Miracle-dz/UniFAR-FTUs huggingface dataset:
Mucopolysaccharidoses I and II: Brief Review of Therapeutic Options and Supportive/Palliative Therapies

Purpose. Mucopolysaccharidoses (MPS) are group of inherited lysosomal storage diseases caused by mutations of enzymes involved in catalyzing different glycosaminoglycans (GAGs). MPS I and MPS II exhibit both somatic and neurological symptoms with a relatively high disease incidence. Hematopoietic stem cell therapy (HSCT) and intravenous enzyme replacement therapy (ERT) have had a significant impact on the treatment and comprehension of disease. This review is aimed at providing a comprehensive evaluation of the pros and cons of HSCT and ERT, as well as an up-to-date knowledge of new drugs under development. In addition, multiple disease management strategies for the uncontrollable manifestations of MPS I and MPS II to improve patients' quality of life are presented. Findings. Natural history of MPS I and MPS II shows that somatic and neurological symptoms occur earlier in severe forms of MPS I than in MPS II. ERT increases life expectancy and alleviates some of the somatic symptoms, but musculoskeletal, ophthalmological, and central nervous system (CNS) manifestations are not controlled. Additionally, life-long treatment burdens and immunogenicity restriction are unintended consequences of ERT application. HSCT, another treatment method, is effective in controlling the CNS symptoms and hence has been adopted as the standard treatment for severe types of MPS I. However, it is ineffective in MPS II, which can be explained by the relatively late diagnosis. In addition, several factors such as transplant age limits or graft-versus-host disease in HSCT have limited its application for patients. Novel therapies, including BBB-penetrable-ERT, gene therapy, and substrate reduction therapy, are under development to control currently unmanageable manifestations. BBB-penetrable-ERT is being studied comprehensively in the hopes of being used in the near future as a method to effectively control CNS symptoms. Gene therapy has the potential to “cure” the disease with a one-time treatment rather than just alleviate symptoms, which makes it an attractive treatment strategy. Several clinical studies on gene therapy reveal that delivering genes directly into the brain achieves better results than intravenous administration in patients with neurological symptoms. Considering new drugs are still in clinical stage, disease management with close monitoring and supportive/palliative therapy is of great importance for the time being. Proper rehabilitation therapy, including physical and occupational therapy, surgical intervention, or medications, can benefit patients with uncontrolled musculoskeletal, respiratory, ophthalmological, and neurological manifestations.
Using acetone for rapid PCR‐amplifiable DNA extraction from recalcitrant woody plant taxa

Premise Quick and effective DNA extraction from plants for subsequent PCR amplification is sometimes challenging when working across diverse plant taxa that may contain a variety of inhibitory compounds. Time‐consuming methods may be needed to overcome these inhibitory effects as well as the effects of various preservation and collection methods to extract DNA from leaf samples. Our objective was to develop a rapid DNA extraction protocol that could be used with diverse plant taxa to produce high‐quality DNA suitable for downstream PCR applications. Methods and Results We tested the efficacy of acetone in extracting DNA from fresh, frozen, oven‐dried, acetone‐fixed, and herbarium leaf material of 22 species from 16 woody and herbaceous plant families. An improved simplified DNA extraction protocol was developed using acetone‐fixed leaf material. The addition of 1% sodium dodecyl sulfate solution resulted in the optimal extraction from all tissue samples. The DNA resulting from the extraction protocol was readily amplified using real‐time PCR assays. Conclusions The protocol described here resulted in the extraction of DNA from recalcitrant plant species that was of sufficient quality and quantity for PCR amplification, as indicated by the low threshold cycle values from real‐time assays. This method is simple, fast, and cost‐effective, and is a reliable tool for extracting high‐quality DNA from plant material containing PCR inhibitors.
Emotional Intelligence as a Protective Factor against Victimization in School Bullying

Previous research has identified the main predictors of being a victim of school bullying. This study focused on the phenomenon of school bullying and its relationship with self-perceived emotional intelligence. The main aim was to analyze the mediating effect of emotional attention, clarity, and repair in relation to school victimization. The sample was made up of 822 primary school pupils from 10 public schools. Data were collected through self-reports, exploring the profile of victims of school bullying, and the dimensions of self-perceived emotional intelligence (PEI). A multivariate analysis and multinomial regression showed a relationship between the two variables; the probability of being a victim of school bullying was 5.14 times higher among pupils with low clarity, 2.72 times higher among pupils with low repair, and 2.62 times higher among pupils with excessive attention. The results demonstrated that the better their emotional regulation and understanding, the less likely pupils are to be victims of school bullying. This confirmed that adequate emotional attention and excellent emotional clarity and repair are protective factors against victimization.
What Is the Relevance in the Passing Action between the Passer and the Receiver in Soccer? Study of Elite Soccer in La Liga

Soccer is a high-complexity sport in which 22 players interact simultaneously in a common space. The ball-holder interacts with their teammates by passing actions, establishing a unique communication among them in the development of the game in its offensive phase. The main aim of the present study was to analyze the pass action according to the trajectory of the ball receiver and the space for receiving the ball in terms of success at the end of play. Twenty La Liga 2018/2019 matches of two elite teams were analyzed. A system of notational analysis was used to create 11 categories based on context, timing and pass analysis. The data were analyzed using chi-squared analysis. The results showed that the main performance indicators were the efficiency of the pass, the zone of the field, the trajectory of the receiver and the reception space of the ball, which presented a moderate association with the end of play (p < 0.001). We concluded that receiving the ball on approach and in separation increased the probability of success by 5% and 7%, respectively, and a diagonal run increased the probability by 7%. Moreover, the combined analysis of these variables would improve the team performance.
COVID-19 and Acute Kidney Injury: A Systematic Review and Meta-Analysis

Background: coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome—coronavirus-2 (SARS-CoV-2)—is an ongoing pandemic with high morbidity and mortality rates. Preliminary evidence suggests that acute kidney injury (AKI) is uncommon in patients with COVID-19 and associated with poor outcomes. Study aims and design: we performed a systematic review of the literature with a meta-analysis of clinical studies to evaluate the frequency of AKI and dialysis requirement in patients who underwent hospitalization due to COVID-19. The incidence of AKI according to the death risk was calculated in these patients. The random-effects model of DerSimonian and Laird was adopted, with heterogeneity and stratified analyses. Results: thirty-nine clinical studies (n = 25,566 unique patients) were retrieved. The pooled incidence of AKI was 0.154 (95% CI, 0.107; 0.201; p < 0.0001) across the studies. Significant heterogeneity was found (p = 0.0001). The overall frequency of COVID-19-positive patients who underwent renal replacement therapy (RRT) was 0.043 (95% CI, 0.031; 0.055; p < 0.0001); no publication bias was found (Egger’s test, p = 0.11). The pooled estimate of AKI incidence in patients with severe COVID-19 was 0.53 (95% CI, 0.427; 0.633) and heterogeneity occurred (Q = 621.08, I2 = 97.26, p = 0.0001). According to our meta-regression, age (p < 0.007) and arterial hypertension (p < 0.001) were associated with AKI occurrence in hospitalized COVID-19 positive patients. The odds ratio (OR) for the incidence of AKI in deceased COVID-19 positive patients was greater than among survivors, 15.4 (95% CI, 20.99; 11.4; p < 0.001). Conclusions: AKI is a common complication in hospitalized COVID-19 positive patients. Additional studies are under way to assess the risk of AKI in COVID-19 patients and to deepen the mechanisms of kidney injury.
Epiphyseal cartilage canal architecture and extracellular matrix remodeling in mucopolysaccharidosis VII dogs at the onset of postnatal growth

ABSTRACT Purpose: Mucopolysaccharidosis (MPS) VII is a genetic, lysosomal storage disease characterized by abnormal accumulation of glycosaminoglycans in cells and tissues. MPS VII patients exhibit multiple failures of endochondral ossification during postnatal growth, including markedly delayed cartilage-to-bone conversion in the vertebrae and long bones. Cartilage canals provide the template for vascularization at the onset of secondary ossification. The objective of this study was to investigate whether abnormal cartilage canal architecture and enzyme-mediated extracellular matrix (ECM) remodeling contribute to delayed cartilage-to-bone conversion in MPS VII. Materials and Methods: The epiphyseal cartilage canal networks of 9-day-old healthy control and MPS VII-affected dog vertebrae were characterized using high-resolution, contrast-free quantitative susceptibility mapping magnetic resonance imaging. Relative expression levels of matrix metalloproteinases (MMPs) 9, 13 and 14 were examined using immunohistochemistry, while tartrate-resistant acid phosphatase (TRAP) and alkaline phosphatase (ALP) were examined using in situ enzyme staining. Results: Interestingly, the density, number, connectivity and thickness of cartilage canals was not significantly different between MPS VII and control vertebrae. Immunohistochemistry revealed diminished MMP-9, but normal MMP-13 and 14 expression by epiphyseal cartilage chondrocytes, while ALP and TRAP enzyme expression by chondrocytes and chondroclasts, respectively, were both diminished in MPS VII. Conclusions: Our findings suggest that while the epiphyseal cartilage canal network in MPS VII is normal at the onset of secondary ossification, expression of enzymes required for cartilage resorption and replacement with mineralized ECM, and initiation of angiogenesis, is impaired.
A novel P2X2‐dependent purinergic mechanism of enteric gliosis in intestinal inflammation

Enteric glial cells (EGC) modulate motility, maintain gut homeostasis, and contribute to neuroinflammation in intestinal diseases and motility disorders. Damage induces a reactive glial phenotype known as “gliosis”, but the molecular identity of the inducing mechanism and triggers of “enteric gliosis” are poorly understood. We tested the hypothesis that surgical trauma during intestinal surgery triggers ATP release that drives enteric gliosis and inflammation leading to impaired motility in postoperative ileus (POI). ATP activation of a p38‐dependent MAPK pathway triggers cytokine release and a gliosis phenotype in murine (and human) EGCs. Receptor antagonism and genetic depletion studies revealed P2X2 as the relevant ATP receptor and pharmacological screenings identified ambroxol as a novel P2X2 antagonist. Ambroxol prevented ATP‐induced enteric gliosis, inflammation, and protected against dysmotility, while abrogating enteric gliosis in human intestine exposed to surgical trauma. We identified a novel pathogenic P2X2‐dependent pathway of ATP‐induced enteric gliosis, inflammation and dysmotility in humans and mice. Interventions that block enteric glial P2X2 receptors during trauma may represent a novel therapy in treating POI and immune‐driven intestinal motility disorders.
The Two Cysteines of Tau Protein Are Functionally Distinct and Contribute Differentially to Its Pathogenicity in Vivo

Although Tau accumulation is clearly linked to pathogenesis in Alzheimer's disease and other Tauopathies, the mechanism that initiates the aggregation of this highly soluble protein in vivo remains largely unanswered. Interestingly, in vitro Tau can be induced to form fibrillar filaments by oxidation of its two cysteine residues, generating an intermolecular disulfide bond that promotes dimerization and fibrillization. The recently solved structures of Tau filaments revealed that the two cysteine residues are not structurally equivalent since Cys-322 is incorporated into the core of the fibril, whereas Cys-291 projects away from the core to form the fuzzy coat. Here, we examined whether mutation of these cysteines to alanine affects differentially Tau mediated toxicity and dysfunction in the well-established Drosophila Tauopathy model. Experiments were conducted with both sexes, or with either sex. Each cysteine residue contributes differentially to Tau stability, phosphorylation status, aggregation propensity, resistance to stress, learning, and memory. Importantly, our work uncovers a critical role of Cys-322 in determining Tau toxicity and dysfunction. SIGNIFICANCE STATEMENT Cysteine-291 and Cysteine-322, the only two cysteine residues of Tau present in only 4-Repeat or all isoforms, respectively, have competing functions: as the key residues in the catalytic center, they enable Tau auto-acetylation; and as residues within the microtubule-binding repeat region are important not only for Tau function but also instrumental in the initiation of Tau aggregation. In this study, we present the first in vivo evidence that their substitution leads to differential consequences on Tau's physiological and pathophysiological functions. These differences raise the possibility that cysteine residues play a potential role in determining the functional diversity between isoforms.
Epidemiology of streptomycin resistant Salmonella from humans and animals in Ethiopia: A systematic review and meta-analysis

Background Streptomycin is used as an epidemiological marker in monitoring programs for antimicrobial resistance in Salmonella serovars and indicates the presence of pentaresistance. However, comprehensive data on streptomycin resistant Salmonella among human, animal, and animal products is lacking in Ethiopia. In this review, we aimed to assess heterogeneity and pooled proportion of Salmonella serovars to streptomycin resistance among human, animal and animal products in Ethiopia. Methods We conducted a systematic review and meta-analysis of published literature from Ethiopia. We used the MEDLINE/ PubMed, Embase, Cochrane Library, and Google Scholar databases to identify genetic and phenotypic data on Salmonella isolates. To determine the heterogeneity and pooled proportion, we used metaprop commands and the random-effects model. Relative and cumulative frequencies were calculated to describe the overall preponderance of streptomycin resistance isolates after arcsine-transformed data. Metan funnel and meta-bias using a begg test were performed to check for publication bias. Results Overall, we included 1475 Salmonella serovars in this meta-analysis. The pooled proportion of streptomycin resistance was 47% (95% CI: 35–60%). Sub-group analysis by target population showed that the proportion of streptomycin resistance in Salmonella serovars was 54% (95% CI: 35–73%) in animal, 44% (95% Cl: 33–59%) in humans and 39% (95% CI: 24–55%) in animals products. The streptomycin resistant Salmonella serovars were statistically increasing from 0.35(95% CI: 0.12–0.58) in 2003 to 0.77(95% CI: 0.64–0.89) in 2018. The level of multidrug-resistant (MDR) Salmonella serovars was 50.1% in the meta-analysis. Conclusion We found a high level of streptomycin resistance, including multidrug, Salmonella serovars among human, animals, and animal products. This resistance was significantly increasing in the last three decades (1985–2018). The resistance to streptomycin among Salmonella serovars isolated from animals was higher than humans. This mandates the continuous monitoring of streptomycin use and practicing one health approach to preventing further development of resistance in Ethiopia. Registration We conducted a systematic review and meta-analysis after registration of the protocol in PROSPERO (CRD42019135116) following the MOOSE (Meta-Analysis of Observational Studies in Epidemiology).
Genetic deletion of connexin 37 causes polyuria and polydipsia

The connexin 37 (Cx37) channel is clustered at gap junctions between cells in the renal vasculature or the renal tubule where it is abundant in basolateral cell interdigitations and infoldings of epithelial cells in the proximal tubule, thick ascending limb, distal convoluted tubule and collecting duct; however, physiological data regarding its role are limited. In this study, we investigated the role of Cx37 in fluid homeostasis using mice with a global deletion of Cx37 (Cx37-/- mice). Under baseline conditions, Cx37-/- had ~40% higher fluid intake associated with ~40% lower urine osmolality compared to wild-type (WT) mice. No differences were observed between genotypes in urinary adenosine triphosphate or prostaglandin E2, paracrine factors that alter renal water handling. After 18-hours of water deprivation, plasma aldosterone and urine osmolality increased significantly in Cx37-/- and WT mice; however, the latter remained ~375 mmol/kg lower in Cx37-/- mice, an effect associated with a more pronounced body weight loss despite higher urinary AVP/creatinine ratios compared to WT mice. Consistent with this, fluid intake in the first 3 hours after water deprivation was 37% greater in Cx37-/- vs WT mice. Cx37-/- mice showed significantly lower renal AQP2 abundance and AQP2 phosphorylation at serine 256 than WT mice in response to vehicle or dDAVP, suggesting a partial contribution of the kidney to the lower urine osmolality. The abundance and responses of the vasopressin V2 receptor, AQP3, NHE3, NKCC2, NCC, H+-ATPase, αENaC, γENaC or Na+/K+-ATPase were not significantly different between genotypes. In summary, these results demonstrate that Cx37 is important for body water handling.
Infection-induced 5′-half molecules of tRNAHisGUG activate Toll-like receptor 7

Toll-like receptors (TLRs) play a crucial role in the innate immune response. Although endosomal TLR7 recognizes single-stranded RNAs, their endogenous RNA ligands have not been fully explored. Here, we report 5′-tRNA half molecules as abundant activators of TLR7. Mycobacterial infection and accompanying surface TLR activation up-regulate the expression of 5′-tRNA half molecules in human monocyte-derived macrophages (HMDMs). The abundant accumulation of 5′-tRNA halves also occur in HMDM-secreted extracellular vehicles (EVs); the abundance of EV-5′-tRNAHisGUG half molecules is >200-fold higher than that of the most abundant EV-microRNA (miRNA). Sequence identification of the 5′-tRNA halves using cP-RNA-seq revealed abundant and selective packaging of specific 5′-tRNA half species into EVs. The EV-5′-tRNAHisGUG half was experimentally demonstrated to be delivered into endosomes in recipient cells and to activate endosomal TLR7. Up-regulation of the 5′-tRNA half molecules was also observed in the plasma of patients infected with Mycobacterium tuberculosis. These results unveil a novel tRNA-engaged pathway in the innate immune response and assign the role of “immune activators” to 5′-tRNA half molecules.
Statistical Features in High-Frequency Bands of Interictal iEEG Work Efficiently in Identifying the Seizure Onset Zone in Patients with Focal Epilepsy

The design of a computer-aided system for identifying the seizure onset zone (SOZ) from interictal and ictal electroencephalograms (EEGs) is desired by epileptologists. This study aims to introduce the statistical features of high-frequency components (HFCs) in interictal intracranial electroencephalograms (iEEGs) to identify the possible seizure onset zone (SOZ) channels. It is known that the activity of HFCs in interictal iEEGs, including ripple and fast ripple bands, is associated with epileptic seizures. This paper proposes to decompose multi-channel interictal iEEG signals into a number of subbands. For every 20 s segment, twelve features are computed from each subband. A mutual information (MI)-based method with grid search was applied to select the most prominent bands and features. A gradient-boosting decision tree-based algorithm called LightGBM was used to score each segment of the channels and these were averaged together to achieve a final score for each channel. The possible SOZ channels were localized based on the higher value channels. The experimental results with eleven epilepsy patients were tested to observe the efficiency of the proposed design compared to the state-of-the-art methods.
Experimental Study of the Guided Wave Directivity Patterns of Thin Removable Magnetostrictive Patches

The characteristics of removable magnetostrictive thin patches are investigated for the generation of guided waves in plates. The directivity patterns of SH, S0 and A0 modes have been measured in a thin metallic plate for different combinations of static and dynamic magnetic field directions. This used different coil geometries such as racetrack and spiral coils to generate the dynamic magnetic field, as well as separate biasing static magnetic fields from permanent magnets. This arrangement generated signals via both Lorentz and magnetostrictive forces, and the resultant emitted guided waves were studied for different dynamic and static magnetic field directions and magnitudes. It is demonstrated that different guided wave modes can be produced by controlling these parameters.
Peritoneal Dialysis Fluid Supplementation with Alanyl-Glutamine Attenuates Conventional Dialysis Fluid-Mediated Endothelial Cell Injury by Restoring Perturbed Cytoprotective Responses

Long-term clinical outcome of peritoneal dialysis (PD) depends on adequate removal of small solutes and water. The peritoneal endothelium represents the key barrier and peritoneal transport dysfunction is associated with vascular changes. Alanyl-glutamine (AlaGln) has been shown to counteract PD-induced deteriorations but the effect on vascular changes has not yet been elucidated. Using multiplexed proteomic and bioinformatic analyses we investigated the molecular mechanisms of vascular pathology in-vitro (primary human umbilical vein endothelial cells, HUVEC) and ex-vivo (arterioles of patients undergoing PD) following exposure to PD-fluid. An overlap of 1813 proteins (40%) of over 3100 proteins was identified in both sample types. PD-fluid treatment significantly altered 378 in endothelial cells and 192 in arterioles. The HUVEC proteome resembles the arteriolar proteome with expected sample specific differences of mainly immune system processes only present in arterioles and extracellular region proteins primarily found in HUVEC. AlaGln-addition to PD-fluid revealed 359 differentially abundant proteins and restored the molecular process landscape altered by PD fluid. This study provides evidence on validity and inherent limitations of studying endothelial pathomechanisms in-vitro compared to vascular ex-vivo findings. AlaGln could reduce PD-associated vasculopathy by reducing endothelial cellular damage, restoring perturbed abundances of pathologically important proteins and enriching protective processes.
Differential requirements for MDM2 E3 activity during embryogenesis and in adult mice

In this study, Humpton et al. present a mouse MDM2 mutant (MDM2 I438K) analogous to human cancer cell mutations that restrains p53 sufficiently for normal growth, but exhibits an enhanced stress response in vitro. Their results are a proof of principle model for therapeutic development, and promote an approach that would inhibit MDM2 E3 activity without preventing MDM2/p53 binding.