bluuebunny/crossref_metadata_2025 huggingface dataset:
Energetics of the Transmembrane Peptide Sorting by Hydrophobic Mismatch
Authors: Fábián Balázs , Javanainen Matti
Published: February 2024

Hydrophobic mismatch between a lipid membrane and embedded transmembrane peptides or proteins plays a role in their lateral localization and function. Earlier studies have resolved numerous mechanisms through which the peptides and membrane proteins adapt to mismatch, yet the energetics of lateral sorting due to hydrophobic mismatch has remained elusive due to the lack of suitable computational or experimental protocols. Here, we pioneer a molecular dynamics simulation approach to study the sorting of peptides along a membrane thickness gradient. Peptides of different lengths tilt and diffuse along the membrane to eliminate mismatch with a rate directly proportional to the magnitude of mismatch. We extract the 2-dimensional free energy profiles as a function of local thickness and peptide orientation, revealing the relative contributions of sorting and tilting, and suggesting their thermally accessible regimes. Our approach can readily be applied to study other membrane systems of biological interest where hydrophobic mismatch, or membrane thickness in general, plays a role.

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Transdifferentiation of Human Dental Pulp Mesenchymal Stem Cells into Spiral Ganglion-like Neurons
Authors: Messat Yassine , Martin-Fernandez Marta , Assou Said , Chung Keshi , Guérin Frederic , Gergely Csilla , Cuisinier Frederic , Zine Azel
Published: February 2024

Spiral ganglion neurons (SGN) carry auditory information from sensory hair cells (HCs) to the brain. These auditory neurons, which are the target neurons of cochlear implants, degenerate following sensorineural hearing loss (SNHL). Prosthetic devices such as cochlear implants function by bypassing lost HCs and stimulating the residual SGNs, allowing restoration of hearing in deaf patients. Emerging cell-replacement therapies for SNHL include replacing damaged SGNs using stem cell-derived otic neuronal progenitors (ONPs). However, the availability of renewable, accessible, and patient-matched sources of human stem cells constitutes a major prerequisite towards cell replacement for auditory nerve recovery. Human dental pulp stem cells (hDPSCs) extracted from human wisdom teeth are self-renewing stem cells that originate from the neural crest during development.

In this study, we developed a stepwisein vitroguidance procedure to differentiate hDPSCs into ONPs and then to SGNs. The procedure relies on the modulation of BMP and TGF-β pathways for neurosphere formation as a first step, then a differentiation step based on two culture paradigms exploiting major signaling pathways (Wnt, Shh, RA) and neurotrophic factors involved in early otic neurogenesis.

Gene and protein expression analyses revealed efficient induction of a comprehensive panel of known ONP and SGN-like cell markers over the course ofin vitrodifferentiation. The use of atomic force microscopy revealed that hDPSC-derived SGN-like cells exhibit similar nanomechanical properties compared to theirin vivoSGN counterparts. Furthermore, neurites extended between hDPSC-derived ONPs and rat SGN explants 4-6 days after co-culturing, suggesting the formation of neuronal contacts. These data indicate that thein vitrodifferentiated cells closely replicate the phenotypic and nanomechanical characteristics of human SGNs, advancing our culture differentiation system to the level to be used in next-generation cochlear implants and/or inner ear cell-based strategies for SNHL.
Cancer-associated fibroblasts reveal aberrant DNA methylation across different types of cancer
Authors: Schmidt Marco , Maié Tiago , Costa Ivan G. , Wagner Wolfgang
Published: February 2024

Cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment. Several studies demonstrated molecular differences between CAFs and normal tissue-associated fibroblasts (NAFs). In this study, we isolated CAFs and NAFs from liver tumors and analyzed their DNA methylation profiles. A subset of the CAFs exhibited aberrant DNA methylation, which was also reflected on gene expression level. The DNA methylation at liver-CAF-specific CG dinucleotides (CpGs) was associated with survival in liver cancer data. An integrative analysis with public datasets of CAFversusNAF in different cancer types, including lung, prostate, esophagus, and gastric cancer, revealed overlapping epigenetic aberrations. CpGs with common aberrations in DNA methylation included cg09809672 (EDARADD), cg07134930 (HDAC4), and cg05935904 (intergenic). Aberrant DNA methylation at these sites was associated with prognosis in several cancer types. Thus, activation of CAFs by the tumor environment is associated with characteristic epigenetic modifications that could be used as biomarkers for disease stratification.
EnhancerNet: a model for enhancer selection in dense regulatory networks recapitulates the dynamics of cell type acquisition
Authors: Karin Omer
Published: February 2024

Understanding how cell identity is encoded in the genome and acquired during differentiation is a central challenge in cell biology. We derive a theoretical framework called “EnhancerNet” that models dense feedback networks involving transcription factors and enhancers, which can be parameterized from terminal cell identities without fitting unobserved variables. EnhancerNet recapitulates the dynamics of enhancer selection and cell type specification via two distinct pathways: direct reprogramming or differentiation through transient, multipotent progenitor states. These pathways capture the hallmarks of their respective counterparts in animal cells, with the model reproducing known reprogramming recipes and the complex hematopoietic differentiation hierarchy. Using EnhancerNet, we show that hierarchical progenitors emerge as transient states during differentiation and propose a method to predict their identity from terminal states. The model explains how new cell types could evolve and highlights the functional importance of distal regulatory elements with dynamic chromatin in multicellular evolution.
Beyond over- or under-sampling: autistic children’s inflexibility in sampling costly information
Authors: Lu Haoyang , Zhang Hang , Yi Li
Published: February 2024

Background

Efficient information sampling is crucial for human inference and decision-making, even for young children. Information sampling is also closely associated with the core symptoms of autism spectrum disorder (ASD), since both the social interaction difficulties and repetitive behaviors suggest that autistic people may sample information from the environment distinctively. Previous research on information sampling in ASD focused mainly on adolescents and adults, and on whether they over- or under-sample. The specific ways in which autistic children sample information, especially when facing explicit costs and adapting to environmental changes, remain unclear.

Methods

We employed an adapted bead task to investigate the sampling behavior of 24 autistic and 41 neurotypical children, matched for age and IQ. In each trial of our experiment, children gathered information about an unknown target isle by drawing samples from it and then guessed the target between two isles based on their samples. In conditions where sampling was costly, children needed to weigh the benefits of information against the costs of acquiring additional samples. Through computational modeling and intricate behavioral measures, we revealed how the two groups of children differed in sampling decisions and underlying cognitive mechanisms.

Results

Under conditions involving costs, autistic children showed less efficient sampling than their neurotypical peers. This inefficiency was due to their increased variability in the number of samples taken across trials rather than a systematic bias. Computational models indicated that while both groups shared a similar decision process, autistic children’s sampling decisions were less influenced by dynamic changes and more driven by recent evidence, thus leading to their increased sampling variation and reduced efficiency.

Limitations

To refine ASD subtyping and correlate symptom severity with behavioral characteristics and computational findings, future research may need larger participant groups and more comprehensive clinical assessments.

Conclusions

This study reveals an inefficiency of autistic children in information sampling and tracks down this inefficiency to their increased sampling variability, primarily due to their cognitive preference for more local and static information. These findings are consistent with several influential behavioral theories of ASD and highlight the needs of a multi-level understanding of cognitive flexibility in ASD.
Stressor-evoked brain activity, cardiovascular reactivity, and subclinical atherosclerosis in midlife adults
Authors: Rasero Javier , Verstynen Timothy D. , DuPont Caitlin M. , Kraynak Thomas E. , Barinas-Mitchell Emma , Scudder Mark R. , Kamarck Thomas W. , Sentis Amy I. , Leckie Regina L. , Gianaros Peter J.
Published: February 2024

Background

Cardiovascular responses to psychological stressors have been separately associated with preclinical atherosclerosis and hemodynamic brain activity patterns across different studies and cohorts; however, what has not been established is whether cardiovascular stress responses reliably link indicators of stressor-evoked brain activity and preclinical atherosclerosis that have been measured in the same individuals. Accordingly, the present study used cross-validation and predictive modeling to test for the first time whether stressor-evoked systolic blood pressure (SBP) responses statistically mediated the association between concurrently measured brain activity and a vascular marker of preclinical atherosclerosis in the carotid arteries.

Methods

624 midlife adults (aged 28-56 years, 54.97% female) from two different cohorts underwent two information-conflict fMRI tasks, with concurrent SBP measures collected. Carotid artery intima-media thickness (CA-IMT) was measured by ultrasonography. A mediation framework that included harmonization, cross-validation, and penalized principal component regression was then employed, while significant areas in possible direct and indirect effects were identified through bootstrapping. Sensitivity analysis further tested the robustness of findings after accounting for prevailing levels of cardiovascular disease risk and brain imaging data quality control.

Results

Task-averaged patterns of hemodynamic brain responses exhibited a generalizable association with CA-IMT, which was mediated by an area-under-the-curve measure of aggregate SBP reactivity. Importantly, this effect held in sensitivity analyses. Implicated brain areas in this mediation included the ventromedial prefrontal cortex, anterior cingulate cortex, insula and amygdala.

Conclusions

These novel findings support a link between stressor-evoked brain activity and preclinical atherosclerosis accounted for by individual differences in corresponding levels of stressor-evoked cardiovascular reactivity.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Household Transmission during the Omicron Era in Massachusetts: A Prospective, Case-Ascertained Study using Genomic Epidemiology
Authors: Banga Jaspreet , Brock-Fisher Taylor , Petros Brittany A. , Dai Eric Y. , Leonelli Ariana T. , Dobbins Sabrina T. , Messer Katelyn S. , Nathanson Audrey B. , Capone Amelia , Littlehale Nancy , Appiah-Danquah Viola , Dim Siang , Moreno Gage K. , Crowther Maura , Lee Kannon A. , DeRuff Katherine C. , MacInnis Bronwyn L. , Springer Michael , Sabeti Pardis C. , Stephenson Kathryn E.
Published: February 2024

Background

Households are a major setting for SARS-CoV-2 infections, but there remains a lack of knowledge regarding the dynamics of viral transmission, particularly in the setting of widespread pre-existing SARS-CoV-2 immunity and evolving variants.

Methods

We conducted a prospective, case-ascertained household transmission study in the greater Boston area in March-July 2022. Anterior nasal swabs, along with clinical and demographic data, were collected for 14 days. Nasal swabs were tested for SARS-CoV-2 by PCR. Whole genome sequencing was performed on high-titer samples.

Results

We enrolled 33 households in a primary analysis set, with a median age of participants of 25 years old (range 2-66); 98% of whom had received at least 2 doses of a COVID-19 vaccine. 58% of households had a secondary case during follow up and the secondary attack rate (SAR) for contacts infected was 39%. We further examined a strict analysis set of 21 households that had only 1 PCR+ case at baseline, finding an SAR of 22.5%. Genomic epidemiology further determined that there were multiple sources of infection for household contacts, including the index case and outside introductions. When limiting estimates to only highly probable transmissions given epidemiologic and genomic data, the SAR was 18.4%.

Conclusions

Household contacts of a person newly diagnosed with COVID-19 are at high risk for SARS-CoV-2 infection in the following 2 weeks. This is, however, not only due to infection from the household index case, but also because the presence of an infected household member implies increased SARS-CoV-2 community transmission. Further studies to understand and mitigate household transmission are needed.

Key Points

When community transmission of SARS-CoV-2 is high, distinguishing household transmissions from independent introductions is difficult with either epidemiologic or genomic data alone. Here, we conducted daily nasal sampling with genomic sequencing to understand the dynamics of viral transmission within households.
Perineuronal nets in the rat medial prefrontal cortex alter hippocampal-prefrontal oscillations and reshape cocaine self-administration memories
Authors: Wingert Jereme C. , Ramos Jonathan D. , Reynolds Sebastian X. , Gonzalez Angela E. , Rose R. Mae , Hegarty Deborah M. , Aicher Sue A. , Bailey Lydia G. , Brown Travis E. , Abbas Atheir I. , Sorg Barbara A.
Published: February 2024

The medial prefrontal cortex (mPFC) is a major contributor to relapse to cocaine in humans and to reinstatement behavior in rodent models of cocaine use disorder. Output from the mPFC is modulated by parvalbumin (PV)-containing fast-spiking interneurons, the majority of which are surrounded by perineuronal nets (PNNs). Here we tested whether chondroitinase ABC (ABC)- mediated removal of PNNs prevented the acquisition or reconsolidation of a cocaine self-administration memory. ABC injections into the dorsal mPFC prior to training attenuated the acquisition of cocaine self-administration. Also, ABC given 3 days prior to but not 1 hr after memory reactivation blocked cue-induced reinstatement. However, reduced reinstatement was present only in rats given anovelreactivation contingency, suggesting that PNNs are required for the updating of a familiar memory. In naive rats, ABC injections into mPFC did not alter excitatory or inhibitory puncta on PV cells but reduced PV intensity. Whole-cell recordings revealed a greater inter-spike interval 1 hr after ABC, but not 3 days later.In vivorecordings from the mPFC and dorsal hippocampus (dHIP) during novel memory reactivation revealed that ABC in the mPFC prevented reward-associated increases in beta and gamma activity as well as phase-amplitude coupling between the dHIP and mPFC. Together, our findings show that PNN removal attenuates the acquisition of cocaine self-administration memories and disrupts reconsolidation of the original memory when combined with a novel reactivation session. Further, reduced dHIP/mPFC coupling after PNN removal may serve as a key biomarker for how to disrupt reconsolidation of cocaine memories and reduce relapse.
A retinotopic reference frame for space throughout human visual cortex
Authors: Szinte Martin , de Hollander Gilles , Aqil Marco , Veríssimo Inês , Dumoulin Serge , Knapen Tomas
Published: February 2024

We perceive a stable visual world across eye movements, despite the drastic retinal transients these movements produce. To explain vision’s spatial stability, it has been suggested that the brain encodes the location of attended visual stimuli in an external, or spatiotopic, reference frame. However, spatiotopy is seemingly at odds with the fundamental retinotopic organization of visual inputs. Here, we probe the spatial reference frame of vision using ultra-high-field (7T) fMRI and single-voxel population receptive field mapping, while independently manipulating both gaze direction and spatial attention. To manipulate spatial attention, participants performed an equally demanding visual task on either a bar stimulus that traversed the visual field, or a small foveated stimulus. To dissociate retinal stimulus position from its real-world position the entire stimulus array was placed at one of three distinct horizontal screen positions in each run. We found that population receptive fields in all cortical visual field maps shift with the gaze, irrespective of how spatial attention is deployed. This pattern of results is consistent with a fully retinotopic reference frame for visual-spatial processing. Reasoning that a spatiotopic reference frame could conceivably be computed at the level of entire visual areas rather than at the level of individual voxels, we also used Bayesian decoding of stimulus location from the BOLD response patterns in visual areas. We found that decoded stimulus locations also adhere to the retinotopic frame of reference, by shifting with gaze position. Again, this result holds for all visual areas and irrespective of the deployment of spatial attention. We conclude that visual locations are encoded in a retinotopic reference frame throughout the visual hierarchy.
Wearable Neural Interfaces: Real-Time Identification of Motor Neuron Discharges in Dynamic Motor Tasks
Authors: Mendez Guerra Irene , Barsakcioglu Deren Y. , Farina Dario
Published: February 2024

Objective

Robustness to non-stationary conditions is essential to develop stable and accurate wearable neural interfaces.

Approach

We propose a novel adaptive electromyography (EMG) decomposition algorithm that builds on blind source separation methods by leveraging the Kullback-Liebler divergence and kurtosis of the signals as metrics for online learning. The proposed approach provides a theoretical framework to tune the adaptation hyperparameters and compensate for non-stationarities in the mixing matrix, such as due to dynamic contractions, and to identify the underlying motor neuron (MN) discharges. The adaptation is performed in real-time (∼22 ms of computational time per 100-ms batches).

Main results

The proposed adaptation algorithm significantly improved all decomposition performance metrics with respect to the absence of adaptation in a wide range of motion of the wrist (80°). The rate of agreement, sensitivity, and precision were ≥ 90% in ≥ 80% of the cases in both simulated and experimentally recorded data, according to a two-source validation approach.

Significance

The findings demonstrate the feasibility of accurately decoding MN discharges in real-time during dynamic contractions from wearable systems mounted at the wrist and forearm. Moreover, the study proposes an experimental validation method for EMG decomposition in dynamic tasks.
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

Retrotransposon 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

In 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.

IMPORTANCE

The 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

Enteric 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.

IMPORTANCE

Bacterial 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

Responding 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.

Importance

The 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

Magnetic 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

The 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

Focusing 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

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Brain-controlled hearing device for scenarios with moving conversations in multi-talker settings, closely mimicking real-world listening environments

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Developed a binaural speech separation model that separates speech of moving talkers while retaining their spatial locations, enhancing auditory perception and auditory attention decoding

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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

Plasmids 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

Protein 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 statement

Viral 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

Interhemispheric 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

Allogeneic 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.
Men’s perceptions and perceived acceptability of their female partner’s use of self-administered intravaginal therapies for treatment of cervical precancer in Kenya
Authors: Mungo Chemtai , Adewumi Konyin , Ellis Grace , Rop Mercy , Adoyo Everlyn , Zou Yating , Rahangdale Lisa
Published: February 2024

Background

Cervical cancer continues to be a major health issue in low- and middle-income countries (LMICs). Despite increasing access to screening, access to precancer treatment remains a significant challenge in LMICs, highlighting a need for innovative, accessible, and resource-appropriate treatment approaches, including self-administered therapies.

Methods

A cross-sectional mixed-methods study was conducted among men aged 25-65 with a current female partner in Kisumu County, Kenya. Participants were sequentially recruited and surveyed to evaluate their understanding of HPV and cervical cancer, their views on screening and treatment, and their attitudes toward self-administered therapies. Focus group discussions with a subset of the survey participants further explored their treatment preferences and perceptions.

Results

Two hundred fourteen men participated in the survey, and 39 men participated in focus group discussions. The median age was 39 years, and 51% had a primary school education or less. Most (96%) were in a committed relationship, and 74% earned $10 or less daily. There was strong support for self-administered topical therapies, with 98% willing to support their partners using such treatments if available. Additionally, most participants were open to supporting necessary abstinence or condom use, though 76% believed their partners might hesitate to request condom use. When given an option, most preferred their partner to self-administer such therapies at home compared to provider administration at a health facility, citing convenience, cost-effectiveness, and privacy. Preferences varied between two potential therapies, 5-Fluorouracil (5FU) and Artesunate, based on their administration frequency, duration, and abstinence requirements. Qualitative findings largely supported the quantitative analysis.

Conclusions

The study demonstrates strong support for self-administered topical therapies for cervical precancer among Kenyan men. Additional research on acceptability, feasibility, and efficacy in different LMICs could pave the way for these therapies to help bridge current cervical precancer treatment gaps in these settings.
Preconception health in adolescence and adulthood across generations in the UK: findings from three British birth cohort studies
Authors: Righton Olivia , Flynn Angela , Alwan Nisreen A. , Schoenaker Danielle
Published: February 2024

Optimising preconception health in women and men holds significant potential for improving pregnancy and offspring health outcomes. To create a picture of the state of preconception health in the UK, this study aimed to describe the prevalence of and changes in preconception health indicators reported in three British birth cohort studies: the 1970 British Birth Cohort Study (BCS70; born in 1970; N=17,198), Next Steps (1989-1990; N=15,770), and Millennium Cohort Study (MCS; 2000-2002; N=19,517). The analysis focused on data obtained during participants’ adolescence (16-17 years) and subsequent follow-ups at 25-26 years for BCS70 and Next Steps. Self-reported preconception indicators were defined in line with a previously published review and reported as proportions.

Across cohorts, data were available for 14 preconception indicators across four domains: health behaviours and weight, reproductive health and family planning, physical health conditions, and wider determinants of health. Findings revealed persistent suboptimal health behaviours in both genders and across generations, including low intakes of fruit. While alcohol, tobacco, and soft drink intake decreased across generations, obesity prevalence surged. This study underscores the need for public health interventions targeting the root causes of adverse health behaviours towards improvement of fruit consumption, further reduction in alcohol, tobacco, and soft drink consumption, and addressing the escalating obesity rates among individuals of reproductive age. Ongoing monitoring is needed to continue tracking these existing indicators over time, while improved data quality and availability of a wider range of preconception indicators are crucial to comprehensively understanding the complexities of preconception health, enabling the development of more targeted and effective interventions.