Miracle-dz/UniFAR-FTUs huggingface dataset:
Plasticity in the Brainstem: Prenatal and Postnatal Experience Can Alter Laterodorsal Tegmental (LDT) Structure and Function

The brainstem has traditionally been considered an area of the brain with autonomous control of mostly homeostatic functions such as heart rate, respiration, and the sleep and wakefulness state, which would preclude the necessity to exhibit the high degree of synaptic or cellular mechanisms of plasticity typical of regions of the brain responsible for flexible, executive control, such as the medial prefrontal cortex or the hippocampus. The perception that the brainstem does not share the same degree of flexibility to alter synaptic strength and/or wiring within local circuits makes intuitive sense, as it is not easy to understand how “soft wiring” would be an advantage when considering the importance of faithful and consistent performance of the homeostatic, autonomic functions that are controlled by the brainstem. However, many of the molecular and cellular requirements which underlie strengthening of synapses seen in brain regions involved in higher-level processing are present in brainstem nuclei, and recent research suggest that the view of the brainstem as “hard wired,” with rigid and static connectivity and with unchanging synaptic strength, is outdated. In fact, information from studies within the last decades, including work conducted in our group, leads us to propose that the brainstem can dynamically alter synaptic proteins, and change synaptic connections in response to prenatal or postnatal stimuli, and this would likely alter functionality and output. This article reviews recent research that has provided information resulting in our revision of the view of the brainstem as static and non-changing by using as example recent information gleaned from a brainstem pontine nucleus, the laterodorsal tegmentum (LDT). The LDT has demonstrated mechanisms underlying synaptic plasticity, and plasticity has been exhibited in the postnatal LDT following exposure to drugs of abuse. Further, exposure of the brain during gestation to drugs of abuse results in alterations in development of signaling pathways in the LDT. As the LDT provides a high degree of innervation of mesoaccumbal and mesocortical circuits involved in salience, as well as thalamocortical circuits involved in control of arousal and orientation, changes in synaptic strength would be expected to alter output, which would significantly impact behavioral state, motivated behavior and directed attention. Further, alterations in developmental trajectory within the LDT following prenatal exposure to drugs of abuse would be expected to impact on later life expression of motivation and arousal.
The Role of NLRP3 and IL-1β in Refractory Epilepsy Brain Injury

Objective: The objective of this study was to investigate the roles and mechanisms of inflammatory mediators NLRP3 and IL-1β in refractory temporal epilepsy brain injury. Method: First, the brain tissue and the peripheral blood of children undergoing intractable temporal lobe epilepsy surgery were analyzed as research objects. The expression levels of NLRP3 in brain tissue and IL-1β in blood were measured. A model of temporal lobe epilepsy was established using wild-type and NLRP3 knockout 129 mice. Pilocarpine was injected intraperitoneally into the experimental group, and isovolumetric saline was injected intraperitoneally into the control group (n = 8 in each group). The expression of IL-1β in the peripheral blood, cerebral cortex, and hippocampus of mice was measured by ELISA at 3 h, 24 h, 3 days, and 7 days after modeling. Fluoro-Jade B (FJB) and TUNEL methods were used to determine necrosis and apoptosis in hippocampal neurons, respectively, and the expression of NLRP3 in the cortex was measured by immunofluorescence methods. Result: (1) The IL-1β levels in the peripheral blood of children with intractable temporal lobe epilepsy were higher than those in the control group (t = 2.813, P = 0.01). There was also a positive correlation between IL-1β expression levels and the onset time of a single convulsion in patients with refractory epilepsy (r = 0.9735, P < 0.05). The expression level of NLRP3 in the cerebral cortex of patients with refractory temporal lobe epilepsy was higher than that in the control group. (2) The expression level of NLRP3 in the hippocampus of wild-type mice increased 3 days after modeling and decreased slightly at 7 days but remained higher than that of the control group. IL-1β levels in peripheral blood were significantly higher than those in the control group at 3 days (t = 8.259, P < 0.0001). The IL-1β levels in the peripheral blood of NLRP3 knockout mice were lower than those in the wild-type group at 3 days (t = 3.481, P = 0.004). At day 7, the neuronal necrosis and apoptosis levels in the CA3 region of the hippocampus decreased. Conclusion: NLRP3 may be involved in the development of refractory temporal lobe epilepsy. Inhibiting NLRP3 may alleviate local brain injury by downregulating the IL-1β expression. The IL-1β levels in the peripheral blood of patients with refractory temporal lobe epilepsy may reflect the severity of convulsions.
Biomarker Acquisition and Quality Control for Multi-Site Studies: The Autism Biomarkers Consortium for Clinical Trials

The objective of the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is to evaluate a set of lab-based behavioral video tracking (VT), electroencephalography (EEG), and eye tracking (ET) measures for use in clinical trials with children with autism spectrum disorder (ASD). Within the larger organizational structure of the ABC-CT, the Data Acquisition and Analytic Core (DAAC) oversees the standardization of VT, EEG, and ET data acquisition, data processing, and data analysis. This includes designing and documenting data acquisition and analytic protocols and manuals; facilitating site training in acquisition; data acquisition quality control (QC); derivation and validation of dependent variables (DVs); and analytic deliverables including preparation of data for submission to the National Database for Autism Research (NDAR). To oversee consistent application of scientific standards and methodological rigor for data acquisition, processing, and analytics, we developed standard operating procedures that reflect the logistical needs of multi-site research, and the need for well-articulated, transparent processes that can be implemented in future clinical trials. This report details the methodology of the ABC-CT related to acquisition and QC in our Feasibility and Main Study phases. Based on our acquisition metrics from a preplanned interim analysis, we report high levels of acquisition success utilizing VT, EEG, and ET experiments in a relatively large sample of children with ASD and typical development (TD), with data acquired across multiple sites and use of a manualized training and acquisition protocol.
Age and Sex Differences in Hearts of Soluble Epoxide Hydrolase Null Mice

Biological aging is an inevitable part of life that has intrigued individuals for millennia. The progressive decline in biological systems impacts cardiac function and increases vulnerability to stress contributing to morbidity and mortality in aged individuals. Yet, our understanding of the molecular, biochemical and physiological mechanisms of aging as well as sex differences is limited. There is growing evidence indicating CYP450 epoxygenase-mediated metabolites of n–3 and n–6 polyunsaturated fatty acids (PUFAs) are active lipid mediators regulating cardiac homeostasis. These epoxy metabolites are rapidly hydrolyzed and inactivated by the soluble epoxide hydrolase (sEH). The current study characterized cardiac function in young and aged sEH null mice compared to the corresponding wild-type (WT) mice. All aged mice had significantly increased cardiac hypertrophy, except in aged female sEH null mice. Cardiac function as assessed by echocardiography demonstrated a marked decline in aged WT mice, notably significant decreases in ejection fraction and fractional shortening in both sexes. Interestingly, aged female sEH null mice had preserved systolic function, while aged male sEH null mice had preserved diastolic function compared to aged WT mice. Assessment of cardiac mitochondria demonstrated an increased expression of acetyl Mn-SOD levels that correlated with decreased Sirt-3 activity in aged WT males and females. Conversely, aged sEH null mice had preserved Sirt-3 activity and better mitochondrial ultrastructure compared to WT mice. Consistent with these changes, the activity level of SOD significantly decreased in WT animals but was preserved in aged sEH null animals. Markers of oxidative stress demonstrated age-related increase in protein carbonyl levels in WT and sEH null male mice. Together, these data highlight novel cardiac phenotypes from sEH null mice demonstrating a sexual dimorphic pattern of aging in the heart.
The Lysosomal Membrane Protein Lamp2 Alleviates Lysosomal Cell Death by Promoting Autophagic Flux in Ischemic Cardiomyocytes

Lysosomal membrane permeabilization (LMP) has recently been recognized as an important cell death pathway in various cell types. However, studies regarding the correlation between LMP and cardiomyocyte death are scarce. Lysosomal membrane-associated protein 2 (Lamp2) is an important component of lysosomal membranes and is involved in both autophagy and LMP. In the present study, we found that the protein content of Lamp2 gradually decreased in response to oxygen, glucose and serum deprivation (OGD) treatment in vitro. To further elucidate its role in ischemic cardiomyocytes, particularly with respect to autophagy and LMP, we infected cardiomyocytes with adenovirus carrying full-length Lamp2 to restore its protein level in cells. We found that OGD treatment resulted in the occurrence of LMP and a decline in the viability of cardiomyocytes, which were remarkably reversed by Lamp2 restoration. Exogenous expression of Lamp2 also significantly alleviated the autophagic flux blockade induced by OGD treatment by promoting the trafficking of cathepsin B (Cat B) and cathepsin D (Cat D). Through drug intervention and gene regulation to alleviate and exacerbate autophagic flux blockade respectively, we found that impaired autophagic flux in response to ischemic injury contributed to the occurrence of LMP in cardiomyocytes. In conclusion, our present data suggest that Lamp2 overexpression can improve autophagic flux blockade probably by promoting the trafficking of cathepsins and consequently conferring cardiomyocyte resistance against lysosomal cell death (LCD) that is induced by ischemic injury. These results may indicate a new therapeutic target for ischemic heart damage.
Normalization Methods on Single-Cell RNA-seq Data: An Empirical Survey

Data normalization is vital to single-cell sequencing, addressing limitations presented by low input material and various forms of bias or noise present in the sequencing process. Several such normalization methods exist, some of which rely on spike-in genes, molecules added in known quantities to serve as a basis for a normalization model. Depending on available information and the type of data, some methods may express certain advantages over others. We compare the effectiveness of seven available normalization methods designed specifically for single-cell sequencing using two real data sets containing spike-in genes and one simulation study. Additionally, we test those methods not dependent on spike-in genes using a real data set with three distinct cell-cycle states and a real data set under the 10X Genomics GemCode platform with multiple cell types represented. We demonstrate the differences in effectiveness for the featured methods using visualization and classification assessment and conclude which methods are preferable for normalizing a certain type of data for further downstream analysis, such as classification or differential analysis. The comparison in computational time for all methods is addressed as well.
Maternal Inulin Supplementation Alters Hepatic DNA Methylation Profile and Improves Glucose Metabolism in Offspring Mice

Scope As a prebiotic, inulin may have a protective effect on glucose metabolism. However, the mechanism of inulin treatment on glucose intolerance in offspring exposed to a maternal high-fat (HF) diet is still not clear. Here, we examined the hepatic DNA methylation profile to determine how maternal inulin supplementation modified glucose metabolism in offspring mice. Procedures Female mice were fed a HF diet, control diet (CON), or a HF diet with inulin supplementation (HF-inulin) during gestation and lactation. Upon weaning, pup livers were obtained. A hepatic genome DNA methylation array was performed. Results Pups exposed to a maternal HF diet exhibited glucose intolerance and insulin resistance. Maternal inulin treatment moderated glucose metabolism. A DNA methylation array identified differentially methylated regions associated with 970 annotated genes from pups exposed to a HF diet in response to maternal inulin treatment. In particular, the wingless-type MMTV integration site family member 5A (Wnt5a) gene was hypermethylated, and the phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha (Pik3c2a), phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 beta (Pik3c2b), and phosphoinositide-3-kinase regulatory subunit 2 (Pik3r2) genes were hypomethylated in inulin-treated pups. Consistently, hepatic Wnt5a gene expression was reduced and Pik3c2a, Pik3c2b, and Pik3r2 gene expression were increased in the inulin group. Conclusion Maternal inulin treatment improved glucose intolerance by changing DNA methylation and gene expression of Wnt5a and Pi3k in mice exposed to a maternal HF diet.
Untangling the Evolution of American Wild Grapes: Admixed Species and How to Find Them

Natural hybridization and introgression are central evolutionary processes in grape genus (Vitis). On the other hand, the interspecific relationships among grapes, the directionality of the inferred admixture events and the parents of hybrids are not yet completely clarified. The grapes are economically important crops characterized by tendrils used to climb on the trees and the fruits harvested by humans especially for the consumption or to produce wines and liquors. The American grapes (ca. 30 species) are recognized as an important resource because they show biotic and abiotic resistances. We analyzed 3,885 genome-wide SNPs from 31 American Vitis species using the TreeMix software combined with the f3 and f4 tests. This approach allowed us to infer phylogenetic relationships and to explore the natural admixture among taxa. Our results confirmed the existence of all hybrid species recognized in literature (V. x champinii, V. x doaniana, V. x novae-angliae, and V. x slavinii), identifying their most likely parent species and provided evidence of additional gene flows between distantly related species. We discuss our results to elucidate the origin of American wild grapes, demonstrating that admixture events have ancient origins. We observe that gene flows have involved taxa currently spread through the southern regions of North America. Consequently, we propose that glacial cycles could have triggered the contact between interfertile taxa promoting local hybridization events. We conclude by discussing the phylogenetic implications of our findings and showing that TreeMix can provide novel insights into the evolutionary history of grapes.
Comprehensive Molecular Profiling for Relapsed/Refractory Pediatric Burkitt Lymphomas—Retrospective Analysis of Three Real-Life Clinical Cases—Addressing Issues on Randomization and Customization at the Bedside

In order to identify reasons for treatment failures when using targeted therapies, we have analyzed the comprehensive molecular profiles of three relapsed, poor-prognosis Burkitt lymphoma cases. All three cases had resembling clinical presentation and histology and all three patients relapsed, but their outcomes differed significantly. The samples of their tumor tissue were analyzed using whole-exome sequencing, gene expression profiling, phosphoproteomic assays, and single-cell phosphoflow cytometry. These results explain different treatment responses of the three histologically identical but molecularly different tumors. Our findings support a personalized approach for patient with high risk, refractory, and rare diseases and may contribute to personalized and customized treatment efforts for patients with limited treatment options like relapsed/refractory Burkitt lymphoma. Summary The main aim of this study is to analyze three relapsed Burkitt lymphoma patients using a comprehensive molecular profiling, in order to explain their different outcomes and to propose a biomarker-based targeted treatment. In cases 1 and 3, the tumor tissue and the host were analyzed prospectively and appropriate target for the treatment was successfully implemented; however, in case 2, analyses become available only retrospectively and his empirically based rescue treatment did not hit the right target of his disease.
DNGR-1, a Dendritic Cell-Specific Sensor of Tissue Damage That Dually Modulates Immunity and Inflammation

DNGR-1 (encoded by CLEC9A) is a C-type lectin receptor (CLR) with an expression profile that is mainly restricted to type 1 conventional dendritic cells (cDC1s) both in mice and humans. This delimited expression pattern makes it appropriate for defining a cDC1 signature and for therapeutic targeting of this population, promoting immunity in mouse models. Functionally, DNGR-1 binds F-actin, which is confined within the intracellular space in healthy cells, but is exposed when plasma membrane integrity is compromised, as happens in necrosis. Upon F-actin binding, DNGR-1 signals through SYK and mediates cross-presentation of dead cell-associated antigens. Cross-presentation to CD8+ T cells promoted by DNGR-1 during viral infections is key for cross-priming tissue-resident memory precursors in the lymph node. However, in contrast to other closely related CLRs such as Dectin-1, DNGR-1 does not activate NFκB. Instead, recent findings show that DNGR-1 can activate SHP-1 to limit inflammation triggered by heterologous receptors, which results in reduced production of inflammatory chemokines and neutrophil recruitment into damaged tissues in both sterile and infectious processes. Hence, DNGR-1 reduces immunopathology associated with tissue damage, promoting disease tolerance to safeguard tissue integrity. How DNGR-1 signals are conditioned by the microenvironment and the detailed molecular mechanisms underlying DNGR-1 function have not been elucidated. Here, we review the expression pattern and structural features of DNGR-1, and the biological relevance of the detection of tissue damage through this CLR.
PET/MRI Radiomics in Patients With Brain Metastases

Although a variety of imaging modalities are used or currently being investigated for patients with brain tumors including brain metastases, clinical image interpretation to date uses only a fraction of the underlying complex, high-dimensional digital information from routinely acquired imaging data. The growing availability of high-performance computing allows the extraction of quantitative imaging features from medical images that are usually beyond human perception. Using machine learning techniques and advanced statistical methods, subsets of such imaging features are used to generate mathematical models that represent characteristic signatures related to the underlying tumor biology and might be helpful for the assessment of prognosis or treatment response, or the identification of molecular markers. The identification of appropriate, characteristic image features as well as the generation of predictive or prognostic mathematical models is summarized under the term radiomics. This review summarizes the current status of radiomics in patients with brain metastases.
TLR2-Melatonin Feedback Loop Regulates the Activation of NLRP3 Inflammasome in Murine Allergic Airway Inflammation

Toll-like receptor 2 (TLR2) is suggested to initiate the activation of NLRP3 inflammasome, and considered to be involved in asthma. The findings that melatonin modulates TLRs-mediated immune responses, together with the suppressing effect of TLRs on endogenous melatonin synthesis, support the possibility that a feedback loop exists between TLRs system and endogenous melatonin synthesis. To determine whether TLR2-melatonin feedback loop exists in allergic airway disease and regulates NLRP3 inflammasome activity, wild-type (WT) and TLR2−/− mice were challenged with OVA to establish allergic airway disease model. Following OVA challenge, WT mice exhibited increased-expression of TLR2, activation of NLRP3 inflammasome and marked airway inflammation, which were all effectively inhibited in the TLR2−/− mice, indicating that TLR2-NLRP3 mediated airway inflammation. Meanwhile, melatonin biosynthesis was reduced in OVA-challenged WT mice, while such reduction was notably rescued by TLR2 deficiency, suggesting that TLR2-NLRP3-mediated allergic airway inflammation was associated with decreased endogenous melatonin biosynthesis. Furthermore, addition of melatonin to OVA-challenged WT mice pronouncedly ameliorated airway inflammation, decreased TLR2 expression and NLRP3 inflammasome activation, further implying that melatonin in turn inhibited airway inflammation via suppressing TLR2-NLRP3 signal. Most interestingly, although melatonin receptor antagonist luzindole significantly reduced the protein expressions of ASMT, AANAT and subsequent level of melatonin in OVA-challenged TLR2−/− mice, it exhibited null effect on leukocytes infiltration, Th2-cytokines production and NLRP3 activity. These results indicate that a TLR2-melatonin feedback loop regulates NLRP3 inflammasome activity in allergic airway inflammation, and melatonin may be a promising therapeutic medicine for airway inflammatory diseases such as asthma.
Verbal Instructions and Motor Learning: How Analogy and Explicit Instructions Influence the Development of Mental Representations and Tennis Serve Performance

To better understand the benefits of using analogy and explicit instructions, the underlying cognitive mechanism remains to be explored. The concept of chunking provides a promising approach to the cognitive mechanism of instructions and can be approximated by analyzing athletes’ mental representations. The purpose of this study was to investigate the influence of analogy and explicit instructions on performance and the cognitive representations of the tennis serve in intermediate participants over the course of a 5-week training period. Junior tennis players (N = 44; M = 11.5 years) were tested on their tennis serve and, based on their initial performance and their individual error patterns, assigned to one of three groups: an analogy group (N = 15), an explicit group (N = 15), or a control group (N = 14). Their performance and their mental representation structures were assessed prior to and after the 5-week training period and again after a retention period of 14 days. Independent of group, findings demonstrated higher velocity from pretest to posttest. Participants in both the analogy and the explicit group showed enhanced accuracy over time and more functional mental representation structures. Thus, both analogy instruction and explicit instruction helped to structure mental representations in their long-term memory.