bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glymphatic System Dysfunction Underlying Schizophrenia Is Associated With Cognitive Impairment
Authors: Tu Ye , Fang Yan , Li Guohui , Xiong Fei , Gao Feng 
Published: April 2024

Abstract

Background and Hypothesis
Despite the well-documented structural and functional brain changes in schizophrenia, the potential role of glymphatic dysfunction remains largely unexplored. This study investigates the glymphatic system’s function in schizophrenia, utilizing diffusion tensor imaging (DTI) to analyze water diffusion along the perivascular space (ALPS), and examines its correlation with clinical symptoms.

Study Design
A cohort consisting of 43 people with schizophrenia and 108 healthy controls was examined. We quantified water diffusion metrics along the x-, y-, and z-axis in both projection and association fibers to derive the DTI-ALPS index, a proxy for glymphatic activity. The differences in the ALPS index between groups were analyzed using a 2-way ANCOVA controlling for age and sex, while partial correlations assessed the association between the ALPS index and clinical variables.

Study Results
People with schizophrenia showed a significantly reduced DTI-ALPS index across the whole brain and within both hemispheres (F = 9.001, P = .011; F = 10.024, P = .011; F = 5.927, P = .044; false discovery rate corrected), indicating potential glymphatic dysfunction in schizophrenia. The group by cognitive performance interaction effects on the ALPS index were not observed. Moreover, a lower ALPS index was associated with poorer cognitive performance on specific neuropsychological tests in people with schizophrenia.

Conclusion
Our study highlights a lower ALPS index in schizophrenia, correlated with more pronounced cognitive impairments. This suggests that glymphatic dysfunction may contribute to the pathophysiology of schizophrenia, offering new insights into its underlying mechanisms.
Familial hemiplegic migraine in Indian children—a tertiary center experience
Authors: Saini Lokesh , Gunasekaran Pradeep Kumar , Tiwari Sarbesh , Choudhary Bharat , Manjunathan Sujatha , Kumar Ashna 
Published: April 2024

Abstract
Familial hemiplegic migraine (FHM), an autosomal dominant subtype of hemiplegic migraine, is a channelopathy presenting with severe headache, visual field defect, paresthesia, unilateral motor deficit, encephalopathy, seizures and aphasia. This cross-sectional study was conducted over 10 months in children aged 1–18 years suspected of hemiplegic migraine at a tertiary care pediatric hospital. Fourteen children were screened and five children with genetically confirmed FHM were included. The symptoms in the study population were paroxysmal hemiparesis (5/5), headache (5/5) and focal seizures (1/5). The hemiplegia episodes lasted from 4 h to 7 days. The mean age at the onset of neurological symptoms was 6.8 ± 0.7 years and the mean age at diagnosis was 12.8 ± 1.7 years, with a mean delay of 6.1 ± 1.9 years for the diagnosis. Neuroimaging during acute episodes revealed accentuated gray, white differentiation in the contralateral cerebral hemisphere with mild effacement of sulcal spaces in T2/fluid-attenuated inversion recovery (FLAIR) images. Genetic testing revealed ATP1A2 mutations (FHM2) in 4/5 and SCN1A (FHM3) in 1/5 patients. All of them (5/5) were initiated on oral topiramate and had favorable treatment responses with a mean follow-up duration of 7 ± 1.4 months. Diagnosis of FHM is mainly clinical and can be confirmed by genetic analysis. Perfusion and diffusion-weighted MRI should be considered during acute headache episodes, as it is mostly normal in symptom-free periods. Routine MRI sequences like T1 weighted, T2 weighted, FLAIR and contrast remain normal even during acute attacks.
CircTHBS1 promotes trophoblast cell migration and invasion and inhibits trophoblast apoptosis by regulating miR‐136‐3p/IGF2R axis
Authors: Guo Yanyan , Huang Chuyi , Qiu Liyan , Fu Jiahui , Xu Cailing , Yang Fang 
Published: April 2024

AbstractThe precise molecular mechanism behind fetal growth restriction (FGR) is still unclear, although there is a strong connection between placental dysfunction, inadequate trophoblast invasion, and its etiology and pathogenesis. As a new type of non‐coding RNA, circRNA has been shown to play a crucial role in the development of FGR. This investigation identified the downregulation of hsa_circ_0034533 (circTHBS1) in FGR placentas through high‐sequencing analysis and confirmed this finding in 25 clinical placenta samples using qRT‐PCR. Subsequent in vitro functional assays demonstrated that silencing circTHBS1 inhibited trophoblast proliferation, migration, invasion, and epithelial mesenchymal transition (EMT) progression and promoted apoptosis. Furthermore, when circTHBS1 was overexpressed, cell function experiments showed the opposite result. Analysis using fluorescence in situ hybridization revealed that circTHBS1 was primarily found in the cytoplasmic region. Through bioinformatics analysis, we anticipated the involvement of miR‐136‐3p and IGF2R in downstream processes, which was subsequently validated through qRT‐PCR and dual‐luciferase assays. Moreover, the inhibition of miR‐136‐3p or the overexpression of IGF2R partially reinstated proliferation, migration, and invasion abilities following the silencing of circTHBS1. In summary, the circTHBS1/miR‐136‐3p/IGF2R axis plays a crucial role in the progression and development of FGR, offering potential avenues for the exploration of biological indicators and treatment targets.
Defective CAPSL function causes impaired retinal angiogenesis through the MYC axis and is associated with familial exudative vitreoretinopathy
Authors: Liu Wenjing , Li Shujin , Yang Mu , Ma Jie , Liu Lu , Fei Ping , Xiang Qianchun , Huang Lulin , Zhao Peiquan , Yang Zhenglin , Zhu Xianjun 
Published: April 2024

AbstractFamilial exudative vitreoretinopathy (FEVR) is a severe genetic disorder characterized by incomplete vascularization of the peripheral retina and associated symptoms that can lead to vision loss. However, the underlying genetic causes of approximately 50% of FEVR cases remain unknown. Here, we report two heterozygous variants, c.88C > T (p.Arg30Ter) and c.247C > T (p.Leu83Phe), in calcyphosine like (CAPSL), from four patients in two unrelated FEVR-affected families. Both variants exhibited compromised CAPSL protein expression. Vascular endothelial cell-specific inactivation ofCapslin postnatal mice resulted in defective sprouting, delayed radial/vertical vascular progression, compromised endothelial proliferation, and impaired cell migration, recapitulating the human FEVR phenotypes.CAPSL-depleted human retinal microvascular endothelial cells (HRECs) exhibited impaired tube formation, decreased cell proliferation, disrupted cell polarity establishment and filopodia/lamellipodia formation, as well as disrupted collective cell migrationin vitro. Transcriptomic and proteomic profiling ofCAPSL-depleted HRECs revealed thatCAPSLabolition inhibited the MYC signaling axis, in which the expression of core MYC targeted genes were profoundly decreased. Furthermore, a combined analysis ofCAPSL-depleted HRECs andc-MYC-depleted human umbilical vein endothelial cells (HUVECs) uncovered similar transcription patterns. Collectively, this study reports a novel FEVR-associated candidate gene,CAPSL, which provides valuable information for genetic counseling and prenatal diagnosis of FEVR. This study also reveals that compromised CAPSL function may causes FEVR through MYC axis, shedding light on the potential involvement of MYC signaling in the pathogenesis of FEVR.
Comparison of spatial transcriptomics technologies using tumor cryosections
Authors: Rademacher Anne , Huseynov Alik , Bortolomeazzi Michele , Wille Sina Jasmin , Schumacher Sabrina , Sant Pooja , Keitel Denise , Okonechnikov Konstantin , Ghasemi David R. , Pajtler Kristian W. , Mallm Jan-Philipp , Rippe Karsten 
Published: April 2024

AbstractBackgroundSpatial transcriptomics (ST) technologies are revolutionizing our understanding of intra-tumor heterogeneity and the tumor microenvironment by revealing single-cell molecular profiles within their spatial tissue context. The rapid evolution ofSTmethods, each with unique features, presents a challenge in selecting the most appropriate technology for specific research objectives. Here, we compare four imaging-basedSTmethods – RNAscope HiPlex, Molecular Cartography, MERFISH/Merscope, and Xenium – together with sequencing-basedST(Visium). These technologies were used to study cryosections of medulloblastoma with extensive nodularity (MBEN), a tumor chosen for its distinct microanatomical features.ResultsOur analysis reveals that automated imaging-basedSTmethods are well suited to delineating the intricate MBEN microanatomy, capturing cell-type-specific transcriptome profiles. We devise approaches to compare the sensitivity and specificity of the different methods together with their unique attributes to guide method selection based on the research aim. Furthermore, we demonstrate how reimaging of slides after theSTanalysis can markedly improve cell segmentation accuracy and integrate additional transcript and protein readouts to expand the analytical possibilities and depth of insights.ConclusionsThis study highlights key distinctions between variousSTtechnologies and provides a set of parameters for evaluating their performance. Our findings aid in the informed choice ofSTmethods and delineate approaches for enhancing the resolution and breadth of spatial transcriptomic analyses, thereby contributing to advancingSTapplications in solid tumor research.
Predicting drug combination response surfaces
Authors: Huusari Riikka , Wang Tianduanyi , Szedmak Sandor , Aittokallio Tero , Rousu Juho 
Published: April 2024

AbstractPrediction of drug combination responses is a research question of growing importance for cancer and other complex diseases. Current machine learning approaches generally consider predicting either drug combination synergy summaries or single combination dose-response values, which fail to appropriately model the continuous nature of the underlying dose-response combination surface and can lead to inconsistencies when a synergy score or a dose-response matrix is reconstructed from separate predictions. We propose a structured prediction method, comboKR, that directly predicts the drug combination response surface for a drug combination. The method is based on a powerful input-output kernel regression technique and functional modeling of the response surface. As an important part of our approach, we develop a novel normalisation between response surfaces that standardizes the heterogeneous experimental designs used to measure the dose-responses, and thus allows training the method with data measured in different laboratories. Our experiments on two predictive scenarios highlight the suitability of the proposed approach especially in the traditionally challenging setting of predicting combination responses for new drugs not available in the training data.
Comparative Analysis of Structural Alignment Algorithms for Protein-Protein Interfaces in Template-Based Docking Studies
Authors: Cankara Fatma , Tuncbag Nurcan , Gursoy Attila , Keskin Ozlem 
Published: April 2024

AbstractProtein-protein interactions are pivotal for various functions within living organisms. Understanding their underlying mechanisms holds significant potential for unraveling cellular processes. There are several methods to identify protein-protein interactions, including but not limited to template-based docking. The power of template docking lies in the template library selection and the quality of structural alignment. Within the scope of our investigation, we specifically delve into the performance of four structural alignment algorithms on one protein interface and four protein structure benchmark sets. This study places particular emphasis on assessing these tools on protein interfaces, composed of non-continuous structure segments, as these interfaces play a crucial role in protein interactions, especially in the context of template-based docking. Notably, our findings indicate that TM-align, despite not being explicitly designed for sequence-order independent alignment, exhibits comparable performance to tools tailored for this purpose while executing in a considerably shorter time frame. Therefore, TM-align emerges as a promising candidate for the crucial structural alignment step in template-docking pipelines.
GαolfRegulates Biochemical Signaling in Neurons Associated with Movement Control and Initiation
Authors: Millett Michael , Heuberger Anika , Castosa Elisabeth Martin , Comite Allison , Wagner Preston , Hall Dominic , Gallardo Ignacio , Chambers Nicole E , Wagner Lloyd , Moehle Mark S 
Published: April 2024

AbstractThe heterotrimeric G-protein α subunit, Gαolf, acts to transduce extracellular signals through G-protein coupled receptors (GPCRs) and stimulates adenylyl cyclase mediated production of the second messenger cyclic adenosine monophosphate. Numerous mutations in theGNALgene, which encodes Gαolf, have been identified as causative for an adult-onset dystonia. These mutations disrupt GPCR signaling cascades inin vitroassays through several mechanisms, and this disrupted signaling is hypothesized to lead to dystonic motor symptoms in patients. However, the cells and circuits that mutations inGNALcorrupt are not well understood. Published patterns of Gαolfexpression outside the context of the striatum are sparse, conflicting, often lack cell type specificity, and may be confounded by expression of the closeGNALhomolog ofGNAS. Here, we use RNAScope in-situ hybridization to quantitatively characterizeGnalmRNA expression in brain tissue from wildtype C57BL/6J adult mice. We observed widespread expression ofGnalpuncta throughout the brain, suggesting Gαolfis expressed in more brain structures and neuron types than previously accounted for. We quantify transcripts at a single cell level, and use neuron type specific markers to further classify and understand patterns ofGNALexpression. Our data suggests that brain regions classically associated with motor control, initiation, and regulation show the highest expression ofGNAL, with Purkinje Cells of the cerebellum showing the highest expression of any neuron type examined. Subsequent conditionalGnalknockout in Purkinje cells led to markedly decreased intracellular cAMP levels and downstream cAMP-dependent enzyme activation. Our work provides a detailed characterization ofGnalexpression throughout the brain and the biochemical consequences of loss of Gαolfsignalingin vivoin neurons that highly expressGnal.
Hearing in categories aids speech streaming at the “cocktail party”
Authors: Bidelman Gavin M. , Bernard Fallon , Skubic Kimberly 
Published: April 2024

AbstractOur perceptual system bins elements of the speech signal into categories to make speech perception manageable. Here, we aimed to test whether hearing speech in categories (as opposed to a continuous/gradient fashion) affords yet another benefit to speech recognition: parsing noisy speech at the “cocktail party.” We measured speech recognition in a simulated 3D cocktail party environment. We manipulated task difficulty by varying the number of additional maskers presented at other spatial locations in the horizontal soundfield (1-4 talkers) and via forward vs. time-reversed maskers, promoting more and less informational masking (IM), respectively. In separate tasks, we measured isolated phoneme categorization using two-alternative forced choice (2AFC) and visual analog scaling (VAS) tasks designed to promote more/less categorical hearing and thus test putative links between categorization and real-world speech-in-noise skills. We first show that listeners can only monitor up to ∼3 talkers despite up to 5 in the soundscape and streaming is not related to extended high-frequency hearing thresholds (though QuickSIN scores are). We then confirm speech streaming accuracy and speed decline with additional competing talkers and amidst forward compared to reverse maskers with added IM. Dividing listeners into “discrete” vs. “continuous” categorizers based on their VAS labeling (i.e., whether responses were binary or continuous judgments), we then show the degree of IM experienced at the cocktail party is predicted by their degree of categoricity in phoneme labeling; more discrete listeners are less susceptible to IM than their gradient responding peers. Our results establish a link between speech categorization skills and cocktail party processing, with a categorical (rather than gradient) listening strategy benefiting degraded speech perception. These findings imply figure-ground deficits common in many disorders might arise through a surprisingly simple mechanism: a failure to properly bin sounds into categories.
Heterologous HSPC transplantation rescues neuroinflammation and ameliorates peripheral manifestations in the mouse model of lysosomal transmembrane enzyme deficiency, MPS IIIC
Authors: Pan Xuefang , Caillon Antoine , Fan Shuxian , Khan Shaukat , Tomatsu Shunji , Pshezhetsky Alexey V. 
Published: April 2024

AbstractMucopolysaccharidosis III type C (MPS IIIC) is an untreatable neuropathic lysosomal storage disease caused by a genetic deficiency of the lysosomal N-acetyltransferase, HGSNAT, catalyzing a transmembrane acetylation of heparan sulfate. HGSNAT is a transmembrane enzyme uncapable of free diffusion between the cells and their cross-correction which limits development of therapies based on the enzyme replacement and gene correction. Since our previous work identified neuroinflammation as a hallmark of the CNS pathology in MPS IIIC, we tested whether it can be corrected by replacement of activated brain microglia with neuroprotective macrophages/microglia derived from a heterologous HSPC transplant.Eight-week-old MPS IIIC (HgsnatP304L) mice were transplanted with HSPC from congenic wild type mice after myeloablation with Busulfan and studied by behaviour test battery staring from the age of 6 months. At the age of ∼8 months, mice were sacrificed to study pathological changes in the brain, heparan sulfate storage and other biomarkers of the disease. We found that the treatment corrected several behaviour deficits including hyperactivity and reduction of socialization, but not a memory decline. It also improved several features of CNS pathology such as microastroglyosis, expression of pro-inflammatory cytokine IL-1β, and accumulation of misfolded amyloid aggregates in cortical neurons. At the periphery, the treatment delayed development of terminal urinary retention, potentially increasing longevity, and reduced blood levels of heparan sulfate. However, we did not observe correction of lysosomal storage phenotype in neurons and heparan sulfate brain levels.Together, our results demonstrate that neuroinflammation in a neurological lysosomal storage disease, caused by defects in a transmembrane enzyme, can be effectively ameliorated by replacement of microglia bearing the genetic defect with the cells from normal healthy donor. They also suggest, that heterologous HSPC transplant, if used together with other methods, such as chaperone therapy or substrate reduction therapy, may constitute an effective combination therapy for MPS IIIC and other disorders with a similar etiology.
The first example of extreme and independent host plant shifts mediated by parasitic plants in insects
Authors: Zelvelder B. , Kergoat G.J. , Benoit L. , Tsuchida T. , Haran J. , Allio R. 
Published: April 2024

AbstractPhytophagous insects have specialized on virtually every plant lineage. Parasitic plants, however, are uncommon hosts. Among insects, only a single lineage of weevils, the Smicronychini, has successfully radiated on both parasitic and non-parasitic plants in a large panel of distantly related Asterid families. This unusual pattern suggests that major host plant shifts have occurred over the course of their diversification. Through the analysis of a phylogenomic dataset, we reconstruct for the first time their evolutionary history and ancestral host plant associations. Our results show that independent host plant shifts occurred both from parasitic to non-parasitic hosts and between distinct parasitic lineages. These results suggest that host shift mechanisms can be driven by ecological opportunities provided by plant-plant interactions. This first evidence of extreme insect host plant shifts mediated by parasitic plant-plant interactions emphasizes the core importance of ecological interactions as driving forces behind insect host plant shifts.
Selective engagement of prefrontal VIP neurons in reversal learning
Authors: Yi Jee Hyun , Yoon Young Ju , Jeong Huijeong , Choe Seo Yeon , Jung Min Whan 
Published: April 2024

ABSTRACTTo gain insights into neural mechanisms enabling behavioral adaptations to complex and multidimensional environmental dynamics, we examined roles of VIP neurons in mouse medial prefrontal cortex (mPFC) in probabilistic reversal learning. Behaviorally, manipulating VIP neuronal activity left probabilistic classical conditioning unaffected but severely impaired reversal learning. Physiologically, conditioned cue-associated VIP neuronal responses changed abruptly after encountering an unexpected reward. They also conveyed strong reward prediction error signals during behavioral reversal, but not before or after, unlike pyramidal neurons which consistently conveyed error signals throughout all phases. Furthermore, the signal’s persistence across trials correlated with reversal learning duration. These results suggest that mPFC VIP neurons play crucial roles in rapid reversal learning, but not in incremental cue-outcome association learning, by monitoring significant deviations from ongoing environmental contingency and imposing error-correction signals during behavioral adjustments. These findings shed light on the intricate cortical circuit dynamics underpinning behavioral flexibility in complex, multifaceted environments.
Atypical epigenetic and small RNA control of degenerated transposons and their fragments in clonally reproducingSpirodela polyrhiza
Authors: Dombey Rodolphe , Buendía-Ávila Daniel , Barragán-Borrero Verónica , Diezma-Navas Laura , Ponce-Mañe Arturo , Vargas-Guerrero José Mario , Elias Rana , Marí-Ordóñez Arturo 
Published: April 2024

AbstractA handful of model plants have provided insight into silencing of transposable elements (TEs) through RNA-directed DNA methylation (RdDM). Guided by 24-nt long small-interfering RNAs (siRNAs), this epigenetic regulation installs DNA methylation and histone modifications like H3K9me2, which can be subsequently maintained independently of siRNAs. However, the genome of the clonally propagating duckweedSpirodela polyrhiza(Lemnaceae) has low levels of DNA methylation, very low expression of RdDM components, and near absence of 24-nt siRNAs. Moreover, some genes encoding RdDM factors, DNA methylation maintenance, and RNA silencing mechanisms are missing from the genome. Here, we investigated the distribution of TEs and their epigenetic marks in theSpirodelagenome. While abundant degenerated TEs have largely lost DNA methylation and H3K9me2 is low, they remain marked by the heterochromatin associated H3K9me1 and H3K27me1 modifications. By contrast, we found high levels of DNA methylation and H3K9me2 in the relatively few intact TEs which are source of 24-nt siRNAs like RdDM-controlled TEs in other angiosperms. The data suggest that, potentially as adaptation to vegetative propagation, RdDM extent, silencing components, and targets are different from other angiosperms, preferentially focused on potentially intact TEs. It also provides evidence for heterochromatin maintenance independently of DNA methylation in flowering plants. These discoveries highlight the diversity of silencing mechanisms that exist in plants and the importance of using disparate model species to discover these mechanisms.