bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancement of brain atlases with laminar coordinate systems: Flatmaps and barrel column annotations
Authors: Bolaños-Puchet Sirio , Teska Aleksandra , Hernando Juan B. , Lu Huanxiang , Romani Armando , Schürmann Felix , Reimann Michael W. 
Published: August 2023

AbstractDigital brain atlases define a hierarchy of brain regions and their locations in three-dimensional Cartesian space. They provide a standard coordinate system in which diverse datasets can be integrated for visualization and analysis. Although this coordinate system has well-defined anatomical axes, it does not provide the best context to work with the complex geometries of layered brain regions such as the neocortex. To address that, we introducelaminar coordinate systemsthat consider the curvature and the laminar structure of the region of interest. These new coordinate systems consist of a principal axis, locally aligned to the vertical direction and measuring depth, and two other axes that describe a flatmap, a two-dimensional representation of the horizontal extents of layers. The main property of the flatmap is that it allows seamless mapping of information back and forth between 2D and 3D spaces, in a way consistent with the principal axis. It involves a structured dimensionality reduction where information is aggregated along depth. We propose a method to enhance brain atlases with laminar coordinate systems and flatmaps based on user specifications and define a set of metrics to characterize the quality of flatmaps. We applied our method to an atlas of rat somatosensory cortex based on Paxinos and Watson’s rat brain atlas, enhancing it with a laminar coordinate system adapted to the geometry of this region. Further, we applied our method to enhance the Allen Mouse Brain Atlas Common Coordinate Framework version 3 with a flatmap of the whole isocortex. We used this flatmap to produce new annotations of 33 individual barrels and barrel columns in the barrel cortex. Thanks to the properties of the flatmap, the resulting annotations are non-overlapping and follow the curvature of the cortex. Additionally, we introduced several applications highlighting the utility of laminar coordinate systems for data visualization and data-driven modeling. We provide a free software implementation of our methods for the benefit of the community.
Dual-specificity protein phosphatase 6 (DUSP6) overexpression reduces amyloid load and improves memory deficits in male 5xFAD mice
Authors: Pan Allen L. , Audrain Mickael , Sakakibara Emmy , Joshi Rajeev , Zhu Xiaodong , Wang Qian , Wang Minghui , Beckmann Noam D. , Schadt Eric E. , Gandy Sam , Zhang Bin , Ehrlich Michelle E. , Salton Stephen R. 
Published: August 2023

AbstractBackgroundDual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal network that regulates late-onset Alzheimer’s disease. Importantly, decreased DUSP6 levels are correlated with an increased clinical dementia rating in human subjects, and DUSP6 levels are additionally decreased in the 5xFAD amyloidopathy mouse model.MethodsAAV5-DUSP6 or AAV5-GFP (control) were stereotactically injected into the dorsal hippocampus (dHc) of female and male 5xFAD or wild type mice to overexpress DUSP6 or GFP. Spatial learning memory of these mice was assessed in the Barnes maze, after which hippocampal tissues were isolated for downstream analysis.ResultsBarnes maze testing indicated that DUSP6 overexpression in the dHc of 5xFAD mice improved memory deficits and was associated with reduced amyloid plaque load, Aß1-40and Aß1-42levels, and amyloid precursor protein processing enzyme BACE1, in male but not in female mice. Microglial activation and microgliosis, which are increased in 5xFAD mice, were significantly reduced by dHc DUSP6 overexpression in both males and females. Transcriptomic profiling of female 5xFAD hippocampus revealed upregulated expression of genes involved in inflammatory and extracellular signal-regulated kinase (ERK) pathways, while dHc DUSP6 overexpression in female 5xFAD mice downregulated a subset of genes in these pathways. A limited number of differentially expressed genes (DEGs) (FDR<0.05) were identified in male mice; gene ontology analysis of DEGs (p<0.05) identified a greater number of synaptic pathways that were regulated by DUSP6 overexpression in male compared to female 5xFAD. Notably, the msh homeobox 3 gene,Msx3, previously shown to regulate microglial M1/M2 polarization and reduce neuroinflammation, was one of the most robustly upregulated genes in female and male wild type and 5xFAD mice overexpressing DUSP6.ConclusionsIn summary, our data indicate that DUSP6 overexpression in dHc reduced amyloid deposition and memory deficits in male but not female 5xFAD mice, whereas reduced neuroinflammation and microglial activation were observed in both males and females. The sex-dependent regulation of synaptic pathways by DUSP6 overexpression, however, correlated with the improvement of spatial memory deficits in male but not female 5xFAD.
KCC2 as a novel biomarker and therapeutic target for motoneuron degenerative disease
Authors: Sahara Khademullah C. , Bourbonnais Julien , Chaineau Mathilde M. , Castellanos-Montiel María José , Keramidis Iason , Legault Alexandra , Paquet Marie-Ève , Abrahao Agessandro , Zinman Lorne , Robertson Janice , Durcan Thomas M. , Woodin Melanie A. , Godin Antoine G. , Koninck Yves De 
Published: August 2023

AbstractHyperexcitability in cells throughout the corticospinal tract is a presymptomatic feature of amyotrophic lateral sclerosis (ALS) associated with lethal motor degeneration1–6. Disinhibition is a possible cause of this hyperexcitability, potentially implicating the central nervous system-specific potassium-chloride cotransporter, KCC2, a core regulator of the strength of GABAergic neurotransmission linked to several neurological disorders7–11. Here, we show that KCC2 is downregulated in the membrane of motor cortex neurons from post-mortem SOD1-, C9orf72- and sporadic ALS is patients. Increased protein levels of KCC2 were found in plasma and cerebral spinal fluid of ALS patients and mice harbouring the SOD1*G93A mutation. Longitudinal analysis of disease progression in both SOD1*G93A and Prp-TDP43*A315T mice revealed a decrease of KCC2 membrane levels in cortical and spinal motor neurons which were already present at the presymptomatic phase. Using KCC2-enhancing compounds, CLP290 and prochlorperazine (PCPZ) restored KCC2 membrane expression and function, delayed motor deficit onset, and extended lifespan up to two months in mutant mice. Human-derived neurons differentiated from iPSC harbouring the SOD1*G93A mutation displayed KCC2 deficits which PCPZ treatment rescued. Acute administration of KCC2 enhancers restored chloride transport in presymptomatic and symptomatic mice and reversed motor neuron hyperexcitability in awake behaving mutant mice. These findings identify KCC2 as both an early biomarker and a disease-modifying therapeutic target for ALS.
Using LLM Models and Explainable ML to Analyse Biomarkers at Single Cell Level for Improved Understanding of Diseases
Authors: Elsborg Jonas , Salvatore Marco 
Published: August 2023

AbstractSingle-cell RNA sequencing (scRNA-seq) technology has significantly advanced our understanding of the diversity of cells and how this diversity is implicated in diseases. Yet, translating these findings across various scRNA-seq datasets poses challenges due to technical variability and dataset-specific biases. To overcome this, we present a novel approach that employs both an LLM-based framework and explainable machine learning to facilitate generalization across single-cell datasets and identify gene signatures to capture disease-driven transcriptional changes.Our approach uses scBERT, which harnesses shared transcriptomic features among cell types to establish consistent cell-type annotations across multiple scRNA-seq datasets. Additionally, we employ a symbolic regression algorithm to pinpoint highly relevant yet minimally redundant models and features for inferring a cell type’s disease state based on its transcriptomic profile. We ascertain the versatility of these cell-specific gene signatures across datasets, showcasing their resilience as molecular markers to pinpoint and characterize disease-associated cell types.Validation is carried out using four publicly available scRNA-seq datasets from both healthy individuals and those suffering from ulcerative colitis (UC). This demonstrates our approach’s efficacy in bridging disparities specific to different datasets, fostering comparative analyses. Notably, the simplicity and symbolic nature of the retrieved gene signatures facilitate their interpretability, allowing us to elucidate underlying molecular disease mechanisms using these models.
Lung-innervating neurons expressingTmc3can induce broncho-constriction and dilation with direct consequences for the respiratory cycle
Authors: Kortmann Jens , Huang Kevin , Tsai Ming-Chi , Barck Kai , Jacobson Amanda , Austin Cary D , Dunlap Debra , Chalouni Cecile , Jeet Surinder , Balestrini Alessia , Storm Elaine , Wilson Mark S , Deng Lunbin , Dourado Michelle , Hackos David , Riol-Blanco Lorena , Kaminker Joshua S. , Turley Shannon J. 
Published: August 2023

AbstractSensory neurons of the vagal ganglia (VG) innervate lungs and play a critical role in maintaining airway homeostasis. However, the specific VG neurons that innervate lungs, and the mechanisms by which these neurons sense and respond to airway insults, are not well understood. Here, we identify a subpopulation of lung-innervating VG neurons defined by their expression ofTmc3. Single cell transcriptomics illuminated several subpopulations ofTmc3+sensory neurons, revealing distinctPiezo2- andTrpv1-expressing subclusters. Furthermore,Tmc3deficiency in VG neurons leads to global and subcluster specific transcriptional changes related to metabolic and ion channel function. Importantly, we show that broncho-constriction and dilation can be modulated through inhibition or activation ofTmc3+VG neurons resulting in a decrease or increase of end-expiratory lung volume, respectively. Together, our data show thatTmc3is a marker of lung-innervating neurons and may play a pivotal role in maintaining fundamental inspiratory and expiratory processes.SignificanceHarnessing the neuronal mechanisms that regulate lung function offers potential alternatives to existing corticosteroid treatment regimens for respiratory illness associated with acute bronchoconstriction including asthma, COPD, and emphysema. Our findings defineTransmembrane channel-like 3,Tmc3, as a marker of lung-innervating sensory neurons, identify distinct subpopulations ofTmc3+ neurons with unique transcriptional profiles, and show that activation or inhibition of these neurons has a significant impact on airway function. Our work highlights potential avenues of novel targeted intervention in respiratory conditions driven by dysfunctional neuronal reflexes.
The association between brain serotonin 2A receptor binding and neuroticism in healthy individuals: A Cimbi database independent replication study
Authors: Høgsted Emma S. , Beliveau Vincent , Ozenne Brice , Madsen Martin K , Svarer Claus , Dam Vibeke NH. , Johansen Annette , Fisher Patrick M. , Knudsen Gitte Moos , Frokjaer Vibe G , Sankar Anjali 
Published: August 2023

ABSTRACTBackgroundUsing the [18F]altanserin tracer to image serotonin 2A receptors (5-HT2AR), we previously showed that there exists a positive association between cortical 5-HT2AR binding and the inward facets of neuroticism, namely depression, anxiety, self-consciousness, and vulnerability. Fairly recently, the [11C]Cimbi-36 tracer was also shown to be a suitable radioligand for imaging 5-HT2Areceptors in the human brain. In the present study, we examined whether our previously reported finding of the association between 5-HT2AR binding and the inward facets of neuroticism can be replicated in an independent sample of healthy individuals scanned using the newer [11C]Cimbi-36 tracer. Furthermore, to determine whether this association of 5-HT2AR binding with neuroticism merely reflects its known relation to stress-coping related indices such as cortisol dynamics. The present study also investigated the potential role of cortisol awakening response on the association between 5-HT2AR binding and the inward facets of neuroticism.MethodsSixty-nine healthy volunteers underwent a [11C]CIMBI-36 scan for the assessment of 5-HT2AR binding, completed the standardized NEO-PI-R personality questionnaire, and provided salivary samples for the determination of cortisol awakening response. A linear latent variable model (LVM) was used to examine the association between 5-HT2AR binding and the inward facets of neuroticism with adjustment for age, sex, cortisol awakening response, and MR scanner. A second latent variable model examined the potential moderating effect of cortisol awakening response on the association between 5-HT2AR binding and the inward facets of neuroticism.ResultsWe replicated a positive association between 5-HT2AR binding and the inward facets of neuroticism (r=0.37, p=0.015). We saw no moderating effect of the cortisol awakening response on this association (p=0.98).ConclusionsIn an independent cohort of healthy individuals imaged with the [11C]CIMBI-36 tracer, we confirm the link between serotonin 2A receptor binding and the inward-directed facets of neuroticism that is independent of cortisol dynamics.
The evolution of autonomy from two cooperative specialists in fluctuating environments
Authors: Chen Xiaoli , Wang Miaoxiao , Luo Laipeng , Liu Xiaonan , An Liyun , Nie Yong , Wu Xiao-Lei 
Published: August 2023

AbstractFrom microbes to humans, organisms perform numerous tasks for their survival, including food acquisition, migration, and reproduction. A complex biological task can be performed by either an autonomous organism or by cooperation among several specialized organisms. However, it remains unclear how autonomy and cooperation evolutionarily switch. For example, it remains unclear whether and how a group of cooperative specialists can evolve into an autonomous organism. Here, we address this question by experimentally evolving a mutualistic microbial consortium composed of two specialists that cooperatively degrade naphthalene. We observed that autonomous genotypes capable of performing the entire naphthalene degradation pathway evolved from two cooperative specialists and came to dominate the microbial community. This evolutionary transition was driven by the horizontal gene transfer between the two specialists. However, this evolution was exclusively observed to occur in the fluctuating environment supplied with either naphthalene or pyruvate, where mutualism and competition between the two specialists alternated. The naphthalene-supplied environment exerts selective pressure that favors the expansion of autonomous genotypes but was associated with both low cell density and low coexistence levels. In contrast, the pyruvate-supplying environment promoted the coexistence and cell density of the cooperative specialists, thereby increasing the likelihood of horizontal gene transfer. Using a mathematical model, we quantitatively demonstrate that environmental fluctuations facilitate the evolution of autonomy through HGT when the relative growth rate and carrying capacity of the cooperative specialists allow enhanced coexistence and higher cell density in the competitive environment. Together, our results demonstrate that mutualistic cooperation can evolve into autonomous organisms through direct genetic exchange under specific conditions, including the alternation of mutualism and competition in fluctuating environments in a manner frequently occurring in nature.
Alpha Oscillations Encode Bayesian Belief Updating Underlying Attentional Allocation in Dynamic Environments
Authors: Li Siying , Seger Carol A. , Liu Meng , Dong Wenshan , Liu Wanting , Chen Qi 
Published: August 2023

AbstractIn a dynamic environment, expectations of the future constantly change based on updated evidence and affect the dynamic allocation of attentional resources.To further investigate the neural mechanisms underlying efficient allocation of attention, we employed a modified Central Cue Posner paradigm in which the probability of cues being valid (that is, accurately indicated the upcoming target location) was manipulated. The proportion of attentional resources allocated to the cued location (α), which was sensitive to precision of predictions on previous trials, was estimated using a hierarchical Bayesian model and was included as a regressor in the analyses of electrophysiological (EEG) data. Our results revealed that before the target appeared, the attentional modulation of alpha oscillations (8∼13Hz) for high-certainty cues (88% valid) were significantly predicted by the attentional resources measure (α). This relationship was not observed under low-certainty conditions (69% and 50% valid cues). After the target appeared, the attentional resources measure (α) correlated with alpha band oscillations only in the valid cue condition and not in the invalid condition. These results provide new insights on how trial-by-trial Bayesian belief updating relates to alpha band encoding environmentally-sensitive allocation of visual spatial attention.
Visual adaptation of opsin gene expression to the aquatic environment in sea turtles
Authors: Terai Yohey , Osada Misa , Kondo Satomi , Tokita Masayoshi 
Published: August 2023

AbstractSeveral vertebrate taxa, cetaceans, sirenia, pinnipeds, and sea snakes have adapted to the marine aquatic environment. In the species of these taxa, marine adaptation has resulted in shifts in the absorption spectra of opsin pigments and/or the degeneration or duplication of opsin genes. Thus, marine adaptation has strongly affected the evolution of opsins. In sea turtles, however, the effect of adaptation from freshwater to marine environments on opsin evolution has not been studied. In this study, we determined the high-throughput RNA sequences extracted from eyes of two sea turtles (green turtle:Chelonia mydas, loggerhead:Caretta caretta) and two freshwater turtle species (three-keeled pond turtle:Mauremys reevesii, softshell turtle:Pelodiscus sinensis) and investigated the amino acid evolution and expression of the opsin gene. We found that most of the sea turtle lineage-specific amino acid substitutions did not alter amino acid properties and did not include previously known substitutions for turning absorption spectra of opsin pigments, suggesting no adaptive amino acid substitutions in the opsins during marine adaptation in sea turtles. Instead, the blue-sensitive opsin (SWS2) gene expression was higher in sea turtles than in freshwater turtles. These results suggest that sea turtles may have adapted their vision to the blue light-rich marine environment by increasingSWS2expression.
Spatiotemporal dynamics of cytokines expression dictate fetal liver hematopoiesis
Authors: Peixoto Marcia Mesquita , Soares-da-Silva Francisca , Bonnet Valentin , Ronteix Gustave , Santos Rita Faria , Mailhe Marie-Pierre , Feng Xing , Pereira João Pedro , Azzoni Emanuele , Anselmi Giorgio , de Bruijn Marella , Baroud Charles N. , Pinto-do-Ó Perpétua , Cumano Ana 
Published: August 2023

AbstractDuring embryogenesis, yolk-sac and intra-embryonic-derived hematopoietic progenitors, comprising the precursors of adult hematopoietic stem cells, converge into the fetal liver. With a new staining strategy, we defined all non-hematopoietic components of the fetal liver and found that hepatoblasts are the major producers of hematopoietic growth factors. We identified mesothelial cells, a novel component of the stromal compartment, producing Kit ligand, a major hematopoietic cytokine.A high-definition imaging dataset analyzed using a deep-learning based pipeline allowed the unambiguous identification of hematopoietic and stromal populations, and enabled determining a neighboring network composition, at the single cell resolution.Throughout active hematopoiesis, progenitors preferentially associate with hepatoblasts, but not with stellate or endothelial cells. We found that, unlike yolk sac-derived progenitors, intra-embryonic progenitors respond to a chemokine gradient created by CXCL12-producing stellate cells. These results revealed that FL hematopoiesis is a spatiotemporal dynamic process, defined by an environment characterized by low cytokine concentrations.
Cognitive effort increases the intensity of rewards
Authors: Wahab Mejda , Mead Nicole L. , Desmercieres Stevenson , Lardeux Virginie , Dugast Emilie , Baumeister Roy F. , Solinas Marcello 
Published: August 2023

AbstractAn important body of literature suggests that exerting intense cognitive effort causes mental fatigue and can lead to unhealthy behaviors such as indulging in high-calorie food and taking drugs. Whereas this effect has been mostly explained in terms of weakening cognitive control, cognitive effort may also bias behavioral choices by amplifying the hedonic and emotional impact of rewards. We report parallel findings with animals and humans supporting this hypothesis. In rats, exerting cognitive effort immediately before access to cocaine self-administration significantly increased drug intake. In addition, exerting cognitive effort increased the psychostimulant effect of cocaine. The effects of cognitive effort on addiction-related behaviors were eliminated and even reversed when animals could rest in their home-cage for 2-4h before access to cocaine self-administration. Among humans, we found that expending cognitive effort increased consumption of tasty (but unhealthy) food by increasing the hedonic enjoyment of consuming the food. In addition, the effects were specific for emotionally relevant stimuli (i.e., food rewards) and did not generalize to judgment about neutral objects. Altogether these data suggest that intense cognitive effort can increase the perceived intensity of rewards and lead to their overconsumption. This effect may contribute to bad decision making induced by excessive cognitive effort and make people more vulnerable to indulge in unhealthy behaviors such as use of addictive drugs.Significance StatementPeople dieting or recovering from addiction frequently report that relapses occur during periods of stress and mental fatigue. Multiple processes may contribute to this, including beliefs about the stress-reducing effects of drugs, beliefs about one’s inability to continue resisting, and lack of energy needed to sustain resistance. Here, we suggest an additional possible process: during a state of mental fatigue, rewards become all the more satisfying, thereby also increasing subsequent desire for them. We report two lines of experiments, one with rats and one with human participants, to show that intense cognitive effort leads to increased enjoyment of rewards and hence increased consumption.