bluuebunny/crossref_metadata_2025 huggingface dataset:
Variable selection for competing risk regression models: recommendations for analyzing data from epidemiological studies
Authors: Mullaert J. , Schmeller Sandra , Austin Peter C. , Latouche A.
Published: November 2024

When fitting competing risks regression models, a variety of variable selection methods exist, including backward selection on the subdistribution hazard, on the cause-specific hazards, and penalized methods. However, a benchmark study comparing these different procedures is lacking.

We conducted an extensive simulation study to compare three variable selection procedures in terms of both model selection ability and predictive accuracy. 5120 datasets were simulated in various conditions aiming at being representative of real applications in clinical epidemiology. Results show that the backward selection procedure can lead to high false discovery rate (FDR) because of implementation choices. Even for scenarios with a high numbers of events per variable (EPV), the true model is rarely identified by any of the tested procedures. Survival predictions were assessed with time-dependent AUC and show similar performances for all methods. We also provide an application on real data from stem cell transplanted patients in hematology.

We conclude that the identification of the true model in competing risk regression is a very difficult task, and suggest some recommendations to analysts: (1) to report event per variable for the event type of interest and (2) to use multiple methods to deal with model uncertainty and avoid implementation pitfalls.
Analysis of 470,000 exome-sequenced UK Biobank participants identifies genes containing rare variants which confer dementia risk
Authors: Gibbons Lily , Curtis David
Published: November 2024

Background

Previous studies have reported that rare coding variants in a handful of genes have major effects on risk of Alzheimer’s disease (AD). A recent exome wide association study (ExWAS) of dementia in a subset of the UK Biobank cohort implicated a number of genes, including five which were novel. Here we report a similar analysis, carried out on the full cohort of 470,000 exome-sequenced participants.

Methods

A score was assigned to each participant depending on individual and/or parental diagnosis of dementia. Regression analysis includingAPOEε3 and ε4 doses as covariates was applied to gene-wise tests for association with loss of function (LOF) and nonsynonymous variants. 45 tests using different pathogenicity predictors were applied to the first cohort of 200,000 participants. Subsequently the 100 genes showing strongest evidence for association were analysed in the second cohort of 270,000 participants, using only the best-performing predictor for each gene.

Results

Three genes achieved statistical significance,TREM2, SORL1andABCA7. The five genes reported as novel in the ExWAS did not produce any appreciable evidence for association in this study. The effects and frequencies of variants in different functional categories were characterised for these genes.

Conclusions

Rare coding variants in a small number of genes have important effects on dementia risk. Further study of individual variant effects might elucidate mechanisms of pathogenesis. Incorporating rare variant effects for individual risk assessment might become important if preventative treatments for dementia become available.
A 2-year longitudinal investigation of insula subregional volumes in early psychosis
Authors: Kittleson Andrew R. , McHugo Maureen , Liu Jinyuan , Vandekar Simon N. , Armstrong Kristan , Rogers Baxter , Woodward Neil D. , Heckers Stephan , Sheffield Julia M.
Published: November 2024

Background

The insula is a heterogeneous cortical region with three cytoarchitectural subregions— agranular, dysgranular, and granular—that have distinct functional roles. Previous cross- sectional studies have shown smaller volume of all insula subregions in individuals with psychotic disorders. However, longitudinal trajectories of insula subregions in early psychosis, and the relationship between subregional volumes and relevant clinical phenomena, such as perceptual aberrations, have not been previously examined.

Methods

66 early psychosis (EP) and 65 healthy comparison (HC) participants completed 2-4 study visits over 2 years. T1-weighted structural brain images were processed using longitudinal voxel- based morphometry in CAT12 and segmented into anatomic subregions. At baseline, participants completed the Perceptual Aberrations Scale (PAS) to capture bodily distortions. The EP group was further examined based on diagnostic trajectory over two years (stable schizophrenia, stable schizophreniform, and conversion from schizophreniform to schizophrenia).

Results

EP participants had smaller insula volumes in all subregions compared to HC participants, and these volumes were stable over two years. Compared to HC, insula volumes were significantly smaller in EP participants with a stable diagnosis of schizophrenia, but other diagnostic trajectory groups did not significantly differ from HC or the stable schizophrenia group. While perceptual aberrations were significantly elevated in EP participants, PAS scores were not significantly related to insula volume.

Conclusions

We find that all insula subregions are smaller in early psychosis and do not significantly decline over two years. These data suggest that all insula subregions are structurally impacted in schizophrenia-spectrum disorders and may be the result of abnormal neurodevelopment.
Association between handgrip strength, handgrip strength asymmetry, and anxiety in Korean older adults: The Korean National Health and Nutrition Examination Survey 2022
Authors: Choi Sang-Youn , Park Su-Min , Park Eun-Cheol
Published: November 2024

Low handgrip strength (HGS) and HGS asymmetry are associated with age-related physical and mental disorders in older adults. This study aimed to examine the association between HGS-related factors and anxiety to evaluate whether HGS assessments can assist in identifying anxiety risk. In total, 1,750 participants from the Korea National Health and Nutrition Examination Survey of 2022 were included in this study. Individuals whose HGS values were below the 20th percentile of the study population stratified by sex were classified into the low-HGS group. Anxiety was assessed using the generalized anxiety disorder with a 7-item scale. Multiple logistic regression was used to analyze the relationship between HGS level and asymmetry and anxiety, adjusting for covariates. Overall, 70 (8.7%) men and 123 (13.0%) women had anxiety. Elevated odds of anxiety were observed in older women with low HGS (adjusted odds ratio: 2.17, 95% confidence interval: 1.31–3.61). There was a positive correlation between the degree of asymmetrical HGS and anxiety among women. This study found positive associations between low HGS, HGS asymmetry, and anxiety in older Korean women. This population may require specific interventions to help maintain good mental health.
Anxiolytic management in eating disorder patients receiving cognitive behavioral therapy: A quality improvement brief report
Authors: Smith Brad E.R. , Greenberg Katelyn A. , Vadapalli Sreya , Garrison Sheldon R.
Published: November 2024

Eating disorders (EDs) are serious lifelong and debilitating health conditions characterized by complex adverse eating behaviors resulting in weight loss and decreased quality of life. One evidence-based treatment is a form of cognitive-behavioral therapy (CBT) called exposure therapy where patients progress through a hierachy of exposures. This treatment approach results in concern related to CBT efficacy for patients concurrently treated with anxiolytic medications. These medications, which are being incorporated into treatment protocols, may impact the anxiety-provoking components of the exposure response, potentially limiting its efficacy. Therefore, patients were assessed in multiple ways to ensure that providers could prescribe anxiolytics without risk to diminishing the well-established response to CBT. To ensure that patients treated with anxiolytics progressed at a similar rate to those who did not receive them, a quality improvement study was conducted to compare all patients in residential, partial hospitalization and intensive outpatient eating disorder treatment programs.
OrthologAL: A Shiny application for quality-aware humanization of non-human pre-clinical high-dimensional gene expression data
Authors: Chowdary Rishika , Suter Robert K. , D’Antuono Matthew , Gomes Cynthia , Stein Joshua , Lee Ki-Bum , Lee Jae K , Ayad Nagi G.
Published: November 2024

Single-cell and spatial transcriptomics provide unprecedented insight into the inner workings of disease. Pharmacotranscriptomic approaches are powerful tools that leverage gene expression data for drug repurposing and treatment discovery in many diseases. Multiple databases attempt to connect human cellular transcriptional responses to small molecules for use in transcriptome-based drug discovery efforts. However, pre-clinical research often requiresin vivoexperiments in non-human species, which makes capitalizing on such valuable resources difficult. To facilitate the application of pharmacotranscriptomic databases to pre-clinical research models and to facilitate human orthologous conversion of non-human transcriptomes, we introduce OrthologAL. OrthologAL leverages the BioMart database to access different gene sets from Ensembl, facilitating the interaction between these servers without needing user-generated code. Researchers can input their single-cell or other high-dimensional gene expression data from any species, and OrthologAL will output a human ortholog-converted dataset for download and use. To demonstrate the utility of this application, we characterized orthologous conversion in single-cell, single-nuclei, and spatial transcriptomic data derived from common pre-clinical models, including patient-derived orthotopic xenografts of medulloblastoma, and mouse and rat models of spinal cord injury. We show that OrthologAL can convert these data types efficiently to that of corresponding orthologs while preserving the dimensional architecture of the original non-human expression data. OrthologAL will be broadly useful for applying pre-clinical, high-dimensional transcriptomics data in functional small molecule predictions using existing human-annotated databases.
The mechanical anisotropy of adipose tissues regulates ovarian cancer invasion
Authors: Gonzalez-Molina Jordi , Nabili Parisa , Marciano Daniele , Abdelnabi Sara , Gultekin Okan , Rasul Mohammed Fatih , Zhang Yikun , Nadal Clémence , Chrysanthou Alexandra , Alkasalias Twana , Salehi Sahar , Balkwill Frances , Lehti Kaisa , Gautrot Julien E.
Published: November 2024

High-grade serous ovarian cancer, the most common and aggressive form of ovarian cancer, generally metastasises to visceral adipose tissues. In these tissues, the extracellular matrix through which ovarian cancer cells adhere and migrate is confined by the presence and preponderance of adipocytes. How cells migrate in this unique environment is not known, yet critical to understanding metastatic progression. To study these processes, we develop biomimetic organo-hydrogels that recreate structural and mechanical properties of human visceral adipose tissues. We show that ovarian cancer cells present invasive tropism towards organo-hydrogels, replicating the behaviour observed in native adipose tissues. This migration is facilitated by the mechanical anisotropy and microstructure of organo-hydrogels and adipose tissues, allowing the formation of cell force-induced migratory tracks, a process regulated by TGFβ in an MMP degradation-independent manner. These results highlight the contribution of adipocytes to tissue biophysical features as a key regulatory factor of ovarian cancer cell migration.
Unlocking the Secrets of Amphibious Plant Adaptation: The Role of RNA Modifications
Authors: Maździarz Mateusz , Krawczyk Katarzyna , Szablińska-Piernik Joanna , Paukszto Łukasz , Szczecińska Monika , Sulima Paweł , Sawicki Jakub
Published: November 2024

Post-transcriptional RNA modifications, such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), and pseudouridine (Ψ), are critical regulators of plant development, stress responses, and environmental adaptation. The modifications m6A, m5C, and Ψ were insufficiently studied in plant stress responses. To investigate the epitranscriptomic landscape of these modifications, we employed direct RNA sequencing (DRS) to analyze native RNA from the amphibious plantRiccia fluitansgrown in both aquatic and terrestrial environments. Our study revealed the presence of Ψ, m5C, and m6A modifications inR. fluitanstranscriptomes from diverse environments. We observed correlations between the occurrence of these modifications and transcript length, as well as poly(A) tail length. Furthermore, we analyzed the expression of genes encoding Ψ synthases and methyltransferases to gain initial insights into the regulatory mechanisms underlying these processes inR. fluitans. By understanding how RNA modifications are regulated in response to environmental changes, we can unlock the secrets of the remarkable adaptability of amphibious plants. This knowledge could have eventually led to the understanding of the mechanisms of plant land colonization.
A reinforcement learning based software simulator for motor brain-computer interfaces
Authors: Liang Ken-Fu , Kao Jonathan C.
Published: November 2024

Intracortical motor brain-computer interfaces (BCIs) are expensive and time-consuming to design because accurate evaluation traditionally requires real-time experiments. In a BCI system, a user interacts with an imperfect decoder and continuously changes motor commands in response to unexpected decoded movements. This “closed-loop” nature of BCI leads to emergent interactions between the user and decoder that are challenging to model. The gold standard for BCI evaluation is therefore real-time experiments, which significantly limits the speed and community of BCI research. We present a new BCI simulator that enables researchers to accurately and quickly design BCIs for cursor control entirely in software. Our simulator replaces the BCI user with a deep reinforcement learning (RL) agent that interacts with a simulated BCI system and learns to optimally control it. We demonstrate that our simulator is accurate and versatile, reproducing the published results of three distinct types of BCI decoders: (1) a state-of-the-art linear decoder (FIT-KF), (2) a “two-stage” BCI decoder requiring closed-loop decoder adaptation (ReFIT-KF), and (3) a nonlinear recurrent neural network decoder (FORCE).
Enhanced immunogenicity of aClostridioides difficileTcdB vaccine adjuvanted with a synthetic dual-TLR ligand adjuvant
Authors: Naz Farha , Hagspiel Nicholas , Xu Feifan , Thompson Brandon , Moreau G. Brett , Young Mary , Herbein Joel , Fox Christopher B , Petri William A , Abhyankar Mayuresh M
Published: November 2024

We report a comprehensive evaluation of the toxin B (TcdB) vaccine adjuvanted with a dual Toll-like receptor ligand liposome adjuvant forClostridioides difficileinfection (CDI). The vaccine completely protected mice from a lethal infection. Compared to alum adjuvanted TcdB, it generated functionally superior systemic antibodies and supported strong memory B cell and gut IgA responses. This pharmaceutically acceptable adjuvant platform holds promise for developing a next-generation CDI vaccine.
Atrial Granules in Atrial Cardiomyocytes as Acidic Calcium Stores
Authors: Akerman Emily , Aston Daniel , Rog-Zielinska Eva , Boland Barry , Schotten Ulrich , Verheule Sander , Capel Rebecca A , Burton Rebecca A.B.
Published: November 2024

Acidic calcium stores significantly influence basal calcium transient amplitude and β-adrenergic responses in cardiomyocytes. Atrial myocytes express a small acidic organelle called atrial granules (AG), which store and excrete atrial natriuretic peptide and are not expressed by healthy ventricular myocytes. AG are known to be acidic with a high calcium content. The number and position of these calcium-rich organelles relative to other signaling sites has not been investigated. Staining of acidic organelles in adult guinea pig cardiomyocytes showed the presence of fluorescent acidic puncta throughout the cytosol. Atrial myocytes exhibited an increased concentration of acidic organelles at the nuclear poles. Live cell fluorescent studies using PBA to inhibit peptidylglycine α-amidating monooxygenase, a crucial component of AG membranes, effectively eliminated staining at the nuclear poles and most acidic puncta in atrial cells. The application of PBA to ventricular myocytes did not affect LysoTracker staining. Electron microscopy studies on goat atrial fibrillation (AF) and sham control tissue, allowed visualization of AGs. Quantitative analysis revealed AGs to be in close apposition to the sarcoplasmic reticulum and mitochondria. AGs were significantly increased in AF goat samples when compared to sinus rhythm from 3D electron tomography images. Our imaging studies suggest that AGs make up a large percentage of atrial acidic stores, with AG associated with the sarcoplasmic reticulum and their number increasing during AF. We raise the question whether the positioning of AGs are strategic to communicate with other calcium organelles. Further studies to investigate whether AGs contribute to physiological calcium signalling are required.
TimeFlies: an snRNA-seq aging clock for the fruit fly head sheds light on sex-biased aging
Authors: Tennant Nikolai , Pavuluri Ananya , O’Connor-Giles Kate , Singh Gunjan , Larschan Erica , Singh Ritambhara
Published: November 2024

Although multiple high-performing epigenetic aging clocks exist, few are based directly on gene expression. Such transcriptomic aging clocks allow us to extract age-associated genes directly. However, most existing transcriptomic clocks model a subset of genes and are limited in their ability to predict novel biomarkers. With the growing popularity of single-cell sequencing, there is a need for robust single-cell transcriptomic aging clocks. Moreover, clocks have yet to be applied to investigate the elusive phenomenon of sex differences in aging. We introduce TimeFlies, a pan-cell-type scRNA-seq aging clock for theDrosophila melanogasterhead. TimeFlies uses deep learning to classify the donor age of cells based on genome-wide gene expression profiles. Using explainability methods, we identified key marker genes contributing to the classification, with lncRNAs showing up as highly enriched among predicted biomarkers. The top biomarker gene across cell types is lncRNA:roX1, a regulator of X chromosome dosage compensation, a pathway previously identified as a top biomarker of aging in the mouse brain. We validated this finding experimentally, showing a decrease in survival probability in the absence of roX1in vivo. Furthermore, we trained sex-specific TimeFlies clocks and noted significant differences in model predictions and explanations between male and female clocks, suggesting that different pathways drive aging in males and females.

Graphical Abstract
Selective Inhibition of Cytosolic PARylation via PARG99: A Targeted Approach for Mitigating FUS-associated Neurodegeneration
Authors: Kodavati Manohar , Maloji Rao Vikas H. , Mitra Joy , Hegde Muralidhar L.
Published: November 2024

Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) are characterized by complex etiologies, often involving disruptions in functions of RNA/DNA binding proteins (RDBPs) such as FUS and TDP-43. The cytosolic mislocalization and aggregation of these proteins are linked to accumulation of unresolved stress granules (SGs), which exacerbate the disease progression. Poly-ADP-ribose polymerase (PARP)-mediated PARylation plays a critical role in this pathological cascade, making it a potential target for intervention. However, conventional PARP inhibitors are limited by their detrimental effects on DNA repair pathways, which are already compromised in ALS. To address this limitation, we investigated a strategy focused on targeting the cytosolic compartment by expressing the cytosol-specific, natural PAR- glycohydrolase (PARG) isoform, PARG99. Using ALS patient derived FUS mutant induced pluripotent cells (iPSCs) and differentiated neurons, we observed elevated levels of FUS in insoluble fractions in mutant cells compared to mutation-corrected isogenic lines. The insoluble FUS as well as TDP-43 levels increased further in sodium arsenite-treated or oxidatively stressed cells, correlating with accumulation of unresolved SGs. Notably, both PARG99 and PARP inhibitors reduced SG formation and insoluble FUS levels, however, PARG99 treated cells exhibited significantly lower DNA damage markers and improved viability under oxidative and arsenite stress. This study highlights the potential of PARG99 as a cytosol-specific intervention to mitigate FUS-associated toxicity while preserving critical nuclear DNA repair mechanisms, offering a promising strategy for addressing the underlying pathology of ALS and potentially other SG-associated neurodegenerative diseases.
Carbon-conserving Bioproduction of Malate in anE. coli-based Cell-Free System
Authors: Cardiff Ryan A. L. , Chowdhury Shaafique , Sugianto Widianti , Tickman Benjamin I. , Burbano Diego Alba , Meyer Pimphan A. , Cook Margaret , King Brianne , Garenne David , Beliaev Alexander S. , Noireaux Vincent , Peralta-Yahya Pamela , Carothers James M.
Published: November 2024

Formate, a biologically accessible form of CO2, has attracted interest as a renewable feedstock for bioproduction. However, approaches are needed to investigate efficient routes for biological formate assimilation due to its toxicity and limited utilization by microorganisms. Cell-free systems hold promise due to their potential for efficient use of carbon and energy sources and compatibility with diverse feedstocks. However, bioproduction using purified cell-free systems is limited by costly enzyme purification, whereas lysate-based systems must overcome loss of flux to background reactions in the cell extract. Here, we engineer anE. coli-based system for an eight-enzyme pathway from DNA and incorporate strategies to regenerate cofactors and minimize loss of flux through background reactions. We produce the industrial di-acid malate from glycine, bicarbonate, and formate by engineering the carbon-conserving reductive TCA and formate assimilation pathways. We show thatin situregeneration of NADH drives metabolic flux towards malate, improving titer by 15-fold. Background reactions can also be reduced 6-fold by diluting the lysate following expression and introducing chemical inhibitors of competing reactions. Together, these results establish a carbon-conserving, lysate-based cell-free platform for malate production, producing 64 μM malate after 8 hours. This system conserves 43% of carbon otherwise lost as CO2and incorporates 0.13 mol CO2equivalents/mol glycine fed. Finally, techno-economic analysis of cell-free malate production from formate revealed that the high cost of lysate is a key challenge to the economic feasibility of the process, even assuming efficient cofactor recycling. This work demonstrates the capabilities of cell-free expression systems for both the prototyping of carbon-conserving pathways and the sustainable bioproduction of platform chemicals.

Highlights

Successfully engineered the carbon-conserving reductive TCA and formate assimilation pathways in a lysate-based cell-free system for production of the C4 industrial di-acid malate from C1 and C2 feedstocks.

Achieved a 6-fold reduction in competition from the endogenous cell-free metabolism by blocking TCA activity using small-molecule inhibitors and lysate dilution.

Increased accumulation of malate by 15-fold in a single-step reaction using cell-free expression of an enzymatic cofactor regeneration system.

Techno-economic analysis identified routes for economically feasible production of malate from renewable feedstocks in a cell-free system by improving conversion efficiency and reducing lysate cost.

Graphical Abstract
Variation in the geometry of concept manifolds across human visual cortex
Authors: St-Yves Ghislain , Kay Kendrick , Naselaris Thomas
Published: November 2024

Brain activity patterns in high-level visual cortex support accurate linear classification of visual concepts (e.g., objects or scenes). It has long been appreciated that the accuracy of linear classification in any brain area depends on the geometry of its concept manifolds—sets of brain activity patterns that encode images of a concept. However, it is unclear how the geometry of concept manifolds differs between regions of visual cortex that support accurate classification and those that don’t, or how it differs between visual cortex and deep neural networks (DNNs). We estimated geometric properties of concept manifolds that, per a recent theory, directly determine the accuracy of simple “few-shot” linear classifiers. Using a large fMRI dataset, we show that variation in classification accuracy across human visual cortex is driven by a variation in a single geometric property: the distance between manifold centers (“geometric Signal”). In contrast, variation in classification accuracy across most DNN layers is driven by an increase in the effective number of manifold dimensions (“Dimensionality”). Despite this difference in the geometric properties that affect few-shot classification performance in the brain and DNNs, we find that Signal and Dimensionality are strongly, negatively correlated: when Signal increases across brain regions or DNN layers, Dimensionality decreases, and vice versa. We conclude that visual cortex and DNNs deploy different geometric strategies for accurate linear classification of concepts, even though both are subject to the same constraint.
Parasite-induced replacement of host microbiota- Impact ofXenos gadagkariparasitization on the microbiota ofPolistes wattii
Authors: Nain Deepak , Rana Anjali , Raychoudhury Rhitoban , Sen Ruchira
Published: November 2024

Abstract

Background

The study of microbiota of social insects under different ecological conditions can provide important insights into the role of microbes in their biology and behaviour.Polistesis one of the most widely distributed and extensively studied genera of social wasps, yet the microbiota of any species ofPolistesor any primitively eusocial wasp is still unknown.Polistes wattiiis an abundantly distributed Asian wasp which hibernates in winter and exhibits a unique biannual nest founding strategy. It is often parasitized by the strepsipteran endoparasiteXenos gadagkari,which changes the morpho-physiology and behaviour of their hosts. In this study we employ 16S rRNA amplicon sequencing, using the Oxford Nanopore platform, to study the microbial community associated withP. wattiiand compared the microbiota of the unparasitized male and femaleP. wattiiwith their parasitized counterparts.

Results

The microbiota of females from preemergence solitary foundress nests differs from the females from the late colony phase of multiple foundress nests. The males and females also differ in their microbiota. To estimate the effect of strepsipteran parasitism on the microbiota ofP. wattii,we compared the unparasitized wasps with that of the female and maleX. gadagkariparasitoids and parasitized wasps. We show that the microbiota of the parasitoids and the parasitized wasps are dominated byWolbachiaandProvidencia.β-diversity differences indicated that the parasitoid replaces and homogenizes the microbiota ofP. wattii.Although the normal microbiota ofP. wattiiresembles that of highly eusocial vespid wasps, we showX. gadagkariparasitization replaces the microbiota ofP. wattiiand it becomes more like the microbiota of strepsipterans. Therefore, it appears thatX. gadagkariand other such strepsipteran parasitoids may have a bigger impact on the biology of their hosts, than previously thought.

Conclusion

This is the first study of microbiota of any primitively eusocial Polistine wasp and any strepsipteran parasitoid associated with a hymenopteran species. Although strepsipteran parasitoids are commonly found in hymenopteran insects, the change on the microbiota of the host due to the parasitism was not known before. This study shows the drastic impact of the parasitoid on the microbiota of the host.
The dual ubiquitin binding mode of SPRTN secures rapid spatiotemporal proteolysis of DNA-protein crosslinks
Authors: Song Wei , Zhao Yichen , Ruggiano Annamaria , Redfield Christina , Newman Joseph A , Zhu Xiaosheng , Cruz-Migoni Abimael , Roddan Rebecca , McHugh Peter , Elliott Paul , Ramadan Kristijan
Published: November 2024

DNA-protein crosslinks (DPCs) are endogenous and chemotherapy-induced genotoxic DNA lesions and, if not repaired, lead to embryonic lethality, neurodegeneration, premature ageing, and cancer. DPCs are heavily polyubiquitinated, and the SPRTN protease and 26S proteasome emerged as two central enzymes for DPC proteolysis. The proteasome recognises its substrates by their ubiquitination status. How SPRTN protease, an essential enzyme for DPC proteolysis, achieves specificity for DPCs still needs to be discovered. We found that the N-terminal SPRTN catalytic region (SprT) possesses a ubiquitin-binding domain named theUbiquitin interface ofSprTDomain (USD). Using multiple biochemical, biophysical, and structural approaches, we reveal that USD binds ubiquitin chains. SPRTN binding to ubiquitin chains via USD leads to ∼ 67-fold higher activation of SPRTN proteolysis towards polyubiquitinated DPCs than the unmodified DPCs. This study reveals the ubiquitination of DPCs is the key signal for SPRTN’s substrate specificity and rapid proteolysis.
Epromoters bind key stress-related transcription factors to regulate clusters of stress response genes
Authors: Malfait Juliette , Wan Jing , Singh Himanshu , Souaid Charbel , Farah Gaëlle , Esnault Cyril , Sarrazin Sandrine , Sieweke Michael , Spicuglia Salvatore
Published: November 2024

Stress insults trigger the rapid and global reprogramming of gene transcription by coordinated recruitment of a limited number of key inducible transcription factors to cis-regulatory elements. Here, we performed a comprehensive analysis of different stress models and observed that co-induced genes are generally located in close genomic proximity. By integrating gene expression and transcription factor binding resources in different stress models, we found an enrichment for clusters whereby only one of the promoters of the cluster recruits the key transcription factors, reminiscent of Epromoters, a type of cis-regulatory elements displaying both promoter and enhancer function. Epromoter-regulated clusters were frequently found irrespectively of the stress or inflammatory response. Predicted Epromoters displayed enhancer activity and regulated clusters of stress-response genes independently of their genomic location. These findings have significant implications for understanding complex gene regulation following the response to acute perturbations.

Teaser

When cells face stress, they undergo rapid changes in gene expression, orchestrated by a handful of key transcription factors. But how do these factors coordinate such a complex response? Our study reveals that “Epromoters”—cis-regulatory elements that combine the functions of both promoters and enhancers help organize stress-response genes into tightly regulated clusters. This discovery not only deepens our understanding of gene regulation in the face of stress but also offers exciting implications for studying inflammation and other acute cellular responses.
Reading Acquisition Drives Linguistic Cross-Modal Convergence in The Left Ventral Occipitotemporal Cortex
Authors: Dębska A , Wang S , Jednoróg K , Pattamadilok C
Published: November 2024

Reading acquisition requires linking visual symbols with speech sounds, leading to the development of neural sensitivity to print. While prior studies have shown the importance of cross-modal integration in spoken language areas, the higher-level visual area (lvOT) processing printed words remained more context-dependent. This longitudinal study investigated whether the lvOT undergoes cross-modal reorganization to facilitate print-speech integration during reading development and how these changes relate to reading skills. We followed children over two years, beginning at the onset of formal reading instruction. We examine lvOT responses to print-specific, speech-specific, and its convergence at whole-brain, region of interest and voxel-based levels. Results showed that with reading experience, the Initial print-specific responses in the lvOT are transformed into responses to both print and speech input. This transformation positively correlates with reading skills, especially in early acquisition stages. These findings suggest that reading acquisition drives cross-modal reorganization within the lvOT, enabling the area to integrate print and speech. They shed light on the broader neural mechanisms supporting reading development.
Reliable odorant sensing but variable associative learning inC. elegans
Authors: Tasnim Samiha , Liu Amber , Jose Antony M.
Published: November 2024

Animals can move towards or away from an odorant. Such chemotaxis has been used as a paradigm for learning when coupled with pre-exposure to the sensed odorant. Here we develop an assay for the nematodeC. elegansthat avoids the typical use of chemical or physical immobilization when measuring the response of worms to odorants. Using two sets of rectangular arenas that are oriented such that worms in one set must move in the opposite direction to worms in the other set for the same response, we found that unfed worms show reproducible movement towards the odorants butanone and benzaldehyde, and away from the odorant nonanone. In addition to the use of opposing orientations to control for gradients of unknown cues outside the arena, we introduce a measure of dispersal to control for locomotion defects and unknown cues within the arena. Since this assay avoids the use of paralytics or physical constraints, it is useful for the analysis of graded responses to a variety of chemicals and the discovery of underlying molecular mechanisms. Using this setup, we found that pre-exposure of unfed worms to butanone to induce an association of starvation with butanone resulted in different extents of such associative learning during different trials – from no learning to learned avoidance. Given this variation in associative learning despite the artificially controlled lab setting, we speculate that in dynamic natural environments such learning might be rare and highlight the challenge in discovering evolutionarily selected mechanisms that could underlie learning in the wild.
Metacognitive Introspection Alters the Dynamics of Pre-Decisional Neural Evidence Accumulation
Authors: Dou Wei , Afrakhteh Shirin , Samaha Jason
Published: November 2024

Metacognitive introspection refers to the capacity to monitor and evaluate one’s own performance, such as when expressing confidence in one’s choice. In the context of perceptual decision making, current computational models of confidence typically assume that confidence is computed after the evidence collection process underlying the initial choice has unfolded. This account predicts that the act of introspection required in order to provide a confidence judgment about one’s decision should have little impact on the dynamics of evidence accumulation leading up to that decision. We tested this by examining whether a neural proxy for perceptual evidence accumulation (the central-parietal positivity; CPP) exhibits different dynamics when participants do or do not rate confidence in their perceptual decisions. Behavioral results showed that confidence introspection increased decision accuracy and response time. Importantly, confidence introspection also resulted in a steeper CPP slope beginning shortly after (∼250 ms) decision evidence was available. We further observed an effector-specific neural signal of confidence evidence which both built up prior to the perceptual choice and which was predictive of the amount of confidence subsequently expressed by the participants. Our results indicate that introspection can alter the dynamics of perceptual evidence accumulation, possibly by acting on the gain of evidence accumulation, and that motor-related confidence signals emerge in tandem with pre-decisional evidence accumulation signals rather than post-choice.
Developmentally-regulated proteolysis by MdfA and ClpCP mediates metabolic differentiation duringBacillus subtilissporulation
Authors: Riley Eammon P. , Lyda Jelani A. , Reyes-Matte Octavio , Sugie Joseph , Kasu Iqra R. , Enustun Eray , Armbruster Emily , Ravishankar Sumedha , Isaacson Rivka L. , Camp Amy H. , Lopez-Garrido Javier , Pogliano Kit
Published: November 2024

Bacillus subtilissporulation entails a dramatic transformation of the two cells required to assemble a dormant spore, with the larger mother cell engulfing the smaller forespore to produce the cell-within-a-cell structure that is a hallmark of endospore formation. Sporulation also entails metabolic differentiation, whereby key metabolic enzymes are depleted from the forespore but maintained in the mother cell. This reduces the metabolic potential of the forespore, which becomes dependent on mother-cell metabolism and the SpoIIQ-SpoIIIA channel to obtain metabolic building blocks necessary for development. We demonstrate that metabolic differentiation depends on the ClpCP protease and a forespore-produced protein encoded by theyjbAgene, which we have renamed MdfA (metabolic differentiation factor A). MdfA is conserved in aerobic endospore-formers and required for spore resistance to hypochlorite. Using mass spectrometry and quantitative fluorescence microscopy, we show that MdfA mediates the depletion of dozens of metabolic enzymes and key transcription factors from the forespore. An accompanying study by Massoni, Evans and collaborators demonstrates that MdfA is a ClpC adaptor protein that directly interacts with and stimulates ClpCP activity. Together, these results document a developmentally-regulated proteolytic pathway that reshapes forespore metabolism, reinforces differentiation, and is required to produce spores resistant to the oxidant hypochlorite.
Chimeric mitochondrial RNA transcripts predict mitochondrial genome deletion mutations in mitochondrial genetic diseases and aging
Authors: Vandiver Amy R. , Herbst Allen , Stothard Paul , Wanagat Jonathan
Published: November 2024

Although it is well understood that mitochondrial DNA (mtDNA) deletion mutations cause incurable diseases and contribute to aging, little is known about the transcriptional products that arise from these DNA structural variants. We hypothesized that mitochondrial genomes containing deletion mutations express chimeric mitochondrial RNAs. To test this, we analyzed human and rat RNA sequencing data to identify, quantitate, and characterize chimeric mitochondrial RNAs. We observe increased chimeric mitochondrial RNA frequency in samples from patients with mitochondrial genetic diseases and in samples from aged humans. The spectrum of chimeric mitochondrial transcripts reflects the known pattern of mtDNA deletion mutations. To test the hypothesis that mtDNA deletions induce chimeric RNA transcripts, we treated 18 month old and 34 month old rats with guanidinopropionic acid to induce high levels of skeletal muscle mtDNA deletion mutations. With mtDNA deletion induction, we demonstrate that the chimeric mitochondrial transcript frequency also increases and correlates strongly with an orthogonal DNA-based mutation assay performed on identical samples. Further, we show that the frequency of chimeric mitochondrial transcripts predicts expression of both nuclear and mitochondrial genes central to mitochondrial function, demonstrating the utility of these events as metrics of age-induced metabolic change. Mapping and quantitation of chimeric mitochondrial RNAs provide an accessible, orthogonal approach to DNA-based mutation assays, offer a potential method for identifying mitochondrial pathology in widely accessible data sets, and open a new area of study in mitochondrial genetics and transcriptomics.
Opening a meV mass window for axionlike particles with a microwave-laser-mixed stimulated resonant photon collider
Authors: Homma Kensuke , Kirita Yuri , Miyamaru Takafumi , Hasada Takumi , Kodama Airi
Published: November 2024

We propose a microwave-laser-mixed three-beam stimulated resonant photon collider, which enables access to axionlike particles in the meV mass range. Collisions between a focused pulse laser beam and a focused microwave pulse beam directly produce axionlike particles (ALPs) and another focused pulse laser beam stimulates their decay. The expected sensitivity in the meV mass range has been evaluated. The result shows that the sensitivity can reach the ALP-photon coupling down to O(10−13)  GeV−1 with 106 shots if 10–100 TW class high-intensity lasers are properly combined with a conventional 100 MW class S-band klystron. This proposal paves the way for identifying the nature of ALPs as candidates for dark matter, independent of any cosmological and astrophysical models.

Published by the American Physical Society
2024
Possible mixing of a diquark-antidiquark with a
pp¯
hadronic molecule
Authors: Karliner Marek , Rosner Jonathan L.
Published: November 2024

We discuss the possibility that the two nearby resonances observed by BESIII partially below the pp¯ threshold might be due to mixing between two metastable states with the same JPC=0−+ quantum numbers, but rather different internal structure. One is a pp¯ hadronic molecule and the other a bound state of a light-quark diquark and an antidiquark, both with spin 1 and isospin 0, a composite color antitriplet and triplet, respectively. The doubling of resonances, one of which may be interpreted as a hadronic molecule, while the other arises from qq¯ annihilation in a state with vacuum quantum numbers, may be a more general feature than the specific case considered here.

Published by the American Physical Society
2024
Constraints on the Dirac spectrum from chiral symmetry restoration
Authors: Giordano Matteo
Published: November 2024

I derive constraints on the Dirac spectrum in the chirally symmetric phase of a gauge theory with two massless fermion flavors. Using only general properties of correlation functions of scalar and pseudoscalar bilinears, I prove that in the chiral limit of vanishing fermion mass m the corresponding susceptibilities and all their derivatives with respect to m2 must be finite. I then use the resulting spectral constraints to show that effective breaking of the anomalous U(1)A symmetry is allowed in the SU(2)A symmetric phase in the chiral limit, and leads to distinctive spectral features: (i) the spectral density must develop a singular O(m4)/λ peak as m→0, (ii) the two-point eigenvalue correlator of near-zero modes must be singular, and (iii) near-zero modes cannot be localized. Moreover, in the symmetric phase the topological charge distribution must be indistinguishable from that of an ideal gas of instantons and anti-instantons of vanishing density, to leading order in m.

Published by the American Physical Society
2024
A framework for developing sustainable architectural entrepreneurship start-ups in Egypt
Authors: Othman Ayman Ahmed Ezzat , Aziz Mariz Nasser Walis , Alamoudy Fatma O.
Published: November 2024

Purpose

This research aims to develop and validate a framework to support the development of sustainable architectural entrepreneurship start-ups (AES) in Egypt by overcoming the challenges that obstruct their development.

Design/methodology/approach

A qualitative and quantitative research methodology was designed to accomplish four objectives. The literature review investigated the concept of entrepreneurship, the challenges of AES in Egypt and Egypt’s Vision 2030. Four case studies were analysed to validate the identified challenges and strategies adopted to overcome these obstacles. A survey questionnaire was conducted with AES founders in Egypt to assess their perception of entrepreneurship, challenges and strategies adopted to overcome these barriers. Finally, a framework was developed and validated to facilitate the development of sustainable AES in Egypt.

Findings

Through a literature review, the research identified the highest 17 challenges that obstruct the development of sustainable AES in Egypt and classified them into six categories. Analysis of case studies confirmed various challenges and strategies adopted to overcome these obstacles. Data analysis showed that “financial”, “awareness, educational and training” represent the most influential challenges to AES in Egypt. Moreover, “self-funding through savings” was ranked the highest strategy employed to overcome the financial challenges, while the “continuous learning and skill development” strategy was adopted to address the challenge of awareness, education and training.

Practical implications

This research presents a practical solution to facilitate the development of sustainable AES in Egypt by overcoming the challenges that obstruct their growth. The framework was explained in a workable way to include the required activities, tools and techniques, involved personnel needed resources and implementation strategies.

Originality/value

This research identified and analysed the challenges of developing sustainable AES and the strategies adopted to overcome these obstacles. It studied a topic that received scant attention in construction literature related to start-ups in architecture, especially in Egypt. Moreover, this research developed and validated a framework consisting of six domains based on the findings of a literature review, case studies and survey questionnaire to facilitate the development of sustainable AES in Egypt, which represents a novel and creative synthesis that adds value to knowledge in a way that has not previously occurred.
Empowering leadership boosts employee innovative job performance: unraveling the role of work stress and regulatory focus
Authors: Li Chao , Wang Zhongming , Hu Honghao
Published: November 2024

Purpose

This paper aims to investigate the relationship between empowering leadership and innovative job performance, with challenge stress and hindrance stress acting as parallel mediators. Additionally, the study examines how promotion focus and prevention focus moderate these dual processes.

Design/methodology/approach

A two-wave survey was employed to validate the theoretical model, gathering data from 449 employees across various industries in Mainland China with a convenience sampling method.

Findings

The results demonstrate that empowering leadership enhances employee innovative job performance by increasing challenge stress and reducing hindrance stress, highlighting the moderating role of regulatory focus. Specifically, a high promotion focus strengthens the positive relationship between empowering leadership and challenge stress, while a high prevention focus weakens the negative relationship between empowering leadership and hindrance stress. The moderated mediation effect of regulatory focus is also verified.

Practical implications

Empowering leaders should be mindful of employees’ dualistic work stress and implement tailored management strategies based on individual regulatory focus to maintain their psychological well-being and enhance innovative performance.

Originality/value

Grounded in job demand-resource (JD-R) theory and a stress perspective, this study develops a dual-path model to explore the impact of empowering leadership on employee innovative job performance through dualistic work stress. This framework enhances our understanding of the mechanisms underlying the effectiveness of empowering leadership and the antecedent factors influencing employee well-being and innovative performance. Furthermore, by examining the role of employees’ regulatory focus, this study clarifies the boundary conditions of empowering leadership effectiveness, addressing inconsistencies in previous research findings.