bluuebunny/crossref_metadata_2025 huggingface dataset:
A Double Machine Learning Approach for the Evaluation of COVID-19 Vaccine Effectiveness under the Test-Negative Design: Analysis of Québec Administrative Data
Authors: Jiang Cong , Talbot Denis , Carazo Sara , Schnitzer Mireille E
Published: December 2024

The test-negative design (TND), which is routinely used for monitoring seasonal flu vaccine effectiveness (VE), has recently become integral to COVID-19 vaccine surveillance, notably in Québec, Canada. Some studies have addressed the identifiability and estimation of causal parameters under the TND, but efficiency bounds for nonparametric estimators of the target parameter under the unconfoundedness assumption have not yet been investigated. Motivated by the goal of improving adjustment for measured confounders when estimating COVID-19 VE among community-dwelling people aged ≥ 60 years in Québec, we propose a one-step doubly robust and locally efficient estimator called TNDDR (TND doubly robust), which utilizes cross-fitting (sample splitting) and can incorporate machine learning techniques to estimate the nuisance functions and thus improve control for measured confounders. We derive the efficient influence function (EIF) for the marginal expectation of the outcome under a vaccination intervention, explore the von Mises expansion, and establish the conditions for−consistency, asymptotic normality and double robustness of TNDDR. The proposed estimator is supported by both theoretical and empirical justifications.
Longitudinal interaction between muscle impairments and gait pathology in growing children with Duchenne muscular dystrophy
Authors: Vandekerckhove Ines , Molenberghs Geert , Van den Hauwe Marleen , Goemans Nathalie , De Waele Liesbeth , Van Campenhout Anja , De Groote Friedl , Desloovere Kaat
Published: December 2024

Aim

The aim of this longitudinal observational cohort study was to investigate the longitudinal interaction between progressive muscle impairments and progressive gait pathology in growing boys with Duchenne muscular dystrophy (DMD).

Methods

Thirty-one boys with DMD (aged 4y7mo-16y5mo), were repeatedly measured between 2015 and 2022, resulting in a total dataset of 152 observations. Fixed dynamometry, goniometry and 3D gait analysis were used to asses lower limb muscle weakness, passive range of motion and gait. Joint random-effects models between gait and muscle impairment outcomes were fitted. The correlation between the random intercepts (ra) and random slopes (rb) indicated the degree to which respectively the starting levels and progression rates over time of two outcomes were related in boys with DMD.

Results

Specific muscle impairments were related to specific gait features, in terms of starting levels (ra=0.470-0.757; p<0.029) and progression rates (rb=0.547-0.812; p<0.024).

Interpretation

The findings improved insights into how specific muscle impairments may contribute to specific gait features in DMD. This could enhance clinical decision making, advance rehabilitation, orthotic and orthopedic interventions, and reveal sensitive outcome measures to prove the efficacy of novel treatments in clinical trials.

What this paper adds

Objective quantification of the relationships between muscle impairments and gait features

Relationships between starting levels of specific muscle impairments and specific gait features

Relationships between progression rates of specific muscle impairments and specific gait features

Improved insights into how muscle impairments may contribute to gait features
Parkinson’s Disease affects the contextual control, but not the expression, of a rapid visuomotor response that initiates visually-guided reaching: Evidence for multiple, interacting motor pathways and implications for motor symptoms in Parkinson’s Disease
Authors: Gilchrist Madeline , Kozak Rebecca A. , Prenger Margaret , Anello Mimma , Hedger Kathryne Van , MacDonald Penny A , Corneil Brian D
Published: December 2024

Despite significant deficits in voluntary motor control, patients with Parkinson’s disease (PD) can generate reflexive or stimulus-driven movements. How are such spared capabilities realized? Here, we recorded upper limb muscle activity in patients with PD and age-matched healthy controls (HCs) as they reached either toward or away from a visual stimulus. The task promoted express visuomotor responses (EVRs), which are brief bursts of muscle recruitment time-locked (<100 ms) to stimulus presentation that are thought to originate from the midbrain superior colliculus. Across two experiments, we observed a remarkable sparing of the latency and magnitude of EVRs in patients with PD, but a decreased ability for patients with PD to contextually modulate the EVR depending on trial instruction. EVR Magnitudes were strikingly strongly correlated with PD Reaction times and Error rates, despite compromised levels of electromyographic (EMG) recruitment in subsequent phases of muscle activity, which predicted lower Peak velocities. Our results are consistent with a differential influence of PD on parallel-but-interacting subcortical and cortical pathways that converge onto brainstem and spinal circuits during reaching. This differential influence is discriminable even within a single trial in the selective sparing of stimulus-aligned but not movement-aligned muscle recruitment, and has implications for our understanding of the motor and cognitive deficits seen in PD.
Recombinant production of spider silk protein in Physcomitrella photobioreactors
Authors: Ramezaniaghdam Maryam , Bohlender Lennard L. , Parsons Juliana , Hoernstein Sebastian N. W. , Decker Eva L. , Reski Ralf
Published: December 2024

Spider dragline silk stands out as a remarkable biomaterial, representing one of nature’s toughest fibres. Its strength rivals that of many synthetic fibres used commercially, rendering it applicable across various industrial and medical domains. However, its widespread utilisation requires cost-effective mass production. Biotechnology presents a promising avenue for achieving this goal, particularly through the production of recombinant dragline silk proteins in transgenic plant systems. This study aimed to assess the feasibility of producing one key protein component of dragline silk, MaSp1, from the western black widow spider,Latrodectus hesperus, (LhMaSp1) in the moss Physcomitrella (Physcomitrium patens). Here, we present the successful recombinant production of spider silk protein containing both the N- and C-terminal domains (NTD and CTD) of LhMaSp1 protein in moss cells. NTD and CTD are necessary domains for protein assembly in spider silk. The production of recombinant LhMaSp1 protein in Physcomitrella was performed in shake flasks and in five-litre photobioreactors and the correct synthesis of LhMaSp1 was provenviamass spectrometry.

Key message

We report the first successful plant-produced recombinant spider silk key protein component containing both the N- and the C-terminal domain.
Dynamic heterogeneity in anE. colistress response regulon mediates gene activation and antimicrobial peptide tolerance
Authors: Blassick Caroline M. , Lugagne Jean-Baptiste , Dunlop Mary J.
Published: December 2024

The bacterial stress response is an intricately regulated system that plays a critical role in cellular resistance to drug treatment. The complexity of this response is further complicated by cell-to-cell heterogeneity in the expression of bacterial stress response genes. These genes are often organized into networks comprising one or more transcriptional regulators that control expression of a suite of downstream genes. While the expression heterogeneity of many of these upstream regulators has been characterized, the way in which this variability affects the larger downstream stress response remains hard to predict, prompting two key questions. First, how does heterogeneity and expression noise in stress response regulators propagate to the diverse downstream genes in their regulons. Second, when expression levels vary, how do multiple downstream genes act together to protect cells from stress. To address these questions, we focus on the transcription factor PhoP, a critical virulence regulator which coordinates pathogenicity in several gram-negative species. We use optogenetic stimulation to precisely control PhoP expression levels and examine how variations in PhoP affect the downstream activation of genes in the PhoP regulon. We find that these downstream genes exhibit differences both in mean expression level and sensitivity to increasing levels of PhoP. These response functions can also vary between individual cells, increasing heterogeneity in the population. We tie these variations to cell survival when bacteria are exposed to a clinically-relevant antimicrobial peptide, showing that high expression of the PhoP-regulon genepmrDprovides a protective effect against Polymyxin B. Overall, we demonstrate that even subtle heterogeneity in expression of a stress response regulator can have clear consequences for enabling bacteria to survive stress.
Trigger Point Injections for Post-Mastectomy Pain Syndrome: A Protocol for a Randomized Double-Blind Clinical Trial (NCT04267315)
Authors: Leite Victor Figueiredo , de Andrade Rodrigo Guimarães , de Brito Christina May Moran
Published: December 2024

INTRODUCTION

Post-Mastectomy Pain Syndrome (PMPS) refers to a condition of chronic pain persisting for more than three months after a breast surgical procedure. It affects 11 to 70% of individuals with breast cancer. The pain has a mixed etiology, often with the frequent presence of associated myofascial pain. Trigger Point Injection (TPI) is a well-established procedure in the treatment of myofascial pain in the general population. However, there are no controlled studies evaluating the efficacy of TPI in the treatment of PMPS.

OBJECTIVE

To evaluate the efficacy of TPI in individuals with PMPS when combined with interdisciplinary rehabilitation and pharmacological treatment.

METHODS

This is the protocol for a double-blind, placebo-controlled clinical trial. Both groups will receive routine care by a Physiatrist and Rehabilitation Team blinded to the allocation. The active group will receive Trigger Point Injections with 1% lidocaine at each identified trigger point once a week for up to three consecutive weeks. The control group will receive subcutaneous infiltrations of saline at the same points and frequency. This protocol was registered at theClinicalTrials.govwebsite (NCT04267315).

STATISTICAL ANALYSIS

Analysis of Covariance (ANCOVA) for between-group differences at baseline, one month, and three months for pain, central sensitization, and functionality (n=120). A significance level of alpha=5% and statistical power of 80% will be employed.
Developmental DNA Methylation in the Parasitoid WaspNasonia vitripennis
Authors: Thomas CL , Mallon EB
Published: November 2024

DNA methylation is a crucial epigenetic mark the development of many insect species, being essential for fertility and the progression of development in a range of organisms. However, the mechanisms underpinning the role of DNA methylation in insect development remains elusive. Furthermore, the patterns of methylation in different species can be varied. Here we aim to profile methylation across metamorphosis in the insect DNA methylation modelNasonia vitripennisfor the first time. We find DNA methylation is at the highest in the embryo, and at the lowest in the larva. We find that the gene expression levels ofNvTetandNvDnmtenzymes compliment the observed methylation patterns. Performing differential methylation analysis we find enriched GO terms for developmentally specific processes and find sites with differential methylation are share homology with developmentally linked transcription factors. Additionally, we identify sites uniquely methylated in each developmental stage, many of which also share homology with developmentally linked transcription factors. In all, we find that methylation is variable in its global methylation levels and site specific methylation throughoutNasonia vitripennisdevelopment, but find no obvious link with gene expression.
The comparative analysis of lineage-pair traits
Authors: Anderson Sean A. S. , Kaushik Sachin , Matute Daniel R.
Published: November 2024

A powerful but poorly understood analysis in ecology and evolutionary biology is the comparative study of lineage-pair traits. “Lineage-pair traits” are characters like ‘diet niche overlap’ and ‘strength of reproductive isolation’ that are defined for pairs of lineages instead of individual taxa. Comparative tests for causal relationships among such variables have led to groundbreaking insights in several classic studies, but the statistical validity of these analyses has been unclear due to the complex dependency structure of the data. Specifically, lineage-pair datasets contain non-independent observations, but studies to-date have relied on untested workarounds for data dependency rather than direct models of linear-pair covariance, and the statistical consequences of non-independence have not been thoroughly explored. Here we consider how evolutionary relatedness among taxa translates into non-independence among taxonomic pairs. We develop models by which phylogenetic signal in an underlying character generates covariance among pairs in a lineage-pair trait. We incorporate the resulting lineage-pair covariance matrix into a modified version of phylogenetic generalized least squares and a new beta regression model suitable for bounded response variables. Both models outperform previous approaches in simulation tests. We re-analyze two empirical datasets and find dramatic improvements in model fit and, in the case of avian hybridization data, an even stronger relationship between pair age and RI than revealed by standard linear regression. We present a new tool, the R packagephylopairs, to allow empiricists from a variety of biological fields to test relationships among pairwise-defined variables in a manner that is statistical robust and more straightforward to implement.
Intragenomic variants of a putative effector drive early-stage infection in a broad host-range rust fungus
Authors: Degnan Rebecca M. , Sawyer Anne , Gardiner Donald M. , Luo Zhenyan , Frampton Rebekah , Schwessinger Benjamin , Mitter Neena , Carroll Bernard J. , Smith Grant R. , McTaggart Alistair R. , Shuey Louise S.
Published: November 2024

Rust fungi are pathogens that impact plants of environmental, agricultural, cultural, and economic importance. Their mechanisms of pathogenicity are not well-understood but are likely governed by effectors, secreted proteins that manipulate host cellular processes to facilitate infection and suppress immune responses. We sought to understand how three effector candidates (EFC1, EFC2, andEFC3) expressed in the first stages ofAustropuccinia psidii(myrtle rust) infection influence pathogenicity. We experimentally tested gene function through application of double-stranded RNA (dsRNA) and characterised the genomic landscape of putative effectors expressed during infection to assess whether putative effectors are needed for infection, and whether they are under selection pressure. One of the three screened candidates,EFC1, met our criteria of an effector in that it was predicted to be secreted, and was needed to cause but not maintain infection. We identified that this effector belongs to a gene family of intragenomic variants in tandem repeats flanked by transposable elements. Single nucleotide polymorphisms among these variants have signatures of non-neutral selection. This effector has predicted structural homology to a glycosaminoglycan-binding domain and may have a role in pectin or chitin-binding. We hypothesise that intragenomic variability in this family of effector genes facilitates host-range versatility in theA. psidii-Myrtaceae pathosystem.
Identification of disease-specific extracellular vesicle-associated plasma protein biomarkers for Duchenne Muscular Dystrophy and Facioscapulohumeral Muscular Dystrophy
Authors: Bayazit Mustafa Bilal , Henderson Don , Nguyen Kim Truc , Reátegui Eduardo , Tawil Rabi , Flanigan Kevin M. , Harper Scott Q. , Saad Nizar Y.
Published: November 2024

Objective

Reliable, circulating biomarkers for Duchenne, Becker and facioscapulohumeral muscular dystrophies (DBMD and FSHD) remain unvalidated. Here, we investigated the plasma extracellular vesicle (EV) proteome to identify disease-specific biomarkers that could accelerate therapy approvals.

Methods

We extracted EVs from the plasma of DBMD and FSHD patients and healthy controls using size-exclusion chromatography, conducted mass spectrometry on the extracted EV proteins, and performed comparative analysis to identify disease-specific biomarkers. We correlated the levels of these biomarkers with clinical outcome measures and confounding factors.

Results

The muscle-associated proteins PYGM, MYOM3, FLNC, MYH2 and TTN were exclusively present in DBMD EVs. PYGM, MYOM3, and TTN negatively correlated with age. PYGM and MYOM3 levels were elevated in patients without cardiomyopathy, and PYGM levels were specifically elevated in ambulatory DMD patients. On the other hand, female FSHD patients displayed significantly higher MBL2 and lower GPLD1 levels. However, male FSHD patients exhibited higher C9 and lower C4BPB levels. Additionally, desmosome proteins JUP and DSP were uniquely found in FSHD males. MBL2 positively correlated with age and C4BPB negatively correlated with FSHD severity in male patients.

Interpretation

Our findings underscore the sensitivity of analyzing circulating EV content to identify disease-specific protein biomarkers for DBMD and FSHD. Our results also emphasize the potential of EV-based biomarker discovery as a promising approach to monitor disease progression as well as effectiveness of therapies in muscular dystrophy, potentially contributing to their approval. Further research with larger cohorts is needed to validate these biomarkers and explore their clinical implications.
Influence of Environmental Exposures on T Follicular Helper Cell Function and Implications on Immunity: a comparison of Bangladeshi and American Children
Authors: Van Fossen Dana , Cho Hyunjae , Wagar Lisa , Ma Jennie Z. , Haque Rashidul , Davis Mark , Petri William A.
Published: December 2024

T follicular helper (Tfh) cells are crucial for B cell activation and subsequent antibody production. This functionality is influenced by surface markers such as CD40L, a costimulatory factor which promotes B cell activation, and CD57 which is a well-known marker of senescence. This study examined age-specific differences in Tfh cell function in Bangladeshi and American children. At age two, Bangladeshi children displayed impaired CD40L upregulation and significant CD57 downregulation upon stimulation. These patterns, not observed in American children of the same age, suggested an exhaustion-like phenotype potentially driven by environmental factors. Predictors of Tfh cell response to stimulation were analyzed using Random Forest and Generalized Estimating Equations (GEE) models. Exclusive breastfeeding duration, antibiotic treatments, diarrheal episodes, and malnutrition were identified as variables that significantly impacted the Tfh response to stimuli. To assess Tfh cell ability to promote antibody responses, we correlated Tfh functionality with antibody concentration post-vaccination and in response to infection with Cryptosporidium, an endemic apicomplexan parasite. Increased CD40L expression upon stimulation correlated positively with anti-Poliovirus type 2/3 neutralizing antibody and anti-Cp17 (a Cryptos-poridium sporozoite antigen) IgA concentrations. In contrast, increased CD57 expression was significantly correlated with decreased anti-Cp17 IgA. This indicates that an activation-supportive phenotype (CD40L+) may be more effective in promoting immunity than a senescent phenotype (CD57+). Together, these findings suggest that early-life environmental exposures may program Tfh cell functionality, impacting immune response potential in settings with high pathogen exposure.

IMPORTANCE

T follicular helper (Tfh) cells are upstream mediators that shape the humoral immune response to specific antigens. The generation of an effective memory response to infection is vital to prevent subsequent reinfections. However, in areas with high burdens of exposure to infections, such as the urban community from Bangladesh studied here, children are consistently exposed to inflammatory pathogens. Specific environmental exposures significantly influenced Tfh cell activation and senescence phenotypes. Additionally, Tfh cell responses correlated with antibody concentrations following vaccination or infection, indicating that environmental factors may play a critical role in shaping effective immunity in early childhood.
Development and Validation of OncoOrigin: An Integrative AI Tool for Primary Cancer Site Prediction
Authors: Brlek Petar , Bulić Luka , Shah Nidhi , Shah Parth , Primorac Dragan
Published: December 2024

Importance

Cancers of unknown primary origin (CUPs) represent a significant diagnostic and therapeutic challenge in the field of oncology. With the limitations of current diagnostic tools in these cases, novel approaches must be brought forward to improve treatment outcomes for these patients.

Objective

The objective of this study was to develop a machine-learning-based software for primary cancer site identification (OncoOrigin), based on genetic data acquired from tumor DNA sequencing.

Design

By design, this was anin silicodiagnostic study.

Setting

This study was conducted using data from the cBioPortal database (accessed on 21 September 2024) and several data processing and machine-learning Python libraries.

Participants

This study involved over 20,000 tumor samples with information on patient age, sex, and the presence of genetic variants in over 600 genes.

Main Outcomes and Measures

The main outcome of interest in this study was machine-learning-based discrimination between cancer type classes, based on the provided data. Model quality was assessed by train set cross-validation and evaluation on a segregated test set. Finally, the optimal model was incorporated with a graphical user interface into the OncoOrigin software. Feature importances for class discrimination were also determined on the optimal model.

Results

Out of the four tested machine-learning estimators, the XGBoostClassifier-based model proved superior on test set evaluation, with a top-2 accuracy of 0.91 and ROC-AUC of 0.97. Class sensitivity values for prostate cancer, breast cancer, melanoma, and colorectal cancer were over 0.85, while all class specificity values were equal to or higher than 0.95. The top 3 significant features were patient sex, and genetic alterations in theAPCandKRASgenes.

Conclusions and Relevance

In this study, we have successfully developed a machine-learning-based software for primary cancer site identification with high-quality evaluation metrics. Through simple clinical implementation, such a tool has the potential to significantly improve the diagnostics and treatment outcomes for patients suffering from CUP.

KEY POINTS

Question

Can a machine-learning-based tool (OncoOrigin) accurately predict the primary cancer site from tumor DNA sequencing data in patients with cancers of unknown primary origin (CUP)?

Findings

In thisin silicostudy, the XGBoostClassifier model demonstrated high predictive performance, achieving a top-2 accuracy of 0.91 and ROC-AUC of 0.97 for the classification of ten cancer types using genetic data from over 20,000 tumor samples.

Meaning

The OncoOrigin software shows potential for improving the diagnosis and treatment of CUP by providing accurate primary cancer site identification based on genetic data.
Methods for analytical validation of novel digital clinical measures: A simulation study
Authors: Turner Simon , Chen Chen , Acosta Rolando , Daza Eric J , Floden Lysbeth , Langford Joss , Simmatis Leif , Terluin Berend , Fromy Piper
Published: December 2024

Analytical validation (AV) is a crucial step in the evaluation of algorithms that process data from sensor-based digital health technologies (sDHTs). AV of novel digital measures can be complicated when reference measures with direct correspondence are not available. To address this, we conducted a simulation study. Data was simulated assuming a latent physical ability trait, indirectly accessed through an sDHT-derived target measure collecting step count data, and the items of a clinical outcome assessment measuring self-reported physical activity. We quantified the ability of two methods to assess the latent relationship between reference and target measures: the Pearson Correlation Coefficient (PCC) (a classical, simple method frequently used for AV), and factor correlations from a two-factor confirmatory factor analysis (CFA) model (a more novel approach to AV, able to capture more complex relationships). Additionally, three multiple linear regression models were used to evaluate if multiple clinical outcome assessment reference measures can more completely represent a target measure of interest.

Our findings show that PCC was more stable, easier to compute, and relatively robust with respect to violations of parametric assumptions than CFA, particularly with small sample sizes. However, CFA was less biased than PCC in all scenarios investigated. We demonstrate that using both PCC and CFA allows a researcher to be more confident that their AV results reflect the true relationship between the sDHT-derived target measure and a reference measure. Finally, regression results suggest that incorporating multiple reference measures with more frequent collection time points can provide a more complete presentation of the sDHT’s analytical validity.

Novel digital measures are being developed at an accelerating pace and promise to revolutionize public health, patient care, and medical product development. Our findings provide investigators with crucial information for choosing appropriate methods to perform rigorous AV of these novel measures.
CRISPRa-mediated activation of genes associated with inherited retinal dystrophies in acutely isolated human cells for diagnostic purposes
Authors: Weber Valentin J. , Reschigna Alice , Gerhardt Maximilian-J. , Hinrichsmeyer Klara S. , Otify Dina Y. , Heigl Thomas , Blaser Frank , Meneau Isabelle , Biel Martin , Michalakis Stylianos , Becirovic Elvir
Published: December 2024

Many patients suffering from inherited diseases do not receive a genetic diagnosis and are therefore excluded as candidates for treatments, such as gene therapies. Analyzing disease-related gene transcripts from patient cells would improve detection of mutations that have been missed or misinterpreted in terms of pathogenicity during routine genome sequencing. However, the analysis of transcripts is complicated by the fact that a biopsy of the affected tissue is often not appropriate, and many disease-associated genes are not expressed in tissues or cells that can be easily obtained from patients. Here, using CRISPR/Cas-mediated transcriptional activation (CRISPRa) we developed a robust and efficient approach to activate genes in skin-derived fibroblasts and in freshly isolated peripheral blood mononuclear cells (PBMCs) from healthy individuals. This approach was successfully applied to blood samples from patients with inherited retinal dystrophies (IRD). We were able to efficiently activate several IRD-linked genes and detect the corresponding transcripts using different diagnostically relevant methods such as RT-qPCR, RT-PCR and long- and short-read RNA sequencing. The detection and analysis of known and unknown mRNA isoforms demonstrates the potential of CRISPRa-mediated transcriptional activation in PBMCs. These results will contribute to ceasing the critical gap in the genetic diagnosis of patients with IRD or other inherited diseases.

Graphical abstract
Spatial position relative to group members affects weight gain in meerkats (Suricata suricatta)
Authors: Mosia Rasekuwane , Demartsev Vlad , le Roux Aliza , Manser Marta B , Strandburg-Peshkin Ariana , Johnson-Ulrich Lily
Published: December 2024

Social animals often face a trade-off between the costs of foraging competition among group members and the benefits of protection from predators offered by group living. The spatial position of an individual in relation to the other group members during foraging can mediate the effects of this trade-off as individuals at the front or edge may have better access to food resources, but also higher predation risk than individuals near the centre of the group. Using meerkats (Suricata suricatta) as a model species, we investigated the effect of individual spatial position within a group on foraging success. We determined the spatial position of individuals in a meerkat group by fitting the animals with high-resolution GPS loggers. As a proxy of foraging success, we used meerkats’ individual body weight differences between the start and the end of daily data collection over foraging periods (3 hours). We found significant individual differences in meerkats’ spatial positions within the group. In addition, age-dependent differences in spatial position became obvious, with younger individuals spending more time in the centre of the group and less time in the front. However, younger individuals who spent more time on the side of the group relative to older individuals had higher daily weight gain, indicating more successful foraging. In older individuals, we found that the dominant females tended to spend more time towards the front of the group, but gained less weight in this location, contrary to the predicted association between front edge of the group and better access to food resources. Our results suggest that the relationship between weight gain and spatial position is highly nuanced and likely dependent on more than just trade-offs between foraging success and predation risk.

Highlights

Spatial position relative to other group members during foraging was a highly repeatable trait for individual meerkats, though time spent near the front of the group was more strongly influenced by individual traits (age, sex, and social rank)

Younger meerkats spent less time in the front and more time in the centre of the group relative to older meerkats, but had the highest foraging success towards the sides of the group

Dominant female meerkats spent more time near the front of the group, but had reduced foraging success in this position

Meerkats may trade-off more than just foraging success and predation risk when making decisions about where to position themselves relative to other group members
Hypoxia inhibits newt skeletal muscle dedifferentiation
Authors: Vdovin Georgii , Walters Hannah E. , Troyanovskiy Konstantin E. , Tsuchiya Yugo , Yun Maximina H
Published: November 2024

Unlike mammals, newts are able to regenerate lost muscle tissue by dedifferentiating postmitotic muscle cells, which re-enter the cell cycle to form myogenic progenitors. This ability is considered central to the process of limb regeneration, yet the mechanisms underlying it remain poorly understood. Here, we leverage high-resolution time course bulk transcriptomics profiling to characterise molecular changes during differentiation and dedifferentiation of newt myotubes. We uncover that myogenesis is accompanied by a metabolic shift from glycolysis to OXPHOS, which is partially reverted upon dedifferentiation. By analysing early events during dedifferentiation, we identify TGFβ and members of the oxygen-responsive HIF family as putative plasticity inducers. We detect a stark, transient upregulation of HIF3A early during dedifferentiation, followed by a gradual downregulation of HIF2A. Finally, we show that hypoxia inhibits myotube cell cycle re-entry. These data provide a valuable resource to identify regulators of cellular plasticity and offer insights into the impact of oxygen signalling in regenerative processes.
Gray matter abnormalities in sight deprivation and sight restoration
Authors: Pedersini Caterina A. , Fracasso Alessio , Dogar Amna , Rokers Bas , Sinha Pawan
Published: November 2024

Blindness provides a unique model for investigating brain plasticity in response to sensory deprivation. While structural changes in both gray and white matter have been widely documented, particularly in cases of early or congenital visual deprivation, gray matter studies have traditionally focused on cortical thickness, often finding cortical thickening in posterior regions. However, other aspects of gray matter integrity, such as cortical myelin content, remain underexplored. In this study, we examined the effects of visual deprivation on cortical structure in a cohort of congenitally blind individuals who received eye surgery during adolescence, expanding beyond conventional measures to include cortical thickness, curvature, and T1-weighted signal intensity. This multi-faceted approach offers a more comprehensive view of cortical adaptations to congenital sensory deprivation.

While blindness offers valuable insights into sensory-driven brain plasticity, an intriguing and unresolved question is whether structural plasticity reverses after sight restoration, enabling typical visual processing circuits to develop despite the initial period of deprivation. To address this, we assessed the effect of sight-recovering eye surgery on gray matter changes. Critically, individuals in this cohort received surgery after the closure of the sensitive period for visual development. We did not find evidence of gray matter changes after surgery. However, in a previous study conducted on the same cohort, we reported that notable plasticity in white matter emerged in this same population. These results suggest that white matter alterations, rather than gray matter changes, may potentially serve as a biomarker of structural plasticity following sight restoration, even beyond the sensitive developmental window.
extgfa: a low-memory on-disk representation of genome graphs
Authors: Dabbaghie Fawaz
Published: December 2024

The representation of genomes and genomic sequences through graph structures has undergone a period of rapid development in recent years, particularly to accommodate the growing size of genome sequences that are being produced. Genome graphs have been employed extensively for a variety of purposes, including assembly, variance detection, visualization, alignment, and pangenomics. Many tools have been developed to work with and manipulate such graphs. However, the majority of these tools tend to load the complete graph into memory, which results in a significant burden even for relatively straightforward operations such as extracting subgraphs, or executing basic algorithms like breadth-first or depth-first search. In procedurally generated open-world games likeMinecraft, it is not feasible to load the complete world into memory. Instead, a mechanism that keeps most of the world on disk and only loads parts when needed is necessary. Accordingly, the world is partitioned into chunks which are loaded or unloaded based on their distance from the player. Furthermore, to conserve memory, the system unloads chunks that are no longer in use based on the player’s movement direction, sending them back to the disk. In this paper, we investigate the potential of employing a similar mechanism on genome graphs. To this end, we have developed a proof-of-concept implementation, which we called “extgfa” (for external GFA). Our implementation applies a similar chunking mechanism to genome graphs, whereby only the necessary parts of the graphs are loaded and the rest stays on disk. We demonstrate that this proof-of-concept implementation improves the memory profile when running an algorithm such as BFS on a large graph, and is able to reduce the memory profile by more than one order of magnitude for certain BFS parameters.

Availability

Our implementation is written inPythonand available on Github under the MIT licensehttps://github.com/fawaz-dabbaghieh/extgfa
An mTurquoise2-based glucose biosensor
Authors: Botman Dennis , Tielman Annemoon , Goedhart Joachim , Teusink Bas
Published: November 2024

Glucose is an important substrate for organisms to acquire energy needed for cellular growth. Despite the importance of this metabolite, single-cell information at a fast time-scale about the dynamics of intracellular glucose levels is difficult to obtain as the current available sensors have drawbacks in terms of pH sensitivity or glucose affinity. To address this, we developed a convenient method to make and screen biosensor libraries using yeast as workhorse. This resulted in TINGL (Turquoise INdicator for GLucose), a robust and specific biosensor for intracellular glucose detection. We calibrated the sensor in vivo through equilibration of internal and external glucose in a yeast mutant unable to phosphorylate glucose. Using this method, we measured dynamic glucose levels in budding yeast during transitions to glucose. We found that glucose concentrations reached levels up to 1 mM as previously determined biochemically. Furthermore, the sensor showed that intracellular glucose dynamics differ based on whether cells are glucose-repressed or not. We believe that this sensor can aid researchers interested in cellular carbohydrate metabolism.
A novel multiplex RNAi therapy simultaneously targetsHif1aandHif2ato defy retinal degeneration in two models of AMD
Authors: Ebner Lynn J. A. , Imsand Cornelia , Karademir Duygu , Peters Florian , Kiessling Eva , Fottner Antonia , Matter Claudia , Fajardo Diego S. , Merolla Luca , Wögenstein Gabriele M. , Tsioti Ioanna , Govers Larissa P. , Blaser Frank , Meneau Isabelle , Boye Sanford L. , Boye Shannon E. , Grimm Christian , Samardzija Marijana
Published: November 2024

Age-related tissue changes lead to reduced oxygen delivery to photoreceptors and the retinal pigment epithelium (RPE), and contribute to the pathology of age-related macular degeneration (AMD). The implication of hypoxia-inducible factors (HIFs) in this process makes them good candidates as therapeutic targets for AMD. We developed a multiplex dual-acting therapy utilizing the shRNAmir system, delivered by a single AAV, that reduces mRNA levels ofHif1ain photoreceptors andHif2ain the RPE. This RNA interference-based strategy demonstrated a strong therapeutic effect, potently preserving photoreceptors and the RPE in two models of pseudo- and true hypoxia up to 61 weeks post-injection. The efficacy of our dual-acting virus proved superior to single-acting viruses targeting onlyHif1ain photoreceptors orHif2ain the RPE. By targeting a common, conserved disease pathway, this gene-agnostic RNAi therapy shows significant potential to protect tissues from chronic hypoxic insults in complex diseases such as AMD.
Fate (or state) of CA2 neurons in a mineralocorticoid receptor knockout
Authors: Harris Erin P. , Jones Stephanie M. , Alexander Georgia M. , Kandemir Başak , Ward James M. , Wang TianYuan , Proaño Stephanie , Xu Xin , Dudek Serena M.
Published: November 2024

Hippocampal area CA2 has emerged as a functionally and molecularly distinct part of the hippocampus and is necessary for several types of social behavior, including social aggression. As part of the unique molecular profile of both mouse and human CA2, the mineralocorticoid receptor (MR;Nr3c2) appears to play a critical role in controlling CA2 neuron cellular and synaptic properties. To better understand the fate (or state) of the neurons resulting from MR conditional knockout, we used a spatial transcriptomics approach. We found that without MRs, ‘CA2’ neurons acquire a CA1-like molecular phenotype. Additionally, we found that neurons in this area appear to have a cell size and density more like that in CA1. These finding support the idea that MRs control at least CA2’s ‘state’ during development, resulting in a CA1-like ‘fate’.
Active Remote Focus Stabilization in Oblique Plane Microscopy
Authors: Nguyen Trung Duc , Rahmani Amir , Ponjavic Aleks , Millett-Sikking Alfred , Fiolka Reto
Published: December 2024

Light-sheet fluorescence microscopy (LSFM) has demonstrated great potential in the life sciences owing to its efficient volumetric imaging capabilities. For long term imaging, the light-sheet typically needs to be stabilized to the detection focal plane for the best imaging results. Current light-sheet stabilization methods rely on fluorescence emission from the sample, which may interrupt the scientific imaging and add to sample photobleaching. Here we show that for oblique plane microscopes (OPM), a subset of LSFM where a single primary objective is used for illumination and detection, light-sheet stabilization can be achieved without expending sample fluorescence. Our method achieves ~43nm axial precision and maintains the light-sheet well within the depth of focus of the detection system for hour-long acquisition runs in a lab environment that would otherwise detune the system. We demonstrate subcellular imaging of the actin skeleton in melanoma cancer cells with a stabilized OPM.
Extracellular Vesicles as Biomarkers for Steatosis Stages in MASLD Patients: an Algorithmic Approach Using Explainable Artificial Intelligence
Authors: Trifylli Eleni Myrto , Angelakis Athanasios , Kriebardis Anastasios G. , Papadopoulos Nikolaos , Fortis Sotirios P. , Pantazatou Vasiliki , Koskinas Ioannis , Kranidioti Hariklia , Koustas Evangelos , Sarantis Panagiotis , Manolakopoulos Spilios , Deutsch Melanie
Published: November 2024

Background & Aims

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as NAFLD, is a leading cause of chronic liver disease worldwide. Current diagnostic methods, including liver biopsies, are invasive and have significant limitations, emphasizing the need for non-invasive alternatives. This study aimed to evaluate extracellular vesicles (EV) as biomarkers for diagnosing and staging steatosis in MASLD patients, utilizing machine learning (ML) and explainable artificial intelligence (XAI).

Methods

This prospective, single-center cohort study was conducted at the GI-Liver Unit, Hippocration General Hospital, Athens. It included 76 MASLD patients with ultrasound-confirmed steatosis and at least one cardiometabolic risk factor. Patients underwent transient elastography for steatosis and fibrosis staging and blood sampling for EV analysis using nanoparticle tracking. Twenty machine learning models were developed. Six to distinguish non-steatosis (S0) from steatosis (S1-S3), and fourteen to identify severe steatosis (S3). Models incorporated EV measurements (size and concentration), anthropomorphic and clinical features, with performance evaluated using AUROC and SHAP-based interpretability methods.

Results

The CB-C1a model achieved, on average on 10 random splits of 5-fold cross validation (5CV) of the train set, an AUROC of 0.71/0.86 (train/test) for distinguishing S0 from S1-S3 steatosis stages, relying on EV metrics alone. The CB-C2h-21 model identified severe steatosis (S3), on average on 10 random splits of 3-fold cross validation (3CV) of the train set, with an AUROC of 0.81/1.00 (train/test), demonstrating superior performance when combining EV with anthropomorphic and clinical features such as diabetes and advanced fibrosis. Key EV features, including mean size and concentration, were identified as important predictors. SHAP analysis highlighted complex non-linear relationships between features and steatosis staging.

Conclusions

EV metrics are promising non-invasive biomarkers for diagnosing and staging MASLD. The integration of ML-enhanced EV analysis with clinical features offers a scalable, patient-friendly alternative to invasive liver biopsies, advancing precision in MASLD management. Further research should refine these methods for broader clinical application.

Graphical Abstract
The rs11150601 intron variant of SETD1A is associated with female schizophrenia in the UK Biobank cohort
Authors: Lehrer Steven , Rheinstein Peter H.
Published: December 2024

Background

Schizophrenia is a complex psychiatric disorder with an estimated heritability of 80%. SETD1A, a gene encoding a histone methyltransferase critical for transcriptional regulation, has been identified as a significant risk factor for schizophrenia. Loss-of-function mutations in SETD1A confer up to a 35-fold increased risk, implicating its role in neurodevelopment and synaptic plasticity.

Methods

Using data from the UK Biobank cohort (468,998 participants), we investigated the association of SETD1A variants with schizophrenia, obesity, and hypertension. Schizophrenia cases were identified using ICD-10 codes, while obesity and hypertension were assessed using specific data fields. Genome-wide association analysis was performed using PLINK, and statistical analyses utilized SPSS v26. Logistic regression assessed the impact of SETD1A intron variant (rs11150601) alongside age, obesity, and hypertension on schizophrenia risk.

Results

Among 1,063 individuals diagnosed with schizophrenia, obesity (p < 0.001) and hypertension (p < 0.001) were significantly more prevalent. The rs11150601 GG genotype was associated with an increased risk of schizophrenia in women (OR 1.6, p < 0.001) but not in men. Logistic regression revealed that obesity, hypertension, and age were independent risk factors for schizophrenia in women. SETD1A genotype exerted a significant sex-specific effect, highlighting its potential role in the biological mechanisms underlying schizophrenia.

Conclusion

Our findings emphasize the role of SETD1A in the genetic architecture of schizophrenia and its comorbidities, particularly in women. The sex-specific effects of SETD1A variants underscore the importance of incorporating biological sex into studies of psychiatric genetics. Further research is warranted to elucidate the mechanisms by which SETD1A influences neurodevelopment and identify therapeutic strategies targeting its epigenetic functions.

Graphical abstract

The rs11150601 intron variant of SETD1A is associated with female schizophrenia but not male schizophrenia.
Intimate Partner Violence Experiences among Men Who Have Sex in Hanoi, Vietnam
Authors: Pham Loc Quang , Sullivan Patrick S. , Gilmore Amanda K. , Kalokhe Ameeta S. , Nguyen Thanh Cong , Nguyen Khanh Duc , Bui Hao Thi Minh , Giang Le Minh
Published: December 2024

Purpose

Intimate partner violence (IPV) victimization is a pressing issue among men who have sex with men (MSM) and has profound health implications. This study aims to estimate the prevalence of IPV and identify factors associated with its occurrence among MSM in Hanoi, Vietnam

Methods

A cross-sectional study was conducted from March to May 2023 at an MSM-friendly sexual health clinic in Hanoi. Participants completed a self-administered questionnaire on a tablet after screening for eligibility. IPV victimization was assessed using a 21-item scale (the IPV-GBM scale). Logistic regression models were used to identify factors associated with IPV victimization in the past 12 months.

Results

Among 309 respondents, the mean age was 28 and half of participants reported using PrEP for 12 months or more. Two-thirds reported IPV victimization in the past 12 months (67%). Emotional IPV (47%) was most prevalent, followed by monitoring (39%), controlling (19%), and physical/sexual IPV (15%). Participants who were reported experiencing IPV in the past 12 months were more likely to be aged ≤ 24 years (aOR = 1.98, 95% CI: 1.14, 3.44), to report preferring the insertive sexual role (aOR = 2.02, 95% CI: 1.10, 3.70), or to report having more sexual partners (2-5 partners vs ≤ 1 partner: aOR = 2.02, 95% CI: 1.10, 3.70; ≥ 5 partners vs. ≤ 1 partner: aOR = 2.02, 95% CI: 1.10, 3.70).

Conclusions

IPV victimization among MSM on PrEP in Hanoi is highly prevalent. Tailored interventions are needed to address these vulnerabilities and promote safer behaviors and healthier relationships. Efforts should prioritize younger MSM. Further research is necessary to explore IPV dynamics across diverse settings.