Miracle-dz/UniFAR-FTUs huggingface dataset:
NF-κB–responsive miRNA-31-5p elicits endothelial dysfunction associated with preeclampsia via down-regulation of endothelial nitric-oxide synthase

Inflammatory cytokines, including tumor necrosis factor-α (TNFα), were elevated in patients with cardiovascular diseases and are also considered as crucial factors in the pathogenesis of preeclampsia; however, the underlying pathogenic mechanism has not been clearly elucidated. This study provides novel evidence that TNFα leads to endothelial dysfunction associated with hypertension and vascular remodeling in preeclampsia through down-regulation of endothelial nitric-oxide synthase (eNOS) by NF-κB–dependent biogenesis of microRNA (miR)-31-5p, which targets eNOS mRNA. In this study, we found that miR-31-5p was up-regulated in sera from patients with preeclampsia and in human endothelial cells treated with TNFα. TNFα-mediated induction of miR-31-5p was blocked by an NF-κB inhibitor and NF-κB p65 knockdown but not by mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase inhibitors, indicating that NF-κB is essential for biogenesis of miR-31-5p. The treatment of human endothelial cells with TNFα or miR-31-5p mimics decreased endothelial nitric-oxide synthase (eNOS) mRNA stability without affecting eNOS promoter activity, resulting in inhibition of eNOS expression and NO/cGMP production through blocking of the functional activity of the eNOS mRNA 3′-UTR. Moreover, TNFα and miR-31-5p mimic evoked endothelial dysfunction associated with defects in angiogenesis, trophoblastic invasion, and vasorelaxation in an ex vivo cultured model of human placental arterial vessels, which are typical features of preeclampsia. These results suggest that NF-κB–responsive miR-31-5p elicits endothelial dysfunction, hypertension, and vascular remodeling via post-transcriptional down-regulation of eNOS and is a molecular risk factor in the pathogenesis and development of preeclampsia.
Message and Delivery Preferences for Online Tobacco Education among Adolescents and Young Adults

Use of cigarettes and noncigarette tobacco products (NCTPs) among adolescents and young adults remains high. Strategies to communicate the risks of cigarettes and NCTPs are needed. Online tobacco education is one such strategy; however, there is little guidance for message development. We conducted four focus groups (n = 39) with adolescent and young adult to identify message and delivery preferences for online tobacco education. Participants evaluated three existing tobacco education websites. Transcripts were coded for preferred tobacco education message content, delivery, and willingness to use online tobacco education. Participants preferred novel, concise facts, embedded links to credible sources, and an anti-industry tone for website messages. Participants expressed an aversion to message strategies that relied on scare tactics or attempted to simulate youth media trends (e.g., overuse of hashtags). To increase exposure, participants recommended using social media to drive engagement. Results serve as guidelines for what information adolescents and young adults desire, as well as how they want this information communicated with online tobacco education. Our findings – youth prefer new, fact-based information that is conveyed concisely, with sources, without authoritative tones, and delivered via social media – provides guidance for how to develop online tobacco education for this at-risk population.
Complex effects of laminopathy mutations on nuclear structure and function

The nuclear lamins are important members of the intermediate filament (IF) family of proteins, involved in structural support and regulation of the nuclear lamina. Different mutations in various members of these type V IF proteins produce a staggering range of human disease phenotypes, which collectively have been termed “laminopathies. ” Compelling examples are the wide range of inherited disorders that result from rare variants in LMNA encoding lamin A/C. These laminopathies include skeletal and cardiac muscle disorders, neuropathies, multisystem progeroid disorders, and lipodystrophies, of which the latter are associated with several metabolic complications. Functions of lamin A/C that have been shown to be compromised by distinct mutations in LMNA include loss of nuclear structural integrity, altered interaction with transcription factors, and changes to post‐translational processing of pre‐lamins. Recently, evidence has emerged that certain LMNA mutations, such as those causing partial lipodystrophy, alter the interaction between chromatin and lamin A, in turn affecting the spatial orientation and distribution of chromatin within the nucleus. Because chromatin organization is exquisitely tied to global patterns of gene expression, the findings suggest a novel mechanism to explain the tissue‐specific impact of a subset of laminopathy‐associated LMNA mutations.
MiR-100 up-regulation enhanced cell autophagy and apoptosis induced by cisplatin in osteosarcoma by targeting mTOR.

OBJECTIVE Mammalian target of rapamycin (mTOR) can negatively regulate cell autophagy, while its expression and activity are associated with the pathogenesis of osteosarcoma. MicroRNA 100 (MiR-100) down-regulation is associated with the pathogenesis and chemo-sensitivity of osteosarcoma. Bioinformatics analysis revealed the targeted relationship between miR-100 and the 3'-UTR of mTOR. We investigate the role of miR-100 in affecting mTOR expression, osteosarcoma cell autophagy, and sensitivity to cisplatin. PATIENTS AND METHODS MiR-100, mTOR, and Beclin-1 expressions in osteosarcoma tissue and normal control were compared. The relationship between miR-100 and mTOR was verified by dual luciferase assay. MiR-100, mTOR, and Beclin-1 levels in MG-63 cells and MG-63/DDP cells were tested. Cell apoptosis was determined by using flow cytometry. Cell malignancy was evaluated by colony formation assay. RESULTS MiR-100 and Beclin-1 significantly declined, while mTOR significantly increased in osteosarcoma tissue compared with that of normal tissue (p<0.05). MiR-100 targeting significantly inhibited mTOR expression compared to that of untreated (p<0.05). MiR-100 expression was down-regulated and mTOR level was elevated in MG-63/DDP cells compared with MG-63 cells (p<0.05). MG-63/DDP cells exhibited reduced cell autophagy and apoptosis, and enhanced colony formation induced by DDP. MiR-100 mimic and/or small interfere mTOR (si-mTOR) significantly promoted Beclin-1 expression, cell autophagy, and cell apoptosis, while attenuated colony formation. CONCLUSIONS MiR-100 declined, while mTOR up-regulated in osteosarcoma tissue. MiR-100 up-regulation enhanced cell autophagy and apoptosis induced by cisplatin via targeted inhibiting of mTOR.
Soil Contamination by a Lead Smelter in Brazil in the View of the Local Residents

A primary lead smelter operated in Santo Amaro City in Brazil from 1960 to 1993, leaving approximately 500,000 tons of industrial dross containing 2–3% of lead and other toxic elements that contaminated the industry grounds and the urban environment. This study aimed to present the local residents’ perception towards soil contamination by the smelter. In a cross-sectional study, 208 residents from randomly selected households were interviewed about dross hazards and proposals for its management. A city map depicts the distribution and concentration of lead, cadmium, arsenic, zinc, nickel, and antimony, measured in the soil of the 39 households with visible smelter dross. Only one site complies with the soil quality reference values; 27 (69.2%) call for preventive measures, and 11 (28.2%) require intervention. The smelter dross continues widely spread over the city. Thirty (76.9%) out of the 39 residents were able to recognize the smelter dross on household surroundings. However, this ability was not associated with the concentrations of toxic elements in the soil of their residences and surroundings. The smelter and the local Prefecture were most frequently held liable for taking soil cleanup actions. The most frequently (38.0%) cited solution for managing the dross found in the households was “to provide the residents with information about health risks related to the dross”.
A randomized controlled trial of working memory and processing speed training in schizophrenia

Abstract Background Although prior research has shown that cognitive training may improve cognition for schizophrenia patients, it is currently unclear which domains of cognition should be targeted in training. One suggestion is to target low- or mid-level cognitive processes. In particular, working memory (WM) and processing speed (PS) have been named as two key areas of impairment in schizophrenia, and two domains of cognition that are linked to higher-order cognition and daily functioning. This study aimed to investigate the near-transfer (transfer of gains to related contexts), far-transfer (transfer of gains to unrelated contexts), and real-world gains associated with WM and PS training in schizophrenia. Methods Eighty-three participants with schizophrenia were recruited and randomly assigned to computerized WM training, PS training, or a no-training control group. Outcome measures included WM, PS, fluid intelligence, executive functioning, social cognition, and daily functioning and symptoms. Results PS training led to significant gains in untrained PS tasks, as well as gains in far-transfer tasks that required speed of processing. WM training did not lead to gains in untrained WM tasks and showed inconsistent effects on some far-transfer tasks. Conclusions These results suggest some benefit of domain-specific cognitive training, specifically PS training, in schizophrenia. Far-transfer of gains to other cognitive domains and to real-world functioning may not occur after targeted WM or PS training, though non-specific effects (e.g. through behavioral activation, increased motivation) may lead to improvements in some tasks. Future studies should continue to investigate the mechanisms by which cognitive training may enhance cognition and functioning in schizophrenia.
Comparison of the Effect of Phenobarbital versus Sodium Valproate in Management of Children with Status Epilepticus

Objectives Acute prolonged seizure is the most common neurological emergency in children. This research was conducted to compare the effect of intravenous phenobarbital and Sodium valproate in control of seizure in children with status epilepticus, referred to emergency ward from Mar to Nov 2013. Materials & Methods In this randomized clinical trial, registered with the code number IRCT2015051722300N1, 80 children aged 6 months to 10 years with prolonged seizure and with no response to one dose of diazepam (0.2 mg/kg) administered through IV injection during the five min were selected. Children were randomly divided into two groups, intervention, and control through permutation blocks. In intervention group, intravenous Sodium valproate (20 mg/kg) and in control group, intravenous phenobarbital (20 mg/kg) were prescribed. Data such as age, gender, history of previous seizure, seizure type, and recovery time after receiving drug was recorded in the form. Data analysis was done through descriptive statistics, Chi-square and Independent t- test. Results Two groups were the same in terms of age and gender and had no statistically significant difference, but they were different in terms of seizure type. In valproate group, 18 patients (45%) and in phenobarbital group, 32 patients (80%) had positive response to the treatment and the chi-square test showed the significant difference. Conclusion With regards to this point that in phenobarbital group, patients had more rapid response to drug in comparison with patients in Sodium valproate group, phenobarbital is a suitable and effective drug for controlling of seizure in children.
Generation and characterization of hepatocellular carcinoma cell lines with enhanced cancer stem cell potential

Hepatocellular carcinoma (HCC) is one of the most common causes for cancer‐related death worldwide with rapidly increasing incidence and mortality rates. As for other types of cancers, also in HCC cancer stem cells (CSCs) are thought to be responsible for tumour initiation, progression and therapy failure. However, as rare subpopulations of tumour tissue, CSCs are difficult to isolate, thus making the development of suitable and reliable model systems necessary. In our study, we generated HepG2 subclones with enriched CSC potential by application of the spheroid formation method and subsequent single‐cell cloning. Analyses in several 2D and 3D cell culture systems as well as a panel of functional assays both in vitro and in vivo revealed that the generated subclones displayed characteristic and sustained features of tumour initiating cells as well as highly aggressive properties related to tumour progression and metastasis. These characteristics could clearly be correlated with the expression of CSC markers that might have prognostic value in the clinical HCC setting. Therefore, we conclude that our CSC enriched HepG2 clones certainly represent suitable model systems to study the role of CSCs during HCC initiation, progression and drug resistance.
Survival and prognostic factors of pulmonary oligometastases treated with stereotactic body radiotherapy

Abstract Background: Stereotactic body radiotherapy (SBRT) for pulmonary oligometastatic disease achieves excellent treatment outcomes in terms of local control and toxicity. Patients treated with SBRT are often elderly and have multiple co-morbidities. This subset of patients may experience different survival as compared to young and fit patients subjected to radical metastasectomies. The purpose of this retrospective study was to evaluate OS and identify factors associated with OS for inoperable pulmonary oligometastases treated with SBRT. Material and methods: Criteria used for selection of patients with oligometastases included: metastases limited to ≤2 organs and in total ≤5 metastases at the time of treatment. Peripheral tumors were treated with 51 Gy to 60 Gy in three fractions or a single fraction of 30 Gy. Central tumors received a dose of 45–60 Gy in 5–8 fractions. Survival probabilities were estimated by means of Kaplan–Meier method and the relation between potential prognostic factors and OS was studied by means of Cox regression analyses. Results: In this study, 327 inoperable pulmonary oligometastases in 206 patients were treated with SBRT from the year 2005 to 2015. Primary sites of pulmonary oligometastases included colorectal carcinoma (n = 118), lung carcinoma (n = 36), melanoma (n = 11), sarcoma (n = 10), breast carcinoma (n = 7), and other tumors sites (n = 24). Median follow-up was 26 months. Median survival was 33 months. The 2-year and 5-year OS rates were 63% and 30%, respectively. On univariate analysis synchronous oligometastases (HR 0.59) and colorectal primary (HR 0.64) were associated with improved OS. On multivariable analysis synchronous oligometastases (HR 0.56), colorectal primary (HR 0.62) and tumor size <3 cm (HR 0.68) were independently associated with OS. Conclusions: SBRT to pulmonary oligometastases was associated with a 2-year OS of 63%. Tumor size <3 cm and colorectal primary tumors experienced improved OS compared to tumors >3 cm and non-colorectal primary tumors.
Learning Discriminators as Energy Networks in Adversarial Learning

We propose a novel framework for structured prediction via adversarial learning. Existing adversarial learning methods involve two separate networks, i.e., the structured prediction models and the discriminative models, in the training. The information captured by discriminative models complements that in the structured prediction models, but few existing researches have studied on utilizing such information to improve structured prediction models at the inference stage. In this work, we propose to refine the predictions of structured prediction models by effectively integrating discriminative models into the prediction. Discriminative models are treated as energy-based models. Similar to the adversarial learning, discriminative models are trained to estimate scores which measure the quality of predicted outputs, while structured prediction models are trained to predict contrastive outputs with maximal energy scores. In this way, the gradient vanishing problem is ameliorated, and thus we are able to perform inference by following the ascent gradient directions of discriminative models to refine structured prediction models. The proposed method is able to handle a range of tasks, e.g., multi-label classification and image segmentation. Empirical results on these two tasks validate the effectiveness of our learning method.
A Self‐Portrait of Michelangelo Buonarroti Hidden in a Drawing from the Ashmolean Museum

The discovery was recently announced in the scientific literature of a self‐caricature of the great Renaissance artist and genius of human anatomy, Michelangelo Buonarroti (1475–1564), concealed in a drawing from 1525. This drawing is held in the collection of the British Museum in London, England. In it, the artist portrayed the Marchesa di Pescara, Vittoria Colonna (1490–1547). The present article considers evidence that Michelangelo may have depicted himself in another portrait of Vittoria Colonna, dated to approximately 1522, which is currently in the collection of the Ashmolean Museum in Oxford, England. This concealed silhouetted figure displays physical features strikingly similar to those depicted in portraits of Michelangelo by his contemporaries, and in the description of the artist by Michelangelo's biographer, Giorgio Vasari (1511–1574): the large body, the shape of the face, the beard and the flattened nose. In this context, the present article could serve to facilitate analyses of the physical form and even of the state of health (from 1522) of one of the foremost anatomists of the Renaissance. Clin. Anat. , 2018. © 2018 Wiley Periodicals, Inc.
Impact of body mass index on the outcome of catheter ablation of atrial fibrillation

Objectives The association between obesity and atrial fibrillation (AF) is well-established. We aimed to evaluate the impact of index body mass index (BMI) on AF recurrence at 12 months following catheter ablation using propensity-weighted analysis. In addition, periprocedural complications and fluoroscopy details were examined to assess overall safety in relationship to increasing BMI ranges. Methods Baseline, periprocedural and follow-up data were collected on consecutive patients scheduled for AF ablation. There were no specific exclusion criteria. Patients were categorised according to baseline BMI in order to assess the outcomes for each category. Results Among 3333 patients, 728 (21.8%) were classified as normal (BMI <25.0 kg/m2), 1537 (46.1%) as overweight (BMI 25.5–29.0 kg/m2) and 1068 (32.0%) as obese (BMI ≥30.0 kg/m2). Procedural duration and radiation dose were higher for overweight and obese patients compared with those with a normal BMI (p=0.002 and p<0.001, respectively). An index BMI ≥30 kg/m2 led to a 1.2-fold increased likelihood of experiencing recurrent AF at 12-months follow-up as compared with overweight patients (HR 1.223; 95% CI 1.047 to 1.429; p=0.011), while no significant correlation was found between overweight and normal BMI groups (HR 0.954; 95% CI 0.798 to 1.140; p=0.605) and obese versus normal BMI (HR 1.16; 95% CI 0.965 to 1.412; p=0.112). Conclusions Patients with a baseline BMI ≥30 kg/m2 have a higher recurrence rate of AF following catheter ablation and therefore lifestyle modification to target obesity preprocedure should be considered in these patients.
Gαi1 and Gαi3mediate VEGF-induced VEGFR2 endocytosis, signaling and angiogenesis

VEGF binding to VEGFR2 leads to VEGFR2 endocytosis and downstream signaling activation to promote angiogenesis. Methods: Using genetic strategies, we tested the requirement of α subunits of heterotrimeric G proteins (Gαi1/3) in the process. Results: Gαi1/3 are located in the VEGFR2 endocytosis complex (VEGFR2-Ephrin-B2-Dab2-PAR-3), where they are required for VEGFR2 endocytosis and downstream signaling transduction. Gαi1/3 knockdown, knockout or dominant negative mutation inhibited VEGF-induced VEGFR2 endocytosis, and downstream Akt-mTOR and Erk-MAPK activation. Functional studies show that Gαi1/3 shRNA inhibited VEGF-induced proliferation, invasion, migration and vessel-like tube formation of HUVECs. In vivo, Gαi1/3 shRNA lentivirus inhibited alkali burn-induced neovascularization in mouse cornea. Further, oxygen-induced retinopathy (OIR)-induced retinal neovascularization was inhibited by intravitreal injection of Gαi1/3 shRNA lentivirus. Moreover, in vivo angiogenesis by alkali burn and OIR was significantly attenuated in Gαi1/3 double knockout mice. Significantly, Gαi1/3 proteins are upregulated in proliferative retinal tissues of proliferative diabetic retinopathy (PDR) patients. Conclusion: These results provide mechanistic insights into the critical role played by Gαi1/3 proteins in VEGF-induced VEGFR2 endocytosis, signaling and angiogenesis.
Effects of Whole Milk Supplementation on Gut Microbiota and Cardiometabolic Biomarkers in Subjects with and without Lactose Malabsorption

The aim of this study was to compare the impact of whole milk supplementation on gut microbiota and cardiometabolic biomarkers between lactose malabsorbers (LM) and absorbers (LA). We performed a pair-wise intervention study of 31 LM and 31 LA, 1:1 matched by age, sex, body mass index, and daily dairy intake. Subjects were required to add 250 mL/day whole milk for four weeks in their routine diet. At the beginning and the end of the intervention period, we collected data on gut microbiota and cardiometabolic biomarkers. Whole milk supplementation significantly increased Actinobacteria (P < 0.01), Bifidobacterium (P < 0.01), Anaerostipe (P < 0.01), and Blautia (P = 0.04), and decreased Megamonas (P = 0.04) in LM, but not LA. Microbial richness and diversity were not affected. The fecal levels of short-chain fatty acids (SCFAs) remained stable throughout the study. Body fat mass (P < 0.01) and body fat percentage (P < 0.01) reduced in both groups, but the changes did not differ between groups. No significant differences in other cardiometabolic markers were found between LM and LA. When compared with LA, whole milk supplementation could alter the intestinal microbiota composition in LM, without significant changes in fecal SCFAs and cardiometabolic biomarkers.
Ocular myasthenia gravis: an update on diagnosis and treatment

Purpose of review Myasthenia gravis is an autoimmune disease that commonly affects the palpebral and extraocular muscles. Ocular myasthenia gravis (OMG) is a variant of the disease that is confined to the ocular muscles but frequently becomes generalized over time. The diagnosis of OMG is often challenging but both clinical and laboratory findings are helpful in confirming the clinical suspicion. This review provides an update on the diagnostic approach and therapeutic options for OMG. Recent findings Antimuscle-specific tyrosine kinase and LDL-related receptor-related protein 4 are newly available serologic testing for myasthenia gravis that can help in increasing the diagnostic sensitivity of OMG. They should be included to the diagnostic algorithm of OMG in appropriate clinical situations. Summary OMG remains a primarily clinical diagnosis, but recent advances in laboratory testing can improve the diagnostic accuracy and should be used in appropriate clinical settings. The mainstay of treatment for OMG has not significantly changed over the past years, but the increasing availability of steroid-sparing agents improved the disease control while minimizing steroid-induced complications.