bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Mechanism and Structural Models of Protein-Mediated Copper Transfer to theArabidopsis thalianaEthylene Receptor ETR1 at the ER Membrane
Authors: Dluhosch Dominik , Kersten Lisa Sophie , Minges Alexander , Schott-Verdugo Stephan , Gohlke Holger , Groth Georg
Published: January 2025

In plants, the gaseous plant hormone ethylene regulates a wide range of developmental processes and stress responses. The small unsaturated hydrocarbon is detected by a family of receptors (ETRs) located in the membrane of the endoplasmic reticulum, which rely on a monovalent copper cofactor to detect this hydrocarbon. The copper-transporting P-type ATPase RAN1 (HMA7), located in the same membrane, is known to be essential for the biogenesis of ETRs. Still, the precise molecular mechanism by which the receptors acquire their copper cofactor remains unclear. A recent study by our laboratory demonstrated a direct interaction between RAN1 and soluble copper chaperones of the ATX1 family with the model ethylene receptor ETR1, providing initial insights into the mechanism by which copper is transferred from the cytosol to the membrane-bound receptors. In this study, we further investigated these interactions with respect to the function of individual domains in complex formation. To this end, we combined biochemical experiments and computational predictions and unraveled the processes and mechanisms by which copper is transferred to ETR1 at the molecular level.
Distinct memory CD4 subset tropism of two CCR5-tropic HIV-1 in a rapid progressor
Authors: Marichannegowda Manukumar Honnayakanahalli , Farah Yasmine , Bose Meera , Sanders-Buell Eric , King David , Francisco Leilani , Eller Leigh Anne , Tovanabutra Sodsai , Michael Nelson L. , Robb Merlin L. , Song Hongshuo
Published: January 2025

CCR5 tropic HIV-1 mainly infect memory CD4+T cells. Memory CD4+T cells are heterogenous which comprise central memory (CM), transitional memory (TM) and effector memory (EM) subsets based on cell differentiation stages. Previous studies demonstrate that low viral burden in the CM subset correlates with long-term non-progressive HIV-1 infection (1, 2) and is a hallmark of non-pathogenetic SIV infection (3, 4). These findings indicate the importance of CD4 subset tropism of HIV/SIV in determining disease progression. However, an important, yet unanswered question is whether CCR5 HIV-1 variants have different memory CD4 subset preferences. Here, we demonstrate clear compartmentalization of two CCR5 HIV-1 in different memory CD4 subsetsin vivo.
Inhibition of SQSTM1/p62 oligomerization and Keap1 sequestration by the Cullin-3 adaptor SHKBP1
Authors: Luan Lin , Cao Xiaofu , Baskin Jeremy M.
Published: January 2025

SQSTM1/p62 is a master regulator of the autophagic and ubiquitination pathways of protein degradation and the antioxidant response. p62 functions in these pathways via reversible assembly and sequestration of additional factors into cytoplasmic phase-separated structures termed p62 bodies. The physiological roles of p62 in these various pathways depends on numerous mechanisms for regulating p62 body formation and dynamics that are incompletely understood. Here, we identify a new mechanism for regulation of p62 oligomerization and incorporation into p62 bodies by SHKBP1, a Cullin-3 E3 ubiquitin ligase adaptor, that is independent of its potential functions in ubiquitination. We map a SHKBP1–p62 protein-protein interaction outside of p62 bodies that limits p62 assembly into p62 bodies and affects the antioxidant response by preventing sequestration and degradation of Keap1. These studies provide a non-ubiquitination-based mechanism for an E3 ligase adaptor in regulating p62 phase separation and cellular responses to oxidative stress.
Development of an RT-RPA assay for La Crosse virus detection provides insights into age-dependent neuroinvasion in mice
Authors: Lumkong Lily , Alatrash Reem , Sridhar Sainetra , Herrera Bobby Brooke
Published: January 2025

La Crosse virus (LACV) is a mosquito-borne arbovirus that causes pediatric encephalitis in North America, primarily affecting children under the age of 16 years of age. Early and accurate diagnosis is crucial to reducing morbidity in this vulnerable population; however, existing molecular and serological methods face limitations in sensitivity, specificity, and accessibility. Here, we present the development of a reverse transcription recombinase polymerase amplification (RT-RPA) assay for LACV detection. Our assay detects LACV within 20 minutes with a limit of detection of 100-1000 viral copies, demonstrating high specificity without cross-reactivity against closely related or geographically relevant arboviruses. We further integrate the RT-RPA assay into a lateral flow format, potentially enabling simple and inexpensive point-of-care diagnosis. To complement our assay development, we investigated viral pathogenesis in a mouse model that recapitulates the age-dependent susceptibility observed in human populations. Using this RT-RPA assay, we reveal that LACV invades the brains of weanling mice as early as 4 days post-infection (dpi) and adult mice by 5 dpi. Surviving adult mice had no detectable virus within their brains by 20 dpi. These results underscore the utility of our RT-RPA-based platform for LACV diagnosis and offer novel insights into the age-dependent temporal dynamics of LACV neuroinvasion and viral clearance.
Supracellular contractility inXenopus laevisembryonic epithelia regulated by extracellular nucleotides and the purinergic G-protein coupled receptor P2Y2
Authors: Joshi Sagar D. , Jackson Timothy R. , Zhang Lin , Stuckenholz Carsen , Davidson Lance A.
Published: January 2025

Extracellular signals regulate epithelial homeostasis, cell fate and pattern cell behaviors during embryogenesis, wound healing, regeneration, and disease progression. Previous studies in our group found cell lysate from intentionally wounded embryos triggers a strong but transient contraction in neighboring epithelia, whether contiguous to the wound site or in non-wounded embryos. We previously identified extracellular ATP (eATP) as a possible candidate. Here we test additional candidates and find several nucleotides including ADP, UTP, and UDP also trigger contractility. Through a temporal and spatial screen of lysate activity, an inhibitor screen, and morpholino knock-down of candidate receptors, we find contractility is mediated by a G-protein coupled purinergic receptor P2Y2 (P2RY2). Activated P2RY2 triggers F-actin assembly and myosin II contractility. Knockdown of P2RY2 or overexpression of mutant G-protein effectors abrogate epithelial contractility when epithelia are exposed to eATP or lysate. We demonstrate that the major contributors to epithelial contractility in lysate are extracellular nucleotide triphosphates ATP and UTP, which are sensed by P2RY2 and transduced through G-proteins to contract the epithelium.

Summary Statement

Contractility of theXenopusembryonic epithelium can be driven by extracellular nucleotides ATP or UTP and actuated by the G-protein coupled purinergic receptor P2Y2 (P2RY2).

Highlights

Extracellular nucleotides ATP and UTP can trigger epithelial contractility.

Epithelia contract in response to (ATP ∼ UTP) > (ADP ∼ UDP) > ADO (adenosine).

The purinergic G-protein coupled receptor P2Y2 is responsible for this contractile response by indirectly modulating actomyosin contractility.
Using Mobile Phone Infrastructure Provides Evidence of a Reduction in Diagnostic Turnaround Times and Improved HIV Viral Load Monitoring in Malawi
Authors: Haggard Rachel , Mwase Christopher , Klyn Brandon , Metz Lynn , Smith Tyler , Cooper Hannah , Chiwandira Brown , Chewere Linley , Green Dylan
Published: January 2025

Background

Malawi has 991,600 people living with HIV and has expanded access to annual HIV viral load (VL) testing to enhance care quality for clients. However, significant delays persist in returning VL results from laboratories to facilities and from sample collection to client receipt. To address this, we implemented a digital viral load results return (VLRR) application, using existing mobile phone platforms (SMS/USSD), to expedite results return to clients and healthcare providers (HCPs).

Methods

VLRR is a digital SMS/USSD platform leveraging mobile phones to reduce turnaround time (TAT) and improve access to VL results. To evaluate the VLRR intervention, we: (1) estimated the TAT for digital results return and compared it to the paper-based process, (2) calculated open rates for digital results, (3) conducted a qualitative evaluation with VLRR users, and (4) estimated the potential cost savings from avoiding unnecessary sample redraws.

Results

From April 2022 to June 2024, HCPs registered 4,067 clients. Before VLRR implementation, the average TAT for clients to receive VL results was 128 days. After VLRR enrollment, it was 48.5 days (a 62.4% improvement) using electronic medical record data. By Q2 2023, VLRR clients and HCPs received results in an average of 30 and 38 days.

The overall open rate for digital results (opened by either a client or HCP) was 72%. Of the clients interviewed, 98% expressed a desire to continue using VLRR, and 100% of HCPs recommended expanding the platform to other HCPs.

Conclusion

VLRR is effective in reducing TAT and improving access to VL results for both clients and HCPs. To enhance uptake and achieve national scale, VLRR can be integrated into Malawi’s existing EMR systems, further reducing TAT and enabling HCPs to deliver higher quality care and improve long-term clinical outcomes.
Sex Differences in the Risk of Bronchopulmonary Dysplasia and Pulmonary Hypertension: A Bayesian Meta-Analysis
Authors: van Westering-Kroon Elke , Hundscheid Tamara M. , Van Mechelen Karen , Bartoš František , Abman Steven H. , Villamor Eduardo
Published: January 2025

Abstract

Background

Bronchopulmonary dysplasia (BPD) is generally considered to be more frequent in males than in females. We conducted a Bayesian model-averaged (BMA) meta-analysis of studies addressing sex differences in the risk of developing different severities of BPD and BPD-associated pulmonary hypertension (BPD-PH).

Methods

We used BMA to calculate Bayes factors (BFs). The BF10is the ratio of the probability of the data under the alternative hypothesis (presence of sex differences) over the probability of the data under the null hypothesis (absence of sex differences). BPD was classified as BPD28 (supplemental oxygen at or during 28 days), BPD36 (oxygen at 36 weeks postmenstrual age), mild, moderate, and severe BPD.

Results

We included 222 studies (541,826 infants). The BMA analysis showed extreme evidence in favor of a male disadvantage in BPD28 (BF10>105), BPD36 (BF10>1021), and severe BPD (BF10=87.55), but not in mild BPD (BF10=0.28), or BPD-PH (BF10=0.54). The evidence for a male disadvantage in BPD decreased as the gestational age of the cohort decreased.

Conclusions

We confirmed the presence of a male disadvantage in moderate-to-severe BPD, but not in less severe forms of BPD or in BPD-PH. The male disadvantage in BPD is much less apparent in the more immature infants.

Impact

This Bayesian meta-analysis confirms that the risk of developing moderate to severe bronchopulmonary dysplasia (BPD) is approximately 20% higher in males than in females.

Sex differences in BPD decrease with decreasing gestational age, are heterogeneous across geographic and sociodemographic settings, and have remained persistently stable over time.

There is no evidence supporting sex differences in pulmonary hypertension associated with BPD.

An important step in the process of individualizing the approach to BPD may be to consider the sex of the infant, as this information can be used to personalize care and potentially improve outcomes.
Multiomic profiling of metastatic potential in estrogen receptor-positive human epidermal growth factor-negative breast cancer
Authors: Mosquim Sergio , Zamore Måns , Vallon-Christersson Johan , Rydén Lisa , Levander Fredrik
Published: January 2025

Metastatic disease is the main cause of breast cancer-related deaths. Given advances in the molecular profiling of tumors, we here aimed at integrating proteome, phosphoproteome and transcriptome data for the profiling of primary tumors to allow for discovery of new subtypes and features predicting lymph node and distant metastases in breast cancer (BC). We analyzed a total of 182 estrogen-receptor (ER) positive, human epidermal growth factor receptor 2 (HER2) negative BC samples using label-free Data Independent Acquisition (DIA) liquid chromatography tandem mass spectrometry (LC-MS/MS), quantifying a total of 13571 protein groups, 7107 phosphopeptides and 13085 expressed genes in at least 70% of the samples. Unsupervised consensus cluster analyses permitted the identification of potential subtypes with differential immune infiltration pattern and survival. Immune deconvolution data was combined with multiomics factor analysis, providing unique insight into different markers for lymph node and distant metastases. In summary, we further developed a protocol for parallel acquisition of matched proteomics, phosphoproteomics and transcriptomics data, resulting in the most comprehensive dataset of its kind and allowing for unique insights into metastatic processes in ER-positive/HER2-negative BC.
Disparities in US public historic cancer mortality data: Advocacy for gastrointestinal cancers, tailored prevention measures, and the inclusion of oversea deaths. -Under-reporting of cancer deaths as sign of health disparity
Authors: Zhang Tingting , Valle Juan , Patel Ashokkumar A. , Lindsey Stacie , Smith Aki , Hung Tony Kin Wai
Published: January 2025

Historically, data from US death certificates, available through the CDC’s WONDER database, have been used to highlight health disparities. The 5 year (2018-2022) underlying-cause-of-death data were analyzed for different race/ethnicity groups. Gastrointestinal (GI) cancers of the colon/rectum, pancreas, liver/bile duct, and stomach contributed to more than a quarter of cancer deaths in the US, calling for focused advocacy. Known disparities for Black non-Hispanic Americans were verified in cancers of the colon/rectum, and pancreas. However, mortality data for “More than one race” non-Hispanic group or non-White Hispanic group appeared unreliable, suggesting that under-reporting is also a sign of health disparity. Age-specific death rates (ASDRs) were calculated to view health disparities in various age groups. Cancers of the colon/rectum, liver, and stomach cause significant mortality in the under-50 population. And minority groups are more likely to die from cancers in the liver or the stomach compared to the White non-Hispanics. Liver cancer crude death rate was lower than expect in Asian Non-Hipanics when compared with the high mortalities of IARC’s GLOBOCAN estimates for Asian countries. Census data were then used to calculate Asian sub-groups’ ASDRs. Significantly higher risks were seen in gastric cancer for Korean Americans and liver cancer for Vietnamese Americans. The Asian Indian group had the lowest death rates across several GI cancers, even in gallbladder cancer. Some immigrants go back to their birth countries at end of life and these deaths are not reflected in WONDER because consulate reports of American citizens’ deaths abroad do not include race/ethnicity data.

SIGNIFICANCE

Gastrointestinal cancers should be advocacy focuses to promote cancer equity. Under-reporting of deaths for minority groups is a sign of health disparity. ASDRs (Age Specific Death Rates) provide bases for tailored screening and prevention. Exclusion of American citizen’s deaths abroad in U.S. public health datasets may mask care access issues faced by immigrant cancer patients who may die overseas. Updating how these deaths are reported will help address this issue.
Meta-analysis of studies on the association between physician characteristics and patient outcomes
Authors: Haslam Alyson , Miller Sarah L. , Prasad Vinay
Published: January 2025

Objective

Physicians have a large role in patient outcomes, and some have questioned whether some physician characteristics lead to better outcomes for the patient. Multiple studies have been conducted on the topic, leading to a variety of conclusions. To determine how frequently studies find favorable patient outcomes, by physician characteristics and the pooled estimated effect.

Methods

By searching PubMed, Web of Science, and Google Scholar, we identified studies that reported the association between physician characteristics (age, experience, sex/gender, race/ethnicity, nationality, and patient/physician characteristic concordance) and patient outcomes (patient outcomes, such as survival/mortality, hospitalization, readmissions, length of stay, and morbidity). We calculated the frequency of studies reporting on each type of physician characteristics and each type of patient outcome, risk of bias in included studies, and pooled estimates of association between physician characteristics and patient outcomes.

Results

Of the 32 included studies, the most common outcome was mortality. There were no differences in outcomes for physicians with more experience, compared with less experience (pooled odds ratio [OR]: 0.99; 95% confidence interval: 0.98 to 1.01; I2: 56.5%), between older and younger physicians (pooled OR: 1.01; 95% confidence interval: 0.97 to 1.05; I2: 68.1%), but there were significantly better outcomes for patients with a female physician, compared to patients with a male physician, although this difference was small and biased (pooled OR: 0.97; 95% confidence interval: 0.96 to 0.98;I2: 35.5%). Selection bias, unaccounted measurement in physician and patient characteristics, and not accounting for unintended exposures limit the findings of these types of studies.

Conclusion

Strategies to improve patient outcomes should focus on other factors. Moreover, when seeking care, patients should be more concerned about physician track record than non-modifiable characteristics.
ACMG Secondary Findings in the Brazilian Rare Genomes Project: Insights from 5,402 genome sequencing
Authors: Perrone Eduardo , Virmond Luiza , Campos Coelho Antonio Victor , De França Marina , Moreno Carolina Araújo , Prota Joana Rosa Marques , Espolaor Jessica Grasiela de Araujo , Migliavacca Michele , Tonholo Silva Thiago Yoshinaga , Quaio Caio Robledo D’Angioli Costa , Ceroni José Ricardo Magliocco , Chen Kelin , Minillo Renata Moldenhauer , Teixeira Anne Caroline Barbosa , Yamada Renata Yoshiko , Cintra Vivian Pedigone , de Santana Lucas Santos , Campilongo Gabriela Pereira , Ribeiro da Silva Renata Martins , Pelegrino Karla de Oliveira , Filho João Bosco de Oliveira , de Almeida Tatiana Ferreira
Published: January 2025

Purpose

Secondary findings (SF) are pathogenic or likely pathogenic variants in genes unrelated to the primary purpose of genetic testing. The American College of Medical Genetics (ACMG) provides guidelines on which SF should be reported, involving 81 genes linked to different conditions. With the increasing use of genome sequencing (GS), SF are more frequently detected, presenting challenges for healthcare systems. The Brazilian population is often underrepresented in genomic studies, which limits population-specific knowledge.

Objective

This study aimed to outline the profile of SF in the Brazilian Rare Genomes Project (BRGP).

Methods

We analyzed retrospectively SF (ACMG) data from GS of 5,402 BRGP individuals.

Results

Of the 5,316 cases who consented to receive SF, 3.6% (191 cases) had at least one SF. The most common genes identified wereTTR, TTN,andBRCA2. SF were mainly related to cardiovascular conditions (40.2%) and cancer predisposition (37.6%). Some variants, such asTTR:c.424G>A; p. (Val142Ile) andTP53:c.1010G>A; p. (Arg337His), were recurrent, reflecting population-specific traits and founder effects. Novel variants were 10.6% of SF.

Conclusion

SF rate varies across studies and populations. While SF can aid early diagnosis, their relevance is debated due to potential psychological and healthcare burdens. Effective genetic counseling and public health policies are essential.
Automatic segmentation of spinal cord lesions in MS: A robust tool for axial T2-weighted MRI scans
Authors: Naga Karthik Enamundram , McGinnis Julian , Wurm Ricarda , Ruehling Sebastian , Graf Robert , Valosek Jan , Benveniste Pierre-Louis , Lauerer Markus , Talbott Jason , Bakshi Rohit , Tauhid Shahamat , Shepherd Timothy , Berthele Achim , Zimmer Claus , Hemmer Bernhard , Rueckert Daniel , Wiestler Benedikt , Kirschke Jan S. , Cohen-Adad Julien , Mühlau Mark
Published: January 2025

Deep learning models have achieved remarkable success in segmenting brain white matter lesions in multiple sclerosis (MS), becoming integral to both research and clinical workflows. While brain lesions have gained significant attention in MS research, the involvement of spinal cord lesions in MS is relatively understudied. This is largely owed to the variability in spinal cord magnetic resonance imaging (MRI) acquisition protocols, high individual anatomical differences, the complex morphology and size of spinal cord lesions - and lastly, the scarcity of labeled datasets required to develop robust segmentation tools. As a result, automatic segmentation of spinal cord MS lesions remains a significant challenge. Although some segmentation tools exist for spinal cord lesions, most have been developed using sagittal T2-weighted (T2w) sequences primarily focusing on cervical spines. With the growing importance of spinal cord imaging in MS, axial T2w scans are becoming increasingly relevant due to their superior sensitivity in detecting lesions compared to sagittal acquisition protocols. However, most existing segmentation methods struggle to effectively generalize to axial sequences due to differences in image characteristics caused by the highly anisotropic spinal cord scans. To address these challenges, we developed a robust, open-source lesion segmentation tool tailored specifically for axial T2w scans covering the whole spinal cord. We investigated key factors influencing lesion segmentation, including the impact of stitching together individually acquired spinal regions, straightening the spinal cord, and comparing the effectiveness of 2D and 3D convolutional neural networks (CNNs). Drawing on these insights, we trained a multi-center model using an extensive dataset of 582 MS patients, resulting in a dataset comprising an entirety of 2,167 scans. We empirically evaluated the model’s segmentation performance across various spinal segments for lesions with varying sizes. Our model significantly outperforms the current state-of-the-art methods, providing consistent segmentation across cervical, thoracic and lumbar regions. To support the broader research community, we integrate our model into the widely-used Spinal Cord Toolbox (v7.0 and above), making it accessible via the command sct deepseg-task seg sc ms lesion axial t2w -i .
Atrophy in multiple system atrophy relates to mitochondrial and oligodendrocytic processes
Authors: Chougar Lydia , Tremblay Christina , Delva Aline , Filiatrault Marie , Vo Andrew , Hansen Justine Y. , Farahani Asa , Misic Bratislav , Khalafi Parsa , Castonguay Charles-Etienne , Rouleau Guy , Corvol Jean-Christophe , Vidailhet Marie , Degos Bertrand , Grabli David , Lehéricy Stéphane , Dagher Alain , Rahayel Shady
Published: January 2025

Objective

To investigate the gene expression and neurobiological underpinnings of brain atrophy in multiple system atrophy (MSA) using imaging transcriptomics and PET-based molecular annotation.

Methods

We derived brain atrophy measurements from the T1-weighted MRI scans of 65 patients with MSA and 181 age- and sex-matched healthy controls. Using postmortem data from the Allen Human Brain Atlas, partial least square (PLS) regression was used to identify gene expression components associated with atrophy. Gene enrichment analyses were performed to investigate the biological processes with enriched genes in regions showing atrophy. Annotation mapping was used to identify the neurochemical systems whose density maps matched atrophy in MSA.

Results

Atrophy in MSA was found to primarily affect deep brain regions, including the cerebellar white matter, pons, putamen, olive nuclei, and substantia nigra. PLS regression on deep brain region atrophy identified two gene expression latent variables, explaining 27.5% of the covariance. Regions with greater atrophy overexpressed genes related to the mitochondrial respiratory chain, particularly proton transmembrane transport and complex I assembly. In addition, cell type analysis revealed that regions with atrophy overexpressed genes related to oligodendrocytes. These patterns were distinct from those found in Parkinson’s disease. Atrophic regions in MSA also displayed less serotonin and GABA receptors and more acetylcholine and noradrenaline receptors.

Interpretation

Regions showing atrophy in MSA show specific features, namely overexpression of genes related to mitochondrial function and oligodendrocytes and distinct neurochemical patterns. This study highlights some of the biological and neurochemical mechanisms underlying selective vulnerability of brain regions in MSA.
A pivot-tether model for nucleosome recognition by the chromosomal passenger complex
Authors: Ruza Reinis R. , Chung Chyi Wei , Gold Danny B.H. , Serena Michela , Roberts Emile , Gruneberg Ulrike , Barr Francis A.
Published: January 2025

Spatial restriction of Aurora B to centromeres during prometaphase and metaphase enables it to phosphorylate proteins necessary for spindle assembly checkpoint signalling and biorientation of chromosomes on the mitotic spindle. Aurora B binding to T3-phosphorylated histone H3 (H3pT3) nucleosomes requires a multivalent targeting module, the chromosomal passenger complex (CPC), consisting of survivin, borealin, and INCENP. To shed light on how these components mediate CPC localisation during prometaphase and metaphase, we determined the structure of the CPC targeting module in complex with haspin-phosphorylated H3pT3-nucleosomes by cryo-electron microscopy. This structure shows how the N-terminus of borealin and the survivin BIR domain act as pivot and flexible tethering points, respectively, to increase CPC affinity for H3pT3 nucleosomes without limiting it to a specific orientation. We demonstrate that this flexible, yet constrained pivot-tether arrangement is important for the control of spindle assembly checkpoint signalling by Aurora B.
Impact of cross-validation designs on cattle behavior prediction using machine learning and deep learning models with tri-axial accelerometer data
Authors: Wang Jin , Yu Ziwen , Chebel Ricardo C. , Yu Haipeng
Published: January 2025

1

Assessing cattle behaviors provides insights into animal health, welfare, and productivity to support on-farm management decisions. Wearable accelerometers offer an alternative approach to traditional human evaluation, providing a more objective and efficient method for predicting cattle behavior. Random cross-validation (CV) is commonly used to evaluate behavior prediction by splitting data into training and testing sets, but it can yield inflated results when records from the same animal are included in both sets. Block CV splits data by block effects, offering a more realistic evaluation but remains underexplored for predicting multi-class imbalanced cattle behavior. Additionally, deep learning (DL) models have not been fully explored for behavior prediction compared to machine learning (ML) models. The objectives of this study were to examine the impact of CV designs on multi-class imbalanced cattle behavior prediction and to compare the performance of ML and DL models. Three ML and two DL models were used to predict the four behaviors of six beef cows from a public tri-axial accelerometer dataset, with model performance evaluated using both hold-out and leave-cow-out CV designs representing random and block CV, respectively. In hold-out CV, ML models achieved accuracies of 0.94 to 0.96 and F1 scores of 0.93 to 0.95, while DL models achieved accuracies of 0.9 to 0.92 and F1 scores of 0.89 to 0.91. In the leave-cow-out CV, ML models obtained accuracies of 0.72 to 0.82 and F1 scores of 0.64 to 0.82, whereas DL models obtained accuracies of 0.76 to 0.82 and F1 scores of 0.64 to 0.76. Generally, ML models outperformed DL models in the hold-out CV, but the multi-layer perceptron DL model demonstrated comparable or superior performance in the leave-cow-out CV. All models performed better with hold-out CV than leave-cow-out CV. Our results suggest that CV designs can affect behavior prediction performance. While a random CV produces seemingly good predictions, these results can be artificially inflated by the data partition. A block CV that strategically partitions data could be a more appropriate design.
High resolution live imaging of tardigrade response to anoxia
Authors: Haapanen-Saaristo Anna-Mari O , Calhim Sara , Paatero Ilkka
Published: January 2025

Tardigrades are well-known for their ability to tolerate extreme environmental conditions such as heat, drought and lack of oxygen by undergoing cryptobiosis. The molecular responses to stress have been studied in detail, but the physiological and morphogenetic changes during cryptobiosis are less understood. We developed new high-resolution fluorescent live microscopy protocols to visualize the tardigrade response to lack of oxygen — anoxybiosis. High-resolution time-lapse imaging enabled morphological analysis at cellular level and analysis of cellular movements during anoxybiosis. These analyses revealed considerable morphological changes and cellular movement of storage cells. Our observations and new imaging protocols can be used to study morphological and cellular response to stress in tardigrades.
Evidence of inbreeding depression on stature in Brown Swiss cattle
Authors: He Qiongyu , Deuber Jessica , Seefried Franz R. , Pausch Hubert , Kadri Naveen
Published: January 2025

Background

Small effective population size and the disproportionately large use of few genetically superior bulls in artificial insemination lead to extensive runs of homozygosity and an increased risk of homozygosity for deleterious alleles in domestic cattle, which may cause inbreeding depression. The adverse effects of inbreeding on phenotypic performance are well established, but the genetic variants contributing to inbreeding depression remain largely unknown. This study aimed to analyse the impacts of inbreeding on stature (measured as height at the sacral bone) in a cohort of 15,306 Brown Swiss (BS) cows that have imputed genotypes at 20 million sequence variants and stature measurements as height at the sacral bone.

Results

The average genomic inbreeding coefficient of the 15,306 BS cows estimated from runs of homozygosity (ROH) was 0.369 (± 0.022). We found a loss in stature, decreasing from a height of 0.076 cm at the sacral bone per 1% increase in inbreeding (p = 1.94e-09). Contributions to inbreeding depression were significant for long (> 2 Mb), medium (0.1 – 2 Mb), and short (50 kb – 0.1 Mb) ROH (p = 1.29e-12, p = 3.20e-04 and p = 1.77e-06, respectively), suggesting that both ancient and recent inbreeding have negative effects on stature. Non-additive association testing identified a novel recessive quantitative trait locus (QTL) for stature on chromosome 25 with the most significantly (p = 2.35e-21) associated SNP residing at 14,535,327 bp. Cows homozygous for the alternate allele of the top associated SNP were 2 cm shorter than heterozygous and reference allele homozygotes. Fine mapping of the QTL identified a splice donor variant (rs447836030 at 25:14,515,474) of the geneABCC6encoding ATP binding cassette subfamily C member 6 which causes exon skipping as both a positional and functional candidate causal variant.

Conclusions

Our study reveals evidence for inbreeding depression on stature in a large cohort of BS cattle. We also uncover a recessive QTL that decreases stature through non-additive association testing. This QTL harbors a high-impact variant affecting a splice donor site ofABCC6which leads to exon skipping, thereby possibly contributing to inbreeding depression. Accumulating non-lethal deleterious alleles in ROH may reduce the overall fitness of the BS cattle population.
Extracellular polymeric substance degradation shapes microbial community diversity
Authors: Pontrelli Sammy , Villi Kian Bigovic , Sichert Andreas , Trouillon Julian , Rutz Adriano , Landry Zachary , Rüdisser Simon H. , Stocker Roman , Sauer Uwe
Published: January 2025

Competition for and exchange of nutrients play crucial roles in shaping microbial community function and dynamics. Although cross-feeding of small metabolites is known to drive carbon exchange among species, the importance of self-produced extracellular polymeric substances (EPS)— which include proteins, polysaccharides, DNA, and humic-like substances— remains less understood. Utilizing chitin-degrading microbial isolates and natural seawater communities, we found that 4–7% of the carbon from chitin degradation is converted into EPS, accounting for nearly a quarter of the exuded carbon. Different sources of EPS were found to select for distinct microbial communities. Through enzyme assays and untargeted metabolomics, we demonstrated that secreted enzymes degrade EPS in multiple steps that influence community diversity: larger oligomers are initially utilized by specialized degraders, while the subsequent breakdown into smaller oligomers, monosaccharides, and amino acids supports non-specialized consumers. These findings highlight the role of EPS as a significant carbon source exchanged between microbes, fueling metabolically diverse populations and enriching our understanding of carbon-mediated microbial interactions.
Convergent flow-mediated mesenchymal force drives embryonic foregut constriction and splitting
Authors: Yan Rui , Hoffmann Ludwig A. , Oikonomou Panagiotis , Li Deng , Lee ChangHee , Gill Hasreet , Mongera Alessandro , Nerurkar Nandan L. , Mahadevan L. , Tabin Clifford J.
Published: January 2025

The transformation of a two-dimensional epithelial sheet into various three-dimensional structures is a critical process in generating the diversity of animal forms. Previous studies of epithelial folding have revealed diverse mechanisms driven by epithelium-intrinsic or -extrinsic forces. Yet little is known about the biomechanical basis of epithelial splitting, which involves extreme folding and eventually a topological transition breaking the epithelial tube. Here, we leverage tracheal-esophageal separation (TES), a critical and highly conserved morphogenetic event during tetrapod embryogenesis, as a model system for interrogating epithelial tube splitting both in vivo and ex vivo. Comparing TES in chick and mouse embryos, we identified an evolutionarily conserved, compressive force exerted by the mesenchyme surrounding the epithelium, as being necessary to drive epithelial constriction and splitting. The compressive force is mediated by localized convergent flow of mesenchymal cells towards the epithelium. We further found that Sonic Hedgehog (SHH) secreted by the epithelium functions as an attractive cue for mesenchymal cells. Removal of the mesenchyme, inhibition of cell migration, or loss of SHH signaling all abrogate TES, which can be rescued by externally applied pressure. These results unveil the biomechanical basis of epithelial splitting and suggest a mesenchymal origin of tracheal-esophageal birth defects.
Co-translational assembly promotes functional diversification of paralogous proteins
Authors: Mallik Saurav , Cisneros Angel F. , Landry Christian R. , Levy Emmanuel D.
Published: January 2025

Homomeric proteins are ubiquitous and mediate myriads of cellular functions. When a gene encoding a homomer duplicates, the resulting paralogs can either form distinct homomers, or evolve into a heteromer containing both paralogs. While such events have extensively shaped proteomes, the molecular mechanisms driving these fates and their associated functional consequences remain largely unknown. Here, we conducted a comprehensive phylogenomic analysis tracing gene duplication histories of 7,377 human paralogs across the eukaryotic lineage and identified their fates using protein interaction data. Simulations and data analyses show that cellular constraints must act as barriers to disfavor heteromerization and promote homomerization. We found that multiple cellular and molecular constraints can serve as barriers, including the lack of co-expression and co-localization. The main barrier, however, is co-translational assembly, which naturally promotes the self-assembly of each paralog from its corresponding mRNA, thus hindering heteromerization. We further established that heteromerization constrains functional divergence, with homomeric paralogs exhibiting stronger signatures of adaptive evolution and functional divergence compared to heteromeric paralogs. Together, these findings identify key biochemical and cellular properties that explain protein function diversification following gene duplication.

One Sentence Summary

Co-translational assembly drives the selective homo-oligomerization of paralogs, which in turn promotes their functional divergence.

Graphical Abstract
Shallow-angle intracranial cannula for repeated infusion and in vivo imaging with multiphoton microscopy
Authors: Hou Steven S. , Yang Joyce , Kwon Yeseo , Pian Qi , Tang Yijing , Dauphinais Christine A. , Calvo-Rodriguez Maria , El Khatib Mirna , Vinogradov Sergei A. , Sakadzic Sava , Bacskai Brian J.
Published: January 2025

Multiphoton microscopy serves as an essential tool for high-resolution imaging of the living mouse brain. To facilitate optical access to the brain during imaging, the cranial window surgery is commonly used. However, this procedure restricts physical access above the imaging area and hinders the direct delivery of imaging agents and drugs. To overcome this limitation, we have developed a cannula delivery system that enables the implantation of a low-profile cannula nearly parallel to the brain surface at angles as shallow as 8 degrees, while maintaining compatibility with multiphoton microscopy. To validate this approach, we perform direct infusion and imaging of various fluorescent cell markers in the brain. Additionally, we successfully demonstrate tracking of degenerating neurons over time in Alzheimer’s disease mice using Fluoro-Jade C. Furthermore, we show longitudinal imaging of brain tissue partial pressure of oxygen using a phosphorescent oxygen sensor. Our developed technique should enable a wide range of new longitudinal imaging studies in the mouse brain.
A synaptic-astrocytic proteomic signature associated with synaptopathy in Alzheimer’s Disease
Authors: Griffiths Jessica , Schneegans Eléonore , Whitwell Harry , Qiu Zhen , Notman Beverley , Cheung Dorcas , Willumsen Nanet , Matthews Paul M , Grant Seth G N , Jackson Johanna S
Published: January 2025

Synapse loss is the greatest correlate of cognitive impairment in Alzheimer’s Disease (AD) and offers a therapeutic avenue alongside disease-modifying therapies. However, the events preceding synapse loss in the human condition have not been well characterised. In this study, we describe a pseudotemporal profile of alterations in the synaptic proteome prior to excitatory synapse loss in humanpost-mortembrain AD tissue using synapse proteomics and synaptome mapping techniques. In a region with early-stage disease pathology, the most predominant changes were pre-synaptic and featured changes in metabolism and exocytosis. In a mid-stage disease state, alongside initial synapse loss, there was a dominance of inhibitory synaptic changes. In a region with late-stage disease pathology and profound synapse loss, post-synaptic changes were most prevalent with a range of canonical synaptic transmission pathways reduced and differential excitatory synapse subtype pathology. Synapse loss was associated with changes in astrocytic proteins which were enriched for those at peri-synaptic astrocytic processes, including an upregulation of complement activation and endocytosis; a signature that differed from the astrocyte cytosolic proteome. Taken together, this provides evidence of a cascade of events leading to synapse loss with multiple points for therapeutic intervention to alleviate cognitive decline in AD. Data are available via ProteomeXchange with identifier PXD056052.
Effects of a magnetic cobalt STM tip on the electronic, magnetic, and spin-dependent transport properties of cobalt phthalocyanine junctions on a Co(111) substrate
Authors: Jaafar Ali , Khalil Tarek
Published: January 2025

The effect of a magnetic scanning tunneling microscopy (STM) tip on electronic, magnetic, and electronic transport properties through the molecular junction STM-tip-Co/CoPc/Co(111) was investigated by mean of electronic structure calculations. The spin transition was studied by varying the distance (passing from the tunneling regime to the contact regime) between the tip and the CoPc molecule in both parallel and antiparallel configurations. Our calculation shows that the transition of spin of the Co atom of a CoPc molecule has led to a change of the sign of the . It is also shown that the characteristic has been influenced by this spin transition of the central atom of the CoPc molecule.

Published by the American Physical Society
2025
Hard processes in multi-TeV ion collisions
Authors: Fuks Benjamin , Marougkas Fotios , Ruiz Richard , Sztandera Alicja
Published: January 2025

Motivated by the ion-collision program at the Large Hadron Collider, plans for its high-luminosity upgrade, and ongoing discussions for multi-TeV future hadron colliders, we systematically investigate hard-scattering, Standard Model processes in many-TeV ion-ion collisions. We focus on the symmetric beam configurations Pb208−Pb208, Xe131−Xe131, C12−C12, and pp, and we catalog total and fiducial cross sections for dozens of processes, ranging from associated-Higgs and multiboson production to associated-top pair production, at next-to-leading order in QCD for nucleon-nucleon collision energies from sNN=1 to 100 TeV. We report the residual scale uncertainties at this order as well as the uncertainties originating from fits of nuclear parton densities. We also discuss the propagation of nuclear dynamics (as encoded in nuclear parton densities) into parton luminosities and ultimately into predictions for cross sections. Finally, we report on the emergence of trends and the reliability of extrapolating cross sections across different nuclei. For Pb-Pb collisions at a hypothetical Future Circular Collider with sNN=39  TeV, O(108) weak bosons, O(105) diboson pairs, O(104) WH and ZH pairs, O(103) triboson events, O(105) high-pT photons events, and O(107) tt¯ pairs can be produced with L=33  nb−1 of data. At sNN=5.52  TeV, one can expect O(10–106) single, multiboson, and top events per 1  nb−1. Decay rates and experimental selection/acceptance rates will impact final event yields and merit further study; as an illustrative example, we focus on select diboson and triboson channels in lead-lead collisions and discuss their observability at the high-luminosity phase of the Large Hadron Collider and the Future Circulate Collider.

Published by the American Physical Society
2025
Hyperbolicity in scalar-Gauss-Bonnet gravity: A gauge invariant study for spherical evolution
Authors: Thaalba Farid , Franchini Nicola , Bezares Miguel , Sotiriou Thomas P.
Published: January 2025

We study spherical evolution in scalar-Gauss-Bonnet gravity with additional Ricci coupling and use the gauge-invariant approach introduced recently by Reall to track well-posedness. Our results show that loss of hyperbolicity when it occurs, is due to the behavior of physical degrees of freedom. They provide further support to the idea that this behavior can be tamed by additional interactions of the scalar. We also point out a limitation of this gauge-invariant approach: the fact that field redefinitions can change the character of the evolution equations.

Published by the American Physical Society
2025
Graviton number radiated during binary inspiral and its link to angular momentum radiation
Authors: Page Don N.
Published: January 2025

The number of gravitons emitted during binary inspiral is found to be remarkably close to (though slightly larger than) the radiated angular momentum in units of 2ℏ. This (∼1%) closeness holds both for an infinitesimal change in the eccentricity, and for the total graviton number emitted during inspiral from a large eccentricity initial orbit down to negligible final eccentricity.

Published by the American Physical Society
2025
Deformations of extremal black holes and the UV
Authors: Chen Calvin Y.-R. , de Rham Claudia , Tolley Andrew J.
Published: January 2025

It has recently been noted that deformations of extremal anti–de Sitter (AdS) black holes in four and higher dimensions are generically nonsmooth or singular on the horizon. Further, it was found that certain deformations of asymptotically flat extremal black holes are marginal, causing the nature of the horizon to be strongly sensitive to UV corrections—in particular, Wilson coefficients associated with consistent UV completions generically lead to worse behavior on the horizon. In this work, we extend the discussion of deformed horizons in the presence of UV corrections to extremal charged black holes in AdS, where we find a tower of marginal perturbations for different black hole masses. We argue that the apparent UV sensitivity of marginal modes is, in fact, a feature of the UV theory, which is correctly reproduced by the effective field theory (EFT), and illustrate this with explicit UV completions confirming the validity of the EFT. We demonstrate that the same holds for a scalar-Maxwell EFT with known UV completion. In the gravitational case, the sign of EFT corrections to marginal perturbations is generally connected with the signs implied by positivity bounds, with UV completions generically leading to worse behavior on the horizon. We conjecture that this result is more generic and use this to derive more general positivity bounds motivated by the weak gravity conjecture, which we illustrate with further evidence.

Published by the American Physical Society
2025
Forecasting long-time dynamics in quantum many-body systems by dynamic mode decomposition
Authors: Kaneko Ryui , Imada Masatoshi , Kabashima Yoshiyuki , Ohtsuki Tomi
Published: January 2025

Reliable numerical computation of quantum dynamics is a fundamental challenge when the long-ranged quantum entanglement plays essential roles as in the cases governed by quantum criticality in strongly correlated systems. Here we apply a method that utilizes reliable short-time data of physical quantities to accurately forecast long-time behavior of the strongly entangled systems. We straightforwardly employ the simple dynamic mode decomposition (DMD), which is commonly used in fluid dynamics. Despite the simplicity of the method, the effectiveness and applicability of the DMD in quantum many-body systems such as the Ising model in the transverse field at the critical point are demonstrated, even when the time evolution at long time exhibits complicated features such as a volume-law entanglement entropy and consequential power-law decays of correlations characteristic of systems with long-ranged quantum entanglements unlike fluid dynamics. The present method, though simple, enables accurate forecasts amazingly at time as long as nearly an order of magnitude longer than that of the short-time training data. Effects of noise on the accuracy of the forecast are also investigated, because they are important especially when dealing with the experimental data. We find that a few percentages of noise do not affect the prediction accuracy destructively.

Published by the American Physical Society
2025