bluuebunny/crossref_metadata_2025_split huggingface dataset:
Behaviorally-relevant features of observed actions dominate cortical representational geometry in natural vision
Authors: Han Jane , Chauhan Vassiki , Philip Rebecca , Taylor Morgan K. , Jung Heejung , Halchenko Yaroslav O. , Gobbini M. Ida , Haxby James V. , Nastase Samuel A. 
Published: November 2024

AbstractWe effortlessly extract behaviorally relevant information from dynamic visual input in order to understand the actions of others. In the current study, we develop and test a number of models to better understand the neural representational geometries supporting action understanding. Using fMRI, we measured brain activity as participants viewed a diverse set of 90 different video clips depicting social and nonsocial actions in real-world contexts. We developed five behavioral models using arrangement tasks: two models reflecting behavioral judgments of the purpose (transitivity) and the social content (sociality) of the actions depicted in the video stimuli; and three models reflecting behavioral judgments of the visual content (people, objects, and scene) depicted in still frames of the stimuli. We evaluated how well these models predict neural representational geometry and tested them against semantic models based on verb and nonverb embeddings and visual models based on gaze and motion energy. Our results revealed that behavioral judgments of similarity better reflect neural representational geometry than semantic or visual models throughout much of cortex. The sociality and transitivity models in particular captured a large portion of unique variance throughout the action observation network, extending into regions not typically associated with action perception, like ventral temporal cortex. Overall, our findings expand the action observation network and indicate that the social content and purpose of observed actions are predominant in cortical representation.
MULTIPLE, REDUNDANT CARBOXYLIC ACID TRANSPORTERS SUPPORT MITOCHONDRIAL METABOLISM INPLASMODIUM FALCIPARUM
Authors: Rajaram Krithika , Rangel Gabriel W. , Munro Justin T. , Nair Sethu C. , Llinás Manuel , Prigge Sean T. 
Published: November 2024

ABSTRACTThe mitochondrion of the deadliest human malaria parasite,Plasmodium falciparum,is an essential source of cellular acetyl-CoA during the asexual blood-stage of the parasite life cycle. Blocking mitochondrial acetyl-CoA synthesis leads to a hypoacetylated proteome and parasite death. We previously determined that mitochondrial acetyl-CoA is primarily synthesized from glucose-derived pyruvate by α-ketoacid dehydrogenases. Here, we asked if inhibiting the import of glycolytic pyruvate across the mitochondrial inner membrane would affect acetyl-CoA production and, thus, could be a potential target for antimalarial drug development. We selected the two predicted mitochondrial pyruvate carrier proteins (PfMPC1 andPfMPC2) for genetic knockout and isotopic metabolite tracing via HPLC-MS metabolomic analysis. Surprisingly, we observed that asexual blood-stage parasites could survive the loss of either or bothPfMPCs with only minor growth defects, despite a substantial reduction in the amount of glucose-derived isotopic labelling into acetyl-CoA. Furthermore, genetic deletion of two additional mitochondrial carboxylic acid transporters – DTC (di/tricarboxylic acid carrier) and YHM2 (a putative citrate/α-ketoglutarate carrier protein) – only mildly affected asexual blood-stage replication, even in the context ofPfMPC deficiency. Although we observed no added impact on the incorporation of glucose carbon into acetyl-CoA in these quadruple knockout mutants, we noted a large decrease in glutamine-derived label in tricarboxylic acid cycle metabolites, suggesting that DTC and YHM2 both import glutamine derivatives into the mitochondrion. Altogether, our results expose redundant routes used to fuel the blood-stage malaria parasite mitochondrion with imported carbon from two major sources – glucose and glutamine.SIGNIFICANCEThe mitochondrion of malaria parasites generates key molecules, such as acetyl-CoA, that are required for numerous cellular processes. To support mitochondrial biosynthetic pathways, the parasites must transport carbon sources into this organelle. By studying how the mitochondrion obtains pyruvate, a molecule derived from glucose, we have uncovered redundant carbon transport systems that ensure parasite survival in red blood cells. This metabolic redundancy poses a challenge for drug development, as it enables the parasite to adapt and survive by relying on alternative pathways when one is disrupted.
Anatomy, histology and ultrastructure of the adult human olfactory peduncle: blood vessel andcorpora amylaceaassessment
Authors: Raspeño-García JF. , González-Granero S. , Herranz-Pérez V. , Cózar-Cuesta A. , Artacho-Pérula E. , Insausti R. , García-Verdugo JM. , de la Rosa-Prieto C. 
Published: November 2024

AbstractThe mammalian olfactory system is responsible for processing volatile chemical stimuli and is composed of several structures including the olfactory epithelium, olfactory bulb, olfactory peduncle (OP), and olfactory cortices. Despite the critical role played by the OP in the transport of information it has remained understudied. In this work, optical, confocal, and electron microscopy were employed to examine the anatomy, histology, and ultrastructure of six human OP specimens (ages 37–84 years). Three concentric layers were identified in coronal sections: the external layer (EL), the axonal layer (AL), and the internal layer (IL). Immunohistochemistry revealed the distribution of neurons and glial cells throughout the OP. Two neuronal morphologies were observed: granule cells and larger pyramidal cells, the latter associated with projection neurons of the anterior olfactory nucleus. Astrocytes were uniformly distributed with a more radial morphology in the EL. Oligodendrocytes were mainly located in the AL. Blood vessels (BVs) were evenly distributed along the OP, with a mean luminal area of 82.9 µm² and a density of 1.26 %, with a significant increase in the IL. CA were abundant, with an average size of 49.3 µm² and a density of 3.23 %. CA clustered near BVs, particularly at tissue edges, with both size and density increasing with age. Notably, CA showed strong associations with astrocytes. This study provides the first detailed qualitative and quantitative data on the internal organization of the human OP, which may contribute to a better understanding of the pathophysiology of some neuropathological disorders.
A comparative study of rigid-body registration algorithms for the alignment of longitudinal structural MRI of the brain
Authors: Jouryabi Yazdan Rezaee , Lashgari Reza , Ardekani Babak A. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: November 2024

AbstractLongitudinal structural MRI (sMRI) may be used to characterize brain morphological changes over time. A key requirement for this approach is accurate rigid-body alignment of longitudinal sMRI. We have recently developed the automatic temporal registration algorithm (ATRA) for this purpose. ATRA is a landmark-based approach capable of registering dozens of serial sMRI simultaneously in an unbiased manner. The aim of the research presented in this paper was to evaluate the accuracy and inverse-consistency of ATRA in comparison to three commonly used sMRI alignment methods: FSL, FreeSurfer, and ANTS. In the absence of a ground truth, it is only possible to quantitatively determine the degree of discrepancy between two algorithms. We propose that if the discrepancy exceeds a certain threshold, the relative accuracy of the two algorithms could be determined visually. We computed the discrepancy between ATRA and each of the three other methods for the alignment of 150 pairs of sMRI taken roughly one year apart. We visually rated the accuracy of alignments in cases where the discrepancy was greater than .5 mm while the rater was agnostic to the registration method. In those instances, ATRA was considered more accurate than FSL in 46 out of 48 cases, more accurate than FreeSurfer in 6 out of 7 cases, and more accurate than ANTS in all 6 cases. ATRA was also the most inverse-consistent method. In addition to being capable of performing unbiased group-wise registration, ATRA is the most accurate algorithm in comparison to several commonly used rigid-body alignment methods.
Association between COVID-19 Disease Severity and T Cell Receptor Repertoire
Authors: Chen Xinyi , Su Yapeng , Dai Chloe , Goldman Jason D. , Heath James R. , Liu Si , Sun Wei 
Published: November 2024

AbstractDuring the COVID-19 pandemic, while most infected individuals experienced mild to moderate symptoms, a significant subset developed severe illness. A clinical test distinguishing between mild and severe cases could inform effective treatment strategies. Toward the latter stages of the pandemic, it became evident that vaccination or prior infection cannot entirely prevent reinfection. However, they are crucial in reducing the risk of severe disease by inducing T-cell memory. T cell receptors (TCRs), which can be obtained from human blood, serve as valuable biomarkers for monitoring T cell responses to SARS-CoV-2 infection. In this study, we investigated the associations between TCR metrics and COVID-19 severity and found significant associations. Furthermore, such associations could depend on the subset of TCRs used (e.g., TCRs from CD8+ T or CD4+ T cells) and when the TCRs were collected.
Human Herpes Virus-8 Oral Shedding Heterogeneity is Due to Varying Rates of Reactivation from Latency and Immune Containment
Authors: Swan David A , Krantz Elizabeth M , Byrne Catherine , Okuku Fred , Nankoma Janet , Mutyaba Innocent , Phipps Warren , Schiffer Joshua T. 
Published: November 2024

Human herpesvirus-8 (HHV-8) is a gamma herpesvirus linked to the development of Kaposi sarcoma (KS). KS is more common in persons living with HIV (PLWH), but endemic KS in HIV-negative individuals is also common in sub-Saharan Africa. HHV-8 shedding occurs in the oral mucosa and is likely responsible for transmission. The mechanistic drivers of different HHV-8 shedding patterns in infected individuals are unknown. We applied stochastic mathematical models to a longitudinal study of HHV-8 oral shedding in 295 individuals in Uganda who were monitored daily with oral swabs. Participants were divided into four groups based on whether they were HIV-negative or positive as well as KS-negative or positive. In all groups, we observed a wide variance of shedding patterns, including no shedding, episodic low viral load shedding, and persistent high viral load shedding. Our model closely replicates patterns in individual data and attributes higher shedding rates to increased rates of viral reactivation, and lower median viral load values to more rapid and effective engagement of cytolytic immune responses. Our model provides a framework for understanding different shedding patterns observed in individuals with HHV-8 infection.KeypointsHHV8 shedding rate is mosty determined by rate of reactivation from latency while viral loads is mostly dteremined by peripheral immune responses.DAS performed all mathematical modeling and editied the paper; EMK performed statistical analysis and edited the paper; CB assisted with modeling; FO, JN and IM designed and implemented the clinical protocols; WP designed and implemented the clinical protocols and edited the paper; JTS conceived the study and write the paper.
Glucose alters the evolutionary response to gentamicin in uropathogenicEscherichia coli
Authors: Choudhary Shalini , Smith Jacob A. , McNally Alan , Hall Rebecca J. 
Published: November 2024

AbstractUrinary tract infections (UTI) are a major health and economic concern. UropathogenicEscherichia coli(UPEC) are the leading cause of UTI, and antibiotic resistant UPEC are increasingly common. The microenvironment of the urinary tract is metabolically distinct, and there is growing interest in understanding the extent to which metabolism may influence UPEC infection and response to antibiotics, and how this varies between individuals. Diabetes, characterised in part by glycosuria, is a known risk factor for UTI and is associated with more severe infections. The role that glucose plays in driving UPEC evolution is unclear. Here, we found that a pathologically-relevant glucose concentration reduced the efficacy of the antibiotic gentamicin against a UPEC strain. Through experimental evolution, we identified mutations in the RNA polymerase sigma factorrpoSassociated with long-term glucose exposure. We found that the presence of gentamicin resulted in mutations in genes includingtrkH, encoding a potassium ion uptake system and linked previously to aminoglycoside resistance, and in the autotransporterhyxB. Strikingly, these mutations were not present in populations exposed to a combination of both glucose and gentamicin. Together, this suggests that whilst glucose may reduce growth inhibition by gentamicin, it may also influence mutation acquisition, providing new avenues for understanding the evolution and treatment of UPEC-mediated UTI in high-risk individuals.
The Integrator complex prevents premature neuronal differentiation through global control of transcription elongation
Authors: Somsen Hedda B. , Eigenhuis Kristel N. , Kuijpers-Korporaal Anne L. , Pelicano de Almeida Mariana , Montoro Ferrer Roberto , Kats Kelsey , Dekker Mike R. , Zuidweg Thuur , Azmani Zakia , van den Hout Mirjam C.G.N. , van IJcken Wilfred F.J. , Huylebroeck Danny , Fornerod Maarten , Poot Raymond A. , van den Berg Debbie L.C. 
Published: November 2024

ABSTRACTTranscription pause-release constitutes a key step in the regulation of gene expression. Pathogenic variants in various pausing regulators have been identified in neurodevelopmental disorders, but how transcription pause-release regulates neural development remains largely unknown. Here we show that a patient-specific in-frame deletion in Integrator subunit 8 (INTS8) that prevents association of this subunit with the Integrator complex results in a global increase in nascent transcription and precocious expression of neuronal genes in progenitor cells. Consequently, differentiating neural progenitors fail to sustain a proliferating progenitor cell population during cortical neuronal network formation, resulting in network collapse. We show that attenuation of RNApol2 pause-release by targeted degradation of BRD4 can revert neuronal gene activation and prevent premature progenitor cell loss. Our data demonstrate that a fine-tuned balance between RNApol2 pausing and elongation is crucial for normal neuronal development and suggest transcription pause-release as a druggable target for neurological defects in developmental disorders.
The oxidative stress response-related peroxiredoxin Tsa1b ofCandida aurisfunctions as a virulence factor that promotes infection
Authors: Areitio Maialen , Rodriguez-Erenaga Oier , Aparicio-Fernandez Leire , Abio-Dorronsoro Lucía , Martin-Souto Leire , Perez-Cuesta Uxue , Buldain Idoia , Zaldibar Beñat , Ruiz-Gaitan Alba , Pemán Javier , Leibundgut-Landmann Salomé , Rementeria Aitor , Antoran Aitziber , Ramirez-Garcia Andoni 
Published: November 2024

ABSTRACTThe difficulty of accurately identifyingCandida aurisand the high resistance rates presented have increased the concern in the healthcare setting. Due to this, the aim of this study was to analyse the fungal response to oxidative stress. To achieve this goal, gene and protein expression were examined using qPCR and two-dimensional electrophoresis, respectively, peroxiredoxin Tsa1b being discovered to be overexpressed under oxidative stress. Besides, its antigenicity was also confirmed by western blotting. Subsequently, the significance of Tsa1b was next investigated by creating and characterizing theC. auris ΔTSA1BandC. auris ΔTSA1B::TSA1Bstrains using CRISPR-Cas9. The findings demonstrated that theΔTSA1Bstrain was more susceptible to oxidative and cell wall stressors than the wild-type strain, which was consistent with an increase in the cell wall β-glucan amounts when grown in the presence of oxidative stress. Furthermore, theΔTSA1Bstrain was also more vulnerable to the presence of dendritic cells and bone marrow-derived macrophages. Finally,in vivoinfections performed inGalleria mellonellaand mice showed a slower progression of the disease in those animals infected with the mutant strain. In conclusion, the peroxiredoxin Tsa1b has been identified as an important protein for theC. aurisresponse to oxidative stress and as a virulence factor, allowing for a more thorough knowledge of the pathobiology of this yeast. This study points out the potential that this protein may have for the development of new diagnostic and therapeutic approaches.HIGHLIGHTSSeveral metabolic proteins are implicated inC. aurisresponse to oxidative stressC. aurisresponse to oxidative stress is influenced by the Tsa1b peroxiredoxinLack of Tsa1b generates more susceptibility to stresses and an altered cell wallC. aurisTsa1b is involved in the fungal interaction with host immune cellsThe Tsa1b ofC. auriscontributes to the progression of the infectionin vivo
Neurogenetic evidence for oscillatory behavior of Lgr3-positive growth control interneurons inDrosophila
Authors: Zanini Rebeca , Pereirinha Joana , Fernandez-Acosta Magdalena , Casimiro Andreia P. , Pinho Mariana , Garelli Andres , Herédia Fabiana , Gontijo Alisson M. 
Published: November 2024

ABSTRACTThe ability of animals to achieve a species-specific size and proportion even in the face of developmental or environmental perturbations is termed developmental stability. InDrosophila, the relaxin/insulin-like peptide 8 (Dilp8) mediates interorgan growth coordination during larval development acting upstream of the neuronal relaxin-like Leucine-rich repeat-containing G protein-coupled receptor (Lgr3). Previous reports have led to a model where Dilp8-dependent Lgr3 activation in two bilateral brain interneurons termedpars intercerebralisLgr3-positive/growth-coordinating Lgr3 (PIL/GCL) neurons leads to their depolarization, which then triggers a neuroendocrine cascade that promotes developmental stability by delaying the larval-to-pupal transition and reducing organ growth concomitantly. However, many fundamental aspects of this model remained to be experimentally proven, most notably the specific requirement of Lgr3 and depolarization in PIL/GCL neurons for developmental stability. Here, we confirm the first part of the model regarding the specific requirement of Lgr3 in PIL/GCL neurons using improved genetic drivers, but, in contrast to the model predictions, we find that both hyper-and depolarized states of these neurons are required for their developmental delay-promoting activity in response to Dilp8. The simplest explanation for this finding is that Lgr3 activation by Dilp8 triggers oscillatory activity of PIL/GCL neurons, and that this is required for the Dilp8-dependent developmental delay. Whether or not such oscillatory behavior would arise from intrinsically pacemaker activity or from network connectivity properties such as feedback inhibition remains to be defined, although we present evidence that both could be involved. Namely, PIL/GCL neurons are positive for Cyclin A, which has been linked with sleep time coordination in adult postmitotic neurons. On the other hand, the neuroanatomy of PIL/GCL neurons is consistent with reciprocally-innervating loop-forming neurons, a common architecture in oscillating circuits and central pattern generators. Finally, we demonstrate through clonal analyses that PIL/GCL neurons represent two distinct neuronal types–a local and a projection neuron–instead of a homogeneous neuronal population as previously thought, revealing a new complexity layer in the developmental stability circuit. Our findings highlight the importance of cell-type specific neurogenetic manipulation, detailed neuroanatomical characterization, and reveal a critical and unanticipatedly complex role for PIL/GCL neurons in the Dilp8-dependent developmental stability pathway.
Microglia promote neurodegeneration and hyperkatifeia during withdrawal and prolonged abstinence from chronic binge alcohol
Authors: McNair Elizabeth , Dawkins Lamar , Ross Grace , Barnett Alexandra , Nakala Puja , Qin Liya , Zou Jian , Nikolova Viktoriya , Moy Sheryl , Coleman Leon G. 
Published: November 2024

AbstractProinflammatory microglial activation and hyperkatifeia during withdrawal are key features or Alcohol Use Disorder (AUD) as well as in rodent models of binge alcohol. However, it is unclear the role microglia play in the development of AUD behavioral phenotypes, particularly negative affect or hyperkatifeia. We hypothesized proinflammatory microglia promote neuronal death and hyperkatifeia during withdrawal and prolonged abstinence. METHODS: Inflammatory and affective responses were measured in adult mice 24h or 4 weeks after 4 or 10 daily binge ethanol exposures (5g/kg/d, i.g.). RT-PCR was used to measure expression of pro-inflammatory genes. FosB immunohistochemistry was measured in stress circuitry central amygdala (CeA), BNST, and infralimbic cortex (IL) as a proxy for neuronal activity. Behavioral testing was performed in additional cohorts to measure anxiety-like behavior (center time in the open field), hyperarousal (acoustic startle), and inflexible negative affect (conditioned fear memory with extinction). To determine the role of proinflammatory microglia, Gi DREADDs were activated in microglia (CX3CR1.CreERT2.hm4di+/-EtOH +/- CNO). RESULTS: Binge ethanol increased pro-inflammatory gene activation both 24h after EtOH and lasting weeks into withdrawal (type I IFNs). Ten ethanol binges increased FosB in stress circuitry during withdrawal while simultaneously reducing BDNF persistently in the dBNST and CeA. Ethanol-treated mice spent less time in the center of the open field (anxiety-like behavior), had increased magnitude of acoustic startle reflex (hyperarousal) during withdrawal with reduced extinction of conditioned fear memory (PTSD phenotype) 4-5 weeks into abstinence. Gi-DREADD inhibition of microglia during alcohol treatment blocked persistent increases in proinflammatory cytokines, prevented ethanol-induced neuronal death (TUNEL), and prevented ethanol-induced hyperkatifeia including anxiety-like behavior and persistent conditioned fear memory. CONCLUSION: These data find a causative role for microglia in the development of negative affect behaviors during alcohol withdrawal. The prevention of these pro-inflammatory effects and behaviors by microglial inhibition reveals the integral role microglia play in the acute and lasting effects of ethanol on behavior in AUD pathogenesis.