bluuebunny/crossref_metadata_2025 huggingface dataset:
A connectome manipulation framework for the systematic and reproducible study of structure–function relationships through simulations
Authors: Pokorny Christoph , Awile Omar , Isbister James B. , Kurban Kerem , Wolf Matthias , Reimann Michael W.
Published: May 2024

Synaptic connectivity at the neuronal level is characterized by highly non-random features. Hypotheses about their role can be developed by correlating structural metrics to functional features. But to prove causation, manipula- tions of connectivity would have to be studied. However, the fine-grained scale at which non-random trends are expressed makes this approach challenging to pursue experimentally. Simulations of neuronal networks provide an alternative route to study arbitrarily complex manipulations in morphologically and biophysically detailed models. Here, we present Connectome-Manipulator, a Python framework for rapid connectome manipulations of large- scale network models in SONATA format. In addition to creating or manipulating the connectome of a model, it provides tools to fit parameters of stochastic connectivity models against existing connectomes. This enables rapid replacement of any existing connectome with equivalent connectomes at different levels of complexity, or transplantation of connectivity features from one connectome to another, for systematic study. We employed the framework in a detailed model of rat somatosensory cortex in two exemplary use cases: transplanting interneuron connectivity trends from electron microscopy data and creating simplified connectomes of excitatory connectivity. We ran a series of network simulations and found diverse shifts in the activity of individual neuron populations causally linked to these manipulations.
Two germ granule eIF4E isoforms reside in different mRNPs to hand offC elegansmRNAs from translational repression to activation
Authors: Gajjar Gita , Huggins Hayden P. , Kim Eun Suk , Huang Weihua , Bonnet Frederic X. , Updike Dustin L. , Keiper Brett D.
Published: May 2024

We studied the function of translation factor eIF4E isoforms in regulating mRNAs in germ cell granules/condensates. Translational control of mRNAs plays an essential role in germ cell gene regulation. Messenger ribonucleoprotein (mRNP) complexes assemble on mRNAs as they move from the nucleus into perinuclear germ granules to exert both positive and negative post-transcriptional regulation in the cytoplasm. InC. elegans, germ granules are surprisingly dynamic mRNP condensates that remodel during development. Two eIF4E isoforms (called IFE-1 and IFE-3), eIF4E-Interacting Proteins (4EIPs), RBPs, DEAD-box helicases, polyadenylated mRNAs, Argonautes and miRNAs all occupy positions in germ granules. Affinity purification of IFE-1 and IFE-3 allowed mass spectrometry and mRNA-Seq to identify the proteins and mRNAs that populate stable eIF4E mRNPs. We find translationally controlled mRNAs (e.g.pos-1, mex-3, spn-4,etc.) enriched in IFE-3 mRNPs, but excluded from IFE-1 mRNPs. These mRNAs also require IFE-1 for efficient translation. The findings support a model in which oocytes and embryos utilize the two eIF4Es for opposite purposes on critically regulated germline mRNAs. Careful colocalization of the eIF4Es with other germ granule components suggests an architecture in which GLH-1, PGL-1 and the IFEs are stratified to facilitate sequential interactions for mRNAs. Biochemical characterization demonstrates opposing yet cooperative roles for IFE-3 and IFE-1 to hand-off of translationally controlled mRNAs from the repressed to the activated state, respectively. The model involves eIF4E mRNPs shuttling mRNAs through nuclear pore-associated granules/condensates to cytoplasmic ribosomes.
Dynamics of male African elephant character durability across time and social contexts
Authors: O'Connell-Rodwell Caitlin E , Berezin Jodie L , Kinzley Colleen , Freeman Patrick T , Sandri Monica N , Kieschnick Dustin , Rodwell Timothy C , Abarca Mariana , Hayssen Virginia
Published: May 2024

Post-dispersal male African elephants (Loxodonta africana) live within complex social networks. To quantify the durability of male elephant character (or personality) within these networks, we employed behavioral repeatability analysis tools across social and environmental contexts. We collected behavioral data from thirty-four individually-identified male elephants at the same waterhole over five field seasons (2007-2011) in Etosha National Park, Namibia. Using repeatability models to assess ten behavioral categories, we found five behaviors (affiliation, aggression, dominance, self-directed anxious, and self-directed comfort) that were consistent at the individual level. Interestingly, some of these behaviors were also significantly repeatable, depending on social context. In particular, the presence of younger males and a keystone male (i.e., the most dominant and socially-integrated individual during our study period) had the biggest impact on adult male behaviors. Surprisingly, the presence of elephants in musth had little impact. Finally, we found that younger individuals were more alike in their overall character profiles than older males, further supporting the hypothesis that male elephants develop unique, yet socially-flexible character types as they age. These results demonstrate that male elephants possess distinct character traits that are also behaviorally adaptable, depending on the social context. Overall, our research further uncovers the complexity of male elephant individuality and social dynamics that can be leveraged to improve in-situ and ex-situ management and conservation decisions for the species.
Genome-wide nucleosome and transcription factor responses to genetic perturbations reveal chromatin-mediated mechanisms of transcriptional regulation
Authors: Moyung Kevin , Li Yulong , Hartemink Alexander J. , MacAlpine David M.
Published: May 2024

Epigenetic mechanisms contribute to gene regulation by altering chromatin accessibility through changes in transcription factor (TF) and nucleosome occupancy throughout the genome. Despite numerous studies focusing on changes in gene expression, the intricate chromatin-mediated regulatory code remains largely unexplored on a comprehensive scale. We address this by employing a factor-agnostic, reverse-genetics approach that uses MNase-seq to capture genome-wide TF and nucleosome occupancies in response to the individual deletion of 201 transcriptional regulators inSaccharomyces cerevisiae, thereby assaying nearly one million mutant-gene interactions. We develop a principled approach to identify and quantify chromatin changes genome-wide, observing differences in TF and nucleosome occupancy that recapitulate well-established pathways identified by gene expression data. We also discover distinct chromatin signatures associated with the up- and downregulation of genes, and use these signatures to reveal regulatory mechanisms previously unexplored in expression-based studies. Finally, we demonstrate that chromatin features are predictive of transcriptional activity and leverage these features to reconstruct chromatin-based transcriptional regulatory networks. Overall, these results illustrate the power of an approach combining genetic perturbation with high-resolution epigenomic profiling; the latter enables a close examination of the interplay between TFs and nucleosomes genome-wide, providing a deeper, more mechanistic understanding of the complex relationship between chromatin organization and transcription.
Perception of task duration affects metabolic cost during split-belt adaptation
Authors: Jeffcoat S.N. , Aragon A. , Kuch A. , Farrokhi S. , Sanchez N.
Published: May 2024

Humans continuously adapt locomotor patterns. Whether metabolic cost reduction is the primary objective or a by-product of the observed biomechanical changes during adaptation is not known. The main goal of our study is to determine if perception of task duration affects the adaptation of locomotor patterns to reduce energetic cost during split-belt walking. We tested the hypothesis that individuals who believe they will sustain a locomotor adaptation task for a prolonged time will reduce metabolic cost by adapting toward a walking pattern associated with lower mechanical work. N=14 participants walked on a split-belt treadmill for 10 minutes with knowledge of task duration (group K), while N=15 participants performed the task under the assumption that they would walk for 30 minutes (group U). Both groups walked for 10 minutes with the belts moving at 1.5 and 0.5 m/s, followed by 6 minutes of walking with both belts at 1.0 m/s. We observed a significant main effect of Time (p<0.001, observed power 1.0) and the interaction of Time×Group (p=0.004, observed power 0.84) on metabolic cost. Participants in the U group had a metabolic cost that was 12% lower during adaptation compared to the K group, which did not reduce metabolic cost during adaptation. The metabolic cost reduction observed in group U was not associated with biomechanical changes during adaptation. Our results indicate that metabolic cost reduction has a primary role in tasks that need to be sustained for a prolonged time, and this reduction is not only related to biomechanical factors.

New and Noteworthy

Individuals can markedly reduce the metabolic cost of a walking adaptation task if they believe they must sustain the task for a prolonged time. The variables typically used to track adaptation do not track the reductions in metabolic cost observed in our study. Metabolic cost reduction can occur without clear changes in biomechanical factors.
Single-cell landscapes of long non-coding RNAs in early vascular endothelial development and hemogenic specification
Authors: Chen Xupeng , Ning Xiaowei , Lu Chenguang , He Han , Yao Yingpeng , Ni Yanli , Zhou Jie , Liu Bing , Hou Siyuan , Lan Yu , Li Zongcheng
Published: May 2024

Understanding the molecular regulation of arterial and hemogenic specification during early embryonic vascular development is crucial for guiding vascular and hematopoietic regeneration. Accumulating evidence emphasizes the role of long non-coding RNAs (lncRNAs) in cell fate decision. However, the dynamic expression and the potential roles of lncRNAs in early vascular development are still unknown. Here, we first constructed a single-cell landscape of lncRNA expression based on the deeply sequenced tag-based single-cell transcriptome data of early embryonic vascular endothelial cells (VECs). We revealed the contribution of lncRNAs to VEC heterogeneity and identified 295 lncRNAs with specific expression in eight VEC populations. Furthermore, we identified a series of lncRNAs potentially involved in regulating the two waves of arterial specification and hemogenic specification. We uncovered a transient downregulation ofH19in the hemogenic endothelial population during endothelial-to-hematopoietic transition. Additionally, we constructed a transcription factor regulatory network composed of 287 regulons for early VEC development. We further revealed differential activation patterns of regulons and modules in the eight VEC populations, and predicted potential lncRNA-regulon regulatory network. Moreover, unsupervised analysis of the lncRNA expression profile revealed novel VEC subpopulations strongly associated with the maturation of VECs, suggesting the prominent roles of lncRNAs in endothelial maturation. In summary, our study fills the gap in understanding of lncRNA regulatory networks in early vascular development and provides insights into the fields of vascular and hematopoietic regeneration research.
Muscle-derived miR-200a-3p through light-intensity exercise may contribute to improve memory dysfunction in type 2 diabetic mice
Authors: Shima Takeru , Onishi Hayate , Terashima Chiho
Published: May 2024

Background

Memory dysfunction associated with type 2 diabetes mellitus (T2DM) poses a considerable threat to overall well-being. Engaging in light-intensity exercise has been shown to exert favorable effects on hippocampal function and molecular profiles, includingMct2mRNA and miR-200a-3p. Nonetheless, a comprehensive understanding of the mechanisms underlying the positive impact of light-intensity exercise remains elusive. Here, we assessed the influence of exosomal miR-200a-3p secretion from gastrocnemius muscles in T2DM mice undergoing light-intensity exercise intervention, focusing on its potential to ameliorate memory dysfunction.

Basic procedures

We initially assessed the effects of light-intensity exercise (7.0 m/min for healthy mice, 5.0 m/min for ob/ob mice, 30 min/day, five days/week, over a four-week period) on memory function, hippocampal mRNA associated with memory function, and the secretion of exosomal miR-200a-3p from their gastrocnemius muscle. Subsequently, the impact of a daily intraperitoneal injection of the miR-200a-3p mimic over a four-week duration was investigated, focusing on its influence on hippocampal dysregulation in ob/ob mice.

Main findings

The light-intensity exercise intervention increased gastrocnemius muscle-derived and plasma exosomal miR-200a-3p levels in ob/ob mice, concomitant with improved memory dysfunction. Intriguingly, the daily intraperitoneal injection of mmu-miR-200a-3p mimic also demonstrated an ameliorative effect on memory function in ob/ob mice. Notably, both the exercise intervention and miR-200a-3p mimic treatment induced downregulation in hippocampalKeap1mRNA and upregulation in mRNA ofHsp90aa1andMct2in ob/ob mice.

Principal conclusions

The current results imply that the augmentation of exosomal miR-200a-3p derived from the gastrocnemius muscle contributes to the amelioration of memory dysfunction in T2DM undergoing light-intensity exercise. Additionally, it is proposed that miR-200a-3p emulates the effects of light-intensity exercise, suggesting a potential therapeutic pathway for addressing hippocampal complications in the context of T2DM.
Immunomodulatory Role of the Stem Cell Circadian Clock in Muscle Repair
Authors: Zhu Pei , Pfrender Eric , Steffeck Adam , Reczek Colleen , Zhou Yalu , Thakkar Abhishek , Gupta Neha , Willbanks Amber , Lieber Richard , Roy Ishan , Chandel Navdeep S , Peek Clara B
Published: May 2024

The circadian clock orchestrates vital physiological processes such as metabolism, immune function, and tissue regeneration, aligning them with the optimal time of day. This study identifies an intricate interplay between the circadian clock within muscle stem cells (SCs) and their capacity to modulate the immune microenvironment during muscle regeneration. We uncover that the SC clock provokes time of day-dependent induction of inflammatory response genes following injury, particularly those related to neutrophil activity and chemotaxis. These responses are driven by rhythms of cytosolic regeneration of the signaling metabolite NAD+. We demonstrate that genetically enhancing cytosolic NAD+ regeneration in SCs is sufficient to induce robust inflammatory responses that significantly influence muscle regeneration. Furthermore, using mononuclear single-cell sequencing of the regenerating muscle niche, we uncover a key role for the cytokine CCL2 in mediating SC-neutrophil crosstalk in a time of day-dependent manner. Our findings highlight a crucial intersection between SC metabolic shifts and immune responses within the muscle microenvironment, dictated by the circadian rhythms, and underscore the potential for targeting circadian and metabolic pathways to enhance tissue regeneration.
Molecular Specializations Underlying Phenotypic Differences in Inner Ear Hair Cells of Zebrafish and Mice
Authors: Giffen Kimberlee P. , Liu Huizhan , Yamane Kacey L. , Li Yi , Chen Lei , Kramer Ken L. , Zallocchi Marisa , He David Z.Z.
Published: May 2024

Hair cells (HCs) are the sensory receptors of the auditory and vestibular systems in the inner ears of vertebrates that selectively transduce mechanical stimuli into electrical activity. Although all HCs have the hallmark stereocilia bundle for mechanotransduction, HCs in non-mammals and mammals differ in their molecular specialization in the apical, basolateral and synaptic membranes. HCs of non-mammals, such as zebrafish (zHCs), are electrically tuned to specific frequencies and possess an active process in the stereocilia bundle to amplify sound signals. Mammalian cochlear HCs, in contrast, are not electrically tuned and achieve amplification by somatic motility of outer HCs (OHCs). To understand the genetic mechanisms underlying differences among adult zebrafish and mammalian cochlear HCs, we compared their RNA-seq-characterized transcriptomes, focusing on protein-coding orthologous genes related to HC specialization. There was considerable shared expression of gene orthologs among the HCs, including those genes associated with mechanotransduction, ion transport/channels, and synaptic signaling. For example, both zebrafish and mouse HCs expressTmc1, Lhfpl5, Tmie, Cib2, Cacna1d, Cacnb2, Otof, PcloandSlc17a8. However, there were some notable differences in expression among zHCs, OHCs, and inner HCs (IHCs), which likely underlie the distinctive physiological properties of each cell type.Tmc2 and Cib3were not detected in adult mouse HCs buttmc2aandbandcib3were highly expressed in zHCs. Mouse HCs expressKcna10,Kcnj13,Kcnj16, andKcnq4, which were not detected in zHCs.Chrna9andChrna10were expressed in mouse HCs. In contrast,chrna10was not detected in zHCs. OHCs highly expressSlc26a5which encodes the motor protein prestin that contributes to OHC electromotility. However, zHCs have only weak expression ofslc26a5, and subsequently showed no voltage dependent electromotility when measured. Notably, the zHCs expressed more paralogous genes including those associated with HC-specific functions and transcriptional activity, though it is unknown whether they have functions similar to their mammalian counterparts. There was overlap in the expressed genes associated with a known hearing phenotype. Our analyses unveil substantial differences in gene expression patterns that may explain phenotypic specialization of zebrafish and mouse HCs. This dataset also includes several protein-coding genes to further the functional characterization of HCs and study of HC evolution from non-mammals to mammals.
Partial observation can induce mechanistic mismatches in data-constrained models of neural dynamics
Authors: Qian William , Zavatone-Veth Jacob A. , Ruben Benjamin S. , Pehlevan Cengiz
Published: May 2024

One of the central goals of neuroscience is to gain a mechanistic understanding of how the dynamics of neural circuits give rise to their observed function. A popular approach towards this end is to train recurrent neural networks (RNNs) to reproduce experimental recordings of neural activity. These trained RNNs are then treated as surrogate models of biological neural circuits, whose properties can be dissected via dynamical systems analysis. How reliable are the mechanistic insights derived from this procedure? While recent advances in population-level recording technologies have allowed simultaneous recording of up to tens of thousands of neurons, this represents only a tiny fraction of most cortical circuits. Here we show that observing only a subset of neurons in a circuit can create mechanistic mismatches between a simulated teacher network and a data-constrained student, even when the two networks have matching single-unit dynamics. In particular, partial observation of models of low-dimensional cortical dynamics based on functionally feedforward or low-rank connectivity can lead to surrogate models with spurious attractor structure. Our results illustrate the challenges inherent in accurately uncovering neural mechanisms from single-trial data, and suggest the need for new methods of validating data-constrained models for neural dynamics.
The fruit fly,Drosophila melanogaster, as a micro-robotics platform
Authors: Iwasaki Kenichi , Neuhauser Charles , Stokes Chris , Rayshubskiy Aleksandr
Published: May 2024

Engineering small autonomous agents capable of operating in the microscale environment remains a key challenge, with current systems still evolving. Our study explores the fruit fly,Drosophila melanogaster, a classic model system in biology and a species adept at microscale interaction, as a biological platform for micro-robotics. Initially, we focus on remotely directing the walking paths of fruit flies in an experimental arena. We accomplish this through two distinct approaches: harnessing the fruit flies’ opto-motor response and optogenetic modulation of its olfactory system. These techniques facilitate reliable and repeated guidance of flies between arbitrary spatial locations. We guide flies along predetermined trajectories, enabling them to scribe patterns resembling textual characters through their locomotion. We enhance olfactory-guided navigation through additional optogenetic activation of positive valence mushroom body output neurons. We extend this control to collective behaviors in shared spaces and navigation through constrained maze-like environments. We further use our guidance technique to enable flies to carry a load across designated points in space, establishing the upper bound on their weight carrying capabilities. Additionally, we demonstrate that visual guidance can facilitate novel interactions between flies and objects, showing that flies can consistently relocate a small spherical object over significant distances. Beyond expanding tools available for micro-robotics, these novel behavioral contexts can provide insights into the neurological basis of behavior in fruit flies.
Blast Traumatic Brain Injury Induces Long-Term Alterations in Inflammatory Gene Expression in Chinchilla Brains
Authors: Schmitt Rebecca , Kaliyappan Kathiravan , Mahajan Supriya D. , Krishnan Muthaiah Vijaya Prakash
Published: May 2024

Blast traumatic brain injury (bTBI) due to high-intensity impulsive noise exposure from explosions and munitions exposure is highly prevalent among military personnel, which leads to diffuse brain injury resulting in a spectrum of brain dysfunction and cognitive deficits. The resultant prolonged neuroinflammation and consequent failure of inflammation resolution is a key contributor to long-term complications, including post-traumatic stress disorder and early-onset of neurodegenerative disease; however, there is little evidence for the duration and extent of long term neuroinflammation in distinct brain regions. To investigate this, due to human-like audiogram, we use chinchillas as anin-vivobTBI model to analyze the relative gene expression of inflammatory markers (TNFα, TGFβ2, Gal1, HSP90, S100B, NRGN, MAPK14, IL8, NFL, and BDNF) in the hippocampus, striatum, and higher centers of the auditory pathway 90 days following varying intensities of blast exposures (144 dB, 155 dB, and 172 dB sound pressure level). Our study revealed aberrant gene expression across all analyzed brain regions and all injury conditions; however, no specific pattern emerged. Many of the inflammatory markers were downregulated, suggesting a possible attempt by the brain to overcome prior inflammation. Conversely, the hippocampus, striatum, inferior colliculus, and medial geniculate body all exhibited upregulation of inflammatory markers, including the TBI prognostic marker, S100B. Thus, chinchilla brains exhibit evidence of prolonged neuroinflammation 90 days following injury, even during mild blast exposure. Ultimately, the observed alterations in the gene expression of inflammatory markers may contribute to the long-term neurological dysfunction and neurodegenerative disease experienced by veterans and other bTBI patients.
Chromatin remodeling protein BPTF regulates transcriptional stability in planarian stem cells
Authors: Verma Prince , Sánchez Alvarado Alejandro , Duncan Elizabeth M.
Published: May 2024

Trimethylation of histone H3 lysine 4 (H3K4me3) correlates strongly with gene expression in many different organisms, yet the question of whether it plays a causal role in transcriptional activity remains unresolved. Although H3K4me3 does not directly affect chromatin accessibility, it can indirectly affect genome accessibility by recruiting the ATP-dependent chromatin remodeling complex NuRF (Nucleosome Remodeling Factor). The largest subunit of NuRF, BPTF/NURF301, binds H3K4me3 specifically and recruits the NuRF complex to loci marked by this modification. Studies have shown that the strength and duration of BPTF binding likely also depends on additional chromatin features at these loci, such as lysine acetylation and variant histone proteins. However, the exact details of this recruitment mechanism vary between studies and have largely been tested in vitro. Here, we use stem cells isolated directly from live planarian animals to investigate the role of BPTF in regulating chromatin accessibility in vivo. We find that BPTF operates at gene promoters and is most effective at facilitating transcription at genes marked by Set1-dependent H3K4me3 peaks, which are significantly broader than those added by the lysine methyltransferase MLL1/2. Moreover, BPTF is essential for planarian stem cell biology and its loss of function phenotype mimics that of Set1 knockdown. Together, these data suggest that BPTF and H3K4me3 are important mediators of both transcription and in vivo stem cell function.
Sex Differences in the Association between Skeletal Muscle Energetics and Perceived Physical Fatigability: The Study of Muscle, Mobility and Aging (SOMMA)
Authors: Gay Emma L. , Coen Paul M. , Harrison Stephanie , Garcia Reagan E. , Qiao Yujia (Susanna) , Goodpaster Bret H. , Forman Daniel E. , Toledo Frederico G. S. , Distefano Giovanna , Kramer Philip A. , Ramos Sofhia V. , Molina Anthony J. A. , Nicklas Barbara J. , Cummings Steven R. , Cawthon Peggy M. , Hepple Russell T. , Newman Anne B. , Glynn Nancy W.
Published: May 2024

Greater perceived physical fatigability and lower skeletal muscle energetics are predictors of mobility decline. Characterizing associations between muscle energetics and perceived fatigability may provide insight into potential targets to prevent mobility decline. We examined associations ofin vivo(maximal ATP production, ATPmax) andex vivo(maximal carbohydrate supported oxidative phosphorylation [max OXPHOS] and maximal fatty acid supported OXPHOS [max FAO OXPHOS]) measures of mitochondrial energetics with two measures of perceived physical fatigability, Pittsburgh Fatigability Scale (PFS, 0-50, higher=greater) and Rating of Perceived Exertion (RPE Fatigability, 6-20, higher=greater) after a slow treadmill walk. Participants from the Study of Muscle, Mobility and Aging (N=873) were 76.3±5.0 years old, 59.2% women, and 85.3% White. Higher muscle energetics (bothin vivoandex vivo) were associated with lower perceived physical fatigability, all p<0.03. When stratified by sex, higher ATPmax was associated with lower PFS Physical for men only; higher max OXPHOS and max FAO OXPHOS were associated with lower RPE fatigability for both sexes. Higher skeletal muscle energetics were associated with 40-55% lower odds of being in the most (PFS≥25, RPE Fatigability≥12) vs least (PFS 0-4, RPE Fatigability 6-7) severe fatigability strata, all p<0.03. Being a woman was associated with 2-3 times higher odds of being in the most severe fatigability strata when controlling for ATPmax but not thein vivomeasures (p<0.05). Better mitochondrial energetics were linked to lower fatigability and less severe fatigability in older adults. Findings imply that improving skeletal muscle energetics may mitigate perceived physical fatigability and prolong healthy aging.
Tonotopy is not preserved in a descending stage of auditory cortex
Authors: Gu Miaoqing , Liang Shanshan , Zhu Jiahui , Li Ruijie , Liu Ke , Wang Xuanyue , Ohl Frank , Zhang Yun , Liao Xiang , Zhang Chunqing , Jia Hongbo , Zhou Yi , Zhang Jianxiong , Chen Xiaowei
Published: May 2024

Previous studies based on layer specificity suggest that ascending signals from the thalamus to sensory neocortex preserve spatially organized information, but it remains unknown whether sensory information descending from sensory neocortex to thalamus also maintains such spatial organization pattern. By focusing on projection specificity, we mapped tone response properties of two groups of cortical neurons in the primary auditory cortex (A1), based on the relationship between their specific connections to other regions and their function in ascending (thalamocortical recipient, TR neurons) or descending (corticothalamic, CT neurons) auditory information. A clear tonotopic gradient was observed among TR, but not CT neurons. Additionally, CT neurons exhibited markedly higher heterogeneity in their frequency tuning and had broader bandwidth than TR neurons. These results reveal that the information flow descending from A1 to thalamus via CT neurons does not arrange tonotopically, suggesting that the descending information flow possibly contributes to higher-order feedback processing of diverse auditory inputs.
Dynamic and topological properties of large-scale brain networks in rapid eye movement behavior disorder
Authors: Li Yidi , Yoshinaga Kenji , Hanakawa Takashi ,   Japan Parkinson’s Progression Markers Initiative (J-PPMI) study group
Published: May 2024

Introduction

There is a lack of research in the existing literature when it comes to analyzing the dynamics of resting-state functional magnetic resonance imaging to understand the underlying mechanisms of isolated rapid eye movement sleep behavior disorder (iRBD). This study aims to contribute to our understanding of abnormalities in brain network dynamics in iRBD and their association with alpha-synucleinopathy. Additionally, I employed graph theoretical metrics to obtain a topological insight into the brain network of iRBD.

Methods

Resting-state fMRI data from 55 iRBD patients and 97 healthy controls (HCs) were utilized. A sliding window approach, functional connectivity analysis, and graph theory analysis were applied to the data. I calculated the mean, standard deviation, skewness, and kurtosis of the time series for both dynamic functional connectivity (dFC) and four graph metrics (clustering coefficient, global efficiency, assortativity coefficients, and eigenvector centrality). Subsequently, I compared the those metrices between iRBDs and HCs. Relationships between clinical scales and abnormal dFC were assessed using a general linear model.

Results

iRBD patients exhibited abnormal mean dFC, particularly in the default mode network, sensorimotor network, basal ganglia network, and cerebellum. Kurtosis of dFC revealed abnormalities between the middle temporal gyrus and cerebellum. Group differences were also observed in the mean eigenvector centrality of the precentral gyrus and thalamus.

Conclusion

The mean of dFC identified impairments putatively in movement functions and various compensatory mechanisms. Moreover, mean eigenvector centrality revealed topological changes in motor-related network in iRBDs. The use of kurtosis as a potential index for extracting dynamic information may provide additional insights into pathophysiology in iRBDs.
Salience Network Segregation Mediates the Effect of Tau Pathology on Mild Behavioral Impairment
Authors: Iordan Alexandru D. , Ploutz-Snyder Robert , Ghosh Bidisha , Rahman-Filipiak Annalise , Koeppe Robert , Peltier Scott , Giordani Bruno , Albin Roger L. , Hampstead Benjamin M.
Published: May 2024

STRUCTURED ABSTRACT

INTRODUCTION

A recently developed mild behavioral impairment (MBI) diagnostic framework standardizes the early characterization of neuropsychiatric symptoms in older adults. However, the links between MBI, brain function, and Alzheimer’s disease (AD) biomarkers are unclear.

METHODS

Using data from 128 participants with diagnosis of amnestic mild cognitive impairment and mild dementia – Alzheimer’s type, we test a novel model assessing direct relationships between AD biomarker status and MBI symptoms, as well as mediated effects through segregation of the salience and default-mode networks.

RESULTS

We identified a mediated effect of tau positivity on MBI through functional segregation of the salience network from the other high-level, association networks. There were no direct effects of AD biomarkers status on MBI.

DISCUSSION

Our findings suggest an indirect role of tau pathology in MBI through brain network dysfunction and emphasize the role of the salience network in mediating relationships between neuropathological changes and behavioral manifestations.
Services in Minoritized Autistic Adolescents and Adults Varying in Language Skills
Authors: Girolamo Teresa , Escobedo Alicia , Ghali Samantha , Greene-Pendelton Kyle , Campos Iván , Ram-Kiran Poornima
Published: May 2024

Background

Racially and ethnically minoritized (minoritized) autistic individuals face intersectional disparities in services access in the transition to adulthood. Our understanding of disparities is limited by systematic exclusion from research and inadequate approaches to characterizing services. To address these gaps and effect advocacy, this study: 1) examined services received, unmet service needs, and barriers in minoritized autistic adolescents and adults, and 2) determined if language, NVIQ, and autism traits predict services when deployed as binary or continuous variables.

Method

Academic and community partners tailored CBPR to a local context. Participants (N= 73, ages 13-30) completed a behavioral assessment protocol. Participants and caregivers provided information on services received, unmet service needs, and barriers to services. Data were analyzed using descriptives and regression.

Results

Participants received multiple services yet had multiple unmet service needs and barriers. Effects of services differed by approach. Language impairment, but not language scores, predicted receiving more services. High levels of autism traits and autism trait scores predicted more unmet service needs.

Implications

While the number of services and unmet service needs were similar to prior work, differences in individual service variables and effects support attention to heterogeneity. Findings support intersectional approaches to CBPR and autism research.

Learning outcomes

After reading the article, the learner will be able to: 1) summarize knowledge gaps about access to services; 2) explain the relevance of tailoring CBPR to a local context; and 3) describe implications of findings for clinicians and autistic individuals.
Obtaining high-resolution cryo-EM structures using a common LaB6, 120-keV electron microscope equipped with a sub 200-keV optimised direct electron detector
Authors: Venugopal Hariprasad , Mobbs Jesse , Taveneau Cyntia , Fox Daniel R. , Vuckovic Ziva , Knott Gavin , Grinter Rhys , Thal David , Mick Stephen , Czarnik Cory , Ramm Georg
Published: May 2024

Cryo-electron microscopy (Cryo-EM) single particle analysis (SPA) has become a major structural biology technique in recent years. High-resolution cryo-EM typically requires higher voltage cryo-TEMs with coherent FEG sources, stable columns, autoloader systems and direct electron detectors. These setups are specialised for Cryo-EM work and are expensive to establish and maintain. More recently the concept of using 100-keV cryo-TEMs has been introduced as a way to make cryo-EM more affordable and hence accessible to a larger group of researchers. So far, the implementation of these 100-keV cryo-TEMs have relied on specialised microscopes with FEG sources as well as more stable optics than usually present on the common 120-keV TEMs. We here explored whether a standard 120-keV TEM, commonly available at many laboratories worldwide, can be upgraded with a direct electron detector and its suitability for high-resolution cryo-EM using a standard side entry cryo-holder. Using this imaging configuration, we were successful in achieving a 2.65Å reconstruction for standard apoferritin. We were also able to resolve a more challenging small 64kDa protein haemoglobin to 4.33Å. Furthermore, we were able to solve an asymmetric 153 kDa membrane protein GPCR (M4 muscarinic acid receptor) to a resolution of 4.4Å. Importantly, all these results were achieved using a standard automated data collection routine implemented through SerialEM, making it feasible to collect large cryo-EM data sets with a side entry cryo-holder. These results showcase a potentially widely accessible solution to obtaining interpretable cryo-EM structures. Furthermore, we envisage that this imaging configuration gives an option for many EM facilities and laboratories to set up a high-quality cryo-EM SPA sample screening capability without the need to procure costly specialised Cryo-TEMs. This could help to considerably lower the economic entry barrier for cryo-EM SPA and contribute to the “democratisation” of cryo-EM.
Diffusion model-based image generation from rat brain activity
Authors: Yamashiro Kotaro , Matsumoto Nobuyoshi , Ikegaya Yuji
Published: May 2024

Brain-computer interface (BCI) technology has gained recognition in various fields, including clinical applications, assistive technology, and human-computer interaction research. BCI enables communication, control, and monitoring of the affective/cognitive states of users. Recently, BCI has also found applications in the artistic field, enabling real-time art composition using brain activity signals, and engaging performers, spectators, or an entire audience with brain activity-based artistic environments. Existing techniques use specific features of brain activity, such as the P300 wave and SSVEPs, to control drawing tools, rather than directly reflecting brain activity in the output image. In this study, we present a novel approach that uses a latent diffusion model, a type of deep neural network, to generate images directly from continuous brain activity. We demonstrate this technology using local field potentials from the neocortex of freely moving rats. This system continuously converted the recorded brain activity into images. Our end-to-end method for generating images from brain activity opens up new possibilities for creative expression and experimentation.
A single-nucleus transcriptomic atlas of medium spiny neurons in the rat nucleus accumbens
Authors: Reiner Benjamin C. , Chehimi Samar N. , Merkel Riley , Toikumo Sylvanus , Berrettini Wade H. , Kranzler Henry R. , Sanchez-Roige Sandra , Kember Rachel L. , Schmidt Heath D. , Crist Richard C.
Published: May 2024

Neural processing of rewarding stimuli involves several distinct regions, including the nucleus accumbens (NAc). The majority of NAc neurons are GABAergic projection neurons known as medium spiny neurons (MSNs). MSNs are broadly defined by dopamine receptor expression, but evidence suggests that a wider array of subtypes exist. To study MSN heterogeneity, we analyzed single-nucleus RNA sequencing data from the largest available rat NAc dataset. Analysis of 48,040 NAc MSN nuclei identified major populations belonging to the striosome and matrix compartments. Integration with mouse and human data indicated consistency across species and disease-relevance scoring using genome-wide association study results revealed potentially differential roles for MSN populations in substance use disorders. Additional high-resolution clustering identified 34 transcriptomically distinct subtypes of MSNs definable by a limited number of marker genes. Together, these data demonstrate the diversity of MSNs in the NAc and provide a basis for more targeted genetic manipulation of specific populations.
A PI(3,5)P2/ESCRT-III axis terminates STING signalling by facilitating TSG101-mediated lysosomal microautophagy
Authors: Shoji Tsumugi , Shinojima Ayumi , Kusumi Satoshi , Koga Daisuke , Mukai Kojiro , Nakayama Jun , Higashiyama Shigeki , Kuchitsu Yoshihiko , Taguchi Tomohiko
Published: May 2024

Stimulator of interferon genes (STING) is critical for the type I interferon response to pathogen- or self-derived cytosolic DNA. STING is degraded by the endosomal sorting complexes required for transport (ESCRT)-driven lysosomal microautophagy (LMA), the impairment of which leads to sustained inflammatory responses. It has been unknown how ESCRT targets STING directly to lysosomes. Here, through kinase inhibitor screening and knockdown experiments of all the individual components of ESCRT, we show that STING degradation requires PIKfyve (a lipid kinase that generates PI(3,5)P2) and CHMP4B/C (components of ESCRT-III subcomplex). Knockdown of Pikfyve or Chmp4b/c results in the accumulation of STING vesicles of a recycling endosomal origin in the cytosol, leading to sustained type I interferon response. CHMP4B/C localize at lysosomes and their lysosomal localization is abolished by interference with PIKfyve activity. Our results identify lysosomal ESCRT-III as a PI(3,5)P2effector, reveal a role of the less characterized phosphoinositide PI(3,5)P2in lysosomal biology, and provide insights into the molecular framework that distinguishes LMA from other cellular processes engaged with ESCRT.
EzReverse – a Web Application for Background Adjustment of Color Images
Authors: Song Xinwei , Goedhart Joachim
Published: May 2024

Fluorescence imaging is extensively utilized in biological research to study biomolecules at the single-cell level. Fluorescence images have a black background due to the inherent nature of fluorescence imaging. The black background fits well with dark themes that are used on screens and presentations. On the other hand, inverting the color images to display the signals on a white background can aid the human visual system in capturing detailed information or subtle features. In addition, white backgrounds match better with printed media. However, current methods to invert or change the background of color images require multiple steps or do not offer flexibility in the adjustment which is important when dealing with complex images without raw data. To facilitate easy access to background inversion and flexible modifications, ezReverse was developed. Two methods are implemented, the first based on color space transformation followed by inverting the lightness, while the second method identifies grayscale values which are subsequently modified. The web app ezReverse is a versatile tool, that accommodates multiple color spaces, kernel filters, and gamma correction for optimal inversion of color images. It is hosted on the Shiny Python platform and can be conveniently accessed online:https://amsterdamstudygroup.shinyapps.io/ezreverse/

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Assessing the potential of vision language models for automated phenotyping ofDrosophila melanogaster
Authors: Paci Giulia , Nanni Federico
Published: May 2024

Model organisms such asDrosophila melanogasterare extremely well suited to performing large-scale screens, which often require the assessment of phenotypes in a target tissue (e.g., wing and eye). Currently, the annotation of defects is either performed manually, which hinders throughput and reproducibility, or based on dedicated image analysis pipelines, which are tailored to detect only specific defects. Here, we assess the potential of Vision Language Models (VLMs) to automatically detect aberrant phenotypes in a dataset ofDrosophilawings and provide their descriptions. We compare the performance of one the current most advanced multimodal models (GPT-4) with an open-source alternative (LLaVA). Via a thorough quantitative evaluation, we identify strong performances in the identification of aberrant wing phenotypes when providing the VLMs with just a single reference image. GPT-4 showed the best performance in terms of generating textual descriptions, being able to correctly describe complex wing phenotypes. We also provide practical advice on potential prompting strategies and highlight current limitations of these tools, especially around misclassification and generation of false information, which should be carefully taken into consideration if these tools are used as part of an image analysis pipeline.
The threePlasmodium falciparumAurora-related kinases display distinct temporal and spatial associations with mitotic structures in asexual blood stage parasites and gametocytes
Authors: Wyss Matthias , Thommen Basil T. , Kofler Jacob , Carrington Eilidh , Brancucci Nicolas M. B. , Voss Till S.
Published: May 2024

Aurora kinases are crucial regulators of mitotic cell cycle progression in eukaryotes. The protozoan malaria parasitePlasmodium falciparumreplicates via schizogony, a specialised mode of cell division characterized by consecutive asynchronous rounds of nuclear division by closed mitosis followed by a single cytokinesis event producing dozens of daughter cells.P. falciparumencodes three Aurora-related kinases (PfARKs) that have been reported essential for parasite proliferation, but their roles in regulating schizogony have not yet been explored in great detail. Here, we engineered transgenic parasite lines expressing GFP-tagged PfARK1-3 to provide a systematic analysis of their expression timing and subcellular localization throughout schizogony as well as in the non-dividing gametocyte stages, which are essential for malaria transmission. We demonstrate that all three PfARKs display distinct and highly specific and exclusive spatiotemporal associations with the mitotic machinery. In gametocytes, PfARK3 is undetectable and PfARK1 and PfARK2 show male-specific expression in late stage gametocytes, consistent with their requirement for endomitosis during male gametogenesis in the mosquito vector. Our combined data suggest that PfARK1 and PfARK2 have non-overlapping roles in centriolar plaque maturation, assembly of the mitotic spindle, kinetochore-spindle attachment and chromosome segregation, while PfARK3 seems to be exquisitely involved in daughter cell cytoskeleton assembly and cytokinesis. These important new insights provide a reliable foundation for future research aiming at the functional investigation of these divergent and possibly drug targetable Aurora-related kinases in mitotic cell division ofPlasmodium falciparumand related apicomplexan parasites.
Business and operational excellence at organisational levels: an integrated methodology for self-assessment
Authors: Alanazi Mohammed Hamdan
Published: May 2024

Purpose

Business and operational excellence models are frequently employed by organisations as self-assessment tools for ensuring continued performance improvement. This paper presents an integrated methodology for excellence self-assessment that is applicable at organisational and functional levels.

Design/methodology/approach

The self-assessment methodology was sequentially developed, based on a theoretical and practical perspective, and a case study was presented.

Findings

This study develops: (1) a framework of excellence enablers and results criteria for each of the organisational, functional (core and supportive processes) and operational levels; (2) a framework of the characteristics of maturity levels of excellence according to enablers, results, organisational context, in addition to other assessment components; (3) a framework of the assessment and improvement steps for achieving excellence.

Originality/value

Although several proposed methodologies are available for the self-assessment of business and operational excellence, these only partially focus on various organisational aspects (such as the organisational and functional level, and organisational context) and are primarily used as business excellence models by non-large organisations. This study aims to fill the research gap in this regard.