bluuebunny/crossref_metadata_2025 huggingface dataset:
L-Dopa-induced changes in aperiodic bursts dynamics relate to individual clinical improvement in Parkinson’s disease
Authors: Agouram Hasnae , Neri Matteo , Angiolelli Marianna , Depannemaecker Damien , Bahuguna Jyotika , Schwey Antoine , Régis Jean , Carron Romain , Eusebio Alexandre , Malfait Nicole , Daucé Emmanuel , Sorrentino Pierpaolo
Published: June 2024

Parkinson’s disease (PD) is a neurodegenerative disease primarily characterized by severe motor symptoms that can be transiently relieved by medication (e.g. levodopa). These symptoms are mirrored by widespread alterations of neuronal activities across the whole brain, whose characteristics at the large scale level are still poorly understood. To address this issue, we measured resting state activities of 11 PD patients using DBS contacts in the subthalamic nucleus (STN) and EEG electrodes over motor areas. Data were recorded for each patient before (OFF-condition) and after (ON-condition) levodopa administration. Neuronal avalanches, i.e. brief bursts of activity with widespread propagation, were detected and quantified on both types of contacts, and used to characterize differences in both conditions. Of particular interest, we noted a larger number of shorter and smaller avalanches in the OFF-condition, and a lesser number of wider and longer avalanches in the ON-condition. This difference turned out to be statistically significant at the group level. Then, we computed the avalanche transition matrices (ATM) to track the contact-wise patterns of avalanche spread. We observed a higher probability that an avalanche would spread within and between STN and motor cortex in the ON-state, with highly significant differences at the group level. Furthermore, we discovered that the increase in overall propagation of avalanches was correlated to clinical improvement after levodopa administration. Our study offers the initial cross-modality assessment of aperiodic activities in PD patients, including levodopa’s effects on cross-regional aperiodic bursts at the individual level, suggesting potential biomarkers for PD electrophysiological alterations.

Significance Statement

Our research focuses on levodopa’s effects on large-scale dynamics in PD using a novel approach involving aperiodic bursts (i.e., neuronal avalanches). To achieve this, we measured resting-state activities of 11 PD patients using DBS contacts in the STN and EEG electrodes placed bilaterally over the motor areas, both before and after levodopa administration. Unlike most studies on beta frequency (13–30 Hz) activities, we examined dynamics through aperiodic bursts across temporal and spatial scales. Instead of focusing on global properties, we tracked the spatial spread of neuronal avalanches across the brain. Our study provides the first assessment of levodopa’s effects on cross-regional aperiodic bursts within and between the STN and motor cortex, and suggests potential electrophysiological biomarkers for PD.
Serum protein and imaging biomarkers after intermittent steroid treatment in muscular dystrophy
Authors: Willis Alexander B. , Zelikovich Aaron S. , Sufit Robert , Ajroud-Driss Senda , Vandenborne Krista , Demonbreun Alexis R. , Batra Abhinandan , Walter Glenn A. , McNally Elizabeth M.
Published: June 2024

Background

Weekly Steroids in Muscular Dystrophy (WSiMD) was a pilot study to evaluate once weekly prednisone in patients with Limb Girdle and Becker muscular dystrophy (LGMD and BMD, respectively). At study endpoint, there were trends towards increased lean mass, reduced fat mass, reduced creatine kinase and improved motor function. The investigation was motivated by studies in mouse muscular dystrophy models in which once weekly glucocorticoid exposure enhanced muscle strength and reduced fibrosis.

Methods

WSiMD participants provided blood samples for aptamer serum profiling at baseline and after 6 months of weekly steroids. A subset completed magnetic resonance (MR) evaluation of muscle at study onset and endpoint.

Results/Conclusions

At baseline compared to age and sex-matched healthy controls, the aggregate serum protein profile in the WSiMD cohort was dominated by muscle proteins, reflecting leak of muscle proteins into serum. Disease status produced more proteins differentially present in serum compared to steroid-treatment effect. Nonetheless, a response to prednisone was discernable in the WSiMD cohort, even at this low dose. Glucocorticoids downregulated muscle proteins and upregulated certain immune process- and matrix-associated proteins. Muscle MR fat fraction showed trends with functional status. The prednisone-responsive markers could be used in larger trial of prednisone efficacy.
Taking the perspective of an embodied avatar modulates the temporal dynamics of vicarious pain and pleasure: a combined Immersive Virtual Reality and EEG study
Authors: Nicolardi V. , Lisi M.P. , Mello M. , Fusaro M. , Tieri G. , Aglioti S.M.
Published: June 2024

Observing negative and positive valence virtual stimuli can influence the onlookers’ subjective and brain reactivity. However, the relationship between vicarious pain and pleasure, observer’s perspective taking and cerebral activity remains underexplored. To address this gap, we asked 24 healthy participants to passively observe pleasant, painful, and neutral stimuli delivered to a virtual hand seen from a first-person (1PP) or third-person perspective (3PP) while undergoing time and time-frequency EEG recording. Participants reported a stronger sense of ownership over the virtual hand seen from a 1PP, rated pain and touch valence appropriately, and more intense than the neutral ones. Distinct EEG patterns emerged across early (N2, early posterior negativity, EPN), late (late positive potential, LPP) event-related potentials, and EEG power. The N2 and EPN components showed greater amplitudes for pain and pleasure than neutral stimuli, particularly in 1PP. The LPP component exhibited lower amplitudes for pleasure than pain and neutral stimuli. Further, theta-band power increased, and alpha power decreased for pain and pleasure stimuli viewed from a 1PP versus a 3PP perspective. In the ultra-late time window, we observed decreased theta, alpha, and beta-band power specifically associated with pleasure stimuli. Our study provides novel evidence that perspective-taking modulates the temporal dynamics of vicarious pain and pleasure.
Energy-based Modelling of Single Actin Filament Polymerisation Using Bond Graphs
Authors: Gawthrop Peter J. , Pan Michael , Rajagopal Vijay
Published: June 2024

Bond graphs provide an energy-based methodology for modelling complex systems in a hierarchical fashion; at the moment, the method allows biological system with both chemical and electrical subsystems to be modelled. Herein, the bond graph approach is extended to include chemomechanical transduction thus extending the range of biological systems to be modelled.

Actin filament polymerisation and force generation is used as an example of chemo-mechanical transduction and it is shown that theTF(transformer) bond graph component provides a practical, and conceptually simple, alternative to the Brownian ratchet approach of Peskin, Odell, Oster & Mogilner. Furthermore it is shown that the bond graph approach leads to the same equation as the Brownian ratchet approach in the simplest case.

The approach is illustrated by showing that flexibility and non-normal incidence can be modelled by simply adding additional bond graph components and that compliance leads to non-convexity of the force-velocity curve.

Energy flows are fundamental to life; for this reason, the energy based approach is utilised to investigate the power transmission by the actin filament and its corresponding efficiency.

The bond graph model is fitted to experimental data by adjusting model physical parameters.
FreeSurfer version-shuffling can boost brain age predictions
Authors: Korbmacher Max , Westlye Lars T. , Maximov Ivan I.
Published: June 2024

Abstract / Key points

The influence of FreeSurfer version-dependent variability in reconstructed cortical features on brain age predictions is average small when varying training and test splits from the same data.

FreeSurfer version differences can lead to some variability in brain age dependent on the choice of algorithm and individual differences in brain morphometry, highlighting the advantage of repeated random train-test splitting.

Shuffling of differently processed FreeSurfer data dependent on the FreeSurfer version increases performance and generalizability of the brain age prediction model.
Non-additivity of the functional properties of individual P450 species and its manifestation in the effects of alcohol consumption on the metabolism of ketamine and amitriptyline
Authors: Ponraj Kannapiran , Gaither Kari A. , Singh Dilip Kumar , Davydova Nadezhda , Zhao Mengqi , Luo Shaman , Lazarus Philip , Prasad Bhagwat , Davydov Dmitri R.
Published: June 2024

To explore functional interconnections between multiple P450 enzymes and their manifestation in alcohol-induced changes in drug metabolism, we implemented a high-throughput study of correlations between the composition of the P450 pool and the substrate saturation profiles (SSP) of amitriptyline and ketamine in a series of 23 individual human liver microsomes preparations from donors with a known history of alcohol consumption. The SSPs were approximated with linear combinations of three Michaelis-Menten equations with globally optimizedKM(substrate affinity) values. This analysis revealed a strong correlation between the rate of ketamine metabolism and alcohol exposure. For both substrates, alcohol consumption caused a significant increase in the role of the low-affinity enzymes. The amplitudes of the kinetic components and the total rate were further analyzed for correlations with the abundance of 11 major P450 enzymes assessed by global proteomics. The maximal rate of metabolism of both substrates correlated with the abundance of CYP3A4, their predicted principal metabolizer. However, except for CYP2D6 and CYP2E1, responsible for the low-affinity metabolism of ketamine and amitriptyline, respectively, none of the other potent metabolizers of the drugs revealed a positive correlation. Instead, in the case of ketamine, we observed negative correlations with the abundances of CYP1A2, CYP2C9, and CYP3A5. For amitriptyline, the data suggest inhibitory effects of CYP1A2 and CYP2A6. Our results demonstrate the importance of functional interactions between multiple P450 species and their decisive role in the effects of alcohol exposure on drug metabolism.
Functional Hierarchy of the Human Neocortex from Cradle to Grave
Authors: Taylor Hoyt Patrick , Thung Kim-Han , Huynh Khoi Minh , Lin Weili , Ahmad Sahar , Yap Pew-Thian
Published: June 2024

Recent evidence indicates that the organization of the human neocortex is underpinned by smooth spatial gradients of functional connectivity (FC). These gradients provide crucial in-sight into the relationship between the brain’s topographic organization and the texture of human cognition. However, no studies to date have charted how intrinsic FC gradient architecture develops across the entire human lifespan. In this work, we model developmental trajectories of the three primary gradients of FC using a large, high-quality, and temporally-dense functional MRI dataset spanning from birth to 100 years of age. The gradient axes, denoted as sensorimotor-association (SA), visual-somatosensory (VS), and modulation-representation (MR), encode crucial hierarchical organizing principles of the brain in development and aging. By tracking their evolution throughout the human lifespan, we provide the first ever comprehensive low-dimensional normative reference of global FC hierarchical architecture. We observe significant age-related changes in global network features, with global markers of hierarchical organization increasing from birth to early adulthood and decreasing there-after. During infancy and early childhood, FC organization is shaped by primary sensory processing, dense short-range connectivity, and immature association and control hierarchies. Functional differentiation of transmodal systems supported by long-range coupling drives a convergence toward adult-like FC organization during late childhood, while adolescence and early adulthood are marked by the expansion and refinement of SA and MR hierarchies. While gradient topographies remain stable during late adulthood and aging, we observe decreases in global gradient measures of FC differentiation and complexity from 30 to 100 years. Examining cortical microstructure gradients alongside our functional gradients, we observed that structure-function gradient coupling undergoes differential lifespan trajectories across multiple gradient axes.
Activation of the muscle-to-brain axis ameliorates neurocognitive deficits in an Alzheimer’s disease mouse model via enhancing neurotrophic and synaptic signaling
Authors: Taha Hash Brown , Birnbaum Allison , Matthews Ian , Aceituno Karel , Leon Jocelyne , Thorwald Max , Godoy-Lugo Jose , Cortes Constanza J.
Published: June 2024

INTRODUCTION

Skeletal muscle regulates central nervous system (CNS) function and health, activating the muscle-to-brain axis through the secretion of skeletal muscle originating factors (‘myokines’) with neuroprotective properties. However, the precise mechanisms underlying these benefits in the context of Alzheimer’s disease (AD) remain poorly understood.

METHODS

To investigate muscle-to-brain axis signaling in response to amyloid β (Aβ)- induced toxicity, we generated 5xFAD transgenic female mice with enhanced skeletal muscle function (5xFAD;cTFEB;HSACre) at prodromal (4-months old) and late (8-months old) symptomatic stages.

RESULTS

Skeletal muscle TFEB overexpression reduced Aβ plaque accumulation in the cortex and hippocampus at both ages and rescued behavioral neurocognitive deficits in 8- months-old 5xFAD mice. These changes were associated with transcriptional and protein remodeling of neurotrophic signaling and synaptic integrity, partially due to the CNS-targeting myokine prosaposin (PSAP).

DISCUSSION

Our findings implicate the muscle-to-brain axis as a novel neuroprotective pathway against amyloid pathogenesis in AD.
The proneurogenic and microglial modulatory properties of botulinum toxin in the hippocampus of aging experimental mice
Authors: Joseph Jerly Helan Mary , Babu Deva Irakkam Mercy Priyadharshini , Kandasamy Mahesh
Published: June 2024

This study explored the neurogenic and microglial modulatory properties of botulinum toxin in the hippocampus of aging experimental mice. Therapeutic botulinum toxin (BoNT) treatment is widely practiced to reduce the excessive discharge of acetylcholine (ACh) in the management of aging and neurological deficits. While the production of new neurons in the adult brain contributes to cognitive functions, age-related diseases with excessive release of ACh and progressive neuroinflammation have been characterized by impaired hippocampal neurogenesis and memory loss. Therefore, we investigated the effect of BoNT on the regulation of hippocampal neurogenesis, focusing on doublecortin (DCX)-positive immature neurons in the hippocampus of aging experimental mice. We also assessed ionized calcium-binding adapter molecule 1 (Iba1)-positive microglia and the expression of cyclooxygenase (COX)-2, a key inflammatory response element, using reverse transcription polymerase chain reaction (RT-PCR). Results revealed a prominent increase in DCX-positive cells in the BoNT-treated animals compared to the control group. Additionally, the reduced number of microglia accompanied by decreased mRNA expression of COX-2 was evident in the BoNT-treated animals. These dual effects suggest that BoNT could be a promising therapeutic agent for mitigating age-related neuroregenerative decline and neuroinflammation responsible for cognitive impairments.
Bacterial Volatile Organic Compound Specialists in the Phycosphere
Authors: Padaki Vaishnavi G. , Mayali Xavier , Weber Peter K. , Giovannoni Stephen J. , Abraham Kaylene , Jacobs Kerry , Collart Lindsay , Halsey Kimberly H.
Published: June 2024

Labile dissolved organic carbon (LDOC) in the oceans accounts for ∼¼ of marine primary production and turns over with a half-life of seconds to days, fueling one of the largest engines of microbial heterotrophic production on the planet. Volatile organic compounds (VOCs) are poorly constrained components of LDOC. Here, we detected 78m/zsignals, corresponding to unique VOCs, including petroleum hydrocarbons, totaling 18.5 nM in the culture medium of a model diatom. In five cocultures with bacteria adapted to grow with this diatom, 1 to 66 VOCs were depleted. Two of the most active VOC consumers,MarinobacterandRoseibium,contained more genes encoding VOC oxidation proteins, and attached to the diatom, suggesting VOC specialism. With NanoSIMS and stable isotope labeling, we confirmed thatMarinobacterincorporated carbon from benzene, one of the depleted VOCs detected in the co-culture. Diatom gross carbon production increased by up to 29% in the presence of VOC consumers, indicating that VOC consumption by heterotrophic bacteria in the phycosphere – a region of rapid organic carbon oxidation that surrounds phytoplankton cells – could impact global rates of gross primary production.
Ecdysteroid-dependent molting in tardigrades
Authors: Yamakawa Shumpei , Hejnol Andreas
Published: June 2024

Molting is a defining feature of the most species-rich animal taxa, the Ecdysozoa, including arthropods, tardigrades, nematodes, and others. In pancrustaceans, such as insects and decapods, molting is regulated by the ecdysteroid (Ecd) hormone and its downstream cascade. However, whether the regulation of molting predates the emergence of the arthropods and represents an ancestral machinery of ecdysozoans remains unclear. Therefore, we investigated the role of Ecd in the molting process of the tardigradeHypsibius exemplaris. We show that the endogenous Ecd level periodically increases during the molting cycle ofH. exemplaris. The pulse treatment with exogenous Ecd induced molting while an antagonist of the Ecd receptor suppressed the molting. Our spatial and temporal gene expression analysis revealed the putative regulatory organs and Ecd downstream cascades. We demonstrate that tardigrade molting is regulated by Ecd hormone, supporting the ancestry of Ecd-dependent molting in panarthropods. Further, we were able to identify the putative neural center of molting regulation in tardigrades, which may represent an ancestral state of panarthropods homologous to the protocerebrum of pancrustaceans. Together, our results suggest that Ecd-dependent molting evolved 100 million years earlier than previously suggested.
Geospatial Analysis and Determinant Factors of Comorbidity Presence in Patients with Diabetes
Authors: Vera-Ponce Víctor Juan , Zuzunaga-Montoya Fiorella E. , Vásquez-Romero Luisa Erika Milagros , Loayza-Castro Joan A. , Sanchez-Tamay Nataly Mayely , Gutierrez De Carrillo Carmen Inés
Published: June 2024

Introduction

The prevalence of diabetes mellitus (DM) has shown a significant increase in recent decades, leading to a rise in associated complications.

Objective

To explore the determinant factors and geographical distribution of comorbidities and their number in patients with diabetes in Peru.

Methods

Cross-sectional study based on a database providing detailed demographic and clinical information on DM patients affiliated with the Comprehensive Health Insurance (SIS: acronym in spanish) in Peru. The dependent variables in this study are twofold: the type of comorbidities present in DM patients and the number of comorbidities they have. Comorbidities were categorized into three groups: DM with obesity/dyslipidemia, DM with hypertension, and DM with mental health disorders. The number of comorbidities was classified as none, one, two, or three comorbidities.

Results

A total of 1,355,354 patients were included. Male patients, older individuals, and those with a longer time since diagnosis have different probabilities of presenting the comorbidities and a higher number of them. Additionally, the geospatial analysis showed apparent regional variations in the prevalence and number of comorbidities, highlighting the influence of environmental and socioeconomic factors and access to healthcare services.

Conclusions

This study identified significant demographic and clinical factors associated with comorbidities in patients with DM in Peru. These findings showed the need for personalized, region-specific diabetes management. Therefore, public health policies should adapt to meet the needs of different regions and groups. Improving healthcare access is crucial, especially where comorbidity prevalence is high. Further education programs must address diet and exercise comorbidities, focusing on vulnerable people.
Respiratory human adenovirus outbreak captured in wastewater surveillance
Authors: Kazmer Katherine R. , Ammerman Michelle L. , Edwards Elizabeth A. , Eisenberg Marisa C. , Gilbert Julie , Montgomery JoLynn P. , Pierce Virginia M. , Weinberg Jason B. , Wigginton Krista R.
Published: June 2024

Adenoviruses present challenges for traditional surveillance methods since there are more than 60 types that infect humans. Wastewater-based surveillance can supplement traditional surveillance methods for gastrointestinal-associated adenoviruses, but the ability to detect trends of respiratory-associated adenoviruses in wastewater remains unclear. We quantified human adenovirus type 4 (HAdV-4) in wastewater settled solids and compared wastewater measurements to clinical cases from an outbreak investigation beginning in late September 2023. The human adenovirus type 4 target was positively correlated with clinical cases (Spearman’s rho = 0.5470, p < 0.0001) and followed a similar trend during the outbreak. We also quantified human adenovirus types 3, 7, 14, 21, 40/41, and a pan-adenovirus assay that targets all types that infect humans. The respiratory adenoviruses comprised a small fraction of the adenoviruses in wastewater and types 40/41, which typically cause gastrointestinal disease, comprised the majority of the detected adenoviruses. The efficacy of adenovirus wastewater surveillance will depend on assay specificity and the public health action available for adenovirus types.

WATER IMPACT STATEMENT

Community adenovirus surveillance is strengthened by wastewater measurements. We evaluated the correlation between wastewater measurements and clinical cases during an outbreak of respiratory adenovirus type 4 infections on a college campus. Results indicate respiratory adenoviruses comprise a small portion of the adenoviruses measured in wastewater and the utility of adenovirus wastewater surveillance depends on the type and public health actionability.

GRAPHICAL ABSTRACT
The Multifaceted Phenotype of Senescent HL-60/S4 Macrophages
Authors: Olins Ada L. , Mark Welch David , Saul Dominik , Prudovsky Igor , Olins Donald E.
Published: June 2024

Every cell has a multifaceted phenotype. Transcriptional analysis of functionally defined groups of genes can provide insight into this phenotypic complexity. In the present study, the mRNA transcriptome of phorbol ester (TPA) differentiated HL-60/S4 macrophage cells was scrutinized using Gene Set Enrichment Analysis (GSEA), which evaluates the strengths of various cellular phenotypes by examining the enrichment of functionally different gene sets. Employing GSEA, we obtained supporting evidence that HL-60/S4 macrophages are senescent, probably a consequence of enriched TGFβ and NOTCH signaling transcripts. There appears to be a reduction of transcripts for heterochromatin, nucleosome formation, and chromatin remodeling phenotypes. In addition, despite upregulated oxidative stress gene transcription, we observed a reduction of DNA damage and repair transcripts. GSEA indicated that transcripts for autophagy, extracellular matrix, and inflammation/inflammasomes are enriched. We also observed that the HL-60/S4 macrophage is enriched for apoptosis gene transcripts, which may promote necrotic death by pyroptosis. The long-term goal of this research direction is to see whether this complex multifaceted phenotypic pattern is shared with other types of macrophages and to determine what mechanisms might exist to coordinate these phenotypic facets within a single cell.
Optimized chemical labeling method for isolation of 8-oxoG-modified RNA, ChLoRox-Seq, identifies mRNAs enriched in oxidation and transcriptome-wide distribution biases of oxidation events post environmental stress
Authors: Burroughs Matthew R. , Sweet Philip J. , Contreras Lydia M.
Published: June 2024

Bulk increases in nucleobase oxidation, most commonly manifesting as the guanine (G) nucleobase modification 8-oxo-7,8-dihydroguanine (8-oxoG), have been linked to several disease pathologies. Elucidating the effects of RNA oxidation on cellular homeostasis is limited by a lack of effective tools for detecting specific regions modified with 8-oxoG. Building on a previously published method for studying 8-oxoG in DNA, we developed ChLoRox-Seq, which works by covalently functionalizing 8-oxoG sites in RNA with biotin. Importantly, this method enables antibody-free enrichment of 8-oxoG-containing RNA fragments for Next Generation Sequencing-based detection of modified regions transcriptome-wide. We demonstrate the high specificity of ChLoRox-Seq for functionalizing 8-oxoG over unmodified nucleobases in RNA and benchmark this specificity to a commonly used antibody-based approach. Key advantages of ChLoRox-Seq include: (1) heightened resolution of RNA oxidation regions (e.g. exon-level) and (2) lower experimental costs. By applying ChLoRox-Seq to mRNA extracted from human lung epithelial cells (BEAS-2B) after exposure to environmentally relevant stress, we observe that 8-oxoG modifications tend to cluster in regions that are G-rich and within mRNA transcripts possessing longer 5’ UTR and CDS regions. These findings provide new insight into the complex mechanisms that bias the accumulation of RNA oxidation across the transcriptome. Notably, our analysis suggests the possibility that most mRNA oxidation events are probabilistically driven and that mRNAs that possess more favorable intrinsic properties are prone to incur oxidation events at elevated rates. ChLoRox-Seq can be readily applied in future studies to identify regions of elevated RNA oxidation in any cellular model of interest.
Prevalence and environmental abundance of the elusive membrane trafficking complex TSET in five cosmopolitan eukaryotic groups
Authors: Penot-Raquin Mathias , Sivia Mandeep , Fafoumi Morenikedji , Larson Raegan , Dorrell Richard G. , Dacks Joel B.
Published: June 2024

Eukaryotic cell biology is largely understood from paradigms established on few model organisms, largely from the animal and fungi (opisthokonts) and to a lesser extent plants. These organisms, however, constitute only a small proportion of eukaryotic diversity, and the principles of their cell biology may not be universal to other, understudied but globally impactful, organisms. Intriguingly, there are cellular components that are present in diverse eukaryotes, but are not in the animals and fungi on which the best developed models of cell biology are derived. Consequently, these components are not included in the generally adopted frameworks of cellular function that are meant to explain eukaryotic biology. The membrane complex TSET is the best studied such example, well established to play a role in cell division and endocytosis in plants. It is found across eukaryotes, but is highly reduced in opisthokonts. Its general prevalence, abundance, and relevance in eukaryotic cellular activity is unclear. Here we show that TSET is encoded in genomes of five cosmopolitan and critical groups of primarily photosynthetic eukaryotes (green algae, red algae, stramenopiles, haptophytes and cryptophytes), with particular prevalence in the green algae and some stramenopile groups. A meta-analysis of published gene expression data from the model diatomPhaeodactylum tricornutumshows that this complex is coregulated with components of the endomembrane trafficking machinery. Moreover, meta-transcriptomic data fromTaraOceans reveals that TSET genes are both present and expressed by diatoms in the wild. These data suggest that TSET may be playing an important and underrecognized role in cellular activities within marine ecosystems. More broadly, the results support the idea that use of systems-level data for non-model organisms can illuminate our understanding of core principles of eukaryotic cell function, and may reveal important and under-appreciated players that deserve to be integrated into the pervasive models of cellular capacity.
Single cell landscape of sex differences in the progression of multiple sclerosis
Authors: Soler-Sáez Irene , Gómez-Cabañes Borja , Grillo-Risco Rubén , Galiana-Roselló Cristina , Barea-Moya Lucas , Carceller Héctor , Dolader-Rabinad Beatriz , del Rey Díez Natalia , Virués-Morales Alejandro , Casanova-Ferrer Franc , Gordillo-González Fernando , Yanguas-Casas Natalia , de la Iglesia-Vayá María , Gil-Perotin Sara , Tepavčević Vanja , Hidalgo Marta R. , García-García Francisco
Published: June 2024

Background

One of the major challenges in addressing multiple sclerosis is to understand its progression trajectory. The pathological process transitions from acute phases predominantly driven by inflammation to progressive clinical profiles where neurodegeneration takes precedence. The factors mediating this heterogeneity remain unresolved. However, it is known that sex plays a crucial role; females are two to three times more likely to suffer from multiple sclerosis, while males suffer from more rapid neurodegeneration with greater severity.

Results

We profiled 48,919 central nervous system and 336,934 peripheral immune cells, covering the multiple sclerosis spectrum. We generated cell-type specific landscapes, including gene signatures from differentially expressed genes, functional profiling, pathway activation, and cell-cell communication networks for females, males, and their sex differential profiles. Among our findings, we revealed that female neurons may exhibit protective mechanisms against neurodegeneration. In the inflammatory-predominant forms, female immune cells present an inflammatory core driven by the AP-1 transcription factor, while male adaptive immune cells exhibit higher mitochondrial impairment. Conversely, larger differences are reported in CD8+ T cells progressive forms, with males exhibiting cytolytic profiles that may promote neurodegeneration. Complete results can be explored in the user-friendly interactive webtoolhttps://bioinfo.cipf.es/cbl-atlas-ms/.

Conclusions

We identified cell-type specific sex differences in brain and immune cells that vary in the spectrum of multiple sclerosis progression. We consider this molecular description of sex differences to be valuable resources to promote future targeted approaches to specific molecular mechanisms considering the sex of the individual.
Network nature of ligand-receptor interactions underlies disease comorbidity in the brain
Authors: Grant-Peters Melissa , Fairbrother-Browne Aine , Hicks Amy , Guo Boyi , Reynolds Regina H. , Huuki-Myers Louise , Eagles Nick , Brenton Jonathan , Garcia-Ruiz Sonia , Wood Nicholas , Gandhi Sonia , Maynard Kristen , Collado-Torres Leonardo , Ryten Mina
Published: June 2024

Neurodegenerative disorders have overlapping symptoms and have high comorbidity rates, but this is not reflected in overlaps of risk genes. We have investigated whether ligand-receptor interactions (LRIs) are a mechanism by which distinct genes associated with disease risk can impact overlapping outcomes. We found that LRIs are likely disrupted in neurological disease and that the ligand-receptor networks associated with neurological diseases have substantial overlaps. Specifically, 96.8% of LRIs associated with disease risk are interconnected in a single LR network. These ligands and receptors are enriched for roles in inflammatory pathways and highlight the role of glia in cross-disease risk. Disruption to this LR network due to disease-associated processes (e.g. differential transcript use, protein misfolding) is likely to contribute to disease progression and risk of comorbidity. Our findings have implications for drug development, as they highlight the potential benefits and risks of pursuing cross-disease drug targets.
Identifying miRNA Signatures Associated with Pancreatic Islet Dysfunction in a FOXA2-Deficient iPSC Model
Authors: Elsayed Ahmed K. , Aldous Noura , Alajez Nehad M. , Abdelalim Essam M.
Published: June 2024

The pathogenesis of diabetes involves complex changes in the expression profiles of mRNA and non-coding RNAs within pancreatic islet cells. Recent progress in induced pluripotent stem cell (iPSC) technology have allowed the modeling of diabetes-associated genes. Our recent study using FOXA2-deficient human iPSC models has highlighted an essential role for FOXA2 in the development of human pancreas. Here, we aimed to provide further insights on the role of microRNAs (miRNAs) by studying the miRNA-mRNA regulatory networks in iPSC-derived islets lacking the FOXA2 gene. Consistent with our previous findings, the absence of FOXA2 significantly downregulated the expression of islet hormones, INS, and GCG, alongside other key developmental genes in pancreatic islets. Concordantly, RNA-Seq analysis showed significant downregulation of genes related to pancreatic development and upregulation of genes associated with nervous system development and lipid metabolic pathways. Furthermore, the absence of FOXA2 in iPSC-derived pancreatic islets resulted in significant alterations in miRNA expression, with 61 miRNAs upregulated and 99 downregulated. The upregulated miRNAs targeted crucial genes involved in diabetes and pancreatic islet cell development. In contrary, the absence of FOXA2 in islets showed a network of downregulated miRNAs targeting genes related to nervous system development and lipid metabolism. These findings highlight the impact of FOXA2 absence on pancreatic islet development and suggesting intricate miRNA-mRNA regulatory networks affecting pancreatic islet cell development.
Vocal error monitoring in the primate auditory cortex
Authors: Eliades Steven J , Tsunada Joji
Published: June 2024

Sensory-motor control requires the integration and monitoring of sensory feedback resulting from our behaviors. This self-monitoring is thought to result from comparisons between predictions of expected sensory consequences of action and the feedback actually received, resulting in activity that encodes feedback error. Although similar mechanisms have been proposed during speech and vocal production, including sensitivity to experimentally-perturbed auditory feedback, evidence for a vocal ‘error signal’ has been limited. Here, we recorded from the auditory cortex of vocalizing non-human primates, using real-time frequency shifts to introduce feedback errors of varying magnitude and direction. We found neural activity that scaled with the magnitude of feedback error in both directions, consistent with vocal error monitoring at both the individual unit and population levels. This feedback sensitivity was greater than that predicted based upon passive sensory responses and was more specific for units in the vocal frequency range. Similar patterns of sensitivity were seen in response to natural variations in produced vocal acoustics. These results provide evidence that the auditory cortex encodes the degree of vocal feedback error using both unit-level error calculations and changes in the population of neurons involved. These mechanisms may provide critical error information necessary for feedback-dependent vocal control.
Epstein-Barr virus noncoding RNA EBER1 promotes the expression of a ribosomal protein paralog to boost oxidative phosphorylation
Authors: Paudel Sita , Lee Nara
Published: June 2024

Epstein-Barr virus (EBV) is a highly successful pathogen that infects ∼95% of the adult population and is associated with diverse cancers and autoimmune diseases. The most abundant viral factor in latently infected cells is not a protein but a noncoding RNA called EBV-encoded RNA 1 (EBER1). Even though EBER1 is highly abundant and was discovered over forty years ago, the function of EBER1 has remained elusive. EBER1 interacts with the ribosomal protein L22, which normally suppresses the expression of its paralog L22-like 1 (L22L1). Here we show that when L22 binds EBER1, it cannot suppress L22L1, resulting in L22L1 being expressed and incorporated into ribosomes. We further show that L22L1-containing ribosomes preferentially translate mRNAs involved in the oxidative phosphorylation pathway. Moreover, upregulation of L22L1 is indispensable for growth transformation and immortalization of resting B cells upon EBV infection. Taken together, our results suggest that the function of EBER1 is to modulate host gene expression at the translational level, thus bypassing the need for dysregulating host gene transcription.
SOD1 Enzymatic Activity in CSF from ALS patients with and withoutSOD1mutations
Authors: Leykam Laura , Forsberg Karin M.E. , Nordström Ulrika , Hjertkvist Karin , Öberg Agneta , Jonsson Eva , Andersen Peter M. , Marklund Stefan L. , Zetterström Per
Published: June 2024

Superoxide dismutase-1 (SOD1) mutations are a common cause of amyotrophic lateral sclerosis (ALS). Intrathecal gene therapy using the antisense-oligo-nucleotide drug tofersen to reduceSOD1expression shows significant effects on disease progression and has recently been approved in the United States and the European Union. However, the discovery of children homozygous for four different inactivatingSOD1mutations developing the Infantile SOD1 Deficiency Syndrome (ISODDES) with injury to both upper and lower motor systems suggests that low SOD1 activities may be deleterious in humans. Monitoring SOD1 activity in cerebrospinal fluid (CSF) from tofersen-treated patients is advisable but difficult due to low levels and the presence of the isoenzyme SOD3. We here present a method to efficiently remove SOD3 from CSF using highly specific immobilized antibodies and subsequent measurement of the SOD activity as a sensitive assay for the SOD1 activity in CSF. We applied the method on CSF samples from ALS patients and controls and used paired erythrocyte samples for comparison. In ALS patients with wildtypeSOD1,the SOD1 activity in CSF was the same as in controls, but patients with mutantSOD1show lower activity in CSF, even patients with mutants previously reported to have full activity in erythrocytes. Activity variation is large among patients carrying the sameSOD1mutation and larger than seen in erythrocytes and in post-mortem central nervous system tissue. SOD1 in CSF shows a high specific activity, indicating that it is mainly native. Lastly, we identified a discrepancy between the SOD1 activity and protein level measured with ELISA in both CSF and erythrocytes. Since antibodies for SOD1 ELISA-quantification are raised against the native wildtype enzyme, the content of mutant SOD1s may be underestimated. Direct analysis of SOD1 enzymatic activity in CSF is therefore a more reliable way to monitor the effect of SOD1-lowering compounds.
Dopamine D1 receptor expression in prefrontal parvalbumin neurons influences distractibility across species
Authors: Joyce Mary Kate P , Ivanov Tsvetoslav G , Krienen Fenna , Mitchell Jude , Ma Shaojie , Inoue Wataru , Nandy Anirvan P , Datta Dibyadeep , Duque Alvaro , Arellano Jon I , Gupta Rahul , Gonzalez-Burgos Guillermo , Lewis David A , Sestan Nenad , McCarroll Steven A , Martinez-Trujillo Julio C , Froudist-Walsh Seán , Arnsten Amy FT
Published: June 2024

Marmosets and macaques are common non-human primate models of cognition, yet marmosets appear more distractible and perform worse in cognitive tasks. The dorsolateral prefrontal cortex (dlPFC) is pivotal for sustained attention, and prior macaque research suggests that dopaminergic modulation and inhibitory parvalbumin (PV) neurons could contribute to distractibility. Thus, we compared the two species using a visual fixation task with distractors, performed molecular and anatomical analyses in dlPFC, and linked functional microcircuitry with cognitive performance using computational modeling. We found that marmosets are more distractible than macaques, and that marmoset dlPFC PV neurons contain higher levels of dopamine-1 receptor (D1R) transcripts and protein, similar to their levels in mice. The modeling indicated that higher D1R expression in marmoset dlPFC PV neurons may increase distractibility by making dlPFC microcircuits more vulnerable to disruptions of their task-related persistent activity, especially when dopamine is released in dlPFC in response to unexpected salient stimuli.
Complex harmonics reveal low-dimensional manifolds of critical brain dynamics
Authors: Deco Gustavo , Sanz Perl Yonatan , Kringelbach Morten L
Published: June 2024

The brain needs to perform time-critical computations to ensure survival. A potential solution lies in the non-local, distributed computation at the whole-brain level made possible by criticality and amplified by the rare long-range connections found in the brain's unique anatomical structure. This non-locality can be captured by the mathematical structure of Schroedinger's wave equation, which is at the heart of the novel CHARM (Complex Harmonics decomposition) framework that performs the necessary dimensional manifold reduction able to extract non-locality in critical spacetime brain dynamics. Using a large neuroimaging dataset of over 1,000 people, CHARM captured the critical, non-local/long-range nature of brain dynamics and the underlying mechanisms were established using a precise whole-brain model. Equally, CHARM revealed the significantly different critical dynamics of wakefulness and sleep. Overall, CHARM is a promising theoretical framework for capturing the low-dimensionality of the complex network dynamics observed in neuroscience and provides evidence that networks of brain regions rather than individual brain regions are the key computational engines of critical brain dynamics.
Evolution of polyamine resistance inStaphylococcus aureusthrough modulation of potassium transport
Authors: Campbell Killian , Kowalski Caitlin H. , Kohler Kristin M. , Barber Matthew F.
Published: June 2024

Microbes must adapt to diverse biotic and abiotic factors encountered in host environments. Polyamines are an abundant class of aliphatic molecules that play essential roles in fundamental cellular processes across the tree of life. Surprisingly, the bacterial pathogenStaphylococcus aureusis highly sensitive to polyamines encountered during infection, and acquisition of a polyamine resistance locus has been implicated in spread of the prominent USA300 methicillin-resistantS. aureuslineage. At present, alternative pathways of polyamine resistance in staphylococci are largely unknown. Here we applied experimental evolution to identify novel mechanisms and consequences ofS. aureusadaption when exposed to increasing concentrations of the polyamine spermine. Evolved populations ofS. aureusexhibited striking evidence of parallel adaptation, accumulating independent mutations in the potassium transporter genesktrAandktrD. Mutations in eitherktrAorktrDare sufficient to confer polyamine resistance and function in an additive manner. Moreover, we find that ktr mutations provide increased resistance to multiple classes of unrelated cationic antibiotics, suggesting a common mechanism of resistance. Consistent with this hypothesis, ktr mutants exhibit alterations in cell surface charge indicative of reduced affinity and uptake of cationic molecules. Finally, we observe that laboratory-evolved ktr mutations are also present in diverse naturalS. aureusisolates, suggesting these mutations may contribute to antimicrobial resistance during human infections. Collectively this study identifies a new role for potassium transport inS. aureuspolyamine resistance with consequences for susceptibility to both host-derived and clinically-used antimicrobials.
Endothelial Drp1 Couples VEGF-induced Redox Signaling with Glycolysis Through Cysteine Oxidation to Drive Angiogenesis
Authors: Nagarkoti Sheela , Kim Young-Mee , Das Archita , Ash Dipankar , A.Vitriol Eric , Read Tracy-Ann , Sudhahar Varadarajan , Hossain Md. Selim , Yadav Shikha , McMenamin Malgorzata , Kelley Stephanie , Lucas Rudolf , Stepp David , Belin de Chantemele Eric J. , Caldwell Ruth B. , Fulton David JR. , Fukai Tohru , Ushio-Fukai Masuko
Published: June 2024

Angiogenesis plays a vital role for postnatal development and tissue repair following ischemia. Reactive oxygen species (ROS) generated by NADPH oxidases (NOXes) and mitochondria act as signaling molecules that promote angiogenesis in endothelial cells (ECs) which mainly relies on aerobic glycolysis for ATP production. However, the connections linking redox signaling with glycolysis are not well understood. The GTPase Drp1 is a member of the dynamin superfamily that moves from cytosol to mitochondria through posttranslational modifications to induce mitochondrial fission. The role of Drp1 in ROS-dependent VEGF signaling and angiogenesis in ECs has not been previously described. Here, we identify an unexpected function of endothelial Drp1 as a redox sensor, transmitting VEGF-induced H2O2signals to enhance glycolysis and angiogenesis. Loss of Drp1 expression in ECs inhibited VEGF-induced angiogenic responses. Mechanistically, VEGF rapidly induced the NOX4-dependent sulfenylation (CysOH) of Drp1 on Cys644, promoting disulfide bond formation with the metabolic kinase AMPK and subsequent sulfenylation of AMPK at Cys299/304via the mitochondrial fission-mitoROS axis. This cysteine oxidation of AMPK, in turn, enhanced glycolysis and angiogenesis.In vivo, mice with EC-specific Drp1 deficiency or CRISPR/Cas9-engineered “redox-dead” (Cys to Ala) Drp1 knock-in mutations exhibited impaired retinal angiogenesis and post-ischemic neovascularization. Our findings uncover a novel role for endothelial Drp1 in linking VEGF-induced mitochondrial redox signaling to glycolysis through a cysteine oxidation-mediated Drp1-AMPK redox relay, driving both developmental and reparative angiogenesis.
Helper NLR immune protein NRC3 evolved to evade inhibition by a cyst nematode virulence effector
Authors: Sugihara Yu , Kourelis Jiorgos , Contreras Mauricio P. , Pai Hsuan , Selvaraj Muniyandi , Toghani AmirAli , Martínez-Anaya Claudia , Kamoun Sophien
Published: June 2024

Parasites can counteract host immunity by suppressing nucleotide binding and leucine-rich repeat (NLR) proteins that function as immune receptors. We previously showed that a cyst nematode virulence effector SPRYSEC15 (SS15) binds and inhibits oligomerisation of helper NLR proteins in the expanded NRC1/2/3 clade by preventing intramolecular rearrangements required for NRC oligomerisation into an activated resistosome. Here we examined the degree to which NRC proteins from multiple Solanaceae species are sensitive to suppression by SS15 and tested hypotheses about adaptive evolution of the binding interface between the SS15 inhibitor and NRC proteins. Whereas all tested orthologs of NRC2 were inhibited by SS15, some natural variants of NRC1 and NRC3 are insensitive to SS15 suppression. Ancestral sequence reconstruction combined with functional assays revealed that NRC3 transitioned from an ancestral suppressed form to an insensitive one over 19 million years ago. Our analyses revealed the evolutionary trajectory of coevolution between a parasite inhibitor and its NLR immune receptor target, identifying key evolutionary transitions in helper NLRs that counteract this inhibition. This work reveals a distinct type of gene-for-gene interaction between parasite or pathogen immunosuppressors and host immune receptors that contrasts with the coevolution between AVR effectors and immune receptors.