Miracle-dz/UniFAR-FTUs huggingface dataset:
Hydroxytyrosol Acetate Inhibits Vascular Endothelial Cell Pyroptosis via the HDAC11 Signaling Pathway in Atherosclerosis

Hydroxytyrosol acetate (HT-AC), a natural polyphenolic compound in olive oil, exerts an anti-inflammatory effect in cardiovascular diseases (CVDs). Pyroptosis is a newly discovered form of programmed inflammatory cell death and is suggested to be involved in the atherosclerosis (AS) process. However, the effect of HT-AC on vascular endothelial cell pyroptosis remains unknown. Thus, we aimed to investigate the effect of HT-AC on vascular endothelial cell pyroptosis in AS and related signaling pathways. In vivo studies showed that HT-AC alleviated the formation of atherosclerotic lesions and inhibited pyroptosis in the aortic intima of ApoE−/− mice fed a high-fat diet (HFD) for 12 weeks. In vitro, we found that HT-AC treatment of human umbilical vein endothelial cells (HUVECs) alleviated tumor necrosis factor-alpha (TNF-α)-induced pyroptosis by decreasing the number of PI positive cells, decreasing the enhanced protein expressions of activated caspase-1 and gasdermin D (GSDMD), as well as by decreasing the release of pro-inflammatory interleukin (IL)-1β and IL-6. Besides, HT-AC down-regulated HDAC11 expression in the aortic intima of HFD-fed ApoE−/− mice and TNF-α-stimulated HUVECs. To determine the underlying mechanism of action, molecular docking and drug affinity responsive target stability (DARTS) were utilized to identify whether HDAC11 protein is a target of HT-AC. The molecular docking result showed good compatibility between HT-AC and HDAC11. DARTS study's result showed that HDAC11 protein may be a target of HT-AC. Further study demonstrated that knockdown of HDAC11 augmented the inhibition of HT-AC on pyroptosis in TNF-α-stimulated HUVECs. These findings indicate that HT-AC might prevent vascular endothelial pyroptosis through down-regulation of HDAC11 related signaling pathway in AS.
Delta Shock Index During Emergency Department Stay Is Associated With in Hospital Mortality in Critically Ill Patients

Background: Delta shock index (SI; i.e., change in SI over time) has been shown to predict mortality and need for surgical intervention among trauma patients at the emergency department (ED). However, the usefulness of delta SI for prognosis assessment in non-traumatic critically ill patients at the ED remains unknown. The aim of this study was to analyze the association between delta SI during ED management and in-hospital outcomes in patients admitted to the intensive care unit (ICU). Method: This was a retrospective study conducted in two tertiary medical centers in Taiwan from January 1, 2016, to December 31, 2017. All adult non-traumatic patients who visited the ED and who were subsequently admitted to the ICU were included. We calculated delta SI by subtracting SI at ICU admission from SI at ED triage, and we analyzed its association with in-hospital outcomes. SI was defined as the ratio of heart rate to systolic blood pressure (SBP). The primary outcome was in-hospital mortality, and the secondary outcomes were hospital length of stay (HLOS) and early mortality. Early mortality was defined as mortality within 48 h of ICU admission. Result: During the study period, 11,268 patients met the criteria and were included. Their mean age was 64.5 ± 15.9 years old. Overall, 5,830 (51.6%) patients had positive delta SI. Factors associated with a positive delta SI were multiple comorbidities (51.2% vs. 46.3%, p < 0.001) and high Simplified Acute Physiology Score [39 (29–51) vs. 37 (28–47), p < 0.001). Patients with positive delta SI were more likely to have tachycardia, hypotension, and higher SI at ICU admission. In the regression analysis, high delta SI was associated with in-hospital mortality [aOR (95% CI): 1.21 (1.03–1.42)] and early mortality [aOR (95% CI): 1.26 (1.07–1.48)], but not for HLOS [difference (95% CI): 0.34 (−0.48 to 1.17)]. In the subgroup analysis, high delta SI had higher odds ratios for both mortality and early mortality in elderly [aOR (95% CI): 1.59 (1.11–2.29)] and septic patients [aOR (95% CI): 1.54 (1.13–2.11)]. It also showed a higher odds ratio for early mortality in patients with triage SBP <100 mmHg [aOR (95% CI): 2.14 (1.21–3.77)] and patients with triage SI ≥ 0.9 [aOR (95% CI): 1.62 (1.01–2.60)]. Conclusion: High delta SI during ED stay is correlated with in-hospital mortality and early mortality in patients admitted to the ICU via ED. Prompt resuscitation should be performed, especially for those with old age, sepsis, triage SBP <100 mmHg, or triage SI ≥ 0.9.
Gestational and Breastfeeding Low-Protein Intake on Blood Pressure, Kidney Structure, and Renal Function in Male Rat Offspring in Adulthood

Background: Our previous studies demonstrated that maternal protein-restricted (low-protein, LP) 16-week-old offspring had pronounced nephron number reduction and arterial hypertension associated with an unchanged glomerular filtration rate (GFR). An enhanced gomerular area may be related to increased glomerular filtration and overflow, which accounts for glomerular filtration barrier breakdown and early glomerulosclerosis. The effect of protein restriction during gestational and breastfeeding periods is unknown. Method: The functional e-structural kidney evaluation was obtained using lithium and creatinine clearance, kidney morphometry, immunoblotting, and immunostaining analysis in 16 and 24-week-old LP offspring compared to age-matched NP progeny. Results: Low protein rats’ progeny had significantly reduced birth weight, without previous catch-up growth phenomena, in parallel with a decreased adiposity index. Transforming growth factor-beta 1 (TGF-β1) glomerular expression was significantly enhanced in the LP group. Also, the LP offspring had a 38% lower nephron number and an increased glomerular volume. They also presented with a higher cardiac index and arterial blood pressure compared with age-matched NP offspring. The LP rats exhibited augmented Na+/K+-ATPase in the proximal segments, and NOS1 immunoreactivity in whole renal tissue was associated with sodium retention in the proximal nephron segments. We also found significantly enhanced collagen content associated with increased TGFβ1 and ZEB1/2 renal immunoreactivity in LP offspring compared with NP offspring. Increased hypertrophy markers in LP podocytes were associated with an amplified IL-6/STAT3 pathway activity. Conclusion: To our knowledge, these are the first data demonstrating renal functional and structural changes in protein restriction during gestation and lactation model of fetal programming. The fetal-programmed adult offspring showed pronounced structural glomerular disorders with an accentuated and advanced fibrosis stage, without a change in the GFR. These findings suggest that the glomerular enhanced TGF-β1 action may induce ZEB1/2 expression that may cause glomeruli epithelial-to-mesenchymal transition. Besides, decreased nephron number in the LP offspring with preserved glomerular function may be related to protective or even attenuate the activated IL-6/STAT3 pathway.
Sequencing of the Canine Cytochrome P450 CYP2C41 Gene and Genotyping of Its Polymorphic Occurrence in 36 Dog Breeds

Cytochrome P450 (CYP) drug metabolizing enzymes play an important role in efficient drug metabolism and elimination. Many CYPs are polymorphic and, thereby, drug metabolism can vary between individuals. In the case of canine CYP2C41, gene polymorphism was identified. However, as the first available canine genome sequences all were CYP2C41 negative, this polymorphism could not be clarified at the genomic level. The present study provides an exact characterization of the CYP2C41 gene deletion polymorphism at the genomic level and presents a PCR-based genotyping method that was used for CYP2C41 genotyping of 1,089 individual subjects from 36 different dog breeds. None of the Bearded Collie, Bernese Mountain, Boxer, Briard, French Bulldog or Irish Wolfhound subjects had the CYP2C41 gene in their genomes. In contrast, in the Chinese Char-Pei, Siberian Husky, Schapendoes and Kangal breeds, the CYP2C41 allele frequency was very high, with values of 67, 57, 43, and 34%, respectively. Interestingly, the site of gene deletion was identical for all CYP2C41 negative dogs, and all CYP2C41 positive dogs showed highly homologous sequence domains upstream and downstream from the CYP2C41 gene. CYP2C41 genotyping can now be routinely used in future pharmacokinetic studies in canines, in order to identify genetically-based poor or extensive drug metabolizers. This, together with more extensive in vitro drug screening for CYP2C41 substrates will help to determine the clinical relevance of CYP2C41, and to optimize drug treatment. Although the relative abundance of the CYP2C41 protein in the canine liver seems to not be very high, this CYP could substantially contribute to hepatic drug metabolism in dogs expressing CYP2C41 from both alleles and, when CYP2C41 shows higher catalytic activity to a given drug than other hepatic metabolic enzymes.
Creative Thinking in Tourette's Syndrome: An Uncharted Topic

This opinion article discusses the literature about creativity in patients with Tourette Syndrome (TS) and provides some suggestions about how this topic might be further exploited. TS is a neurodevelopmental disorder, with an onset occurring before the age of 18 (Robertson, 2011). The main symptom is the presence of tics, of which one or multiple sound tics and multiple motor tics (American Psychiatric Association, 2013). TS is associated with other potential impairments, such as cognitive anomalies, physical pain, impairment in daily activities, emotional and behavioral problems (Cavanna et al., 2013; Morand-Beaulieu et al., 2017). Despite these problems, high levels of creativity have been reported in TS patients. Examples of eminent individuals, e.g., W. A. Mozart (Ashoori and Jankovic, 2007), allegedly affected by TS, have been described (Szejko et al., 2019). On these premises, researchers studied more recent cases of TS patients showing creative aptitudes and measured the average levels of creative skills in samples of TS patients, to speculate about the reasons why these patients excel in creativity.
Organizing Psycho-Oncological Care for Cancer Patients: The Patient’s Perspective

Background Cancer patients often suffer from psychological distress during or after cancer treatment, but the use of psycho-oncological care among cancer patients is limited. One of the reasons might be that the way psycho-oncological care is organized, does not fit patients’ preferences. This study aimed to obtain detailed insight into cancer patients’ preferences regarding the organization of psycho-oncological care. Methods 18 semi-structured interviews were conducted among cancer patients. Patients completed psycho-oncological treatment between 2015 and 2020 at the psychology department in a general hospital or a center specialized in psychological cancer care in the Netherlands. The interview comprised questions related to preferences regarding the institute where to receive treatment, the psychologist who provides treatment, and the type of treatment, as well as questions related to experienced barriers and facilitators to receive psycho-oncological care. Interviews were digitally recorded and transcribed verbatim. Data were analyzed individually by two coders into key issues and themes. Results Regarding the institute, easy accessibility and prompt availability of psychol-oncological care were considered important. Regarding the psychologist, most participants had a strong preference to be treated by a psychologist specialized in cancer or other somatic diseases. Individual face-to-face therapy was preferred above other types of treatment. Several barriers were mentioned to receive psycho-oncological treatment, among which poor accessibility to psycho-oncological care, lack of knowledge on the possibilities for psycho-oncological treatment, and stigma. Most frequently mentioned facilitators were being assertive to ask for help, having a good relationship with the healthcare professional, and the integration of psycho-oncological support within medical cancer care. Conclusion From the patient’s perspective, the organization of psycho-oncological care for cancer patients should focus on easy accessibility and availability, delivered by specialized psychologists, and integration in medical cancer care. Online and group therapy are acceptable, but individual face-to-face therapy is preferred. It is warranted to increase awareness on psycho-oncological care targeting both patients and healthcare providers.
Capturing T Lymphocytes’ Dynamic Interactions With Human Neural Cells Using Time-Lapse Microscopy

To fully perform their functions, T lymphocytes migrate within organs’ parenchyma and interact with local cells. Infiltration of T lymphocytes within the central nervous system (CNS) is associated with numerous neurodegenerative disorders. Nevertheless, how these immune cells communicate and respond to neural cells remains unresolved. To investigate the behavior of T lymphocytes that reach the CNS, we have established an in vitro co-culture model and analyzed the spatiotemporal interactions between human activated CD8+ T lymphocytes and primary human astrocytes and neurons using time-lapse microscopy. By combining multiple variables extracted from individual CD8+ T cell tracking, we show that CD8+ T lymphocytes adopt a more motile and exploratory behavior upon interacting with astrocytes than with neurons. Pretreatment of astrocytes or neurons with IL-1β to mimic in vivo inflammation significantly increases CD8+ T lymphocyte motility. Using visual interpretation and analysis of numerical variables extracted from CD8+ T cell tracking, we identified four distinct CD8+ T lymphocyte behaviors: scanning, dancing, poking and round. IL-1β-pretreatment significantly increases the proportion of scanning CD8+ T lymphocytes, which are characterized by active exploration, and reduces the proportion of round CD8+ T lymphocytes, which are less active. Blocking MHC class I on astrocytes significantly diminishes the proportion of poking CD8+ T lymphocytes, which exhibit synapse-like interactions. Lastly, our co-culture time-lapse model is easily adaptable and sufficiently sensitive and powerful to characterize and quantify spatiotemporal interactions between human T lymphocytes and primary human cells in different conditions while preserving viability of fragile cells such as neurons and astrocytes.
Delirium in Children Undergoing Hematopoietic Cell Transplantation: A Multi-Institutional Point Prevalence Study

Introduction: Delirium occurs frequently in adults undergoing hematopoietic cell transplantation, with significant associated morbidity. Little is known about the burden of delirium in children in the peri-transplant period. This study was designed to determine delirium rates, define risk factors (demographic and treatment related), and establish feasibility of multi-institutional bedside screening for delirium in children undergoing hematopoietic cell transplant. Methods: This is a multi-institutional point prevalence study. All subjects were prospectively screened for delirium twice daily using the Cornell Assessment of Pediatric Delirium over a 10-day period. De-identified data, including basic demographics and daily characteristics, were extracted from the electronic medical record. Results: Eleven North American institutions were included, 106 children were enrolled, and 883 hospital days were captured. Delirium screening was successfully completed on more than 98% of the study days. Forty-eight children (45%) developed delirium over the course of the 10-day study. Children were diagnosed with delirium on 161/883 study days, for an overall delirium rate of 18% per day. Higher delirium rates were noted in children <5 years old (aOR 0.41 for children over 5 years), and in association with specific medications (melatonin, steroids, and tacrolimus). Conclusion: Delirium was a frequent occurrence in our study cohort, with identifiable risk factors. Delirium screening is highly feasible in the pediatric hematopoietic cell transplant patient population. A large-scale prospective longitudinal study following children throughout their transplant course is urgently needed to fully describe the epidemiology of pediatric delirium, explore the effects of delirium on patient outcomes, and establish guidelines to prevent and treat delirium in the peri-transplant period.
Macro and Trace Elements in Hemp (Cannabis sativa L.) Cultivated in Greece: Risk Assessment of Toxic Elements

The accumulation of hazardous contaminants in Cannabis sativa L. raises warning signs regarding possible adverse effects on human health due to the consumption of herbal medicines and/or other herbal edible products made from cannabis. Thus, there is an urge to investigate the levels of hazardous contaminants, such as heavy metals, in cannabis plant. In the present study, 29 macro and trace elements, including both beneficial and toxic elements (heavy metals and metalloids), were investigated in 90 samples of Cannabis sativa L. collected from Greece. According to the results, the detected concentrations of macro elements in the leaves/flowers of cannabis ranged between 28 and 138,378 ppm, and of trace elements between 0.002 and 1352.904 ppm. Although the concentrations of elements varied among the samples, their accumulation pattern was found to be similar, with the contribution of toxic elements to the total concentration of trace elements being below 1%. The detected levels of the most toxic elements were below the prescribed limits established by the WHO, while the calculated THQ and CR values showed no risk (non-carcinogenic and carcinogenic) for the population exposed to the current cannabis samples. Positive correlation between the concentration of elements and cannabis geographical origin and variety was observed. Cannabis leaves/flowers were more contaminated with trace and macro elements than seeds.
Colchicine Blocks Tubulin Heterodimer Recycling by Tubulin Cofactors TBCA, TBCB, and TBCE

Colchicine has been used to treat gout and, more recently, to effectively prevent autoinflammatory diseases and both primary and recurrent episodes of pericarditis. The anti-inflammatory action of colchicine seems to result from irreversible inhibition of tubulin polymerization and microtubule (MT) assembly by binding to the tubulin heterodimer, avoiding the signal transduction required to the activation of the entire NLRP3 inflammasome. Emerging results show that the MT network is a potential regulator of cardiac mechanics. Here, we investigated how colchicine impacts in tubulin folding cofactors TBCA, TBCB, and TBCE activities. We show that TBCA is abundant in mouse heart insoluble protein extracts. Also, a decrease of the TBCA/β-tubulin complex followed by an increase of free TBCA is observed in human cells treated with colchicine. The presence of free TBCA is not observed in cells treated with other anti-mitotic agents such as nocodazole or cold shock, neither after translation inhibition by cycloheximide. In vitro assays show that colchicine inhibits tubulin heterodimer dissociation by TBCE/TBCB, probably by interfering with interactions of TBCE with tubulin dimers, leading to free TBCA. Manipulation of TBCA levels, either by RNAi or overexpression results in decreased levels of tubulin heterodimers. Together, these data strongly suggest that TBCA is mainly receiving β-tubulin from the dissociation of pre-existing heterodimers instead of newly synthesized tubulins. The TBCE/TBCB+TBCA system is crucial for controlling the critical concentration of free tubulin heterodimers and MT dynamics in the cells by recycling the tubulin heterodimers. It is conceivable that colchicine affects tubulin heterodimer recycling through the TBCE/TBCB+TBCA system producing the known benefits in the treatment of pericardium inflammation.
DHCR24 Knock-Down Induced Tau Hyperphosphorylation at Thr181, Ser199, Thr231, Ser262, Ser396 Epitopes and Inhibition of Autophagy by Overactivation of GSK3β/mTOR Signaling

Accumulating evidences supported that knock-down of DHCR24 is linked to the pathological risk factors of AD, suggesting a potential role of DHCR24 in AD pathogenesis. However, the molecular mechanism link between DHCR24 and tauopathy remains unknown. Here, in order to elucidate the relationship between DHCR24 and tauopathy, we will focus on the effect of DHCR24 on the tau hyperphosphorylation at some toxic sites. In present study, we found that DHCR24 knock-down significantly lead to the hyperphosphorylation of tau sites at Thr181, Ser199, Thr231, Ser262, Ser396. Moreover, DHCR24 knock-down also increase the accumulation of p62 protein, simultaneously decreased the ratio of LC3-II/LC3-I and the number of autophagosome compared to the control groups, suggesting the inhibition of autophagy activity. In contrast, DHCR24 knock-in obviously abolished the effect of DHCR24 knock-down on tau hyperphosphrylation and autophagy. In addition, to elucidate the association between DHCR24 and tauopathy, we further showed that the level of plasma membrane cholesterol, lipid raft-anchored protein caveolin-1, and concomitantly total I class PI3-K (p110α), phospho-Akt (Thr308 and Ser473) were significantly decreased, resulting in the disruption of lipid raft/caveola and inhibition of PI3-K/Akt signaling in silencing DHCR24 SH-SY5Y cells compared to control groups. At the same time, DHCR24 knock-down simultaneously decreased the level of phosphorylated GSK3β at Ser9 (inactive form) and increased the level of phosphorylated mTOR at Ser2448 (active form), leading to overactivation of GSK3β and mTOR signaling. On the contrary, DHCR24 knock-in largely increased the level of membrane cholesterol and caveolin-1, suggesting the enhancement of lipid raft/caveola. And synchronously DHCR24 knock-in also abolished the effect of DHCR24 knock-down on the inhibition of PI3-K/Akt signaling as well as the overactivation of GSK3β and mTOR signaling. Collectively, our data strongly supported DHCR24 knock-down lead to tau hyperphosphorylation and the inhibition of autophagy by a lipid raft-dependent PI3-K/Akt-mediated GSK3β and mTOR signaling. Taking together, our results firstly demonstrated that the decrease of plasma membrane cholesterol mediated by DHCR24 deficiency might contribute to the tauopathy in AD and other tauopathies.
Antibodies and Vaccines Target RBD of SARS-CoV-2

The novel human coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which gives rise to the coronavirus disease 2019 (COVID-19), has caused a serious threat to global public health. On March 11, 2020, the WHO had officially announced COVID-19 as a pandemic. Therefore, it is vital to find effective and safe neutralizing antibodies and vaccines for COVID-19. The critical neutralizing domain (CND) that is contained in the receptor-binding domain (RBD) of the spike protein (S protein) could lead to a highly potent neutralizing antibody response as well as the cross-protection of other strains of SARS. By using RBD as an antigen, many neutralizing antibodies are isolated that are essential to the therapeutics of COVID-19. Furthermore, a subunit vaccine, which is based on the RBD, is expected to be safer than others, thus the RBD in the S protein is a more important target for vaccine development. In this review, we focus on neutralizing antibodies that are targeting RBD as well as the vaccine based on RBD under current development.