bluuebunny/crossref_metadata_2025_split huggingface dataset:
ChAHP2 and ChAHP control diverse retrotransposons by complementary activities
Authors: Ahel Josip , Pandey Aparna , Schwaiger Michaela , Mohn Fabio , Basters Anja , Kempf Georg , Andriollo Aude , Kaaij Lucas , Hess Daniel , Bühler Marc 
Published: February 2024

ABSTRACTRetrotransposon control in mammals is an intricate process that is effectuated by a broad network of chromatin regulatory pathways. We previously discovered ChAHP, a protein complex with repressive activity against SINE retrotransposons, composed of the transcription factor ADNP, chromatin remodeler CHD4, and HP1 proteins. Here we identify ChAHP2, a protein complex homologous to ChAHP, wherein ADNP is replaced by ADNP2. ChAHP2 is predominantly targeted to ERVs and LINEs, via HP1β-mediated binding of H3K9 trimethylated histones. We further demonstrate that ChAHP also binds these elements in a mechanistically equivalent manner to ChAHP2, and distinct from DNA sequence-specific recruitment at SINEs. Genetic ablation of ADNP2 alleviates ERV and LINE1 repression, which is synthetically exacerbated by additional depletion of ADNP. Together, our results reveal that the ChAHP and ChAHP2 complexes function to control both non-autonomous and autonomous retrotransposons by complementary activities, further adding to the complexity of mammalian transposon control.
Limit of detection ofSalmonellaser. Enteritidis using culture-based versus culture-independent diagnostic approaches
Authors: Bradford L.M. , Yao L. , Anastasiadis C. , Cooper A.L. , Blais B. , Deckert A. , Reid-Smith R. , Lau C. , Diarra M.S. , Carrillo C. , Wong A. 
Published: February 2024

ABSTRACTIn order to prevent the spread of foodborne illnesses, the presence of pathogens in the food chain is monitored by government agencies and food producers. The culture-based methods currently employed are sensitive but time-and labour-intensive, leading to increasing interest in exploring culture-independent diagnostic tests (CIDTs) for pathogen detection. However, sensitivity and reliability of these CIDTs relative to current approaches has not been well established. To address this issue, we conducted a comparison of the limit of detection (LOD50) forSalmonellabetween a culture-based method and three CIDT methods: qPCR (targetinginvAandstn), metabarcode (16S) sequencing, and shotgun metagenomic sequencing. Samples of chicken feed and chicken caecal contents were spiked withSalmonellaserovar Enteritidis and subjected to culture-and DNA-based detection methods. To explore the impact of non-selective enrichment on LOD50, all samples underwent both immediate DNA extraction and an overnight enrichment prior to gDNA extraction. In addition to this spike-in experiment, feed and caecal samples acquired from the field were tested with culturing, qPCR, and metabarcoding. In general, LOD50was comparable between qPCR and shotgun sequencing methods. Overnight microbiological enrichment resulted in an improvement in LOD50with up to a three log decrease, comparable to culture-based detection. However,Salmonellareads were detected in some unspiked feed samples, suggesting false-positive detection ofSalmonella. Additionally, the LOD50in feeds was three logs lower than in caecal contents, underscoring the impact of background microbiota onSalmonelladetection using all methods.IMPORTANCEThe appeal of CIDTs is increased speed with lowered cost, as well as the potential to detect multiple pathogen species in a single analysis and to monitor other areas of concern such as antimicrobial resistance genes or virulence factors. Understanding the sensitivity of CIDTs relative to current approaches will help determine the feasibility of implementing these methods in pathogen surveillance programs.
Gene regulation of infection-associated L-tartrate metabolism inSalmonella entericaserovar Typhimurium
Authors: Rojas Vivian K. , Winter Maria G. , Jimenez Angel G. , Tanner Natasha W. , Crockett Stacey L. , Spiga Luisella , Hendrixson David R. , Winter Sebastian E. 
Published: February 2024

ABSTRACTEnteric pathogens such asSalmonella entericaserovar Typhimurium experience spatial and temporal changes to the metabolic landscape throughout infection. Host reactive oxygen and nitrogen species non-enzymatically convert monosaccharides to alpha hydroxy acids, including L-tartrate.Salmonellautilizes L-tartrate early during infection to support fumarate respiration, while L-tartrate utilization ceases at later time points due to the increased availability of exogenous electron acceptors such as tetrathionate, nitrate, and oxygen. It remains unknown howSalmonellaregulates its gene expression to metabolically adapt to changing nutritional environments. Here, we investigated how the transcriptional regulation for L-tartrate metabolism inSalmonellais influenced by infection-relevant cues. L-tartrate induces the transcription ofttdBAU, genes involved in L-tartrate utilization. L-tartrate metabolism is negatively regulated by two previously uncharacterized transcriptional regulators TtdV (STM3357) and TtdW (STM3358), and both TtdV and TtdW are required for sensing of L-tartrate. The electron acceptors nitrate, tetrathionate, and oxygen repressttdBAUtranscription via the two-component system ArcAB. Furthermore, regulation of L-tartrate metabolism is required for optimal fitness in a mouse model ofSalmonella-induced colitis. TtdV, TtdW, and ArcAB allow for the integration of two cues, substrate availability and availability of exogenous electron acceptors, to control L-tartrate metabolism. Our findings provide novel insights into howSalmonellaprioritizes utilization of different electron acceptors for respiration as it experiences transitional nutrient availability throughout infection.IMPORTANCEBacterial pathogens must adapt their gene expression profiles to cope with diverse environments encountered during infection. This coordinated process is carried out by the integration of cues that the pathogen senses to fine-tune gene expression in a spatiotemporal manner. Many studies have elucidated the regulatory mechanisms on howSalmonellasense metabolites in the gut to activate or repress its virulence program, however our understanding of howSalmonellacoordinates its gene expression to maximize the utilization of carbon and energy sources found in transitional nutrient niches is not well understood. In this study, we discovered howSalmonellaintegrates two infection-relevant cues, substrate availability and exogenous electron acceptors, to control L-tartrate metabolism. From our experiments, we propose a model for how L-tartrate metabolism is regulated in response to different metabolic cues in addition to characterizing two previously unknown transcriptional regulators. This study expands our understanding of how microbes combine metabolic cues to enhance fitness during infection.
Proteolytic control of FixT by the Lon protease impacts FixLJ signaling inCaulobacter crescentus
Authors: Yigit Kubra , Chien Peter 
Published: February 2024

AbstractResponding to changes in oxygen levels is critical for aerobic microbes. InCaulobacter crescentus, low oxygen is sensed by the FixL-FixJ two-component system which induces multiple genes, including heme biosynthesis, to accommodate microaerobic conditions. The FixLJ inhibitor FixT is also induced under low oxygen conditions and is degraded by the Lon protease, which together provides negative feedback proposed to adjust FixLJ signaling thresholds during changing conditions. Here, we address if the degradation of FixT by the Lon protease contributes to phenotypic defects associated with loss of Lon. We find that Δlonstrains are deficient in FixLJ-dependent heme biosynthesis, consistent with elevated FixT levels as deletion offixTsuppresses this defect. Transcriptomics validate this result as there is diminished expression of many FixLJ-activated genes in Δlon. However, no physiological changes in response to microaerobic conditions occurred upon loss of Lon, suggesting that FixT dynamics are not a major contributor to fitness in oxygen limiting conditions. Similarly, stabilization of FixT in Δlonstrains does not contribute to any known Lon-related fitness defect, such as cell morphology defects or stress sensitivity. In fact, cells lacking both FixT and Lon are compromised in viability during adaptation to long term aerobic growth. Our work highlights the complexity of protease-dependent regulation of transcription factors and explains the molecular basis of defective heme accumulation in Lon-deficientCaulobacter.ImportanceThe Lon protease shapes protein quality control, signaling pathways, and stress responses in many bacteria species. Loss of Lon often results in multiple phenotypic consequences. In this work, we found a connection between the Lon protease and deficiencies in heme accumulation that then led to our finding of a global change in gene expression due to degradation of a regulator of the hypoxic response. However, loss of degradation of this regulator did not explain other phenotypes associated with Lon deficiencies demonstrating the complex and multiple pathways that this highly conserved protease can impact.
A next-generation, histological atlas of the human brain and its application to automated brain MRI segmentation
Authors: Casamitjana Adrià , Mancini Matteo , Robinson Eleanor , Peter Loïc , Annunziata Roberto , Althonayan Juri , Crampsie Shauna , Blackburn Emily , Billot Benjamin , Atzeni Alessia , Puonti Oula , Balbastre Yaël , Schmidt Peter , Hughes James , Augustinack Jean C , Edlow Brian L , Zöllei Lilla , Thomas David L , Kliemann Dorit , Bocchetta Martina , Strand Catherine , Holton Janice L , Jaunmuktane Zane , Iglesias Juan Eugenio 
Published: February 2024

AbstractMagnetic resonance imaging (MRI) is the standard tool to image the human brainin vivo. In this domain, digital brain atlases are essential for subject-specific segmentation of anatomical regions of interest (ROIs) and spatial comparison of neuroanatomy from different subjects in a common coordinate frame. High-resolution, digital atlases derived from histology (e.g., Allen atlas [7], BigBrain [13], Julich [15]), are currently the state of the art and provide exquisite 3D cytoarchitectural maps, but lack probabilistic labels throughout the whole brain. Here we presentNextBrain, a next - generation probabilistic atlas of human brain anatomy built from serial 3D histology and corresponding highly granular delineations of five whole brain hemispheres. We developed AI techniques to align and reconstruct ∼10,000 histological sections into coherent 3D volumes with joint geometric constraints (no overlap or gaps between sections), as well as to semi-automatically trace the boundaries of 333 distinct anatomical ROIs on all these sections. Comprehensive delineation on multiple cases enabled us to buildthe first probabilistic histological atlas of the whole human brain. Further, we created a companion Bayesian tool for automated segmentation of the 333 ROIs in anyin vivoorex vivobrain MRI scan using theNextBrainatlas. We showcase two applications of the atlas: automated segmentation of ultra-high-resolutionex vivoMRI and volumetric analysis of Alzheimer’s disease and healthy brain ageing based on ∼4,000 publicly availablein vivoMRI scans. We publicly release: the raw and aligned data (including an online visualisation tool); the probabilistic atlas; the segmentation tool; and ground truth delineations for a 100 μm isotropicex vivohemisphere (that we use for quantitative evaluation of our segmentation method in this paper). By enabling researchers worldwide to analyse brain MRI scans at a superior level of granularity without manual effort or highly specific neuroanatomical knowledge,NextBrainholds promise to increase the specificity of MRI findings and ultimately accelerate our quest to understand the human brain in health and disease.
Senolytic treatment depletes microglia and decreases severity of experimental autoimmune encephalomyelitis
Authors: Drake Sienna Sage , Zaman Aliyah , Gianfelice Christine , Hua Elizabeth M.-L. , Heale Kali , Afanasiev Elia , Stratton Jo Anne , Fournier Alyson 
Published: February 2024

AbstractThe role of senescence in disease contexts is complex, however there is considerable evidence that depletion of senescent cells improves outcomes in a variety of contexts particularly related to aging, cognition, and neurodegeneration. Here, the effect of a bioinformatically-rationalized senolytic was tested in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis (MS). Single-cell analysis from brain tissue isolated from mice subjected to EAE identified microglia with a strong senescence signature including the presence of BCL2-family member transcripts. Cells expressing Bcl2l1 had higher expression of pro-inflammatory and senescence genes than their negative counterparts in EAE, suggesting they may exacerbate inflammation. Notably, in human single-nucleus sequencing from MS, BCL2L1 positive microglia were strongly enriched in lesions with active inflammatory pathology, and likewise demonstrated increased expression of immune related genes suggesting they may contribute to the active lesion pathology and tissue damage in chronic active lesions. Employing a small molecule BCL2 inhibitor, Navitoclax (ABT-263), significantly reduced the presence of microglia in the EAE spinal cord, suggesting that these cells can be targeted by senolytic treatment. ABT-263 treatment had a profound effect on EAE mice, decreasing motor symptom severity, improving visual acuity, promoting neuronal survival, and decreasing white matter inflammation. Together, these results provide evidence to support the idea that senescent glia may exacerbate inflammation resulting in negative outcomes in neuroinflammatory disease and that removing them may ameliorate disease.
Brain-controlled augmented hearing for spatially moving conversations in multi-talker environments
Authors: Choudhari Vishal , Han Cong , Bickel Stephan , Mehta Ashesh D. , Schevon Catherine , McKhann Guy M. , Mesgarani Nima 
Published: February 2024

ABSTRACTFocusing on a specific conversation amidst multiple interfering talkers presents a significant challenge, especially for the hearing-impaired. Brain-controlled assistive hearing devices aim to alleviate this problem by separating complex auditory scenes into distinct speech streams and enhancing the attended speech based on the listener’s neural signals using auditory attention decoding (AAD). Departing from conventional AAD studies that relied on oversimplified scenarios with stationary talkers, we present a realistic AAD task that mirrors the dynamic nature of acoustic settings. This task involves focusing on one of two concurrent conversations, with multiple talkers taking turns and moving continuously in space with background noise. Invasive electroencephalography (iEEG) data were collected from three neurosurgical patients as they focused on one of the two moving conversations. We propose an enhanced brain-controlled assistive hearing system that combines AAD and a binaural speaker-independent speech separation model. The separation model unmixes talkers while preserving their spatial location and provides talker trajectories to the neural decoder to improve auditory attention decoding accuracy. Our subjective and objective evaluations show that the proposed system enhances speech intelligibility and facilitates conversation tracking while maintaining spatial cues and voice quality in challenging acoustic environments. This research demonstrates the potential of our approach in real-world scenarios and marks a significant step towards developing assistive hearing technologies that adapt to the intricate dynamics of everyday auditory experiences.TAKEAWAYS-Brain-controlled hearing device for scenarios with moving conversations in multi-talker settings, closely mimicking real-world listening environments-Developed a binaural speech separation model that separates speech of moving talkers while retaining their spatial locations, enhancing auditory perception and auditory attention decoding-Proposed system enhances speech intelligibility and reduces listening effort in realistic acoustic scenes
Evolution of a Plasmid Regulatory Circuit Ameliorates Plasmid Fitness Cost
Authors: Elg Clinton A. , Mack Erin , Rolfsmeier Michael , McLean Thomas C. , Kosterlitz Olivia , Soderling Elizabeth , Narum Solana , Rowley Paul A. , Thomas Christopher M. , Top Eva M. 
Published: February 2024

ABSTRACTPlasmids play a major role in rapid adaptation of bacteria by facilitating horizontal transfer of diverse genes, most notably those conferring antibiotic resistance. While most plasmids that replicate in a broad range of bacteria also persist well in diverse hosts, there are exceptions that are poorly understood. We investigated why a broad-host range plasmid, pBP136, originally found in clinicalBordetella pertussisisolates, quickly became extinct in laboratoryEscherichia colipopulations. Through experimental evolution we found that inactivation of a previously uncharacterized plasmid gene,upf31, drastically improved plasmid maintenance inE. coli. This gene inactivation resulted in decreased transcription of the global plasmid regulators (korA,korB,andkorC)and numerous genes in their regulons. It also caused transcriptional changes in many chromosomal genes primarily related to metabolism.In silicoanalyses suggested that the change in plasmid transcriptome may be initiated by Upf31 interacting with the plasmid regulator KorB. Expression ofupf31 in transnegatively affected persistence of pBP136Δupf31as well as the closely related archetypal IncP-1β plasmid R751, which is stable inE. coliand natively encodes a truncatedupf31allele. Our results demonstrate that while theupf31allele in pBP136 might advantageously modulate gene expression in its original host,B. pertussis, it has harmful effects inE. coli. Thus, evolution of a single plasmid gene can change the range of hosts in which that plasmid persists, due to effects on the regulation of plasmid gene transcription.
Point mutation in a virus-like capsid drives symmetry reduction to form tetrahedral cages
Authors: Szyszka Taylor N. , Andreas Michael P. , Lie Felicia , Miller Lohra M. , Adamson Lachlan S. R. , Fatehi Farzad , Twarock Reidun , Draper Benjamin E. , Jarrold Martin F. , Giessen Tobias W. , Lau Yu Heng 
Published: February 2024

AbstractProtein capsids are a widespread form of compartmentalisation in nature. Icosahedral symmetry is ubiquitous in capsids derived from spherical viruses, as this geometry maximises the internal volume that can be enclosed within. Despite the strong preference for icosahedral symmetry, we show that simple point mutations in a virus-like capsid can drive the assembly of novel symmetry-reduced structures. Starting with the encapsulin fromMyxococcus xanthus, a 180-mer bacterial capsid that adopts the well-studied viral HK97 fold, we use mass photometry and native charge detection mass spectrometry to identify a triple histidine point mutant that forms smaller dimorphic assemblies. Using cryo-EM, we determine the structures of a precedented 60-mer icosahedral assembly and an unprecedented 36-mer tetrahedron that features significant geometric rearrangements around a novel interaction surface between capsid protomers. We subsequently find that the tetrahedral assembly can be generated by triple point mutation to various amino acids, and that even a single histidine point mutation is sufficient to form tetrahedra. These findings represent the first example of tetrahedral geometry across all characterised encapsulins, HK97-like capsids, or indeed any virus-derived capsids reported in the Protein Data Bank, revealing the surprising plasticity of capsid self-assembly that can be accessed through minimal changes in protein sequence.Significance statementViral capsids are cage-like protein assemblies that preferentially adopt icosahedral symmetry to maximise their internal volume for housing genetic material. This icosahedral preference extends to encapsulins, a widespread family of bacterial protein cages which evolved from viral capsids. Counter to this fundamental geometric preference, the formation of well-defined tetrahedral cages from a single amino acid substitution in an encapsulin reveals the surprising geometric flexibility of a common viral protein fold. These findings suggest that protein oligomerisation is far more permissive than intuitively expected, where serendipitous interactions between proteins arising from minimal mutations can cascade to form vast architectural changes. The ability to redesign protein architectures through simple mutations should enable biotechnological advances in vaccine development, drug delivery, and enzymatic biomanufacturing.
Cholinergic modulation of interhemispheric inhibition in the mouse motor cortex
Authors: Handa Takashi , Zhang Qing , Aizawa Hidenori 
Published: February 2024

AbstractInterhemispheric inhibition (IHI) of the homotopic motor cortex is believed to be effective for accurate unilateral motor function. However, the cellular mechanisms underlying IHI during unilateral motor behavior remain unclear. Furthermore, the impact of the neuromodulator acetylcholine (ACh) on IHI and the associated cellular mechanisms are not well understood. To address this knowledge gap, we conducted recordings of neuronal activity from the bilateral motor cortex of mice during the paw-reaching task. Subsequently, we analyzed interhemispheric spike correlation at the cell-pair level, classifying putative cell types to explore the underlying cellular circuitry mechanisms of IHI. We found a cell-type pair-specific enhancement of the interhemispheric spike correlation when the mice were engaged in the reaching task. We also found that the interhemispheric spike correlation was modulated by pharmacological ACh manipulation. The local field responses to contralateral excitation differed along the cortical depths, and muscarinic receptor antagonism enhanced the inhibitory component of the field response in deep layers. The muscarinic subtype M2 receptor is predominantly expressed in deep cortical neurons, including GABAergic interneurons. These results suggest that GABAergic interneurons expressing muscarinic receptors in deep layers mediate the neuromodulation of IHI in the homotopic motor cortex.
Optimizing Stem Cell Infusion Timing in the Prevention of Acute Graft versus Host Disease
Authors: Hou Yiwen , Wu Yue , Zhang Zhonglin , Wang Liang , Liu Zhiwei , Tang Baolin , Song Kaidi , Sun Guangyu , Zhu Xiaoyu , Zhan Cheng 
Published: February 2024

SUMMARYAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is a cornerstone treatment for a broad spectrum of malignant and nonmalignant hematological disorders. However, the success of allo-HSCT is often overshadowed by acute graft-versus-host disease (aGVHD), a life-threatening complication with limited preventive options. Here, we found that the incidence and severity of aGVHD after allo-HSCT are highly dependent on the circadian timing of stem cell infusion. The incidence rate of aGVHD in patients decreased by approximately 50% for early infusion (before 2:00 pm) compared to later infusion (after 2:00 pm). Early-infused patients also experienced significantly lower three-year transplant-related mortality and improved GVHD-free, relapse-free survival. Animal studies using an aGVHD mouse model show that this improvement is mainly due to the recipient’s rhythm rather than the donor’s. Mechanistically, compared with late infusions, early infusions significantly reduced the levels of the pro-inflammatory cytokine IL-1α following the conditioning regimen and subsequently suppressed T-cell activation and differentiation after transplantation. Our study suggests that scheduling stem cell infusions early in the day could be a simple yet transformative intervention for the prevention of aGVHD.