution of cortical excitation and inhibition in disparity selectivity.

Significance Statement

The visual system must correctly match elements from the left and right eye for proper reconstruction of binocular depth. At the earliest part of binocular processing, false matches can activate depth detectors, however, the activation to false matches is absent in the ventral visual stream. We tested whether GABAergic inhibition contributes to the suppression of false matches in the ventral stream by measuring GABAergic inhibition and glutamatergic excitation in the human visual cortex during the presentation of correct and false matches. Correct matches increased excitation in response in the early visual cortex, and false matches increased excitation and decreased in the ventral visual cortex. These results suggest a role for excitation and inhibition in distinguishing depth cues for stereoscopic vision.
Identification of Growth Differentiation Factor-15 as An Early Predictive Biomarker for Metabolic Dysfunction-Associated Steatohepatitis: A Nested Case-control Study of UK Biobank Proteomic Data
Authors: Wang Hao , Xu Xiaoqian , Sun Yameng , You Hong , Jia Jidong , He You-Wen , Kong Yuanyuan
Published: September 2024

Background & Aims

The lack of non-invasive biomarkers for the early prediction of patients with metabolic dysfunction-associated steatohepatitis (MASH) is a major challenge for timely intervention. This study aims to determine the predictive capability for MASH long before its diagnosis by using six previously identified diagnostic biomarkers for metabolic dysfunction-associated steatotic liver disease (MASLD) with proteomic data from the UK Biobank.

Methods

A nested case-control study comprising of a MASH group and three age- and sex-matched controls groups (metabolic dysfunction-associated steatosis, viral hepatitis, and normal liver controls) were conducted. Olink proteomics, anthropometric and biochemical data at baseline levels were obtained from the UK Biobank. The baseline levels of CDCP1, FABP4, FGF21, GDF15, IL-6 and THBS2 were analyzed prospectively to determine their predictive accuracy for subsequent diagnosis with a mean lag time of over 10 years.

Results

At baseline, GDF15 demonstrated the best performance for predicting MASH occurrence at 5 and 10 years later, with an AUC of 0.90 at 5 years and 0.86 at 10 years. A predictive model based on four biomarkers (GDF15, FGF21, IL-6, and THBS2) showed AUCs of 0.88 at both 5 and 10 years. Furthermore, a protein-clinical model that included these four circulating protein biomarkers along with three clinical factors (BMI, ALT and TC) yielded AUCs of 0.92 at 5 years and 0.89 at 10 years.

Conclusion

GDF15 at baseline levels outperformed other individual circulating protein biomarkers for the early prediction of MASH. Our data suggest that GDF15 and the GDF15-based model may be used as easy-to-implement tools to identify patients with high risk of developing MASH at a mean lag time of over 10 years.
A Comprehensive Proteogenomic and Spatial Analysis of Innate and Acquired Resistance of Metastatic Melanoma to Immune Checkpoint Blockade Therapies
Authors: Wei Shiyou , Du Kuang , Lan Hongbin , Yang Zhenyu , Deng Yulan , Wei Zhi , Frederick Dennie T. , Lee Jinho , Labrie Marilyne , Tian Tian , Moll Tabea , Chen Yeqing , Sullivan Ryan J. , Mills Gordon , Boland Genevieve M. , Flaherty Keith T. , Liu Lunxu , Herlyn Meenhard , Zhang Gao
Published: September 2024

While a subset of patients with metastatic melanoma achieves durable responses to immune checkpoint blockade (ICB) therapies, the majority ultimately exhibit either innate or acquired resistance to these treatments. However, the molecular mechanisms underlying resistance to ICB therapies remain elusive and are warranted to elucidate. Here, we comprehensively investigated the tumor and tumor immune microenvironment (TIME) of paired pre- and post-treatment tumor specimens from metastatic melanoma patients who were primary or secondary resistance to anti-CTLA-4 and/or anti-PD-1/PD-L1 therapies. Differentially expressed gene (DEG) analysis and single-sample gene set enrichment analysis (ssGSEA) with transcriptomic data identified cell cycle and c-MYC signaling as pathway-based resistance signatures. And weighted gene co-expression network analysis (WGCNA) revealed the activation of a cross-resistance meta-program involving key signaling pathways related to tumor progression in ICB resistant melanoma. Moreover, spatially-resolved, image-based immune monitoring analysis by using NanoString’s digital spatial profiling (DSP) and Cyclic Immunofluorescence (CyCIF) showed infiltration of suppressive immune cells in the tumor microenvironment of melanoma with resistance to ICB therapies. Our study reveals the molecular mechanisms underlying resistance to ICB therapies in patients with metastatic melanoma by conducting such integrated analyses of multi-dimensional data, and provides rationale for salvage therapies that will potentially overcome resistance to ICB therapies.

Statement of translational relevance

This study paves the way for the creation of innovative therapeutic strategies, aimed at subverting resistance to immune checkpoint blockade (ICB) therapies in metastatic melanoma patients. By unraveling the specific molecular mechanisms underlying resistance, scientists can design effective alternative treatments that target pathways such as pathways associated with cell cycle dysregulation and c-MYC signaling. Furthermore, through the application of advanced immune monitoring techniques such as NanoString Digital Spatial Profiling (DSP) and Cyclic Immunofluorescence (CyCIF), this study has significantly enriched our understanding of the tumor microenvironment. This enhanced characterization facilitates the discovery of potential biomarkers that may forecast a patient’s response to ICB treatment. Ultimately, these advancements could potentially refine patient outcomes and foster the development of more personalized cancer treatments in the future.
Multi-center improvement in screening for dystonia in young people with cerebral palsy
Authors: Aravamuthan Bhooma R. , Lott Emma , Pehlivan Esra , Chintalapati Keerthana , Grenard Deborah , Roge Desiree , Gelineau-Morel Rose , Kyle Dante , Becu Christie , Kruer Michael , Katus Linn , Gross Paul , Bailes Amy ,   Cerebral Palsy Research Network
Published: September 2024

Background and Objectives

Dystonia is a common, debilitating, and often treatment refractory motor symptom of cerebral palsy (CP), affecting 70-80% of this population based on research assessments. However, routine clinical evaluation for dystonia in CP has failed to match these expected numbers. Addressing this diagnostic gap is a medical imperative because the presence of dystonia rules in or out certain treatments for motor symptoms in CP. Therefore, our objective was to optimize rates of clinical dystonia screening to improve rates of clinical dystonia diagnosis.

Methods

Using the quality improvement (QI) infrastructure of the Cerebral Palsy Research Network (CPRN), we developed and implemented interventions to increase the documentation percentage of five features of dystonia in young people with CP, aged 3-21 years old. This QI initiative was implemented by seven physiatry and pediatric movement disorders physicians at four tertiary-care pediatric hospitals between 10/10/21 and 7/1/23. We collected visit data cross-sectionally across all participating sites every 2 weeks and tracked our progress using control charts.

Results

We assessed 847 unique visits, mostly for established patients (719/847, 85%) who were 9.2 years old on average (95% CI 8.8-9.5). By 4/10/22, the mean percentage of dystonia screening elements documented across all sites rose from 39% to 90% and the mean percentage of visits explicitly documenting the presence or absence of dystonia rose from 65% to 94%. By 10/23/22, the percentage of visits diagnosing dystonia rose from 57% to 74%. These increases were all sustained through the end of the study period in 7/1/23.

Discussion

Using a rigorous QI-driven process across four member sites of a North American learning health network (CPRN), we demonstrated that we could increase screening for dystonia and that this was associated with increased clinical dystonia diagnosis, matching expected research-based rates. We propose that similar screening should take place across all sites caring for people with CP.
A Systematic Review of Air Pollution Exposure and Brain Structure and Function during Development
Authors: Morrel Jessica , Dong Michelle , Rosario Michael A. , Cotter Devyn L. , Bottenhorn Katherine L. , Herting Megan M.
Published: September 2024

Objectives

Air pollutants are known neurotoxicants. In this updated systematic review, we evaluate new evidence since our 2019 systematic review on the effect of outdoor air pollution exposure on childhood and adolescent brain structure and function as measured by magnetic resonance imaging (MRI).

Methods

Using PubMed and Web of Science, we conducted an updated literature search and systematic review of articles published through March 2024, using key terms for air pollution and functional and/or structural MRI. Two raters independently screened all articles using Covidence and implemented the risk of bias instrument for systematic reviews informing the World Health Organization Global Air Quality Guidelines.

Results

We identified 222 relevant papers, and 14 new studies met our inclusion criteria. Including six studies from our 2019 review, the 20 publications to date include study populations from the United States, Netherlands, Spain, and United Kingdom. Studies investigated exposure periods spanning pregnancy through early adolescence, and estimated air pollutant exposure levels via personal monitoring, geospatial residential estimates, or school courtyard monitors. Brain MRI occurred when children were on average 6-14.7 years old; however, one study assessed newborns. Several MRI modalities were leveraged, including structural morphology, diffusion tensor imaging, restriction spectrum imaging, arterial spin labeling, magnetic resonance spectroscopy, as well as resting-state and task-based functional MRI. Air pollutants were associated with widespread brain differences, although the magnitude and direction of findings are largely inconsistent, making it difficult to draw strong conclusions.

Conclusion

Prenatal and childhood exposure to outdoor air pollution is associated with structural and functional brain variations. Compared to our initial 2019 review, publications doubled—an increase that testifies to the importance of this public health issue. Further research is needed to clarify the effects of developmental timing, along with the downstream implications of outdoor air pollution exposure on children’s cognitive and mental health.

Highlights

Air pollutants have emerged as ubiquitous neurotoxicants

This field of study has grown substantially in the last 5 years

Exclusion of highly exposed populations poses a barrier to result generalizability

Longitudinal investigations are needed to understand developmental impacts of AP

Additional research should aim to clarify which children may be most vulnerable

Abstract Figure

Graphical Abstract
Predicting cancer patient mortality within 30 days of radiotherapy consultation to inform palliative radiotherapy fractionation decisions
Authors: Kiser Kendall J. , Vaidyanathan Ashish , Schuelke Matthew J. , Denzer Joshua , Landreth Trudy , Abraham Christopher D. , Wilcox Adam B.
Published: September 2024

Background

Radiation and medical oncologists evaluate patients’ risk of imminent mortality with scales like Karnofsky Performance Status (KPS) and predicate treatment decisions on these evaluations. However, we hypothesized that statistical models derived from structured electronic health record (EHR) data could predict patient deaths within 30 days of radiotherapy consultation better than models developed only with patient age and physician-reported KPS.

Methods

Clinical data from patients who consulted in a radiotherapy department from June 2018 – February 2024 were abstracted from EHR databases, including patient demographics, laboratory results, medications, comorbidities, KPS, cancer stages, oncologic treatment histories, oncologist notes, radiologist reports, and pathologist narratives. A subset of structured features known or believed to be associated with mortality were curated and used to train and test logistic regression, random forest, and gradient-boosted decision classifiers.

Results

Of 38,262 patients, 951 (2.5%) died within 30 days of radiotherapy consultation. From 34.5 gigabytes of tabular data, 2,977 clinical features were chosen or derived by a radiation oncologist, then reduced to 1,000 features using ANOVA F values. Using an event probability classification threshold of 0.2, optimized logistic regression, random forest, and gradient-boosted decision classifiers tested with high accuracy (0.97, 0.98, and 0.98, respectively) and F1 scores (0.50, 0.54, and 0.52). The areas under receiver operating and precision-recall curves for the random forest model were respectively 0.94 and 0.55, which outperformed a model trained only with patient age and KPS (0.61 and 0.06). Models prominently weighed features that were rationally associated with mortality.

Conclusion

Statistical models developed from a physician-curated feature space of structured EHR data predicted patient deaths within 30 days of radiotherapy consultation better than a model developed only with a patient’s age and physician-assessed KPS. With clinically explicable feature weights, these models could influence treatment decisions such as the length of palliative radiotherapy courses.
Modeling the effects of COVID-19 mobility disruptions on RSV transmission in Seattle, Washington
Authors: Srinivas Duddu Atchuta , Elgamal Islam , Camacho-Mateu José , Holubowska Olena , Rella Simon A. , Bents Samantha J. , Viboud Cécile , Hansen Chelsea L. , Pullano Giulia , Perofsky Amanda C.
Published: September 2024

Abstract

Introduction

Respiratory Syncytial Virus (RSV) infection is a major cause of acute respiratory hospitalizations in young children and older adults. In early 2020 most countries implemented non-pharmaceutical interventions (NPIs) to slow the spread of SARS-CoV-2. COVID-19 NPIs disrupted the transmission of RSV on a global scale, and many locations did not experience widespread re-circulation until late 2020 or 2021. Here, we use a mechanistic transmission model informed by cellphone mobility data to determine which aspects of population behavior had the greatest influence on post-pandemic RSV rebound in Seattle, Washington.

Methods

We used aggregated mobile device location data to characterize within-city mixing, visitor in-flows, and foot traffic to points of interest in Seattle. We fit an age-structured epidemiological model to data on weekly RSV hospitalizations, allowing for reductions in transmission due to declines in mobility during the pandemic. We compared model fits to observed data to assess which mobility behaviors best capture RSV dynamics during the first two post-pandemic waves in Seattle.

Results

In Seattle, COVID-19 NPIs perturbed RSV seasonality from 2020 to 2022. Seattle experienced a small out-of-season outbreak in Summer 2021 and an atypically large and early wave in Fall 2022. RSV transmission models incorporating mobility network connectivity (measured as the average shortest path length between Seattle neighborhoods) or the inflow of visitors from outside of Seattle best captured the timing and magnitude of the first two post-pandemic waves. Models including foot traffic to schools or child daycares or within-neighborhood movement produced poor fits to observed data.

Conclusions

Our results suggest that case importations from other regions and local spread between neighborhoods had the greatest influence on the timing of RSV reemergence in Seattle. These findings contribute to the understanding of behavioral factors underlying RSV epidemic spread and can inform the timing of preventative measures, such as the administration of immunoprophylaxis.
Prevalence and determinants of modern contraception use among persons with disabilities in low- and middle-income countries: a systematic review and meta-analysis
Authors: Chowdhury Atika Rahman , Khanam Shimlin Jahan , Islam Mohammad Zahidul , Khandaker Gulam , Khan Md Nuruzzaman
Published: September 2024

Background

Persons with disabilities should require the same level of access to contraception as the general population. However, the extent of contraception use among this group is underexplored in low- and middle-income countries (LMICs).

Objective

This study aimed to determine the prevalence of modern contraception use among persons with disabilities in LMICs and identify the key determinants.

Methods

In June 2024, we conducted a systematic search across six databases to identify studies on disability and modern contraception in LMICs. The primary outcomes were the prevalence of modern contraception use and its determinants among persons with disabilities. Summary estimates were calculated using fixed or random-effects meta-analysis, depending on the level of heterogeneity.

Results

A total of 19 studies were identified, with 11 included in the meta-analysis. The pooled prevalence of modern contraception use among persons with disabilities was 31.4% (95% CI: 26.5, 36.2), with significant heterogeneity across respondent characteristics. Five factors were significantly associated with higher contraception use: age over 25 years, having some level of education, being in a higher wealth quintile, adequate knowledge of family planning, and being in a formal marital relationship.

Conclusion

This study reveals a significantly lower prevalence of modern contraception use among persons with disabilities in LMICs. Improving access to education, addressing social norms, and strengthening healthcare systems may contribute to increase contraception access and uptake among persons with disabilities in LMICs.
Deep learning for classifying neuronal morphologies: combining topological data analysis and graph neural networks
Authors: Kanari Lida , Schmidt Stanislav , Casalegno Francesco , Delattre Emilie , Banjac Jelena , Negrello Thomas , Shi Ying , Meystre Julie , Defferrard Michaël , Schürmann Felix , Markram Henry
Published: September 2024

The shape of neuronal morphologies plays a critical role in determining their dynamical properties and the functionality of the brain. With an abundance of neuronal morphology reconstructions, a robust definition of cell types is important to understand their role in brain functionality. However, an objective morphology classification scheme is hard to establish due to disagreements on the definition of cell types, on which subjective views of field experts show significant differences. The robust grouping of neurons based on their morphological shapes is important for generative models and for establishing a link between anatomical properties and other modalities, such as biophysical and transcriptomic information. We combine deep learning techniques with a variety of mathematical descriptions of neurons and evaluate the classification accuracy of different methods. We demonstrate that various methodologies, including graph neural networks, topological morphology descriptors, and morphometrics, consistently perform with the highest accuracy for a variety of datasets. Based on these methods, we present a robust classification of both inhibitory and excitatory cell types in the rodent cortex and propose a generalized scheme for a consistent classification of neurons into classes.
Selective expansion of motor cortical projections in the evolution of vocal novelty
Authors: Isko Emily C. , Harpole Clifford E. , Zheng Xiaoyue Mike , Zhan Huiqing , Davis Martin B. , Zador Anthony M. , Banerjee Arkarup
Published: September 2024

Deciphering how cortical architecture evolves to drive behavioral innovations is a long-standing challenge in neuroscience and evolutionary biology. Here, we leverage a striking behavioral novelty in the Alston’s singing mouse (Scotinomys teguina), compared to the laboratory mouse (Mus musculus), to quantitatively test models of motor cortical evolution. We used bulk tracing, serial two-photon tomography, and high-throughput DNA sequencing of over 76,000 barcoded neurons to discover a specific and substantial expansion (∼200%) of orofacial motor cortical (OMC) projections to the auditory cortical region (AudR) and the midbrain periaqueductal gray (PAG), both implicated in vocal behaviors. Moreover, analysis of individual OMC neurons’ projection motifs revealed preferential expansion of exclusive projections to AudR. Our results imply that selective expansion of ancestral motor cortical projections can underlie behavioral divergence over short evolutionary timescales, suggesting potential mechanisms for the evolution of enhanced cortical control over vocalizations—a crucial preadaptation for human language.
Variant Evolution Graph: Can We Infer How SARS-CoV-2 Variants are Evolving?
Authors: Das Badhan , Heath Lenwood S.
Published: September 2024

The SARS-CoV-2 virus has undergone mutations over time, leading to genetic diversity among circulating viral strains. This genetic diversity can affect the characteristics of the virus, including its transmissibility and the severity of symptoms in infected individuals. During the pandemic, this frequent mutation creates an enormous cloud of variants known as viral quasispecies. Most variation is lost due to the tight bottlenecks imposed by transmission and survival. Advancements in next-generation sequencing have facilitated the rapid and cost-effective production of complete viral genomes, enabling the ongoing monitoring of the evolution of the SARS-CoV-2 genome. However, inferring a reliable phylogeny from GISAID (the Global Initiative on Sharing All Influenza Data) is daunting due to the vast number of sequences. In the face of this complexity, this research proposes a new method of representing the evolutionary and epidemiological relationships among the SARS-CoV-2 variants inspired by quasispecies theory. We aim to build a Variant Evolution Graph (VEG), a novel way to model viral evolution in a local pandemic region based on the mutational distance of the genotypes of the variants. VEG is a directed acyclic graph and not necessarily a tree because a variant can evolve from more than one variant; here, the vertices represent the genotypes of the variants associated with their human hosts, and the edges represent the evolutionary relationships among these variants. A disease transmission network, DTN, which represents the transmission relationships among the hosts, is also proposed and derived from the VEG. We downloaded the genotypes of the variants recorded in GISAID, which are complete, have high coverage, and have a complete collection date from five countries: Somalia (22), Bhutan (102), Hungary (581), Iran (1334), and Nepal (1719). We ran our algorithm on these datasets to get the evolution history of the variants, build the variant evolution graph represented by the adjacency matrix, and infer the disease transmission network. Our research represents a novel and unprecedented contribution to the field of viral evolution, offering new insights and approaches not explored in prior studies.
Multifaceted roles of H2B mono-ubiquitylation in D-loop metabolism during homologous recombination repair
Authors: Hung Shih-Hsun , Liang Yuan , Heyer Wolf-Dietrich
Published: September 2024

Repairing DNA double-strand breaks is crucial for maintaining genome integrity, which occurs primarily through homologous recombination (HR) inS. cerevisiae.Nucleosomes, composed of DNA wrapped around a histone octamer, present a natural barrier to end-resection to initiate HR, but the impact on the downstream HR steps of homology search, DNA strand invasion and repair synthesis remain to be determined. Displacement loops (D-loops) play a pivotal role in HR, yet the influence of chromatin dynamics on D-loop metabolism remains unclear. Using the physical D-loop capture (DLC) and D-loop extension (DLE) assays to track HR intermediates, we employed genetic analysis to reveal that H2B mono-ubiquitylation (H2Bubi) affects multiple steps during HR repair. We infer that H2Bubi modulates chromatin structure, not only promoting histone degradation for nascent D-loop formation but also stabilizing extended D-loops through nucleosome assembly. Furthermore, H2Bubi regulates DNA resectionviaRad9 recruitment to suppress a feedback control mechanism that dampens D-loop formation and extension at hyper-resected ends. Through physical and genetic assays to determine repair outcomes, we demonstrate that H2Bubi plays a crucial role in preventing break-induced replication and thus promoting genomic stability.

Graphical Abstract

Highlights

H2Bubi is epistatic to H2A.Z and INO80 in promoting homology search and D-loop formation

H2Bubi stabilizes extended D-loop

Excessive resection counteracts D-loop formation and extension

H2Bubi promotes crossover events and limits the frequency of break-induced replication outcomes in HR repair
Purkinje cells in Crus I and II encode the visual stimulus and the impending choice as monkeys learn a reinforcement based visuomotor association task
Authors: Ipata Anna E. , Fascianelli Valeria , De Zeeuw Chris I. , Sendhilnathan Naveen , Fusi Stefano , Goldberg Michael E.
Published: September 2024

Visuomotor association involves linking an arbitrary visual cue to a well-learned movement. Transient inactivation of Crus I/II impairs primates’ ability to learn new associations and delays motor responses without affecting the kinematics of the movement. The simple spikes of Purkinje cells in the Crus regions signal cognitive errors as monkeys learn to associate specific fractal stimuli with movements of the left or right hand. Here we show that as learning progresses, the simple spike activity of individual neurons becomes more selective for stimulus-response associations, with selectivity developing closer to the appearance of visual stimuli. Initially, most neurons respond to both associations, irrespective of the identity of the stimulus and the associated movement, but as learning advances, more neurons distinguish between specific stimulus-hand associations. Using a linear decoder, it was found that in early learning stages, the visual stimulus can be decoded only when the choice can also be decoded. As learning improves, the visual stimulus is decoded earlier than the choice. A simple model can replicate the observed simple spike signals and the monkeys’ behavior in both the early and late learning stages.
Neural and verbal responses to attachment-schema narratives differ based on past and current caregiving experiences
Authors: Lee Caroline S , Cohen Samantha S , Hutchinson Samuel , Tottenham Nim , Baldassano Christopher
Published: September 2024

Children's caregiving experiences impact the internal models they use to process new emotional events. Examining inter-subject functional correlation in 7- to 15-year-olds during narrative movies depicting separation and reunion, we find that secure attachment to current caregivers plays a larger role than early adversity in shaping prefrontal-amygdala connectivity. Secure attachment also decreased the emphasis in later memory on separation elements in the narrative.
Surface-mediated Bacteriophage Defense Incurs Fitness Tradeoffs for Interbacterial Antagonism
Authors: Tsai Chia-En , Wang Feng-Qi , Yang Chih-Wen , Yang Ling-Li , Nguyen Thao V. , Chen Yung-Chih , Chen Po-Yin , Hwang Ing-Shouh , Ting See-Yeun
Published: September 2024

Bacteria in polymicrobial habitats are constantly exposed to biotic threats from bacteriophages (or “phages”), antagonistic bacteria, and predatory eukaryotes. These antagonistic interactions play crucial roles in shaping the evolution and physiology of bacteria. To survive, bacteria have evolved mechanisms to protect themselves from such attacks, but the fitness costs of resisting one threat and rendering bacteria susceptible to others remain unappreciated. Here, we examined the fitness consequences of phage resistance inSalmonella enterica, revealing that phage-resistant variants exhibited significant fitness loss upon co-culture with competitor bacteria. These phage-resistant strains display varying degrees of lipopolysaccharide (LPS) deficiency and increased susceptibility to contact-dependent interbacterial antagonism, such as the type VI secretion system (T6SS). Utilizing mutational analyses and atomic force microscopy, we show that the long-modal length O-antigen of LPS serves as a protective barrier against T6SS-mediated intoxication. Notably, this competitive disadvantage can also be triggered independently by phages possessing LPS-targeting endoglycosidase in their tail spike proteins, which actively cleave the O- antigen upon infection. Our findings reveal two distinct mechanisms of phage-mediated LPS modifications that modulate interbacterial competition, shedding light on the dynamic microbial interplay within mixed populations.
Pervasive findings of directional selection realize the promise of ancient DNA to elucidate human adaptation
Authors: Akbari Ali , Barton Alison R. , Gazal Steven , Li Zheng , Kariminejad Mohammadreza , Perry Annabel , Zeng Yating , Mittnik Alissa , Patterson Nick , Mah Matthew , Zhou Xiang , Price Alkes L. , Lander Eric S. , Pinhasi Ron , Rohland Nadin , Mallick Swapan , Reich David
Published: September 2024

We present a method for detecting evidence of natural selection in ancient DNA time-series data that leverages an opportunity not utilized in previous scans: testing for a consistent trend in allele frequency change over time. By applying this to 8433 West Eurasians who lived over the past 14000 years and 6510 contemporary people, we find an order of magnitude more genome-wide significant signals than previous studies: 347 independent loci with >99% probability of selection. Previous work showed that classic hard sweeps driving advantageous mutations to fixation have been rare over the broad span of human evolution, but in the last ten millennia, many hundreds of alleles have been affected by strong directional selection. Discoveries include an increase from ∼0% to ∼20% in 4000 years for the major risk factor for celiac disease atHLA-DQB1; a rise from ∼0% to ∼8% in 6000 years of blood type B; and fluctuating selection at theTYK2tuberculosis risk allele rising from ∼2% to ∼9% from ∼5500 to ∼3000 years ago before dropping to ∼3%. We identify instances of coordinated selection on alleles affecting the same trait, with the polygenic score today predictive of body fat percentage decreasing by around a standard deviation over ten millennia, consistent with the “Thrifty Gene” hypothesis that a genetic predisposition to store energy during food scarcity became disadvantageous after farming. We also identify selection for combinations of alleles that are today associated with lighter skin color, lower risk for schizophrenia and bipolar disease, slower health decline, and increased measures related to cognitive performance (scores on intelligence tests, household income, and years of schooling). These traits are measured in modern industrialized societies, so what phenotypes were adaptive in the past is unclear. We estimate selection coefficients at 9.9 million variants, enabling study of how Darwinian forces couple to allelic effects and shape the genetic architecture of complex traits.
Spatiotemporal Patterns of Gene Expression During Development of a Complex Colony Morphology
Authors: Cromie Gareth A. , Tan Zhihao , Hays Michelle , Sirr Amy , Dudley Aimée M.
Published: September 2024

Clonal communities of single celled organisms, such as bacterial or fungal colonies and biofilms, are spatially structured, with subdomains of cells experiencing differing environmental conditions. In the development of such communities, cell specialization is not only important to respond and adapt to the local environment but has the potential to increase the fitness of the clonal community through division of labor. Here, we examine colony development in a yeast strain (F13) that produces colonies with a highly structured “ruffled” phenotype in the colony periphery and an unstructured “smooth” phenotype in the colony center. We demonstrate that in the F13 genetic background deletions of transcription factors can either increase(dig1Δ,sfl1Δ) or decrease(tec1Δ) the degree of colony structure. To investigate the development of colony structure, we carried out gene expression analysis on F13 and the three deletion strains using RNA-seq. Samples were taken early in colony growth (day2), which precedes ruffled phenotype development in F13, and from the peripheral and central regions of colonies later in development (day5), at which time these regions are structured and unstructured (respectively) in F13. We identify genes responding additively and non-additively to the genotype and spatiotemporal factors and cluster these genes into a number of different expression patterns. We identify clusters whose expression correlates closely with the degree of colony structure in each sample and include genes with known roles in the development of colony structure. Individual deletion of 26 genes sampled from different clusters identified 5 with strong effects on colony morphology (BUD8,CIS3,FLO11,MSB2andSFG1), all of which eliminated or greatly reduced the structure of the F13 outer region.
Connectomic analysis of taste circuits inDrosophila
Authors: Walker Sydney R. , Peña-Garcia Marco , Devineni Anita V.
Published: September 2024

Our sense of taste is critical for regulating food consumption. The fruit flyDrosophilarepresents a highly tractable model to investigate mechanisms of taste processing, but taste circuits beyond sensory neurons are largely unidentified. Here, we use a whole-brain connectome to investigate the organization ofDrosophilataste circuits. We trace pathways from four populations of sensory neurons that detect different taste modalities and project to the subesophageal zone (SEZ). We find that second-order taste neurons are primarily located within the SEZ and largely segregated by taste modality, whereas third-order neurons have more projections outside the SEZ and more overlap between modalities. Taste projections out of the SEZ innervate regions implicated in feeding, olfactory processing, and learning. We characterize interconnections between taste pathways, identify modality-dependent differences in taste neuron properties, and use computational simulations to relate connectivity to predicted activity. These studies provide insight into the architecture ofDrosophilataste circuits.
Split of the pseudocritical temperatures of chiral and confinement-deconfinement transitions by a temperature gradient
Authors: Yang Ji-Chong , Li Wen-Wen , Yue Chong-Xing
Published: September 2024

Searching of the critical endpoint (CEP) of the phase transition of quantum chromodynamics (QCD) matter in experiments is of great interest. The temperature in the fireball at a collider is location dependent, however, most theoretical studies address the scenario of uniform temperature. In this work, the effect of temperature gradients is investigated using lattice QCD approach. We find that the temperature gradient catalyzes chiral symmetry breaking, meanwhile the temperature gradient increases the Polyakov loop in the confined phase but suppresses the Polyakov loop in the deconfined phase. Furthermore, the temperature gradient decreases the pseudocritical temperature of chiral transition but increases the pseudocritical temperature of the confine-deconfine transition. It is also found that the temperature gradient can drive the system away from the singularity, implying that the CEP in the T−μ plane may move in the direction of the first-order phase transition in the phase diagram due to the temperature gradient.

Published by the American Physical Society
2024
Atomic binding corrections for high-energy fixed target experiments
Authors: Plestid Ryan , Wise Mark B.
Published: September 2024

High-energy beams incident on a fixed target may scatter against atomic electrons. To a first approximation, one can treat these electrons as free and at rest. For precision experiments, however, it is important to be able to estimate the size of, and when necessary calculate, subleading corrections. We discuss atomic binding corrections to relativistic lepton-electron scattering. We analyze hydrogen in detail, before generalizing our analysis to multi-electron atoms. Using the virial theorem, and many-body sum rules, we find that the corrections can be reduced to measured binding energies, and the expectation value of a single one-body operator. We comment on the phenomenological impact for neutrino flux normalization and an extraction of hadronic vacuum polarization from elastic muon electron scattering at MUonE.

Published by the American Physical Society
2024
Holographic RG flows in a 3D gauged supergravity at finite temperature
Authors: Golubtsova Anastasia , Nikolaev Alexander , Podoinitsyn Mikhail
Published: September 2024

In this paper, we consider finite-temperature holographic renormalization group (RG) flows in D=3 N=(2,0) gauged truncated supergravity coupled to a sigma model with a hyperbolic target space. In the context of the holographic duality, fixed points (CFTs) at finite temperature are described by anti–de Sitter (AdS) black holes. We come from the gravity equations of motion to a 3D autonomous dynamical system, which critical points can be related to fixed points of dual field theories. Near-horizon black hole solutions correspond to infinite points of this system. We use Poincaré transformations to project the system on R3 into the 3D unit cylinder such that the infinite points are mapped onto the boundary of the cylinder. We explore numerically the space of solutions. We show that the exact RG flow at zero temperature is the separatrix for asymptotically AdS black hole solutions if the potential has one extremum, while for the potential with three extrema the separatrices are RG flows between AdS fixed points. We find near-horizon analytical solutions for asymptotically AdS black holes using the dynamical equations. We also present a method for constructing full analytical solutions.

Published by the American Physical Society
2024
Simultaneous Measurement of the Half-Life and Spectral Shape of
In115

β
Decay with an Indium Iodide Cryogenic Calorimeter
Authors: Pagnanini L. , Benato G. , Carniti P. , Celi E. , Chiesa D. , Corbett J. , Dafinei I. , Di Domizio S. , Di Stefano P. , Ghislandi S. , Gotti C. , Helis D. L. , Knobel R. , Kostensalo J. , Kotila J. , Nagorny S. , Pessina G. , Pirro S. , Pozzi S. , Puiu A. , Quitadamo S. , Sisti M. , Suhonen J. , Kuznetsov S.
Published: September 2024

Current bounds on the neutrino Majorana mass are affected by significant uncertainties in the nuclear calculations for neutrinoless double-beta decay. A key issue for a data-driven improvement of the nuclear theory is the actual value of the axial coupling constant gA, which can be investigated through forbidden β decays. We present the first measurement of the 4th-forbidden β decay of In115 with a cryogenic calorimeter based on indium iodide. Exploiting the enhanced spectrum-shape method for the first time to this isotope, our study accurately determines simultaneously spectral shape, gA, and half-life. The interacting shell model, which best fits our data, indicates a half-life for this decay at T1/2=(5.26±0.06)×1014  yr.

Published by the American Physical Society
2024
Higher-order Poincaré spheres and spatiospectral Poincaré beams
Authors: Fickler R. , Kopf L. , Ornigotti M.
Published: September 2024

Light with a complex structure has become a powerful tool in many studies in classical and quantum optics. Here, we introduce a visual representation of light that is structured simultaneously in space, frequency, and polarization in the form of a higher-order Poincaré sphere and describe interesting links to its fundamental counterpart. We leverage the description to show and experimentally generate light possessing all possible polarization states across its spatiospectral shape, which we term spatiospectral Poincaré beams. By extending the powerful description of higher-order Poincaré spheres to the spatiospectral domain, our work will help to gain a deeper understanding and to develop beneficial applications of structured light.

Published by the American Physical Society
2024
Optimizing quantum tomography via shadow inversion
Authors: Caprotti Andrea , Morris Joshua , Dakić Borivoje
Published: September 2024

In quantum information theory, the accurate estimation of observables is pivotal for quantum information processing, playing a crucial role in computational and communication protocols. This work introduces a technique for estimating such objects, leveraging an underutilized resource in the inversion map of classical shadows that greatly refines the estimation cost of target observables without incurring any additional overhead. A generalized framework for computing and optimizing additional degrees of freedom in the homogeneous space of the shadow inversion is given that may be adapted to a variety of near-term problems. In the special case of local measurement strategies, we show feasible optimization leading to an exponential separation in sample complexity versus the standard approach and, in an exceptional case, we give nontrivial examples of optimized postprocessing for local measurements, achieving the same efficiency as the global Cliffords shadows.

Published by the American Physical Society
2024