bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic network regulating phosphatidic acid homeostasis revealed using membrane editing coupled to proximity labeling
Authors: Tei Reika , Baskin Jeremy M. 
Published: September 2024

ABSTRACTCellular lipid metabolism is subject to strong homeostatic regulation, but players involved in and mechanisms underlying these pathways remain mostly uncharacterized. Here, we develop and exploit a “Feeding–Fishing” approach coupling membrane editing using optogenetic lipid-modifying enzymes (feeding) with organelle membrane proteomics via proximity labeling (fishing) to elucidate molecular players and pathways involved in homeostasis of phosphatidic acid (PA), a multifunctional lipid central to glycerolipid metabolism. By performing proximity biotinylation using a membrane-tethered TurboID alongside membrane editing to selectively deliver phosphatidic acid to the same membrane, we identified numerous PA-metabolizing enzymes and lipid transfer proteins enriched in and depleted from PA-fed membranes. Subsequent mechanistic analysis established that PA homeostasis in the cytosolic leaflets of the plasma membrane and of lysosomes is governed by a select subset of PA metabolic pathways and, via divergent molecular mechanisms, several members of the lipid transfer protein superfamily capable of mediating interorganelle lipid transport. More broadly, the interfacing of membrane editing with organelle membrane proteomics using proximity labeling represents a powerful and generalizable strategy for revealing mechanisms governing lipid homeostasis.
Discovery of three novel neutralizing antibody epitopes on the human astrovirus capsid spike and mechanistic insights into virus neutralization
Authors: Lanning Sarah , Aguilar-Hernández Nayeli , Serrão Vitor Hugo B , López Tomás , O’Rourke Sara M. , Lentz Adam , Ricemeyer Lena , Espinosa Rafaela , López Susana , Arias Carlos F. , DuBois Rebecca M. 
Published: September 2024

AbstractHuman astroviruses (HAstVs) are a leading cause of viral childhood diarrhea that infect nearly every individual during their lifetime. Although human astroviruses are highly prevalent, no approved vaccine currently exists. Antibody responses appear to play an important role in protection from HAstV infection, however knowledge about the neutralizing epitope landscape is lacking, as only 3 neutralizing antibody epitopes have previously been determined. Here, we structurally define the epitopes of 3 uncharacterized HAstV-neutralizing monoclonal antibodies: antibody 4B6 with X-ray crystallography to 2.67 Å, and antibodies 3H4 and 3B4 simultaneously with single-particle cryogenic-electron microscopy to 3.33 Å. We assess the epitope locations relative to conserved regions on the capsid spike and find that while antibodies 4B6 and 3B4 target the upper variable loop regions of the HAstV spike protein, antibody 3H4 targets a novel region near the base of the spike that is more conserved. Additionally, we found that all 3 antibodies bind with high affinity, and they compete with receptor FcRn binding to the capsid spike. These studies inform which regions of the HAstV capsid can be targeted by monoclonal antibody therapies and could aid in rational vaccine design.ImportanceHuman astroviruses infect nearly every child in the world, causing diarrhea, vomiting, and fever. Despite the prevalence of human astroviruses, little is known about how antibodies block virus infection. Here, we determined high-resolution structures of the astrovirus capsid protein in complex with three virus-neutralizing antibodies. The antibodies bind distinct sites on the capsid spike domain. We find that the antibodies block virus attachment to human cells and prevent capsid spike interaction with the human neonatal Fc receptor. These findings support the use of the human astrovirus capsid spike as an antigen in a vaccine to prevent astrovirus disease.
Phase-Dependent Stimulation of the Hippocampus: A Computational Modeling Approach
Authors: Lee Hsin-Pei , Arginteanu Toren , Kudela Pawel , Anderson William S. , Salimpour Yousef 
Published: September 2024

AbstractPhase-amplitude coupling (PAC) between brain oscillations of different frequencies plays a fundamental role in neural processing, and phase-dependent neuromodulation has emerged as a promising strategy to modulate PAC. In the hippocampus, theta-gamma PAC is critically involved in memory-related functions and information propagation. Computational models provide a valuable platform for investigating the neurobiological mechanisms underlying phase- dependent effects, bypassing the limitations of in vivo and in vitro experiments. In this study, we extended a previously published computational model of the hippocampal CA3 region using the NEURON and Python environments. A closed-loop autoregressive (AR) forward prediction model was employed to sample the network’s local field potential (LFP) in real time, enabling the precise calculation of phase-locked stimulus time points. Our results demonstrated the successful delivery of phase-locked current injections to all neuronal populations at both the peak and trough of theta oscillations. Phase-specific alterations in the theta band were observed during stimulation, along with enhanced theta-gamma coupling induced by peak-phase stimulation. Single neuron activity analysis highlighted the critical role of oriens lacunosum- moleculare (OLM) cells in modulating phase-dependent network dynamics. These findings underscore the potential of closed-loop stimulation systems to modulate PAC, with significant implications for the treatment of neurological disorders characterized by abnormal oscillatory activity, such as Alzheimer’s disease and other memory-related disorders.Significance StatementBy employing a computational model of the hippocampal CA3 region, we reveal the ability of the phase-dependent stimulation technique to modulate phase-amplitude coupling, a critical mechanism in memory and information processing. Our findings highlight the importance of precise phase-locked stimulation and the key role of specific interneurons in regulating network dynamics. These insights lay the groundwork for developing targeted neuromodulation therapies to restore normal oscillatory patterns in the brain, with promising implications for treating memory-related neurological disorders.
Combined transcriptomic, connectivity, and activity profiling of the medial amygdala using highly amplified multiplexedin situhybridization (hamFISH)
Authors: Edwards Mathew D. , Yin Ziwei , Sueda Risa , Gubanova Alina , Xu Chang S. , Lakner Virág , Murchie Megan , Lee Chi-Yu , Ng Kristal , Farrell Karolina , Faraway Rupert , Ganguly Subham , Jacobs Elina , Bintu Bogdan , Isogai Yoh 
Published: September 2024

AbstractIn situtranscriptomic technologies provide a promising avenue to link gene expression, connectivity, and physiological properties of neural cell types. Commercialized methods that allow the detection of hundreds of genesin situ, however, are expensive and therefore typically used for generating unimodal reference data rather than for resource-intensive multimodal analyses. A major bottleneck is the lack of a routine means to efficiently generate cell type data. Here, we have developed hamFISH (highly amplified multiplexedin situhybridization), which enables the sequential detection of 32 genes using multiplexed branched DNA amplification. We used hamFISH to profile the projection, activity, and transcriptomic diversity of the medial amygdala (MeA), a critical node for innate social and defensive behaviors in mice. In total, we profiled 643,834 cells and classified neurons into 16 inhibitory and 10 excitatory types, many of which were found to be spatially clustered. We then examined the organization of outputs of these cells and activation profiles during different social contexts. Therefore, by facilitating multiplexed detection of single molecule RNAs, hamFISH provides a streamlined and versatile platform for multimodal profiling of specific brain nuclei.
Exploiting correlations across trials and behavioral sessions to improve neural decoding
Authors: Zhang Yizi , Lyu Hanrui , Hurwitz Cole , Wang Shuqi , Findling Charles , Hubert Felix , Pouget Alexandre ,   International Brain Laboratory, Varol Erdem , Paninski Liam 
Published: September 2024

AbstractTraditional neural decoders model the relationship between neural activity and behavior within individual trials of a single experimental session, neglecting correlations across trials and sessions. However, animals exhibit similar neural activities when performing the same behavioral task, and their behaviors are influenced by past experiences from previous trials. To exploit these informative correlations in large datasets, we introduce two complementary models: a multi-session reduced-rank model that shares similar behaviorally-relevant statistical structure in neural activity across sessions to improve decoding, and a multi-session state-space model that shares similar behavioral statistical structure across trials and sessions. Applied across 433 sessions spanning 270 brain regions in the International Brain Laboratory public mouse Neuropixels dataset, our decoders demonstrate improved decoding accuracy for four distinct behaviors compared to traditional approaches. Unlike existing deep learning approaches, our models are interpretable and efficient, uncovering latent behavioral dynamics that govern animal decision-making, quantifying single-neuron contributions to decoding behaviors, and identifying different activation timescales of neural activity across the brain. Code:https://github.com/yzhang511/neural_decoding.
Polysaccharide BAP1 ofBifidobacterium adolescentisCCDM 368 attenuates ovalbumin-induced allergy through inhibition of Th2 immunity in mice
Authors: Pacyga-Prus Katarzyna , Hornikova Tereza , Šrůtková Dagmar , Leszczyńska-Nowak Katarzyna , Zabłocka Agnieszka , Schwarzer Martin , Górska Sabina 
Published: September 2024

AbstractAllergies have become a growing problem and the number of cases is increasing yearly. Administration of postbiotics, well-defined bacterial molecules, is gaining attention as a novel and promising strategy to ameliorate the allergic burden. The BAP1 polysaccharide (PS) ofBifidobacterium adolescentisCCDM 368, was previously characterized by us regarding its structure andin vitroimmunomodulatory properties. Here, to decipher the effect of BAP1 on immune system development, it was intranasally (i.n.) administered to germ-free mice. We observed increased IgA in bronchoalveolar lavage (BAL) fluid, decreased CCL2 production, and higherRorcgene expression in the lung. The intranasal administration of BAP1 reduced lung inflammation and decreased eosinophils numbers in BAL in the ovalbumin-induced allergy mouse model. Moreover, BAP1 decreased OVA-specific IgE levels in sera and Th2-related cytokines in OVA-stimulated splenocytes and lung cells. Finally, increasedRorcand inhibitedIl10gene expression were observed in lung tissue indicating their possible role in BAP1 function. Our findings support and expand on our previousin vitro and ex vivostudies by demonstrating that BAP1, with a unique chemical structure, induces a specific immunomodulatory effect in the host and could be potentially used for alleviating allergic diseases.Graphical abstract
A hybrid bioprinting-electrospinning platform integrating nanofibers and mesenchymal cell spheroids for customizable wound healing dressings
Authors: Hosseini Seyede Atefe , Planz Viktoria , Stelzer Ernst H. K. , Windbergs Maike , Pampaloni Francesco 
Published: September 2024

AbstractWe introduce a platform for the fabrication of customizable wound healing dressing. The platform integrates electrospun nanofibers, bioprinted hydrogels, and cellular spheroids into hierarchical, fiber-reinforced hybrid constructs. The construct leverages the mechanical strength of polycaprolactone (PCL) nanofibers and the ECM-like properties of GelMA/PEGDA hydrogel. These materials support the incorporation of bone marrow-derived mesenchymal stem cell (BM-hMSC) spheroids, which act as a supportive “cell niche,” enhancing the viability of the hMSC during and after bioprinting, and facilitating their spreading across the construct during the maturation phase. The characterization of the hybrid constructs demonstrated strong structural integrity and enhanced mechanical properties, making them well-suited for clinical wound dressing applications.In vitroassays, including live/dead staining, MTT assays, and scratch assays, revealed increased cell attachment, proliferation, and migration. The spheroids maintained their viability over extended periods, significantly contributing to wound closure in the scratch assay. This innovative approach, which combines electrospinning and light-based bioprinting, offers a promising strategy for the development of customizable wound dressings that closely adapt to the complex architecture of human skin. The bioprinting approach allows for the creation of tailored geometries for specific clinical requirements. Future research will focus on optimizing scaffold design and conducting long-termin vivostudies to validate the platform’s clinical potential.
Positive feedback regulation between RpoS and BosR in the Lyme disease pathogen
Authors: Raghunandanan Sajith , Priya Raj , Lin Gaofeng , Alanazi Fuad , Zoss Andrew , Warren Elise , Yang X. Frank 
Published: September 2024

ABSTRACTInBorrelia burgdorferi, the Lyme disease pathogen, differential gene expression is primarily controlled by the alternative sigma factor RpoS (σS). Understanding how RpoS levels are regulated is crucial for elucidating howB. burgdorferiis maintained throughout its enzootic cycle. Our recent studies have shown that a homolog of Fur/PerR repressor/activator, BosR, functions as an RNA-binding protein that controls therpoSmRNA stability. However, the mechanisms of regulation of BosR, particularly in response to host signals and environmental cues, remain largely unclear. In this study, we revealed a positive feedback loop between RpoS and BosR, where RpoS post-transcriptionally regulates BosR levels. Specifically, mutation or deletion ofrpoSsignificantly reduced BosR levels, while artificial induction ofrpoSresulted in a dose-dependent increase in BosR levels. Notably, RpoS does not affectbosRmRNA levels but instead modulates the turnover rate of the BosR protein. Furthermore, we demonstrated that environmental cues do not directly influencebosRexpression but instead inducerpoStranscription and RpoS production, thereby enhancing BosR protein levels. This discovery adds a new layer of complexity to the RpoN-RpoS pathway and suggests the need to re-evaluate the factors and signals previously believed to regulate RpoS levels through BosR.IMPORTANCELyme disease is the most prevalent arthropod-borne infection in the United States. The etiological agent,Borreliella(orBorrelia)burgdorferi, is maintained in nature through an enzootic cycle involving a tick vector and a mammalian host. RpoS, the master regulator of differential gene expression, plays a crucial role in tick transmission and mammalian infection ofB. burgdorferi. This study reveals a positive feedback loop between RpoS and a Fur/PerR homolog. Elucidating this regulatory network is essential for identifying potential therapeutic targets to disruptB. burgdorferi’s enzootic cycle. The findings also have broader implications for understanding the regulation of RpoS and Fur/PerR family in other bacteria.
Conformational trajectory of the HIV-1 fusion peptide during CD4-induced envelope opening
Authors: Thakur Bhishem , Katte Revansiddha H. , Xu Wang , Janowska Katarzyna , Sammour Salam , Henderson Rory , Lu Maolin , Kwong Peter D. , Acharya Priyamvada 
Published: September 2024

AbstractThe hydrophobic fusion peptide (FP), a critical component of the HIV-1 entry machinery, is located at the N terminal stretch of the envelope (Env) gp41 subunit1–3. The receptor-binding gp120 subunit of Env forms a heterodimer with gp41 and assembles into a trimer, in which FP is accessible for antibody binding3. Env conformational changes or “opening” that follow receptor binding result in FP relocating to a newly formed interprotomer pocket at the gp41-gp120 interface where it is sterically inaccessible to antibody4. The mechanistic steps connecting the entry-related transition of antibody accessible-to-inaccessible FP configurations remain unresolved. Here, using SOSIP-stabilized Env ectodomains5, we visualized atomic-level details of a functional entry intermediate, where partially open Env was bound to receptor CD4, co-receptor mimetic antibody 17b, and FP-targeting antibody VRC34.01, demonstrating that FP remains antibody accessible despite substantial receptor-induced Env opening. We determined a series of structures delineating stepwise opening of Env from its closed state to a newly resolved intermediate and defining downstream re-organizations of the gp120-gp41 interface that ultimately resulted in FP burial in an antibody-inaccessible configuration. Our studies improve our understanding of HIV-1 entry and provide information on entry-related conformation reorganization of a key site of HIV vulnerability to neutralizing antibody.
EEG frontal alpha asymmetry mediates the association between maternal and child internalizing symptoms in childhood
Authors: Sacks Dashiell D. , Wang Yiyi , Abron Asja , Mulligan Kaitlin M. , Kelsey Caroline M. , Xie Wanze , Nelson Charles A. , Enlow Michelle Bosquet 
Published: September 2024

AbstractBackgroundAnxiety and depression are highly prevalent in youth and can cause significant distress and functional impairment. The presence of maternal anxiety and depression are well-established risk factors for child internalizing psychopathology, yet the responsible mechanisms linking the two remain unclear.MethodsWe examined the potential mediating and moderating roles of EEG frontal alpha asymmetry (FAA) in the intergenerational transmission of internalizing symptoms in a longitudinal sample ofN= 323 mother-child dyads. Self-report maternal internalizing symptoms were evaluated at child age 3 years and 5 years, child EEG at 5 years, and parent-report child internalizing symptoms at age 7 years. Mediation was evaluated via bootstrapped (N= 5000) confidence intervals.ResultsWe found significant associations among maternal internalizing (anxiety, depressive) symptoms at child ages 3 and 5 years, child FAA at age 5 years, and child internalizing symptoms at age 7 years. There was a significant mediation effect, whereby greater maternal anxiety and depressive symptoms at age 3 years were significantly associated with greater relative right FAA in children at age 5 years, which, in turn, was significantly associated with greater child internalizing symptoms at age 7 years (ps<.001). There was no moderating effect of FAA on the association between maternal internalizing symptoms at age 5 years and child internalizing symptoms at age 7 years.ConclusionsGreater right frontal asymmetry may be a neurophysiological mechanism that mediates the intergenerational transmission of internalizing symptoms.
Education as a Proxy for Cognitive Reserve: Moderating Effects on White Matter Hyperintensity Burden in Healthy Aging and Cognitive Decline
Authors: Elkana Odelia , Beheshti Iman ,   Alzheimer’s Disease Neuroimaging Initiative
Published: September 2024

ABSTRACTBackgroundCognitive reserve, often approximated by levels of education, is thought to protect against the deleterious effects of brain pathology on cognitive function. White matter hyperintensities (WMHs) are commonly associated with aging and cognitive decline, and higher WMH burden has been linked to the progression from healthy cognitive status (HC) to mild cognitive impairment (MCI). Understanding how cognitive reserve, as indicated by education, influences the relationship between WMH burden and cognitive outcomes can provide valuable insights for interventions aimed at delaying cognitive decline.ObjectiveThis study investigates the moderating role of education, as a proxy for cognitive reserve, on the relationship between WMH burden and the transition from HC to MCI.MethodsData were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, focusing on participants classified as cognitively healthy at baseline. A total of 153 cognitively healthy adults at the baseline were split into two groups: one group (n=85) remained cognitively healthy for at least 7 years, while the other group (n=68) progressed to MCI within 7 years. A multiple linear regression model was used to examine the interaction between group membership, baseline age, education, and sex in predicting WMH loads. The primary focus was on the interaction between group membership and education to assess the protective effect of cognitive reserve.ResultsThe regression model explained 18.5% of the variance in WMH load. The analysis revealed statistically significant interaction between group membership and education on WMH loads (Interaction term: β = -0.097, p = 0.047), indicating that higher education levels are associated with a reduced WMH burden among individuals who progressed to MCI. The main effect of education alone was not significant, nor were the interactions involving sex (p > 0.05).ConclusionThese findings support the hypothesis that education, as a proxy for cognitive reserve, provides a protective effect against the accumulation of WMH burden in older adults. The results suggest that higher cognitive reserve may mitigate the impact of neurodegenerative processes, thereby delaying the transition from HC to MCI. This underscores the importance of educational attainment in the preservation of cognitive health during aging.
Evaluating and Comparing Measures of Aperiodic Neural Activity
Authors: Donoghue Thomas , Hammonds Ryan , Lybrand Eric , Washcke Leonhard , Gao Richard , Voytek Bradley 
Published: September 2024

AbstractNeuro-electrophysiological recordings contain prominent aperiodic activity – meaning irregular activity, with no characteristic frequency – which has variously been referred to as 1/f (or 1/f-like activity), fractal, or ‘scale-free’ activity. Previous work has established that aperiodic features of neural activity is dynamic and variable, relating (between subjects) to healthy aging and to clinical diagnoses, and also (within subjects) tracking conscious states and behavioral performance. There are, however, a wide variety of conceptual frameworks and associated methods for the analyses and interpretation of aperiodic activity – for example, time domain measures such as the autocorrelation, fractal measures, and/or various complexity and entropy measures, as well as measures of the aperiodic exponent in the frequency domain. There is a lack of clear understanding of how these different measures relate to each other and to what extent they reflect the same or different properties of the data, which makes it difficult to synthesize results across approaches and complicates our overall understanding of the properties, biological significance, and demographic, clinical, and behavioral correlates of aperiodic neural activity. To address this problem, in this project we systematically survey the different approaches for measuring aperiodic neural activity, starting with an automated literature analysis to curate a collection of the most common methods. We then evaluate and compare these methods, using statistically representative time series simulations. In doing so, we establish consistent relationships between the measures, showing that much of what they capture reflects shared variance – though with some notable idiosyncrasies. Broadly, frequency domain methods are more specific to aperiodic features of the data, whereas time domain measures are more impacted by oscillatory activity. We extend this analysis by applying the measures to a series of empirical EEG and iEEG datasets, replicating the simulation results. We conclude by summarizing the relationships between the multiple methods, emphasizing opportunities for re-examining previous findings and for future work.