Miracle-dz/UniFAR-FTUs huggingface dataset:
Neuronal and Glial Distribution of Tau Protein in the Adult Rat and Monkey

Tau is a microtubule-associated protein for which the physiological functions remain a topic of vigorous investigation. Additionally, tau is a central player in the pathogenesis of several diseases such as Alzheimer’s disease and several frontotemporal dementias. A critical variable to understanding tau in physiological and disease contexts is its normal localization within cells of the adult CNS. Tau is often described as an axon-specific (or enriched) and neuron-specific protein with little to no expression in glial cells, all of which are untrue. Understanding normal tau distribution also impacts interpretation of experimental results and hypotheses regarding its role in disease. Thus, we set out to help clarify the normal localization of tau in the adult CNS of middle-aged rats and rhesus macaque using the hippocampus as a representative brain structure. The physiological concentration of tau in the rat hippocampus was 6.6 μM and in white matter was 3.6 μM as determined by quantitative sandwich ELISAs. We evaluated the cellular localization of tau using multiple tau-specific antibodies with epitopes to different regions, including Tau1, Tau5, Tau7, R1, and two novel primate-specific antibodies NT9 and NT15. In the rat and monkey, tau was localized within the somatodendritic and axonal compartments, as well as a subset of neuronal nuclei. Semi-quantitative fluorescence intensity measurements revealed that depending on the specific reagent used the somatodendritic tau is relatively equal to, higher than, or lower than axonal tau, highlighting differential labeling of tau with various antibodies despite its distribution throughout the neuron. Tau was strongly expressed in mature oligodendrocytes and displayed little to no expression in oligodendrocyte precursor cells, astrocytes or microglia. Collectively, the data indicate tau is ∼3 – 7 μM under physiological conditions, is not specifically enriched in axons, and is normally found in both neurons and mature oligodendrocytes in the adult CNS. The full landscape of tau distribution is not revealed by all antibodies suggesting availability of the epitopes is different within specific neuronal compartments. These findings set the stage for better understanding normal tau distributions and interpreting data regarding the presence of tau in different compartments or cell types within disease conditions.
Foreign Language Learning as Cognitive Training to Prevent Old Age Disorders? Protocol of a Randomized Controlled Trial of Language Training vs. Musical Training and Social Interaction in Elderly With Subjective Cognitive Decline

Introduction: With aging comes a reduction of cognitive flexibility, which has been related to the development of late-life depression and progression of general cognitive decline. Several factors have been linked to attenuating such decline in cognitive flexibility, such as education, physical exercise and stimulating leisure activities. Speaking two or more languages has recently received abundant attention as another factor that may build up cognitive reserve, thereby limiting the functional implications of compromised cognition that accompany old age. With the number of older adults reaching record levels, it is important to attenuate the development of old-age disorders. Learning to speak a foreign language might offer a powerful tool in promoting healthy aging, but up to date effect studies are sparse. Here, the protocol that forms the foundation of the current study is presented. The present study aims to: (1) examine the effects of a foreign language training on cognitive flexibility and its neural underpinnings, and on mental health; and (2) assess the unique role of foreign language training vs. other cognitive or social programs. Method: One-hundred and ninety-eight Dutch elderly participants reporting subjective cognitive decline are included and randomized to either a language intervention, a music intervention, or a social control intervention. During 3 to 6 months, the language group learns English, the music group learns to play the guitar and the social group participates in social meetings where art workshops are offered. At baseline, at a 3-month follow-up, and at 6 months after termination of the training program, clinical, cognitive and brain activity measurements (combined EEG and fNIRS methods) are taken to assess cognitive flexibility and mental health. Discussion: This is the first trial addressing combined effects of language learning in elderly on cognition, language proficiency, socio-affective measures, and brain activity in the context of a randomized controlled trial. If successful, this study can provide insights into how foreign language training can contribute to more cognitively and mentally healthy years in older adulthood. Clinical Trial Registration: The trial is registered at the Netherlands Trial Register, July 2, 2018, trial number NL7137. https://www.trialregister. nl/trial/7137.
A Nudibranch Marine Extract Selectively Chemosensitizes Colorectal Cancer Cells by Inducing ROS-Mediated Endoplasmic Reticulum Stress

The present study shows the putative antiproliferative mechanism of action of the previously analytically characterized nudibranch extract (Dolabella auricularia, NB) and its different effects in colon cancer cells vs. nontumor colon cells. NB extract increased the accumulation of reactive oxygen species (ROS) and increased endoplasmic reticulum (ER) stress via stimulation of the unfolded protein response. Stress scavengers, N-acetylcysteine (NAC) and 4-phenylbutyric acid (4-PBA), decreased the stress induced by NB. The results showed that NB extract increased ER stress through overproduction of ROS in superinvasive colon cancer cells, decreased their resistance threshold, and produced a nonreturn level of ER stress, causing DNA damage and cell cycle arrest, which prevented them from achieving hyperproliferative capacity and migrating to and invading other tissues. On the contrary, NB extract had a considerably lower effect on nontumor human colon cells, suggesting a selective effect related to stress balance homeostasis. In conclusion, our results confirm that the growth and malignancy of colon cancer cells can be decreased by marine compounds through the modification of one of the most potent resistance mechanisms present in tumor cells; this characteristic differentiates cancer cells from nontumor cells in terms of stress balance.
Glibenclamide Advantage in Treating Edema After Intracerebral Hemorrhage (GATE-ICH): Study Protocol for a Multicenter Randomized, Controlled, Assessor-Blinded Trial

Introduction: Brain edema after acute intracerebral hemorrhage (ICH) plays a critical role in the secondary injury of ICH and may heighten the potential for a poor outcome. This trial aims to explore the efficacy of small doses of oral glibenclamide in perihematomal edema (PHE) and the prognosis of patients with ICH. Methods and Analysis: The GATE-ICH trial is a multicenter randomized, controlled, assessor-blinded trial. A total of 220 adult patients with acute primary ICH in 28 study centers in China will be randomized to the glibenclamide group (glibenclamide plus guideline-recommended ICH management) or the control group (guideline-recommended ICH management). Multivariate logistic regression will be used to analyze the relationship between the treatments and primary outcome. Study Outcomes: The primary efficacy outcome is the proportion of poor functional outcomes (modified Rankin Scale ≥3) at 90 days after enrollment. The secondary efficacy outcomes include changes in the volume of ICH and PHE between the baseline and follow-up computed tomography scans as well as the clinical scores between the baseline and follow-up assessments. Discussion: The GATE-ICH trial will assess the effects of small doses of oral glibenclamide in reducing the PHE after ICH and improving the 90-day prognosis of patients. Clinical Trial Registration: www.clinicaltrials. gov. , NCT03741530. Registered on November 8, 2018. Trial Status: Protocol version: May 6, 2019, Version 5. Recruitment and follow-up of patients is currently ongoing. This trial will be end in the second quarter of 2021.
Caspase-11-Gasdermin D-Mediated Pyroptosis Is Involved in the Pathogenesis of Atherosclerosis

Background: Pyroptosis is a form of cell death triggered by proinflammatory signals. Recent studies have reported that oxidized phospholipids function as caspase-11 agonists to induce noncanonical inflammasome activation in immune cells. As the levels of oxidized phospholipids derived from ox-LDL are largely elevated in atherosclerotic lesions, this study sought to determine whether oxidized lipids trigger pyroptosis and subsequent inflammation in the pathogenesis of atherosclerosis. Methods and Results: In our current study, after integrating transcriptomic data available from the Gene Expression Omnibus with data from hyperlipidemic mice and ox-LDL-treated peritoneal macrophages, we discovered that caspase-4/11-gasdermin D-associated inflammatory signaling was significantly activated. Consistently, the mRNA expression of caspase-4 and gasdermin D was upregulated in peripheral blood mononuclear cells from patients with coronary heart disease. In particular, the expression of caspase-4 was closely associated with the severity of lesions in the coronary arteries. An in vivo study showed that caspase-11-gasdermin D activation occurred in response to a high-fat/high-cholesterol (HFHC) diet in ApoE−/− mice, while caspase-11 deletion largely attenuated the volume and macrophage infiltration of atherosclerotic lesions. An in vitro mechanistic study showed that caspase-11-mediated inflammation occurred partly via gasdermin D-mediated pyroptosis in macrophages. Suppressing gasdermin D in HFHC-fed ApoE−/− mice via delivery of an adeno-associated virus markedly decreased lesion volume and infiltrating macrophage numbers. Conclusion: Caspase-11-gasdermin D-mediated pyroptosis and the subsequent proinflammatory response in macrophages are involved in the pathogenesis of atherosclerosis. Therefore, targeting the caspase 11-gasdermin D may serve as an alternative strategy for the treatment of atherosclerosis.
Staging Encystation Progression in Giardia lamblia Using Encystation-Specific Vesicle Morphology and Associating Molecular Markers

Differentiation into environmentally resistant cysts is required for transmission of the ubiquitous intestinal parasite Giardia lamblia. Encystation in Giardia requires the production, processing and transport of Cyst Wall Proteins (CWPs) in developmentally induced, Golgi-like, Encystation Specific Vesicles (ESVs). Progress through this trafficking pathway can be followed by tracking CWP localization over time. However, there is no recognized system to distinguish the advancing stages of this process which can complete at variable rates depending on how encystation is induced. Here, we propose a staging system for encysting Giardia based on the morphology of CWP1-stained ESVs. We demonstrate the molecular distinctiveness of maturing ESVs at these stages by following GlRab GTPases through encystation. Previously, we established that Giardia’s sole Rho family GTPase, GlRac, associates with ESVs and has a role in regulating their maturation and the secretion of their cargo. As a proof of principle, we delineate the relationship between GlRac and ESV stages. Through proteomic studies, we identify putative interactors of GlRac that could be used as additional ESV stage markers. This staging system provides a common descriptor of ESV maturation regardless of the source of encysting cells. Furthermore, the identified set of molecular markers for ESV stages will be a powerful tool for characterizing trafficking mutants that impair ESV maturation and morphology.
Efficacy and Safety of Adalimumab in Noninfectious Uveitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: Patients with noninfectious uveitis (NIU) are at risk of systemic side effects of long-term glucocorticoid therapy and uncontrolled inflammatory complications. In urgent need to identify more aggressive therapies, adalimumab (ADA) may be the right choice. Objectives: To summarize the current evidence from randomized controlled trials (RCTs) regarding the efficacy and safety of ADA in the treatment of NIU. Methods: We searched Pubmed, Embase, Web of Science, Cochrane Library databases, and Clinical Trials Registry for qualifying articles from their inception to November 19, 2020, with no language restriction. Randomized controlled trials comparing ADA with conventional routine treatment in noninfectious uveitis patients of any age, gender, or ethnicity were included. The primary outcome was the time to treatment failure (TF). The secondary outcomes were the change in best-corrected visual acuity (BCVA), change in the anterior chamber (AC) cell grade, change in vitreous haze (VH) grade, and adverse events (AEs). Main results: The six studies comprised 605 participants in all, and the sample size of each study ranged from 16 to 225. The overall pooled results of the primary outcome (HR = 0.51; 95% CI, 0.41 to –0.63) showed that ADA nearly halved the risk of treatment failure compared to placebo for NIU patients. The pooled mean difference of change in BCVA was -0.05 (95% CI, −0.07 to −0.02). The pooled mean difference of change in AC cell grade and VH grade was −0.29 (95% CI, −0.62 to −0.05) and −0.21 (95% CI, −0.32 to −0.11), respectively. The incidence of AEs in the ADA group was numerically higher than that of AEs in the placebo group (2,237 events and 9.40 events per patient-year, equivalent to 1,257 events and 7.79 events per patient-year). Conclusion: This meta-analysis of six RCTs further confirmed that ADA considerably lowered the risk of treatment failure or visual loss, and moderately reduced AC cell grades and VH grades with slightly more AEs, as compared to placebo. ADA is both effective and safe in treating NIU. Systematic Review Registration: [https://clinicaltrials.gov], identifier [CRD42020217909].
Teachers’ Experiences of Facilitators and Barriers to Implement Theme-Based Cooperative Learning in a Swedish Context

Implementing Evidence-Based Practice (EBP) in school settings can be challenging. This case study presents barriers and facilitators expressed by kindergarten teachers (N = 6) during the implementation of a theme-based cooperative learning project over the course of a semester. During three group interviews, at the start, mid-point, and end, the teachers expressed their thoughts and experiences about the project. The Theoretical Domains Framework (TDF) was used to identify and analyze barriers and facilitators throughout the project. The importance of organizational investment, collegial connection and collaboration, the pedagogical fit of the EBP, and plans for long-term change were highlighted as beneficial factors for successful implementation in this case study.
What's Happened to Italian Adolescents During the COVID-19 Pandemic? A Preliminary Study on Symptoms, Problematic Social Media Usage, and Attachment: Relationships and Differences With Pre-pandemic Peers

Italian adolescents were confined at home for 3 months due to the COVID-19 pandemic, which exposed them to feelings of fear, uncertainty, and loneliness that may have increased their vulnerability to emotional-behavioral symptoms (e.g., anxiety) and binge-eating attitudes. Potential risk factors for these psychopathological symptoms are problematic social media usage and attachment insecurity. Therefore, this study aimed: (1) to assess emotional-behavioral symptoms, binge eating, problematic social media usage, and attachment representations of adolescents during the pandemic, comparing them with prepandemic similar samples; (2) to investigate relationships among variables, exploring the role of problematic social media usage and insecure attachment as risk factors for more psychopathological symptoms. Participants were 62 community adolescents aged 12–17 years, enrolled through schools, and assessed online through the following measures: Youth Self-Report for emotional-behavioral problems, Binge-Eating Scale for binge eating, Social Media Disorder Scale for problematic social media usage, and the Friends and Family Interview for attachment. The main results were: (1) 9.4% of adolescents showed clinical rates of emotional-behavioral symptoms and 4.8% of binge eating attitudes. The comparison with pre-pandemic samples revealed that pandemic teenagers showed lower internalizing, but higher other problems (e.g., binge drinking, self-destructive behaviors) and more problematic social media usage than pre-pandemic peers. No differences in binge-eating attitudes and attachment were revealed (76% secure classifications). (2) Problematic social media usage was related to more binge eating and emotional-behavioral problems, predicting 5.4% of both delinquent and attention problems. Attachment disorganization predicted 16.5% of internalizing problems, somatic complaints, and social and identity-related problems. In conclusion, confinement did not increase adolescents' internalizing symptoms -i.e., vulnerability to mood disorders of an anxious-depressive type- which even decreased. However, teenagers may have expressed their discomfort through other problems and symptoms of social media disorder. Further studies should explore the role of adolescents' problematic social media usage and attachment insecurity as risk factors for additional psychopathological symptoms.
Combination of Urine Exosomal mRNAs and lncRNAs as Novel Diagnostic Biomarkers for Bladder Cancer

Background The recent discovery of miRNAs and lncRNAs in urine exosomes has emerged as promising diagnostic biomarkers for bladder cancer (BCa). However, mRNAs as the direct products of transcription has not been well evaluated in exosomes as biomarkers for BCa diagnosis. The purpose of this study was to identify tumor progression-related mRNAs and lncRNAs in urine exosomes that could be used for detection of BCa. Methods RNA-sequencing was performed to identify tumor progression-related biomarkers in three matched superficial tumor and deep infiltrating tumor regions of muscle-invasive bladder cancer (MIBC) specimens, differently expressed mRNAs and lncRNAs were validated in TCGA dataset (n = 391) in the discovery stage. Then candidate RNAs were chosen for evaluation in urine exosomes of a training cohort (10 BCa and 10 healthy controls) and a validation cohort (80 BCa and 80 healthy controls) using RT-qPCR. The diagnostic potential of the candidates were evaluated by receiver operating characteristic (ROC) curves. Results RNA sequencing revealed 8 mRNAs and 32 lncRNAs that were significantly upregulated in deep infiltrating tumor region. After validation in TCGA database, 10 markedly dysregulated RNAs were selected for further investigation in urine exosomes, of which five (mRNAs: KLHDC7B, CASP14, and PRSS1; lncRNAs: MIR205HG and GAS5) were verified to be significantly dysregulated. The combination of the five RNAs had the highest AUC to disguising the BCa (0.924, 95% CI, 0.875–0.974) or early stage BCa patients (0.910, 95% CI, 0.850 to 0.971) from HCs. The expression levels of these five RNAs were correlated with tumor stage, grade, and hematuria degrees. Conclusions These findings highlight the potential of urine exosomal mRNAs and lncRNAs profiling in the early diagnosis and provide new insights into the molecular mechanisms involved in BCa.
Data Driven Cell Cycle Model to Quantify the Efficacy of Cancer Therapeutics Targeting Specific Cell-Cycle Phases From Flow Cytometry Results

Many chemotherapeutic drugs target cell processes in specific cell cycle phases. Determining the specific phases targeted is key to understanding drug mechanism of action and efficacy against specific cancer types. Flow cytometry experiments, combined with cell cycle phase and division round specific staining, can be used to quantify the current cell cycle phase and number of mitotic events of each cell within a population. However, quantification of cell interphase times and the efficacy of cytotoxic drugs targeting specific cell cycle phases cannot be determined directly. We present a data driven computational cell population model for interpreting experimental results, where in-silico populations are initialized to match observable results from experimental populations. A two-stage approach is used to determine the efficacy of cytotoxic drugs in blocking cell-cycle phase transitions. In the first stage, our model is fitted to experimental multi-parameter flow cytometry results from untreated cell populations to identify parameters defining probability density functions for phase transitions. In the second stage, we introduce a blocking routine to the model which blocks a percentage of attempted transitions between cell-cycle phases due to therapeutic treatment. The resulting model closely matches the percentage of cells from experiment in each cell-cycle phase and division round. From untreated cell populations, interphase and intermitotic times can be inferred. We then identify the specific cell-cycle phases that cytotoxic compounds target and quantify the percentages of cell transitions that are blocked compared with the untreated population, which will lead to improved understanding of drug efficacy and mechanism of action.
Time Pressure and Health-Related Loss of Productivity in University Students: The Mediating Role of Exhaustion

Introduction: Being present at work when sick is not just prevalent in employees. Since university is also a demanding context, there is a growing interest in this phenomenon in university students. Especially students with mental health issues show a higher degree of productivity loss. However, little research has examined the causes of these productivity losses—especially in university students. Therefore, we examined health-related (burnout) and non-health-related (time pressure) aspects that lead to productivity losses in the long run. Methods: We decided to examine the effect from time pressure on health-related loss of productivity, mediated by exhaustion. This assumption is in line with the health impairment process proposed by the Study Demands-Resources (SD-R) framework. To examine this assumption properly, we conducted a longitudinal study with three occasions. We surveyed 392 students in three waves over 1 year and performed structural equation modeling (SEM) to confirm the assumptions longitudinally. Results: In line with our assumptions, time pressure predicted burnout which, in turn, predicted health-related loss of productivity in the long run. Hence—as assumed by the SD-R framework—burnout serves as a mediator between study demands and negative outcomes such as loss of productivity. Discussion: Our study is the first that uncovers health-related and non-health-related causes of health-related productivity loss in university students. Thus, we were able to confirm SD-R's health impairment process longitudinally. Since we know that time pressure serves as a major antecedent for burnout and health-related loss of productivity, we are well-advised to establish appropriate interventions to reduce students' time pressure.