Miracle-dz/UniFAR-FTUs huggingface dataset:
Isolation and initial structure-functional characterization of endogenous tRNA-derived stress-induced RNAs

ABSTRACT Recent transcriptome-wide studies have identified a diverse pool of transfer RNA (tRNA)-derived RNAs or tRNA-derived fragments (tRFs). Some of these RNAs have been demonstrated to be functional and involved in multiple biological processes ranging from the regulation of gene expression to transgenerational epigenetic inheritance. Post-transcriptional maturation of tRNAs includes various processing events including extensive decoration by various RNA modifications, which are required for correct tRNA folding and stability. Moreover, tRNA modifications determine the pattern and specificity of tRNA cleavage. The major drawbacks of many studies in the field of tRFs are that most of them used synthetic RNAs that closely mimic endogenous tRFs in their sequence, yet lack RNA modification that is found in vivo. Here, we developed a simple method to isolate tRNA-derived stress-induced RNAs (tiRNAs), a specific subset of tRFs. Our approach is scalable, cost-effective and relies on the purification of individual tiRNAs based on a sequence-specific RNA/DNA isolation technique using DNA probes. Our method facilitates functional studies of tiRNAs by addressing how physiological RNA modifications within tRNA fragments affect their biological activities. Here, we report pilot functional studies on selected endogenous tiRNAs, namely tiRNAAla and tiRNAGly. We show that natural 5ʹ-tiRNAAla molecules assemble into G-quadruplex structures, and endogenous 5ʹ-tiRNAGly possesses translation inhibition activity.
The ‘entourage effect’ or ‘hodge-podge hashish’: the questionable rebranding, marketing, and expectations of cannabis polypharmacy

ABSTRACT Introduction The concept of a cannabis ‘entourage effect’ was first coined as a hypothetical afterthought in 1998. Since then, multiple scientific reviews, lay articles, and marketing campaigns have promoted the effect as a wholly beneficial manifestation of polypharmacy expected to modulate the therapeutic effects of cannabis and its derivatives. There is reason to wonder at the authenticity of such claims. Areas covered A broad definition of the entourage effect is presented, followed by brief summaries of the nature of cannabis polypharmacy and the commonly cited contributing phytochemicals, with special attention to their attendant adverse effects. A critical analysis is then offered of the primary literature that is often portrayed as suggestive of the effect in existing reviews, with further studies being drawn from PubMed and Google Scholar searches. A final discussion questions the therapeutic value of the entourage effect and offers alternate perspectives on how it might be better interpreted. Expert opinion Claims of a cannabis entourage effect invoke ill-defined and unsubstantiated pharmacological activities which are commonly leveraged toward the popularization and sale of ostensible therapeutic products. Overestimation of such claims in the scientific and lay literature has fostered their misrepresentation and abuse by a poorly regulated industry.
Glucose regulates hypoxia‐induced NLRP3 inflammasome activation in macrophages

Although the intimate linkage between hypoxia and inflammation is well known, the mechanism underlying this linkage has not been fully understood. Nucleotide‐binding oligomerization domain‐like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is an intracellular multiprotein complex that regulates interleukin‐1β (IL‐1β) secretion and pyroptosis, and is implicated in the pathogenesis of sterile inflammatory diseases. Here, we investigated the regulatory mechanism of NLRP3 inflammasome activation in response to hypoxia in macrophages. Severe hypoxia (0.1% O2) induced the processing of pro‐IL‐1β, pro‐caspase‐1, and gasdermin D, as well as the release of IL‐1β and lactate dehydrogenase in lipopolysaccharide (LPS)‐primed murine macrophages, indicating that hypoxia induces NLRP3 inflammasome‐driven inflammation and pyroptosis. NLRP3 deficiency and a specific caspase‐1 blockade inhibited hypoxia‐induced IL‐1β release. Hypoxia‐induced IL‐1β release and cell death were augmented under glucose deprivation, and an addition of glucose in the media negatively regulated hypoxia‐induced IL‐1β release. Under hypoxia and glucose deprivation, hypoxia‐induced glycolysis was not driven and subsequently, the intracellular adenosine triphosphates (ATPs) were depleted. Atomic absorption spectrometry analysis showed a reduction of intracellular K+ concentrations, indicating the K+ efflux occurring under hypoxia and glucose deprivation. Furthermore, hypoxia and glucose deprivation‐induced IL‐1β release was significantly prevented by inhibition of K+ efflux and KATP channel blockers. In vivo experiments further revealed that IL‐1β production was increased in LPS‐primed mice exposed to hypoxia (9.5% O2), which was prevented by a deficiency of NLRP3, an apoptosis‐associated speck‐like protein containing a caspase recruitment domain, and caspase‐1. Our results demonstrate that NLRP3 inflammasome can sense intracellular energy crisis as a danger signal induced by hypoxia and glucose deprivation, and provide new insights into the mechanism underlying hypoxia‐induced inflammation.
An Investigation of the Mechanism of Rapid Relief of Ulcerative Colitis Induced by Five-flavor Sophora Flavescens Enteric-coated Capsules Based on Network Pharmacology

Aim and Objective: Five-Flavor Sophora flavescens Enteric-Coated Capsules (FSEC) are the only proprietary Chinese medicine approved for the treatment of ulcerative colitis (UC) in China. Phase II and III clinical trials have shown that the curative effect of FSEC in relieving UC was not inferior to that of mesalazine granules and enteric-coated tablets, but its pharmacological mechanism is unclear. Therefore, the network pharmacology is used to reveal the more comprehensive effective components and targets of FSEC in the treatment of UC. Methods: We screened the components of FSEC based on the TCMSP database, determined the action targets of these compounds through target fishing, and integrated the UC disease targets of several disease gene databases. The FSEC-UC composite targets were obtained by matching the two results, and then a PPI network was constructed to analyze the relationship between these targets, and the core targets were selected by topological correlation parameters. Finally, GO-BP and KEGG enrichment analyses were carried out using the clusterProfiler software package. Results: One hundred and sixty active components of FSEC were identified and 77 targets were obtained. Of these, 30 core targets were the main targets of FESC in the treatment of UC. And quercetin, kaempferol, luteolin and mangiferin were regarded as the core active components of FSEC. The results screened by GO and KEGG enrichment analysis showed that FSEC played a comprehensive therapeutic role in immune recognition, anti-inflammation and antioxidation mainly through IL-17, TNF, Toll-like receptor, NF-kappa B, and Th17 cell differentiation. Conclusion: The molecular mechanism of UC remission induced by FSEC was predicted by network pharmacology. These findings provide an important theoretical basis for further study of the effective substances and mechanism of FSEC in the treatment of UC.
Clinical Utility of the Risk Analysis Index as a Prospective Frailty Screening Tool within a Multi-practice, Multi-hospital Integrated Healthcare System

Supplemental Digital Content is available in the text Objective: The goal of this project was to first address barriers to implementation of the Risk Analysis Index (RAI) within a large, multi-hospital, integrated healthcare delivery system, and to subsequently demonstrate its utility for identifying at-risk surgical patients. Background: Prior studies demonstrate the validity of the RAI for evaluating preoperative frailty, but they have not demonstrated the feasibility of its implementation within routine clinical practice. Methods: Implementation of the RAI as a frailty screening instrument began as a quality improvement initiative at the University of Pittsburgh Medical Center in July 2016. RAI scores were collected within a REDCap survey instrument integrated into the outpatient electronic health record and then linked to information from additional clinical datasets. NSQIP-eligible procedures were queried within 90 days following the RAI, and the association between RAI and postoperative mortality was evaluated using logistic regression and Cox proportional hazards models. Secondary outcomes such as inpatient length of stay and readmissions were also assessed. Results: RAI assessments were completed on 36,261 unique patients presenting to surgical clinics across five hospitals from July 1 to December 31, 2016, and 8,172 of these underwent NSQIP-eligible surgical procedures. The mean RAI score was 23.6 (SD 11.2), the overall 30-day and 180-day mortality after surgery was 0.7% and 2.6%, respectively, and the median time required to collect the RAI was 33 [IQR 23–53] seconds. Overall clinic compliance with the recommendation for RAI assessment increased from 58% in the first month of the study period to 84% in the sixth and final month. RAI score was significantly associated with risk of death (HR=1.099 [95% C.I.: 1.091 – 1.106], p < 0.001). At an RAI cutoff of ≥37, the positive predictive values for 30- and 90-day readmission were 14.8% and 26.2%, respectively, and negative predictive values were 91.6% and 86.4%, respectively. Conclusions: The RAI frailty screening tool can be efficiently implemented within multi-specialty, multi-hospital healthcare systems. In the context of our findings and given the value of the RAI in predicting adverse postoperative outcomes, health systems should consider implementing frailty screening within surgical clinics.
Cytotoxic and Apoptotic Induction Potential of Extracts from Fermented Citrullus vulgaris Thunb. Seeds on Cervical and Liver Cancer Cells

Abstract The anti-cancer activities of many fermented foods and beverages are now scientifically established. Ogiri-egusi is a condiment prepared from fermentation of Citrullus vulgaris (melon) seeds and consumed in many countries of West Africa. Its anti-oxidative and anti-hyperlipidaemic properties have been reported. This study investigated the anti-cancer activities of the aqueous and methanolic extracts from ogiri-egusi. Cytotoxicity was investigated using the MTT and colony-formation inhibition assays while flow-cytometer based Apopercentage assay was used to quantify apoptosis in extracts-treated cervical and liver cancer and normal human fibroblast cells. The inhibitory concentration responsible for killing 50% of cells after 24 h by the aqueous extract in KMST-6, HeLa, and Hep-G2 cells were estimated at 1.610, 1.020, and 1.507 mg/mL respectively. While these values reduced with increasing incubation time in cancer cells it increased in the non-cancer cell. Furthermore, the extract significantly induced apoptosis in HeLa (97 ± 0.18%) and Hep-G2 (73 ± 6.73%) cells. These findings were corroborated by cells morphologic presentations and inhibition of colony formation assay. These findings suggest that the aqueous extract from fermented Citrullus vulgaris seeds might be a nutraceutical with potential anti-cancer properties.
Elevated Th17 cell frequencies and Th17/Treg ratio are associated with airway hyperresponsiveness in asthmatic children

Abstract Introduction: The elevation of T helper (Th)17 cell frequencies and the imbalance of Th17/regulatory T (Treg) cells occur in asthma pathogenesis. Airway hyperresponsiveness (AHR) is a cardinal feature of asthma, and Th17 responses can promote AHR. We hypothesized that changes in Th17 cells and the Th17/Treg ratio correlate with AHR in asthmatic children. Methods: Twenty asthmatic children and twenty healthy children were included in the study. The peak expiratory flow (PEF) % pred, forced expiratory volume in 1 s (FEV1) % pred and the FEV1/forced vital capacity (FVC) ratio were measured in all subjects. Methacholine challenge test (MCT) was performed in asthmatic children. Flow cytometric analysis was used to determine the proportions of Th17 and Treg cells in peripheral blood mononuclear cells. ELISA was used to assess serum levels of interleukin (IL)-17A and IL-10. Results: Th17 cell frequencies (2.272 ± 0.207% in asthmatics, 1.193 ± 0.131% in controls, P < 0.01) and Th17/Treg ratios (0.371 ± 0.0387 in asthmatics, 0.183 ± 0.020 in controls, P < 0.01) were significantly increased in asthmatic children compared to controls. In asthmatic children, the MCT grade had positive correlations with the Th17 cell frequencies [r = 0.718, P < 0.01], serum IL-17A level [r = 0.753, P < 0.01] and Th17/Treg ratio [r = 0.721, P < 0.01], while the log10PD20-FEV1 value was negatively correlated with the Th17 cell frequencies [r = −0.654, P < 0.01], serum IL-17A level [r = −0.652, P < 0.01] and Th17/Treg ratio [r = −0.625, P < 0.01]. Conclusion: Th17 cell, IL-17A and Th17/Treg ratio were positively correlated with AHR in asthmatic children. It may be helpful to monitor Th17 cells and the Th17/Treg ratio as indicators of AHR in clinical practice.
Role of biochar in anaerobic microbiome enrichment and methane production enhancement during olive mill wastewater biomethanization

The current research work attempted to investigate, for the first time, the impact of biochar addition, on anaerobic digestion of olive mill wastewater with different initial chemical oxygen demand loads in batch cultures (10 g/L, 15 g/L, and 20 g/L). Methane yields were compared by applying one-way analysis of variance (ANOVA) followed by post-hoc Tukey’s analysis. The results demonstrated that adding at 5 g/L biochar to olive mill wastewater with an initial chemical oxygen demand load of 20 g/L increased methane yield by 97.8% and mitigated volatile fatty acid accumulation compared to the control batch. According to the results of microbial community succession revealed by the Illumina amplicon sequencing, biochar supplementation significantly increased diversity of the microbial community and improved the abundance of potential genera involved in direct interspecies electron transfer, including Methanothrix and Methanosarcina. Consequently, biochar can be a promising alternative in terms of the recovery of metabolic activity during anaerobic digestion of olive mill wastewater at a large scale.
The impact of African-trained neurosurgeons on sub-Saharan Africa.

OBJECTIVE Sub-Saharan Africa (SSA) represents 17% of the world's land, 14% of the population, and 1% of the gross domestic product. Previous reports have indicated that 81/500 African neurosurgeons (16.2%) worked in SSA-i.e., 1 neurosurgeon per 6 million inhabitants. Over the past decades, efforts have been made to improve neurosurgery availability in SSA. In this study, the authors provide an update by means of the polling of neurosurgeons who trained in North Africa and went back to practice in SSA. METHODS Neurosurgeons who had full training at the World Federation of Neurosurgical Societies (WFNS) Rabat Training Center (RTC) over the past 16 years were polled with an 18-question survey focused on demographics, practice/case types, and operating room equipment availability. RESULTS Data collected from all 21 (100%) WFNS RTC graduates showed that all neurosurgeons returned to work to SSA in 12 different countries, 90% working in low-income and 10% in lower-middle-income countries, defined by the World Bank as a Gross National Income per capita of ≤ US$995 and US$996-$3895, respectively. The cumulative population in the geographical areas in which they practice is 267 million, with a total of 102 neurosurgeons reported, resulting in 1 neurosurgeon per 2.62 million inhabitants. Upon return to SSA, WFNS RTC graduates were employed in public/private hospitals (62%), military hospitals (14.3%), academic centers (14.3%), and private practice (9.5%). The majority reported an even split between spine and cranial and between trauma and elective; 71% performed between 50 and more than 100 neurosurgical procedures/year. Equipment available varied across the cohort. A CT scanner was available to 86%, MRI to 38%, surgical microscope to 33%, endoscope to 19.1%, and neuronavigation to 0%. Three (14.3%) neurosurgeons had access to none of the above. CONCLUSIONS Neurosurgery availability in SSA has significantly improved over the past decade thanks to the dedication of senior African neurosurgeons, organizations, and volunteers who believed in forming the new neurosurgery generation in the same continent where they practice. Challenges include limited resources and the need to continue expanding efforts in local neurosurgery training and continuing medical education. Focus on affordable and low-maintenance technology is needed.
Equilibrium radionuclide angiography compared with tissue doppler imaging for detection of right ventricular dyssynchrony and prediction of acute response to cardiac resynchronization therapy

Abstract Objective: The aim of this study was to compare tissue doppler imaging (TDI) and equilibrium radionuclide angiography (ERNA) for detection of right ventricular (RV) dyssynchrony and prediction of the acute response to cardiac resynchronization therapy (CRT). Methods: This study was approved by the local ethics committee of Huai’an First People's Hospital. Patient consent was not provided due to the use of completely anonymous images from which the individual could not be identified in this study. Thirty-three patients with nonischemic dilated cardiomyopathy underwent both TDI and ERNA before and within 48 hour after CRT implantation. RV dyssynchrony was measured with TDI using the difference in time to peak systolic velocity between the RV free wall and ventricular septum (RV-T). With ERNA, the standard of RV mean phase angle and RV phase standard deviation (RVmPA% and RVPSD%) were assessed. Results: Moderate positive correlations were observed among baseline RVmPA%, RVPSD% and RV-T (r = 0.689 and 0.716, P < .001). Twenty patients (61%) with a reduction of at least 15% in LV end-systolic volume were categorized as acute responders after CRT. Responders showed significant reduction in RVmPA% and RVPSD% after CRT (53.60 ± 4.15% to 43.95 ± 6.88% and 14.00 ± 2.41% to 10.40 ± 1.67%, P < .05), whereas RV-T remained unchanged (50.10 ± 10.28 ms to 49.25 ± 13.64ms, NS). Receiver operating characteristic curve showed that the cut-off value of RV-T was 48.5ms, yielding 65% sensitivity and 77% specificity to predict acute respond to CRT. The cut-off value of RVmPA% was 49.5%, yielding 85% sensitivity and 85% specificity and the cut-off value of RVPSD% was 11.5%, yielding 85% sensitivity and 92% specificity. Conclusion: ERNA might be an appropriate alternative to TDI for assessment of RV dyssynchrony. Either RVmPA% or RVPSD% was highly predictive for acute response to CRT.
The Rate of Acquisition of Carbapenemase-Producing Enterobacteriaceae among Close Contact Patients Depending on Carbapenemase Enzymes

Background Carbapenemase-producing Enterobacteriaceae (CPE) are highly drug-resistant pathogens. Screening the contacts of newly-identified CPE patients is crucial for nosocomial transmission control. We evaluated the acquisition rate of CPE in close contacts as a function of CPE genotype. Materials and Methods This study was conducted in Asan Medical Center, a 2,700-bed, tertiary teaching hospital in Seoul, Korea, between November 2010 and October 2017. Index cases were defined as patients with positive tests for CPE from any infected or colonized site during hospitalization who had no direct epidemiologic linkage with existing CPE patients; close contact patients were defined as those whose hospital stay overlapped with the stay of an index case for at least one day and who occupied the same room or intensive care unit (ICU). Secondary patients were defined as those who produced positive CPE culture isolates from surveillance cultures that had the same CPE enzyme as that of the index case patients. Results A total of 211 index case patients and 2,689 corresponding contact patients were identified. Of the contact patients, 1,369 (50.9%) including 649 New-Delhi metallo-beta-lactamase-1 (NDM-1) and 448 Klebsiella pneumoniae carbapenemase (KPC)-producing CPE exposures were screened, and 44 secondary patients (3.2%; 95% confidence interval 2.3 - 4.3%) were positive for NDM-1-producing CPE (16 patients) and KPC-producing (24 patients) CPE. The CPE acquisition rate (5.4%) for KPC-producing CPE exposures was significantly higher than that for NDM-1 exposures (2.7%) (P = 0.01). Conclusion The CPE acquisition rate was 3.2% among close contacts sharing a multi-patient room, with about a two-fold higher risk of KPC-producing CPE than NDM-1-producing CPE.
A retrospective study

To explore whether mosaic/aneuploid embryos can be transferred when there is no normal embryo available for transplant. The clinical pregnancy outcomes and amniocentesis outcomes of transplantedmosaic embryos during 28 preimplantation genetic testing (PGT) cycles were retrospectively analyzed. Chromosomes of 4 donatedmosaic blastocysts were comprehensively screened by next-generation sequencing. About 10 (35.7%) of the 28 transferredmosaic embryos were implanted and had a gestational sac. But 5 womenmiscarried due to lack of fetal heartbeat between the 7th and 12th week of pregnancy. Five women had full-term pregnancies and gave birth to 5 healthy babies. Three of the 4 donated mosaic blastocysts had normal trophectoderm and inner cell mass, but the other 1 had abnormal embryonic cell mass. When no normal transplantable embryo is available in the PGT cycles, but the underlying risk must be fully informed. Abbreviations: aCGH = array comparative genomic hybridization, ICM = inner cell mass, IVF = in-vitro fertilization, NGS = nextgeneration sequencing, PGT = preimplantation genetic testing, PGT-A = preimplantation genetic testing for aneuploidy, PGT-SR = preimplantation genetic testing for chromosomal structural rearrangements, qPCR = real-time quantitative polymerase chain reaction.
Regulation of NRF2 by Na+/K+-ATPase: implication of tyrosine phosphorylation of Src

Abstract Tumors adapt well to the imbalanced redox status created by rapid growth and limited nutrient availability because they highly express high levels of NRF2 to counteract oxidative stress. Therefore, inhibition of NRF2 is currently considered a feasible strategy for development of chemotherapeutic agents. In the present study, we identified that Na+/K+-ATPase regulates NRF2 in A549 cells. Suppression of Na+/K+-ATPase by convallatoxin or siRNAs downregulates NRF2 in A549 cells, and this event is mediated by Ca2+-dependent induction of CSK1 and subsequent phosphorylation of SRC at Tyr 527. Consistent with this finding, knocking down the α1 or β1 subunit of Na+/K+-ATPase promotes the generation of intracellular ROS by cisplatin and potentiates cisplatin-induced apoptosis and autophagy in A549 cells. Our study reveals that the signaling axis composed of Na+/K+-ATPase, CSK1, and tyrosine phosphorylation of Src could be a useful target for development of NRF2 inhibitors.