Miracle-dz/UniFAR-FTUs huggingface dataset:
Extracellular vesicles: new players in regulating vascular barrier function

Extracellular vesicles (EVs) have attracted rising interests in the cardiovascular field not only because they serve as serological markers for circulatory disorders but also because they participate in important physiological responses to stress and inflammation. In the circulation, these membranous vesicles are mainly derived from blood or vascular cells, and they carry cargos with distinct molecular signatures reflecting the origin and activation state of parent cells that produce them, thus providing a powerful tool for diagnosis and prognosis of pathological conditions. Functionally, circulating EVs mediate tissue-tissue communication by transporting bioactive cargos to local and distant sites, where they directly interact with target cells to alter their function. Recent evidence points to the critical contributions of EVs to the pathogenesis of vascular endothelial barrier dysfunction during inflammatory response to injury or infection. In this review, we provide a brief summary of the current knowledge on EV biology and advanced techniques in EV isolation and characterization. This is followed by a discussion focusing on the role and mechanisms of EVs in regulating blood-endothelium interactions and vascular permeability during inflammation. We conclude with a translational perspective on the diagnostic and therapeutic potential of EVs in vascular injury or infectious diseases, such as COVID-19.
Regulation of Hemogenic Endothelial Cell Development and Function.

Embryonic definitive hematopoiesis generates hematopoietic stem and progenitor cells (HSPCs) essential for establishment and maintenance of the adult blood system. This process requires the specification of a subset of vascular endothelial cells to become blood-forming, or hemogenic, and the subsequent endothelial-to-hematopoietic transition to generate HSPCs therefrom. The mechanisms that regulate these processes are under intensive investigation, as their recapitulation in vitro from human pluripotent stem cells has the potential to generate autologous HSPCs for clinical applications. In this review, we provide an overview of hemogenic endothelial cell development and highlight the molecular events that govern hemogenic specification of vascular endothelial cells and the generation of multilineage HSPCs from hemogenic endothelium. We also discuss the impact of hemogenic endothelial cell development on adult hematopoiesis. Expected final online publication date for the Annual Review of Physiology, Volume 83 is February 10, 2021. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
High Performance Liquid Chromatography Survey on Changes in Pigment Content in Ripening Grapes of Syrah. An Approach to Anthocyanin Metabolism

Three clones of Syrah grapes were studied during maturation using high performance liquid chromatography in order to observe changes in composition and to follow the evolution of the main anthocyanin contents. The reported percentages and contents allow the studied clones to be compared and also show kinetic disparities in anthocyanin and sugar formation. Except for cyanidin, which is the precursor of the other pigments, the anthocyanin composition is quickly set up after veraison and remains nearly stable until the grapes mature. Nevertheless, delphinidin drops in concentration as soon as biosynthesis ceases, and the percentage in malvidin gradually increases. Every sudden variation indicates an anomaly in pigment metabolism and means that the formation process is coming to an end. In an ideal behavior, the levels of cyanidin and delphinidin first peak three to four weeks after veraison, then decrease rapidly, whereas peonidin and malvidin are always being formed. The level of petunidin peaks by the third week and is stable thereafter. Changes in concentration of malvidin 3-glucoside esters correspond to those of the glucoside.
Clinical Trials of Stem Cell Therapy for Cerebral Ischemic Stroke

Despite recent developments in innovative treatment strategies, stroke remains one of the leading causes of death and disability worldwide. Stem cell therapy is currently attracting much attention due to its potential for exerting significant therapeutic effects on stroke patients. Various types of cells, including bone marrow mononuclear cells, bone marrow/adipose-derived stem/stromal cells, umbilical cord blood cells, neural stem cells, and olfactory ensheathing cells have enhanced neurological outcomes in animal stroke models. These stem cells have also been tested via clinical trials involving stroke patients. In this article, the authors review potential molecular mechanisms underlying neural recovery associated with stem cell treatment, as well as recent advances in stem cell therapy, with particular reference to clinical trials and future prospects for such therapy in treating stroke.
Differentiation Between Ischemic and Hemorrhagic Strokes – A Pilot Study with Transtemporal Investigation of Brain Parenchyma Elasticity Using Ultrasound Shear Wave Elastography

Abstract Introduction Ultrasound shear wave elastography is well established in diagnostics of several parenchymatous organs and is recommended by respective guidelines. So far, research about applications in relevant neurological conditions is missing, especially in adults. Here we aimed to examine the method for the differentiation of ischemic (IS) and hemorrhagic strokes (HS) and cerebral mass effects. Materials & Methods 50 patients with a confirmed diagnosis of HS or IS were enrolled in this prospective study. 2D shear wave elastography was performed on the ipsilateral and the contralateral side with a modified acoustic radiation force impulse (ARFI) technique (ElastPQ mode, Philips). Lesion volumetry was conducted based on computed tomography data for correlation with elastography results. Results Elastography measurements (EM) revealed a highly significant difference between IS and HS with mean values of 1.94 and 5.50 kPa, respectively (p < 0.00 001). Mean values of brain tissue on the non-affected side were almost identical (IS 3.38 (SD = 0.63); HS 3.35 (SD = 0.66); p = 0.91). With a sensitivity of 0.98 and a specificity of 0.99, a cut-off value of 3.52 kPa for discrimination could be calculated. There was a significant correlation of mass effect represented by midline shift and EM values on the contralateral side (Pearson correlation coefficient = 0.68, p < 0.0003). Conclusion Ultrasound brain parenchyma elastography seems to be a reliable sonographic method for discriminating between large IS and HS and for detecting and tracking conditions of intracerebral mass effects.
A meta‐analysis of anthropogenic impacts on physiological stress in wild primates

As humanity continues to alter the environment extensively, comprehending the effect of anthropogenic disturbances on the health, survival, and fitness of wildlife is a crucial question for conservation science. Many primate populations occupy suboptimal habitats prone to diverse anthropogenic disturbances that may be sources of acute and chronic stress. Quantification of glucocorticoid (GC) concentrations has repeatedly been used to explore the impact of disturbances on physiological stress. Although it is still debated, prolonged elevation of GC levels may impair reproduction, growth, and immune system activity of individuals. We quantified the effect of anthropogenic disturbances on physiological stress in primates with a global meta‐analysis based on data from 26 articles, covering 24 distinct species in 13 different countries. Anthropogenic disturbances were classified into 6 distinct categories: habitat loss, habitat degradation, ongoing logging, hunting, tourism, and other human activities. We calculated effect sizes (Hedges’ g) with the standardized mean difference in GC concentrations between primates affected by human activity and their undisturbed conspecifics. We ran random‐effects models and subgroup analyses to estimate the overall effect as well as a cumulative effect size for each disturbance category. Overall, primates inhabiting sites subject to anthropogenic disturbances exhibited significantly higher GC levels (g = 0.60; 95% CI: 0.28–0.93). Habitat loss and hunting were overall associated with increased GC concentrations, whereas the cumulative effects of the other disturbances were not statistically significant. Biologically, high GC levels may increase fitness by enabling individuals to overcome the challenges linked to anthropogenic disturbances. However, primates in disturbed environments may have sustained elevated GC levels. To strengthen future research, it is necessary to control confounding factors systematically (e.g., diet, reproductive status, predatory pressure, and resource availability) and improve understanding of the link between GC levels and the health, fitness, and survival of animals.
The anticoagulant effects of ethyl pyruvate in whole blood samples

Background Ethyl pyruvate (EP), the ethyl ester of pyruvate, has proven antiinflammatory and antioxidative properties. Additionally, anticoagulant properties have been suggested recently. EP, therefore, is a potentially antiatherosclerotic drug. We aimed to investigate whether EP possesses antiplatelet and anticoagulant properties particularly in the physiological environment of whole blood. Methods We investigated the effects of increasing concentrations of EP on platelet function, on the course of clot development, and on standard coagulation times. Additionally, clot ultrastructure using scanning electron microscopy was analysed. Results EP exerted significant antiplatelet actions: i) Impedance aggregometry amplitudes (11.7 ± 3.0 ohm, 0 μg/mL EP) dose dependently decreased (7.8 ± 3.1 ohm, 1000 μg/mL EP; -33.3%). ATP exocytosis (0.87 ± 0.24 nM, 0 μg/mL EP) measured by the luminiscent method dose-dependently decreased (0.56 ± 0.14 nM, 1000 μg/mL; -35.6%). ii) Closure times (104.4 ± 23.8 s, 0 μg/mL EP) using the Platelet function analyzer were dose-dependently prolonged (180.5 ± 82.5 s, 1000 μg/mL EP; +72.9%) using membranes coated with collagen/ADP. iii) Surface coverage (15.9 ± 5.1%, 0 μg/mL EP) dose-dependently decreased (9.0 ± 3.7%, 1000 μg/mL EP; -43.4%) using the Cone and Platelet analyzer. EP also exerted significant anticoagulant actions: Coagulation times (177.9 ± 37.8, 0 μg/mL EP) evaluated by means of thrombelastometry were dose-dependently prolonged (212.8 ± 57.7 s, 1000 μg/mL EP; +19.6%). Activated partial thromboplastin times (31.5 ± 1.8 s, 0 μg/mL EP) were dose-dependently prolonged (35.6 ± 2.3 s, 1000 μg/mL EP; +13.0%). Prothrombin times (0.94 ± 0.02 INR, 0 μg/mL EP) were dose-dependently prolonged (1.09 ± 0.04 INR, 1000 μg/mL EP; +16.0%). Conclusion We found that EP possesses antiplatelet and anticoagulant properties in whole blood. Together with its proven anti-inflammatory and antioxidative properties, EP is a potentially antiatherogenic drug.
tRFtarget: a database for transfer RNA-derived fragment targets

Abstract Transfer RNA-derived fragments (tRFs) are a new class of small non-coding RNAs and play important roles in biological and physiological processes. Prediction of tRF target genes and binding sites is crucial in understanding the biological functions of tRFs in the molecular mechanisms of human diseases. We developed a publicly accessible web-based database, tRFtarget (http://trftarget.net), for tRF target prediction. It contains the computationally predicted interactions between tRFs and mRNA transcripts using the two state-of-the-art prediction tools RNAhybrid and IntaRNA, including location of the binding sites on the target, the binding region, and free energy of the binding stability with graphic illustration. tRFtarget covers 936 tRFs and 135 thousand predicted targets in eight species. It allows researchers to search either target genes by tRF IDs or tRFs by gene symbols/transcript names. We also integrated the manually curated experimental evidence of the predicted interactions into the database. Furthermore, we provided a convenient link to the DAVID® web server to perform downstream functional pathway analysis and gene ontology annotation on the predicted target genes. This database provides useful information for the scientific community to experimentally validate tRF target genes and facilitate the investigation of the molecular functions and mechanisms of tRFs.
Germline PAX5 mutation predisposes to familial B acute lymphoblastic leukemia.

In recent years, through whole genome analyses, convincing evidence for the contribution of genetic predisposition to childhood B-cell precursor - acute lymphoblastic leukemia (BCP-ALL) due to altered PAX5 has been provided. A recurrent mutation p.Gly183Ser affecting the octapeptide domain has been described in three unrelated families and a p.Arg38His mutation affecting the DNA-binding paired domain reported in another one. We strengthen here the assumption of the inherited character of familial BCP-ALL by identifying the PAX5 p.Arg38His mutation in a family in which the three children developed BCP-ALL. One relapsed two years after his initial diagnosis and was allografted with his brother's cells before the latter developed BCP-ALL. The patient allografted relapsed later from donor-related cells. By syngeneic transplantations in mice, we showed that p.Arg38His expression does not abrogate the engraftment capacity of transduced Pax5-/- pro-B cells unlike wild type PAX5-rescued Pax5-/- pro-B cells and can predispose to BCP-ALL. Through functional and molecular analyses, we demonstrated that p.Arg38His acts as a hypomorphic variant altering the pattern of expression of PAX5 target genes. Our data highlight the importance of transcriptional deregulation, particularly of genes involved in B cell differentiation in familial BCP-ALL. We demonstrated that inherited genetic basis of susceptibility to BCP-ALL has been underestimated and should be considered before any familial allograft.
Inhibition of Staphylococcus aureus LC 554891 by Moringa oleifera Seed Extract either Singly or in Combination with Antibiotics

Bacterial outbreaks caused by Staphylococcus aureus (S. aureus) are interesting due to the existence of multidrug resistant (MDR) isolates. Therefore, there is a need to develop novel ways to control such MDR S. aureus. In this study, some natural agents such as honey bee (HB), extracts of either Moringa oleifera seeds (MSE), or leaves (MLE) and essential oils of garlic, clove, and moringa were studied for their inhibitory activity against this S. aureus pathogen. About 100 food samples including beef luncheon (n = 25), potato chips (n = 50), and corn flakes (n = 25) were investigated for possible pollution with the S. aureus bacteria. The isolated bacteria suspected to belong S. aureus that grew well onto Baird–Parker agar (Oxoid) and shiny halo zones and positive coagulase reaction were selected and identified by API-Kits; all of them that were approved belong to S. aureus (18 strains). The sensitivity of the obtained 18 S. aureus bacterial strains to 12 antibiotics were evaluated; all of them were resistant to ofloxacin; however, other antibiotics tested showed variable results. Interestingly, the S. aureus No. B3 isolated from beef luncheon was resistant to 10 antibiotics out of 12 ones tested. Multiple antibiotic resistance index (MAR) of this S. aureus strain was about 83.3%. Therefore, its identification was confirmed by sequencing of a 16S rRNA gene which approved a successful biochemical identification carried out by API Kits and such strain was designated S. aureus LC 554891. The genome of such strain appeared to contain mecA gene encoding methicillin resistance; it was found to contain hla, hlb, tsst-1, and finbA that encode α-blood hemolysis, β-blood hemolysis, toxic shock syndrome gene, and fibrinogen-binding protein gene, respectively. In addition, the virulence factors viz. sea; seb; sec encoding enterotoxins were detected in the DNA extracted from S. aureus B3 strain. Aqueous extract of Moringa oleifera seeds (MSE) showed inhibitory activity against S. aureus LC 554891 better than that obtained by tetracycline, essential oils or HB. Minimum inhibitory concentration (MIC) of MSE was 20µg/mL. Instrumental analysis of MSE showed 14 bioactive chemical compounds. Combinations of both MSE and tetracycline showed distinctive inhibitory activity against S. aureus LC 554891 than that obtained by either tetracycline or MSE singly.
General Aspects of Metal Ions as Signaling Agents in Health and Disease

This review focuses on the current knowledge on the involvement of metal ions in signaling processes within the cell, in both physiological and pathological conditions. The first section is devoted to the recent discoveries on magnesium and calcium-dependent signal transduction—the most recognized signaling agents among metals. The following sections then describe signaling pathways where zinc, copper, and iron play a key role. There are many systems in which changes in intra- and extra-cellular zinc and copper concentrations have been linked to important downstream events, especially in nervous signal transduction. Iron signaling is mostly related with its homeostasis. However, it is also involved in a recently discovered type of programmed cell death, ferroptosis. The important differences in metal ion signaling, and its disease-leading alterations, are also discussed.
Trajectories in severe persistent pain after groin hernia repair: a retrospective analysis

Abstract Objectives Severe persistent post-surgical pain (PPSP) remains a significant healthcare problem. In the third most common surgical procedure in the U.K., groin hernia repair, including 85,000 surgeries, estimated 1,500–3,000 patients will annually develop severe PPSP. While the trajectory of PPSP is generally considered a continuation of the acute post-surgery pain, recent data suggest the condition may develop with a delayed onset. This study evaluated pain-trajectories in a consecutive cohort referred from groin hernia repair-surgeons to a tertiary PPSP-center. Potential explanatory variables based on individual psychometric, sensory, and surgical profiles were analyzed. Methods Patients completed graphs on pain trajectories and questionnaires on neuropathic pain, pain-related functional assessments, and psychometrics. Surgical records and quantitative sensory testing profiles were obtained. Pain trajectories were normalized, and pre- and post-surgical segments were analyzed by a normalized area-under-the-curve (AUC) technique. Principal component analysis (PCA) was applied to the explanatory variables. Significant PCA-components were further examined using multiple logistic regression models. Results In 95 patients, the AUC identified groups of post-surgical pain trajectories (p<0.0001): group I (n=48), acute high-intensity pain progressing to PPSP; group II (n=28), delayed onset of PPSP; group III (n=7), repeat-surgery gradually inducing PPSP. Data from groups IV (n=3) and V (n=9) were not included in the statistical analysis due to small sample size and data heterogeneity, respectively. The PCA/logistic analyses indicated that neuropathic pain scores, composite pain scores, and pain-related functional assessments were explanatory variables for groups I and II. Conclusions Pain trajectories in PPSP after groin hernia repair are heterogeneous but can be classified into meaningful groups. Examination of pain trajectories, mirroring the transition from acute to severe persistent post-surgical pain, has the potential of uncovering clinically relevant pathophysiological mechanisms.
Reply to Tournier, “Pandemic Legion History More Complex than Previously Thought”

We thank Dr. Tournier for his comments, which highlight the importance of using modern tools and modern knowledge to look backwards in time to try to understand new disease emergences. We want to emphasize for readers that we neither believe nor meant to imply that phylogenetic dating of viruses and bacteria strictly reflects what is referred to as “emergence. ” It is accepted, for example, that the first human infections with HIV probably occurred at some time between the late 1800s and early 1900s, and yet we date the emergence of HIV/AIDS …
Seasonal Dynamics of Leaf Stoichiometry of Phragmites australis: A Case Study From Yangguan Wetland, Dunhuang, China

Leaf stoichiometry can enhance our understanding of leaf elements’ (C, N and P) concentrations and their corresponding ratios in an ecosystem with seasonal environment changes. This study quantified the seasonal dynamics of leaf stoichiometry of P. australis from Yangguan wetland, Dunhuang, China as a case study example. The leaf C concentration (LC) of P. australis changed between seasons and was 392.26 (g·kg−1), 417.35 (g·kg−1) and 392.58 (g·kg−1) in spring, summer and autumn, respectively. Leaf N and P concentrations (LN and LP) were 23.49 (g·kg−1), and 17.54 (g·kg−1) and 5.86 (g·kg−1), and 1.00 (g·kg−1), 0.75 (g·kg−1) and 0.16 (g·kg−1), respectively, in the three seasons. The maximum (77.68) and the minimum values (17.00) of LC:LN were observed in the autumn and spring, respectively. Seasonal variations in LC:LP also showed a similar trend, with the greatest value of 3015.91 in autumn and the lowest value of 429.39 in spring. However, the highest (45.67) and the lowest values (24.18) of LN:LP were observed in autumn and summer, respectively, indicating that the growth of P. australis was mainly affected by P. Based on these results, it can be concluded that P. australis adopted a competition strategy during the early growth stage but took on a defense life strategy at the late growth stage to cope with various environments.
One Year’s Treatment with the Glucagon-Like Peptide 1 Receptor Agonist Liraglutide Decreases Hepatic Fat Content in Women with Nonalcoholic Fatty Liver Disease and Prior Gestational Diabetes Mellitus in a Randomized, Placebo-Controlled Trial

Prior gestational diabetes mellitus (pGDM) is associated with increased risk of nonalcoholic fatty liver disease (NAFLD). Treatment with glucagon-like peptide 1 (GLP-1) receptor agonists has shown beneficial effects in NAFLD patients. We evaluated the effect of the GLP-1 analogue liraglutide on NAFLD features in women with pGDM. Eighty-two overweight/obese, nondiabetic women with pGDM were included. We performed abdominal ultrasound, transient elastography with controlled attenuation parameter (CAP), and blood sampling at baseline and after 1 year. Thirty-seven women were randomized to liraglutide (1.8 mg once-daily) and 45 to placebo. Based on the ultrasound scan, 18 women (22%) had ultrasound-verified NAFLD at baseline and of these, 10 (56%) received liraglutide treatment. After 1 year, eight participants no longer had steatosis, four in each treatment group. The number of participants who developed NAFLD was similar in the two treatment groups; five in the liraglutide group and six in the placebo group (p = 0.74). Compared to placebo, liraglutide reduced the CAP-assessed intrahepatic fat content (−28 (−44;−11) vs. 2 (−13;18) dB/m, p < 0.01) and body weight (−4.7 (−6.4;−2.9) vs. −1.4 (−3;0.3) kg, p < 0.01). One-year’s liraglutide treatment had no effect on the presence of ultrasound-diagnosed NAFLD in overweight/obese nondiabetic women with pGDM, but reduced body weight and steatosis assessed by transient elastography with CAP.