bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractNeurodegenerative 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

AbstractFormate, 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.HighlightsSuccessfully 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

AbstractBrain 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

AbstractBackgroundThe 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.ResultsThe 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.ConclusionThis 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

SUMMARYDNA-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

AbstractStress 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.TeaserWhen 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

AbstractReading 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

AbstractAnimals 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

AbstractMetacognitive 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

AbstractBacillus 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.
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
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

PurposeThis 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/approachA 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.FindingsThrough 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 implicationsThis 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/valueThis 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.