bluuebunny/crossref_metadata_2025 huggingface dataset:
Connectivity at fine scale: mapping structural connective fields by tractography of short association fibresin vivo
Authors: Attar Fakhereh Movahedian , Kirilina Evgeniya , Edwards Luke J. , Haenelt Daniel , Pine Kerrin J. , Trampel Robert , Chaimow Denis , Weiskopf Nikolaus
Published: May 2024

The extraordinary number of short association fibres (SAF) connecting neighbouring cortical areas is a prominent feature of the large gyrified human brain. The contribution of SAF to the human connectome is largely unknown because of methodological challenges in mapping them. We present a method to characterise cortico–cortical connectivity mediated by SAF in topologically organised cortical areas. We introduce the ‘structural connective fields’ (sCF) metric which specifically quantifies neuronal signal propagation and integration mediated by SAF. This new metric complements functional connective field metrics integrating across contributions from short- and long-range white matter and intracortical fibres. Applying the method in the human early visual processing stream, we show that SAF preserve cortical functional topology. Retinotopic maps of V2 and V3 could be predicted from retinotopy in V1 and SAF connectivity. The sCF sizes increased along the cortical hierarchy and were smaller than their functional counterparts, in line with the latter being additionally broadened by long-range and intracortical connections.In vivosCF mapping provides insights into short-range cortico– cortical connectivity in humans comparable to tract tracing studies in animal research and is an essential step towards creating a complete human connectome.

Highlights

Non-invasive mapping of Short Association Fibre (SAF) connectivity via diffusion-weighted MRI-based probabilistic tractography accurately predicted cortical functional neuroanatomy.

The novel structural Connective Fields (sCF) concept provides a quantitative measure of cortico-cortical integration facilitated by SAF, complementing the existing functional Connective Field (CF) concept.

Sub-millimeter resolution diffusion-weighted MRI enables tractography and connective field modeling of SAF, unlocking applications previously restricted to invasive tract tracing in animal studies.
Unveiling the crucial role of betaine: Modulation of GABA homeostasis via SLC6A1 transporter (GAT1)
Authors: Bhatt Manan , Lazzarin Erika , Alberto-Silva Ana Sofia , Domingo Guido , Zerlotti Rocco , Gradisch Ralph , Bazzone Andre , Sitte Harald H. , Stockner Thomas , Bossi Elena
Published: May 2024

Betaine is an endogenous osmolyte that exhibits therapeutic potential by mitigating various neurological disorders. However, the underlying cellular and molecular mechanisms responsible for its neuroprotective effects remain puzzling.

In this study, we describe a possible mechanism behind the positive impact of betaine in preserving neurons from excitotoxicity. Using electrophysiology, mass spectroscopy, radiolabelled cellular assay, and molecular dynamics simulation we demonstrate that betaine at mM concentration acts as a slow substrate of GAT1 (slc6a1), the predominant GABA transporter in the central nervous system. Intriguingly, when betaine is present at low concentration (0.01-3 mM) with GABA (at concentration <K0.5), it blocks the GABA reuptake. This GAT1 modulation occurs through the temporal inhibition of the transporter, i.e., the prolonged occupancy by betaine impedes the rapid transition of the transporter to the inward conformation. The temporal inhibition results in a crucial regulatory mechanism contributing to the maintenance of GABA homeostasis, preserving neurons from excitotoxicity.
Excitatory and inhibitory synapses form a tight subcellular balance along dendrites that decorrelates over development
Authors: Horton Sally , Mastrolia Vincenzo , Jackson Rachel , Kemlo Sarah , Pereira Machado Pedro M. , Carbajal Maria Alejandra , Hindges Robert , Fleck Roland A. , Aguiar Paulo , Neves Guilherme , Burrone Juan
Published: May 2024

A balance between excitation and inhibition is crucial for neurotypical brain function. Indeed, disruptions in this relationship are frequently associated with the pathophysiology of neurodevelopmental disorders. Nevertheless, how this balance is established during the dynamic period of neurodevelopment remains unexplored. Using multiple techniques, includingin uteroelectroporation, electron microscopy and electrophysiology, we reveal a tight correlation in the distribution of excitatory and inhibitory synapses along dendrites of developing CA1 hippocampal neurons. This balance was present within short dendritic stretches (<20µm), and surprisingly, was most pronounced during early development, sharply declining with maturity. The tight matching between excitation and inhibition was unexpected, as inhibitory synapses lacked an active zone when formed and exhibited compromised evoked release. We propose that inhibitory synapses form as a stabilising scaffold, to counterbalance growing excitation levels. This relationship diminishes over time, suggesting a critical role for a subcellular balance in early neuronal function and circuit formation.
Feeling Senseless Sensations: A Crossmodal study of mismatching tactile and virtual visual experience
Authors: Lehser Caroline , Hillyard Steven A. , Strauss Daniel J.
Published: May 2024

To create highly immersive experiences in virtual reality (VR) it is important to not only include the visual sense but also to involve multimodal sensory input. To achieve optimal results, the temporal and spatial synchronization of these multimodal inputs is critical. It is therefore necessary to find methods to objectively evaluate the synchronization of VR experiences with a continuous tracking of the user. In this study a passive touch experience was incorporated in a visual–tactile VR setup using VR glasses and tactile sensations in mid–air. Inconsistencies of multimodal perception were intentionally integrated into a discrimination task. The participants’ electroencephalogram (EEG) was recorded to obtain neural correlates of visual-tactile mismatch situations. The results showed significant differences in the event-related potentials (ERP) between match and mismatch situations. A biphasic ERP configuration consisting of a positivity at 120 ms and a later negativity at 370 ms was observed following a visual–tactile mismatch. This late negativity could be related to the N400 that is associated with semantic incongruency. These results provide a promising approach towards the objective evaluation of visual–tactile synchronization in virtual experiences.
Heart-brain coupling and its relevance for individual trait characteristics
Authors: Karjalainen Suvi , Kujala Jan , Aro Tuija , Parviainen Tiina
Published: May 2024

A bulk of recent neurophysiological research has focused on how bodily functions are intertwined with neural activity, but the dynamic heart-brain coupling and its relevance for individual trait characteristics remains largely unexamined. Thus, our aim was to investigate how ongoing oscillatory brain activity is modulated by the natural fluctuations in heart rate variability (HRV). We further explored whether heart-brain coupling is associated with individual trait characteristics. Magnetoencephalography (MEG) together with electrocardiography (ECG) were used to record neural activity and HRV during rest. Self-reported trait characteristics were examined using Behavioral Inhibition and Activation Systems Scale (BIS/BAS) and attunement to internal bodily sensations using Body Vigilance Scale (BVS). Statistically significant increases were observed for low HRV vs. high HRV state in alpha and beta power (p< 0.05) indicating that oscillatory brain activity is modulated by fluctuations in HRV. Moreover, we demonstrated that heart-brain coupling was associated with self-reported behavioral approach and avoidance tendencies. The results of the moderator analysis further indicated that the relationship between heart-brain coupling and trait characteristics is at least partly moderated by the attunement to internal bodily sensations. Our findings bring insights to the intricate interplay between cardiac and neural signaling and its relationship with individual trait characteristics.

Highlights

Oscillatory brain activity is modulated by the natural fluctuations in HRV

Alpha and beta power increase during states of lower parasympathetic activity

Heart-brain coupling is linked with self-reported individual trait characteristics

This association is influenced by the attunement to the internal bodily milieu
The retina’s neurovascular unit: Müller glial sheaths and neuronal contacts
Authors: Grimes William N. , Berson David M. , Sabnis Adit , Hoon Mrinalini , Sinha Raunak , Tian Hua , Diamond Jeffrey S.
Published: May 2024

The neurovascular unit (NVU), comprising vascular, glial and neural elements, supports the energetic demands of neural computation, but this aspect of the retina’s trilaminar vessel network is poorly understood. Only the innermost vessel layer – the superficial vascular plexus (SVP) – is ensheathed by astrocytes, like brain capillaries, whereas glial ensheathment in other layers derives from radial Müller glia. Using serial electron microscopy reconstructions from mouse and primate retina, we find that Müller processes cover capillaries in a tessellating pattern, mirroring the tiled astrocytic endfeet wrapping brain capillaries. However, gaps in the Müller sheath, found mainly in the intermediate vascular plexus (IVP), permit different neuron types to contact pericytes and the endothelial cells directly. Pericyte somata are a favored target, often at spine-like structures with a reduced or absent vascular basement lamina. Focal application of adenosine triphosphate (ATP) to the vitreal surface evoked Ca2+signals in Müller sheaths in all three vascular layers. Pharmacological experiments confirmed that Müller sheaths express purinergic receptors that, when activated, trigger intracellular Ca2+signals that are amplified by IP3-controlled intracellular Ca2+stores. When rod photoreceptors die in a mouse model of retinitis pigmentosa (rd10), Müller sheaths dissociate from the deep vascular plexus (DVP) but are largely unchanged within the IVP or SVP. Thus, Müller glia interact with retinal vessels in a laminar, compartmentalized manner: glial sheathes are virtually complete in the SVP but fenestrated in the IVP, permitting direct neural-to-vascular contacts. In the DVP, the glial sheath is only modestly fenestrated and is vulnerable to photoreceptor degeneration.
Chromosome-scale genome assembly of the Hunt bumble bee, Bombus huntii Greene, 1860, a species of agricultural interest
Authors: Koch Jonathan Berenguer Uhuad , Sim Sheina B. , Scheffler Brian , Lozier Jeffrey D. , Geib Scott M.
Published: May 2024

The Hunt bumble bee,Bombus huntii, is a widely distributed pollinator in western North America. The species produces large colony sizes in captive rearing conditions, experiences low parasite and pathogen loads, and has been demonstrated to be an effective pollinator of tomatoes grown in controlled environment agriculture systems. These desirable traits have galvanized producer efforts to develop commercialB. huntiicolonies for growers to deliver pollination services to crops. To better understandB. huntiibiology and support population genetic studies and breeding decisions, we sequenced and assembled theB. huntiigenome from a single haploid male. High-fidelity sequencing of the entire genome using PacBio, along with HiC sequencing, led to a comprehensive contig assembly of high continuity. This assembly was further organized into a chromosomal arrangement, successfully identifying 18 chromosomes spread across the 317.4 Mb assembly with a BUSCO score indicating >98% completeness. Synteny analysis demonstrates shared chromosome number (n= 18) withB. terrestris, a species belonging to a different subgenus, matching the expectation that presence of 18 haploid chromosomes is an ancestral trait at least between the subgeneraPyrobombusandBombus sensu stricto. In conclusion, these assembly outcomes, alongside the minimal tissue sampled destructively, showcase techniques for producing efficient, comprehensive, and continuous genome arrangements.
A function of Spalt proteins in heterochromatin organization and maintenance of genomic DNA integrity
Authors: Ostalé Cristina M. , Azpiazu Natalia , Peropadre Ana , Martín Mercedes , Ruiz-Losada Mireya , López-Varea Ana , Viales Rebecca R. , Girardot Charles , Furlong Eileen E.M. , de Celis Jose F.
Published: May 2024

The phylogenetically conserved Spalt proteins regulate gene expression and participate in a variety of cell fate choices during multicellular development, generally acting as transcriptional repressors in different gene regulatory networks. Paradoxically, besides their roles as DNA sequence-specific transcription factors, Spalt proteins show a consistent localization to heterochromatic regions. They can act through interactions with the Nucleosome remodeling and deacetylase complex (NuRD) to promote closing of open chromatin domains, but their activities as epigenetic regulators also rely on interactions with DNA Methyltransferases or with the Lysine-specific histone demethylase LSD1, suggesting that they can participate in multiple regulatory mechanisms. Here we describe several major consequences of loss ofspaltfunction inDrosophilacells, including changes in chromatin accessibility affecting mostly pericentromeric heterochromatin, the generation of DNA damage, alterations in the localization of chromosomes within the nucleus in polyploid cells of the salivary glands and miss-expression of transposable elements. We suggest that most of these effects are related to roles of Spalt proteins in the regulation of heterochromatin formation. We propose thatDrosophilaSpalt proteins have two complementary functions, acting as sequence-specific transcriptional repressors on specific target genes and regulating more global gene silencing through the generation or maintenance of heterochromatic domains.
Lateral Prefrontal Theta Oscillations Causally Drive a Computational Mechanism Underlying Conflict Expectation and Adaptation
Authors: Martínez-Molina María Paz , Valdebenito-Oyarzo Gabriela , Soto-Icaza Patricia , Zamorano Francisco , Figueroa-Vargas Alejandra , Carvajal-Paredes Patricio , Stecher Ximena , Salinas César , Valero-Cabré Antonie , Polania Rafael , Billeke Pablo
Published: May 2024

Adapting our behavior to environmental demands relies on our capacity to perceive and manage potential conflicts within our surroundings. While evidence implicates the involvement of the lateral prefrontal cortex and theta oscillations in detecting conflict stimuli, their roles in conflict expectation remain elusive. Consequently, the exact computations and neural mechanisms underlying these cognitive processes still need to be determined. To address this gap, we employed an integrative approach involving cognitive computational modeling, fMRI, TMS, and EEG. Our results revealed a computational process underlying conflict expectation, which correlated with activity in the superior frontal gyrus (SFG). Furthermore, rhythmic TMS in the theta range applied over the SFG, but not over the inferior frontal junction, induced endogenous theta activity, enhancing computations associated with conflict expectation. These findings provide compelling evidence for the causal involvement of SFG theta activity in learning and allocating cognitive resources to address forthcoming conflict stimuli.

Significant Statement

Alterations in the processing of expectations of conflict events have been associated with several neuropsychiatric disorders that significantly affect the quality of life for many individuals. This article describes a cognitive computation underlying the conflict expectation and its causal neural mechanism involving theta brain activity in the superior frontal gyrus (SFG). Thus, unraveling this mechanism holds promise for developing interventions to address cognitive alterations related to anticipation of conflict events in neuropsychiatric disorders, improving overall cognitive function and quality of life.
Corticocortical and Corticomuscular Connectivity Dynamics in Standing Posture: Electroencephalography Study
Authors: Fujio Kimiya , Takeda Kenta , Obata Hiroki , Kawashima Noritaka
Published: May 2024

Cortical involvements, including those in the sensorimotor, frontal, and occipitoparietal regions, are important mechanisms of neural control in human standing. Previous research has shown that cortical activity and corticospinal excitability vary flexibly in response to postural demand. However, it is unclear how corticocortical and corticomuscular connectivity is dynamically modulated during standing balance and over time. This study investigated the dynamics of this connectivity using electroencephalography (EEG) and electromyography (EMG). The EEG and EMG were measured in different 4 positions: sitting (ST), normal quiet standing (QS), one-leg standing (ON), and standing on a piece of wood (WD). For corticomuscular connectivity, we concentrated on sway-varying connectivity in the timing of peak velocity of postural sway in the anteroposterior direction. For the corticocortical connectivity, the time-varying connectivity was quantified, particularly in the θ-band connectivity which is linked to error identification, using a sliding-window approach. The study found that corticomuscular connectivity from the brain to the lower-limb muscle was strengthened during the sway peak in the γ- and β-frequency bands, while the connectivity strength from the muscle to the brain was decreased in the θ- and α-band. For the time-varying connectivity, the θ-connectivity in all time-epoch was divided into 7 states including both posture-relevant and -irrelevant clusters. In one of the 7 states, the strong connectivity pairs were concentrated in the mid-central region and the proportion of epochs from the ON and WD conditions was significantly higher, indicating a functional role for posture balance. These findings shed light on electrodynamic connectivity which varies in response to postural demand. Those dynamics, particularly in the θ-band connectivity, can be used for ongoing monitoring and/or intervention for postural disability.
Double training reveals an interval-invariant subsecond temporal structure in the brain
Authors: Guan Shu-Chen , Xiong Ying-Zi , Yu Cong
Published: May 2024

Subsecond temporal perception is critical for understanding time-varying events. Many studies suggest that subsecond timing is an intrinsic property of neural dynamics, distributed across sensory modalities and brain areas. Furthermore, we hypothesize the existence of a more abstract and conceptual representation of subsecond time, which may guide the temporal processing of distributed mechanisms. However, one major challenge to this hypothesis is that learning in temporal interval discrimination (TID) consistently fails to transfer from trained intervals to untrained intervals. To address this issue, here we examined whether this interval specificity can be removed with double training, a procedure we originally created to eliminate various specificities in visual perceptual learning. Specifically, participants practiced the primary TID task, the learning of which per se was specific to the trained interval (e.g., 100 ms). In addition, they also received exposure to a new interval (e.g., 200 ms) through a secondary and functionally independent tone-frequency discrimination (FD) task. This double training successfully enabled complete transfer of TID learning to the new interval, indicating that training improved an interval-invariant component of temporal interval perception, which supports our general proposal of an abstract and conceptual representation of subsecond time in the brain.
Relationships between arts participation, social cohesion, and wellbeing: An integrative review and conceptual model
Authors: Sonke Jill , Pesata Virginia , Colverson Aaron , Morgan-Daniel Jane , Rodriguez Alexandra K. , Carroll Gray Davidson , Burch Shanaé , Abraham Abel , Akram Seher , Marjani Stefany , Belden Cassandra , Karim Hiba
Published: May 2024

Arts and cultural strategies have increasingly been engaged by the public health sector to enhance social cohesion, health, and wellbeing, as well as to address the significant health risks posed by social isolation and loneliness. While increasing studies document relationships between arts participation, social cohesion, and wellbeing uniquely, few studies have investigated the relationships between all three and, to date, no evidence synthesis has been conducted on this topic. To address this gap, this integrative review aimed to identify, describe, and synthesize research on arts participation, social cohesion, and wellbeing in a community context by addressing the question: what is the evidence base regarding relationships between arts participation, social cohesion, and well-being? Literature searches were conducted using 10 databases, and 18 articles met inclusion criteria – 16 original research articles and two reviews. Results provide insights on modes and forms of arts participation used, and offer four themes that articulate dimensions of and relationships between arts participation, social cohesion, and well-being, as distilled from the studies. Further, this review offers a conceptual model derived from these themes. The model depicts the relationships found between these concepts in the articles and highlights specific components of these relationships that may help to guide future practice, research, and policy that seeks to leverage the power of the arts to build social cohesion and wellbeing in communities. Prospective studies are needed to test these relationships as well as the potential role of social cohesion as a mechanism for building well-being in communities.
Factors influencing long-term recovery in critically ill COVID-19 survivors: A prospective multicentre cohort study
Authors: Didriksson Ingrid , Frigyesi Attila , Spångfors Martin , Leffler Märta , Reepalu Anton , Nilsson Anna , Annborn Martin , Lybeck Anna , Friberg Hans , Lilja Gisela
Published: May 2024

Background

Long-term outcomes after critical COVID-19 have not been sufficiently studied. This study aimed to describe changes in functional outcome and health-related quality of life (HRQoL) assessed at 3 and 12 months in a cohort of critically ill COVID-19 survivors. A secondary aim was to investigate factors associated with good functional outcome and HRQoL at 12 months.

Methods

This prospective multicentre cohort study included critically ill COVID-19 patients admitted to six intensive care units in Sweden between May 2020 and May 2021. Surviving patients were invited to face-to-face follow-ups at 3 and 12 months. A good functional outcome was a Glasgow outcome scale extended ≥7. HRQoL was assessed by the physical and mental component summary of the SF-36v2®, with T-scores ≥45 representing a good HRQoL. Factors associated with good functional outcome and HRQoL at 12 months were explored by multivariable logistic regression.

Results

A good functional outcome was found in 93/264 (35%) and 138/217 (64%) of survivors at 3 and 12 months, respectively. There was a significant improvement in the SF-36v2® Physical component summary (PCS) between 3 and 12 months (mean 40 versus 44, p<0.001). The SF-36v2® Mental component summary (MCS) was within the normal range at 3 months, with no significant change at 12 months (mean 46 versus 48, p=0.05). Older age was associated with a good functional outcome. Low clinical frailty and absence of diabetes mellitus were associated with a good physical HRQoL. A shorter duration of mechanical ventilation was associated with a good outcome for all three outcome measures.

Conclusion

Between 3 and 12 months, functional outcome and physical aspects of HRQoL significantly improved, indicating continued recovery up to at least one year after critical COVID-19. Low frailty, less comorbidity, and shorter duration of mechanical ventilation were associated with better long-term outcomes, while old age was associated with better functional outcome.

Study registration

ClinicalTrials.govIdentifier:NCT04974775, registered April 28, 2020.
Early detection of Alzheimer’s disease pathophysiology using 3D virtual reality navigation: a correlational study with genetic and plasma biomarkers
Authors: Shima Sayuri , Ohdake Reiko , Mizutani Yasuaki , Tatebe Harutsugu , Koike Riki , Kasai Atsushi , Bagarinao Epifanio , Ueda Akihiro , Ito Mizuki , Hata Junichi , Ishigaki Shinsuke , Tokuda Takahiko , Takashima Akihiko , Watanabe Hirohisa
Published: May 2024

BACKGROUND

We investigated the association between path-integration (PI) errors related to entorhinal cortex function detectable using a 3D virtual reality (VR) navigation system and various biomarkers to explore its potential as an early AD indicator.

METHODS

The PI capabilities of 111 healthy adults were assessed using a head-mounted 3D VR system. Demographic and cognitive assessments, AD-related plasma biomarkers, and apolipoprotein E genotypes were also evaluated. Predictive factors for PI errors were identified using multivariate linear regression, logistic regression, and random forest.

RESULTS

PI errors positively correlated with age, plasma levels of glial fibrillary acidic protein [GFAP], neurofilament light, and p-tau181. Multivariate analysis identified plasma GFAP and p-tau181 levels as significant predictors. Random forest analysis and receiver operating characteristic curves underscored plasma p-tau181 levels as the most substantial predictor.

DISCUSSION

PI errors, particularly in conjunction with plasma p-tau181 levels, could reflect early AD pathophysiology, highlighting their potential as early biomarkers.
DROP-DEEP: Dimensionality Reduction for Polygenic Risk Score Using Deep Learning Approach
Authors: Kaufman Hadasa , Hochenberg Yarden , Linial Michal , Rappoport Nadav
Published: May 2024

Motivation

Advances in sequencing technologies have enabled the early detection of genetic diseases and the development of personalized medicine. However, the variance explained by genetic variations is typically small compared to the heritability estimates. Consequently, there is a pressing need to develop enhanced polygenic risk score (PRS) prediction models. We seek an approach that transcends the limitations of the routinely used additive model for PRS.

Results

Here we present DROP-DEEP, a novel method for calculating PRS that enhances the explanation of the heritability variance of complex traits by incorporating high-dimensional genetic interactions. The first stage of DROP-DEEP employs an unsupervised approach to reduce dimensionality, while the second stage involves training a prediction model using a supervised machine-learning algorithm. Notably, the first stage of training is phenotype-agnostic. Thus, while it is computationally intensive, it is performed only once. Its output can serve as input for predicting any chosen trait or disease. We evaluated the efficacy of the DROP-DEEP dimensionality reduction models using principal component analysis (PCA) and deep neural networks (DNN). All models were trained using the UK Biobank (UKB) dataset with over 340,000 subjects and a set of approximately 460,000 single nucleotide variants (SNVs) across the genome. The results of DROP-DEEP, which was established for patients diagnosed with hypertension, outperformed other approaches. We extended the analysis to include an additional five binary and continuous phenotypes, each repeated five times for reproducibility assessment. For each phenotype, DROP-DEEP results were compared to commonly used PRS methodologies, and the performance of all models was discussed.

Conclusion

Our approach overcomes the need for variable selection while maintaining computational feasibility. We conclude that the DROP-DEEP approach exhibits significant advantages compared to commonly used PRS methods and can be used efficiently for hundreds of genetic traits.

Availability and Implementation

All the codes and the trained dimensionality reduction models are available at:https://github.com/HadasaK1/DROP-DEEP.
regionalpcs: improved discovery of DNA methylation associations with complex traits
Authors: Eulalio Tiffany , Sun Min Woo , Gevaert Olivier , Greicius Michael D. , Montine Thomas J. , Nachun Daniel , Montgomery Stephen B.
Published: May 2024

We have developed the regional principal components (rPCs) method, a novel approach for summarizing gene-level methylation. rPCs address the challenge of deciphering complex epigenetic mechanisms in diseases like Alzheimer’s disease (AD). In contrast to traditional averaging, rPCs leverage principal components analysis to capture complex methylation patterns across gene regions. Our method demonstrated a 54% improvement in sensitivity over averaging in simulations, offering a robust framework for identifying subtle epigenetic variations. Applying rPCs to the AD brain methylation data in ROSMAP, combined with cell type deconvolution, we uncovered 838 differentially methylated genes associated with neuritic plaque burden—significantly outperforming conventional methods. Integrating methylation quantitative trait loci (meQTL) with genome-wide association studies (GWAS) identified 17 genes with potential causal roles in AD, includingMS4A4AandPI-CALM. Our approach is available in the Bioconductor packageregionalpcs, opening avenues for research and facilitating a deeper understanding of the epigenetic landscape in complex diseases.
Reduction of Neuroinflammation and Seizures in a Mouse Model of CLN1 Batten Disease using the Small Molecule Enzyme Mimetic, N-Tert-Butyl Hydroxylamine
Authors: Fyke Zach , Johansson Rachel , Scott Anna I. , Wiley Devin , Chelsky Daniel , Zak Joseph D. , Nakouzi Nader Al , Koster Kevin P. , Yoshii Akira
Published: May 2024

Infantile neuronal ceroid lipofuscinosis (CLN1 Batten Disease) is a devastating pediatric lysosomal storage disease caused by pathogenic variants in theCLN1gene, which encodes the depalmitoylation enzyme, palmitoyl-protein thioesterase 1 (PPT1). CLN1 patients present with visual deterioration, psychomotor dysfunction, and recurrent seizures until neurodegeneration results in death, typically before fifteen years of age. Histopathological features of CLN1 include aggregation of lysosomal autofluorescent storage material (AFSM), as well as profound gliosis. The current management of CLN1 is relegated to palliative care. Here, we examine the therapeutic potential of a small molecule PPT1 mimetic, N-tert-butyl hydroxylamine (NtBuHA), in aCln1−/−mouse model. Treatment with NtBuHA reduced AFSM accumulation both in vitro and in vivo. Importantly, NtBuHA treatment inCln1−/−mice reduced neuroinflammation, mitigated epileptic episodes, and normalized motor function. Live cell imaging ofCln1−/−primary cortical neurons treated with NtBuHA partially rescued aberrant synaptic calcium dynamics, suggesting a potential mechanism contributing to the therapeutic effects of NtBuHA in vivo. Taken together, our findings provide supporting evidence for NtBuHA as a potential treatment for CLN1 Batten Disease.
Social anxiety links of amygdala switch cross puberty
Authors: Zhou Quan , Zhou Zi-Xuan , Wang Yin-Shan , Zuo Xi-Nian
Published: May 2024

Socioemotional functions have been linked to the amygdala through molecular mechanisms observed in animals. However, these links remain largely unestablished in the development of the human amygdala during puberty. By precisely tracing the amygdala with longitudinal data spanning childhood and adolescence, our aim is to capture the dynamic relationship between social anxiety and amygdala geometry. Around the onset of puberty (10-11.5 years), we detected shifting associations between amygdala volume and social anxiety. Higher social anxiety is associated with a larger amygdala in mid-childhood but a smaller amygdala in early adolescence. Further geometry analysis revealed regional deformations that underpinned the shift. Our findings reconcile inconsistent results from previous studies and respect the intrinsic dimension of development in resolving amygdala-anxiety links during puberty.
First Detection of Recombinant Enterovirus G Carrying a Torovirus Papain-like cysteine protease Gene from India
Authors: Sawant PM , Lavania M , Kulkarni A
Published: May 2024

Enterovirus G (EV-G) comprising 20 genotypes (G1-G20) are associated with in a various disease conditions in pig populations. The recombination between homologous EV-G is a driving force behind evolution but the recombination with virus from heterologous family is rare event. Presently, two types of recombinant EV-G strains containing torovirus papain like cysteine protease (PLCP) at 2C-3A junction (Type I) and in place of structural proteins (Type II) are reported. The present study conducted to reveal RNA virome in diarrheic piglet’s faeces retrieved genome coding for complete polyprotein of EV-G1. The detected EV-G1 strain represents first type I recombinant from India. The polyprotein of strain exhibiting 97% amino acid identity was closely related with Chinese strain. Furthermore, the EV-G1-PLCP strain was found to be originated from South Korean, Chinese, and Japanese strains with breakpoints at nucleotide (nt) position 1323 and 4725. Genetic and phylogenetic analysis of VP1 and PLCP of study strain demonstrated its closeness to EV-G1-PLCP strains from South Korea KOR/KNU-1811/2018/G1-PLCP. The present study advances the knowledge about genetic evolution of EV-G from gaining virulence gene from different virus family.
CD4 downregulation precedes Env expression and protects HIV-1-infected cells from ADCC mediated by non-neutralizing antibodies
Authors: Richard Jonathan , Sannier Gérémy , Zhu Li , Prévost Jérémie , Marchitto Lorie , Benlarbi Mehdi , Beaudoin-Bussières Guillaume , Kim Hongil , Sun Yaping , Chatterjee Debashree , Medjahed Halima , Bourassa Catherine , Delgado Gloria-Gabrielle , Dubé Mathieu , Kirchhoff Frank , Hahn Beatrice H. , Kumar Priti , Kaufmann Daniel E. , Finzi Andrés
Published: May 2024

HIV-1 envelope glycoprotein (Env) conformation substantially impacts antibody-dependent cellular cytotoxicity (ADCC). Envs from primary HIV-1 isolates adopt a prefusion “closed” conformation, which is targeted by broadly-neutralizing antibodies (bnAbs). CD4 binding drives Env into more “open” conformations, which are recognized by non-neutralizing Abs (nnAbs). To better understand Env-Ab and Env-CD4 interaction in CD4+ T cells infected with HIV-1, we simultaneously measured antibody binding and HIV-1 mRNA expression using multiparametric flow cytometry and RNA-flow fluorescentin situhybridization (FISH) techniques. We observed thatenvmRNA is almost exclusively expressed by HIV-1 productively-infected cells that already downmodulated CD4. This suggest that CD4 downmodulation precedesenvmRNA expression. Consequently, productively-infected cells express “closed” Envs on their surface, which renders them resistant to nnAbs. Cells recognized by nnAbs were allenvmRNA negative, indicating Ab binding through shed gp120 or virions attached to their surface. Consistent with these findings, treatment of HIV-1 infected humanized mice with the ADCC mediating nnAb A32 failed to lower viral replication or reduce the size of the viral reservoir. These findings confirm the resistance of productively-infected CD4+ T cells to nnAbs-mediated ADCC and question the rationale of immunotherapy approaches using this strategy.

Graphical abstract
Nanoscale analysis of functionally diverse glutamatergic synapses in the neocortex reveals input and layer-specific organization
Authors: Jones Grace , Akter Yeasmin , Shifflett Victoria , Hruska Martin
Published: May 2024

Discovery of synaptic nanostructures suggests a molecular logic for the flexibility of synaptic function. We still have little understanding of how functionally diverse synapses in the brain organize their nanoarchitecture due to challenges associated with super-resolution imaging in complex brain tissue. Here, we characterized single-domain camelid nanobodies for the 3D quantitative multiplex imaging of synaptic nano-organization in 6 µm brain cryosections using STED nanoscopy. We focused on thalamocortical (TC) and corticocortical (CC) synapses along the apical-basal axis of layer 5 pyramidal neurons as models of functionally diverse glutamatergic synapses in the brain. Spines receiving TC input were larger than CC spines in all layers examined. However, TC synapses on apical and basal dendrites conformed to different organizational principles. TC afferents on apical dendrites frequently contacted spines with multiple aligned PSD-95/Bassoon nanomodules, which are larger. TC spines on basal dendrites contained mostly one aligned PSD-95/Bassoon nanocluster. However, PSD-95 nanoclusters were larger and scaled with spine volume. The nano-organization of CC synapses did not change across cortical layers. These results highlight striking nanoscale diversity of functionally distinct glutamatergic synapses, relying on afferent input and sub-cellular localization of individual synaptic connections.
Amyloid Accelerator Polyphosphate Implicated as the Mystery Density in α-Synuclein Fibrils
Authors: Huettemann Philipp , Mahadevan Pavithra , Lempart Justine , Tse Eric , Dehury Budheswar , Edwards Brian F. P. , Southworth Daniel R. , Sahoo Bikash R. , Jakob Ursula
Published: May 2024

Aberrant aggregation of α-Synuclein is the pathological hallmark of a set of neurodegenerative diseases termed synucleinopathies. Recent advances in cryo-electron microscopy have led to the structural determination of the first synucleinopathy-derived α-Synuclein fibrils, which contain a non-proteinaceous, “mystery density” at the core of the protofilaments, hypothesized to be highly negatively charged. Guided by previous studies that demonstrated that polyphosphate (polyP), a universally conserved polyanion, significantly accelerates α-Synuclein fibril formation, we conducted blind docking and molecular dynamics simulation experiments to model the polyP binding site in α-Synuclein fibrils. Here we demonstrate that our models uniformly place polyP into the lysine-rich pocket, which coordinates the mystery density in patient-derived fibrils. Subsequentin vitrostudies and experiments in cells revealed that substitution of the two critical lysine residues K43 and K45 leads to a loss of all previously reported effects of polyP binding on α-Synuclein, including stimulation of fibril formation, change in filament conformation and stability as well as alleviation of cytotoxicity. In summary, our study demonstrates that polyP fits the unknown electron density present inin vivoα-Synuclein fibrils and suggests that polyP exerts its functions by neutralizing charge repulsion between neighboring lysine residues.
IL-13 and IL-17A Activate β1 Integrin through an NF-kB/Rho kinase/PIP5K1γ pathway to Enhance Force Transmission in Airway Smooth Muscle
Authors: Ngo Uyen , Shi Ying , Woodruff Prescott , Shokat Kevan , DeGrado William , Jo Hyunil , Sheppard Dean , Sundaram Aparna B.
Published: May 2024

Integrin activation resulting in enhanced adhesion to the extracellular matrix plays a key role in fundamental cellular processes. Although G-protein coupled receptor-mediated integrin activation has been extensively studied in non-adherent migratory cells such as leukocytes and platelets, much less is known about the regulation and functional impact of integrin activation in adherent stationary cells such as airway smooth muscle. Here we show that two different asthmagenic cytokines, IL-13 and IL-17A, activate type I and IL-17 cytokine receptor families respectively, to enhance adhesion of muscle to the matrix. These cytokines also induce activation of β1 integrins as detected by the conformation-specific antibody HUTS-4. Moreover, HUTS-4 binding is significantly increased in the smooth muscle of patients with asthma compared to healthy controls, suggesting a disease-relevant role for aberrant integrin activation. Indeed, we find integrin activation induced by a β1 activating antibody, the divalent cation manganese, or the synthetic peptide β1-CHAMP, dramatically enhances force transmission in collagen gels, mouse tracheal rings, and human bronchial rings even in the absence of cytokines. We further demonstrate that cytokine-induced activation of β1 integrins is regulated by a common pathway of NF-kB-mediated induction of RhoA and its effector Rho kinase, which in turn stimulates PIP5K1γ-mediated synthesis of PIP2resulting in β1 integrin activation. Taken together, these data identify a previously unknown pathway by which type I and IL-17 cytokine receptor family stimulation induces functionally relevant β1 integrin activation in adherent smooth muscle and help explain the exaggerated force transmission that characterizes chronic airways diseases such as asthma.

SIGNIFICANCE STATEMENT

Integrin activation plays a central role in regulating cellular adhesion and migration. While chemokine-mediated integrin activation has been extensively studied in circulating cells, the role and impact of other cytokine families on non-migratory cells remains incompletely characterized. Here, we demonstrate in airway smooth muscle that asthmagenic cytokines IL-13 and IL-17A stimulate type I and IL-17 cytokine receptor families to induce β1 integrin activation and enhance adhesion. We also identify a common pathway linking NF-kB/RhoA/Rho kinase with PIP5K1γ/PIP2/β1 integrin activation. We show that airway biopsies from asthmatic patients have increased active β1 integrin staining in the muscle, and furthermore that β1 integrin activation alone dramatically enhances force transmission, underscoring the disease-relevant impact of cytokine-mediated integrin activation in adherent muscle.
The ANTsX Ecosystem for Mapping the Mouse Brain
Authors: Tustison Nicholas James , Chen Min , Kronman Fae N , Duda Jeffrey T , Gamlin Clare , Tustison Mia G , Kunst Michael , Dalley Rachel , Sorensen Staci A. , Wang Quanxin , Ng Lydia , Kim Yongsoo , Gee James C
Published: May 2024

Precision mapping techniques coupled with high resolution image acquisition of the mouse brain permit the study of the spatial organization of gene expression and their mutual interaction for a comprehensive view of salient structural/functional relationships. Such research is facilitated by standardized anatomical coordinate systems, such as the well-known Allen Common Coordinate Framework (AllenCCFv3), and the ability to spatially map to such standardized spaces. The Advanced Normalization Tools Ecosystem is a comprehensive open-source software toolkit for generalized quantitative imaging with applicability to multiple organ systems, modalities, and animal species. Herein, we illustrate the utility of ANTsX for generating precision spatial mappings of the mouse brain and potential subsequent quantitation. We describe ANTsX-based workflows for mapping domain-specific image data to AllenCCFv3 accounting for common artefacts and other confounds. Novel contributions include ANTsX functionality for velocity flow-based mapping spanning the spatiotemporal domain of a longitudinal trajectory which we apply to the Developmental Common Coordinate Framework. Additionally, we present an automated structural morphological pipeline for determining volumetric and cortical thickness measurements analogous to the well-utilized ANTsX pipeline for human neuroanatomical structural morphology which illustrates a general open-source framework for tailored brain parcellations.
HCF101 is a novel component of the CIA cytosolic iron-sulfur synthesis pathway in the human pathogenToxoplasma gondii
Authors: Renaud Eléa A. , Maupin Ambre J.M. , Berry Laurence , Bals Julie , Bordat Yann , Demolombe Vincent , Rofidal Valérie , Vignols Florence , Besteiro Sébastien
Published: May 2024

Several key cellular functions depend on proteins harboring an iron-sulfur (Fe-S) cofactor. As these Fe-S proteins localize to several subcellular compartments, they require a dedicated machinery for cofactor assembly. For instance, in plants and algae there are Fe-S cluster synthesis pathways localizing to the cytosol, but also present in the mitochondrion and in the chloroplast, two organelles of endosymbiotic origin.Toxoplasma gondiiis a plastid-bearing parasitic protist responsible for a pathology affecting humans and other warm-blooded vertebrates. We have characterized theToxoplasmahomologue of HCF101, originally identified in plants as a protein transferring Fe-S clusters to photosystem I subunits in the chloroplast. Contrarily to plants, we have shown that HCF101 does not localize to the plastid in parasites, but instead is an important component of the cytosolic Fe-S assembly (CIA) pathway which is vital forToxoplasma. While the CIA pathway is widely conserved in eukaryotes, it is the first time the involvement of HCF101 in this pan-eukaryotic machinery is established. Moreover, as this protein is essential for parasite viability and absent from its mammalian hosts, it constitutes a novel and promising potential drug target.
KipOTIA detoxifies 5-oxoproline and promotes the growth ofClostridioides difficile
Authors: Lee Cheyenne D. , Rizvi Arshad , McBride Shonna M.
Published: May 2024

Clostridioides difficileis an anaerobic enteric pathogen that disseminates in the environment as a dormant spore. ForC. difficileand other sporulating bacteria, the initiation of sporulation is a regulated process that prevents spore formation under favorable growth conditions. InBacillus subtilis, one such mechanism for preventing sporulation is the Kinase Inhibitory Protein, KipI, which impedes activation of the main sporulation kinase. In addition, KipI functions as part of a complex that detoxifies the intermediate metabolite, 5-oxoproline (OP), a harmful by-product of glutamic acid. In this study, we investigate the orthologous Kip proteins inC. difficileto determine their roles in the regulation of sporulation and metabolism. Using deletion mutants inkipIAand the fullkipOTIAoperon, we show that unlike inB. subtilis,the Kip proteins have no significant impact on sporulation. However, we found that thekipoperon encodes a functional oxoprolinase that facilitates detoxification of OP. Further, our data demonstrate that KipOTIA not only detoxifies OP, but also allows OP to be used as a nutrient source that supports the robust growth ofC. difficile, thereby facilitating the conversion of a toxic byproduct of metabolism into an effective energy source.