BACKGROUND & AIMS Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in nonalcoholic steatohepatitis (NASH). We evaluated the safety and anti-fibrotic effect of selonsertib, a selective inhibitor of ASK1, in patients with advanced fibrosis due to NASH. METHODS We conducted two randomized, double-blind, placebo-controlled, phase 3 trials of selonsertib in patients with NASH and bridging fibrosis (F3, STELLAR-3) or compensated cirrhosis (F4, STELLAR-4). Patients were randomized 221 to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 weeks. Liver biopsies were performed at screening and week 48 and noninvasive tests of fibrosis (NITs) were evaluated. The primary efficacy endpoint was the proportion of patients with ≥1-stage improvement in fibrosis without worsening of NASH at week 48. Additional endpoints included changes in NITs, progression to cirrhosis (in STELLAR-3), and liver-related clinical events. RESULTS Neither trial met the primary efficacy endpoint. In STELLAR-3, fibrosis improvement without worsening of NASH was observed in 10% (31/322, p=0.49 vs placebo), 12% (39/321, p=0.93 vs placebo), and 13% (21/159) of patients in the selonsertib 18 mg, selonsertib 6 mg, and placebo groups, respectively. In STELLAR-4, the primary endpoint was achieved in 14% (51/354; p=0.56), 13% (45/351; p=0.93), and 13% (22/172) of patients, respectively. Although selonsertib led to dose-dependent reductions in hepatic phospho-p38 expression indicative of pharmacodynamic activity, it had no significant effect on liver biochemistry, NITs, progression to cirrhosis, or adjudicated clinical events. The rates and types of adverse events were similar among selonsertib and placebo groups. CONCLUSIONS Forty-eight weeks of selonsertib monotherapy had no anti-fibrotic effect in patients with bridging fibrosis or compensated cirrhosis due to NASH. V.BACKGROUND AND AIMS Non-alcoholic fatty liver disease (NAFLD) could play a catalyst role on the development of metabolic comorbidities, although the magnitude of this effect in metabolically healthy NAFLD patients remains unclear. We assessed the role of biopsy-proven NAFLD on the risk of developing type 2 diabetes mellitus (T2DM) and other metabolic comorbidities (arterial hypertension (AHT), and dyslipidemia) in metabolically healthy patients. METHODS From HEPAmet Registry (N=1030), we included 178 biopsy-proven NAFLD patients with a metabolically healthy status, defined by the absence of baseline T2DM, AHT, and dyslipidemia. Hepamet Fibrosis Score (HFS), NAFLD Fibrosis Score, and FIB-4 were calculated. Follow-up was computed from the biopsy to the diagnosis of T2DM, AHT, or dyslipidemia. RESULTS During a follow-up of 5.6+4.4 years, T2DM occurred in 9% (16/178), AHT in 8.4% (15/178), low HDL in 9.6% (17/178), and hypertriglyceridemia in 23.6% (42/178) of patients. In multivariate analysis, significant fibrosis predicted T2DM and AHT. Independent variables related to T2DM appearance were significant fibrosis [HR 2.95 (CI95% 1.19-7.31); p=0.019], glucose levels [p=0.008], age [p=0.007] and BMI [p=0.039]. AHT was independently linked to significant fibrosis [HR 2.39 (CI95% 1.14-5.10); p=0.028], age [p=0.0001], BMI [p=0.006], glucose [p=0.021] and platelets [p=0.050]. The annual incidence rate of T2DM was higher in patients with significant fibrosis (4.4 vs. 1.2 cases per 100 person-years), and increased in presence of obesity, similar than AHT (4.6 vs. 1.1 cases per 100 person-years). HFS >0.12 predicted the risk of T2DM (25% (4/16) vs. HFS 0.12, but not FIB4 or NFS predicted the occurrence of T2DM. BACKGROUND/PURPOSE Despite the importance of sleep for athletic performance, there is a lack of normative sleep data and sex comparisons in collegiate athletes. The primary purpose of our study was to assess the prevalence of insufficient sleep in collegiate athletes, with a secondary aim to compare male and female athletes. PROCEDURES Participants included 121 collegiate athletes (65 men and 56 women) from six team sports and three individual sports. Subjective assessments of sleep included at-home sleep diary, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and Insomnia Severity Index (ISI). Objective assessments of sleep included three consecutive off-season weekdays of wrist actigraphy to assess total sleep time (TST) and sleep efficiency (SE). MAIN FINDINGS Actigraphy revealed that 94% of student-athletes received 10. Objective TST was not different between sexes (6.7±0.1 vs. 6.7±0.1 hours, p=0.99), but females demonstrated higher SE (87±1 vs. 82±1%, p less then 0.01) and lower WASO (31±2 vs. 38±2 min, p=0.02). Male athletes significantly overestimated TST (i.e., subjective minus objective TST) when compared to female athletes (Δ0.7±0.1 vs. Δ0.3±0.1 hours/night; p less then 0.01). https://www.selleckchem.com/products/sto-609.html PSQI, ISI, and ESS were not different between sexes. CONCLUSIONS The majority of male and female collegiate athletes received less than age-recommended levels of sleep, and 44% subjectively reported poor sleep quality, mild severity insomnia, and/or excessive daytime sleepiness. Sex differences were observed in male and female collegiate athletes. OBJECTIVES Examine the associations of sleep problems with health-risk behaviors and psychological well-being in a representative sample of Canadian adults. DESIGN Cross-sectional. SETTING The 2011-2012 Canadian Community Health Survey (CCHS, conducted by Statistics Canada). PARTICIPANTS Of all individuals taking part in the 2011-2012 CCHS, 42,600 participants aged ≥18 years from five provinces/territories (Nova Scotia, Quebec, Manitoba, Alberta, and Yukon) who participated in the sleep survey module were selected for this study. MEASUREMENTS Health conditions were self-reported. Sleep problems referred to extreme sleep durations (either less then 5 or ≥10 hours) and insomnia symptom. Health-risk behaviors included physical inactivity, daily smoking, highly sedentary behavior, and insufficient fruit and vegetable consumption. Worse psychological well-being included having worse self-rated general health, worse self-rated mental health, and worse sense of belonging, and being dissatisfied with life. RESULTS The participants represented 10,614,600 Canadian adults aged ≥18 years from the five abovementioned provinces/territories. A significantly higher prevalence of all health-risk behaviors and worse psychological well-being was found among participants with extreme sleep durations (than those with 7 to less then 8 hours) and insomnia symptom (than those without insomnia symptom). After multivariate adjustment, extreme sleep durations and insomnia symptom were still independently associated with increased odds of all health-risk behaviors and worse psychological well-being. CONCLUSIONS Both extreme sleep durations and insomnia symptom were independently associated with health-risk behaviors and worse psychological well-being among Canadian adults. The increasing challenge of antibiotic resistance stimulates the search for novel antibacterial agents, especially such that would be effective against multi-drug resistant bacterial strains. Fortunately, natural compounds are excellent sources of potentially new drug leads. Particularly interesting in this context are polyether antibiotic salinomycin (SAL) and its semi-synthetic derivatives, as they exhibit large spectrum of bioactivity. We synthesized and evaluated the antibacterial activity of a series of SAL analogs; four singly (2-3, 15, 17) and two doubly modified (16, 18) derivatives were found to show excellent inhibitory activity not only against planktonic Gram(+) bacterial cells, but also towards select strains of methicillin-resistant staphylococci with the MIC values of 1-4 µg mL-1. Of note, the most promising candidates were more effective in preventing bacterial biofilm formation than unmodified SAL and a commonly used antibiotic - ciprofloxacin. Furthermore, we proved that rational modification of C20 hydroxyl of SAL may reduce genotoxic properties of the obtained analogs. Mechanistically, the structure-activity relationship studies suggested that electroneutral transport mechanism could be beneficial in terms of ensuring high antibacterial activity of SAL derivatives. Peptide nucleic acid (PNA), a synthetic DNA mimic that is devoid of the (deoxy)ribose-phosphate backbone yet still perfectly retains the ability to recognize natural nucleic acids in a sequence-specific fashion, can be employed as a tool to modulate gene expressions via several different mechanisms. The unique strength of PNA compared to other oligonucleotide analogs is its ability to bind to nucleic acid targets with secondary structures such as double-stranded and quadruplex DNA as well as RNA. This digest aims to introduce general readers to the advancement in the area of modulation of DNA/RNA functions by PNA, its current status and future research opportunities, with emphasis on recent progress in new targeting modes of structured DNA/RNA by PNA and PNA-mediated gene editing. The naturally occurring host defense peptide (HDP), aurein 2.2, secreted by the amphibian Litoria aurea, acts as a moderate antibacterial, affecting Gram positive bacteria such as Staphylococcus aureus by forming selective ion pores. In a quest to find more active analogues of aurein 2.2, peptides 73 and 77 were discovered. These peptides were rich in arginine and tryptophan and found to have MICs of 4 μg/mL. Here we examined what impact the increased charge from +2 to +3 and a slight increase in hydrophobic moment relative to aurein 2.2 had on the mechanism of action of these two analogues. Using a time-kill assay, both peptides 73 and 77 were found to kill bacteria more effectively than the parent peptide. Using solution CD and NMR, the peptides were found to not adopt a continuous α-helical structure, i.e. the analogues were not helical from residue 1-13 like the parent peptide. Results obtained from oriented CD (OCD), DiSC35 and pyranine assays and a gel retardation experiment showed that the peptides did not function by membrane perturbation and further showed that peptide 73 and 77 did not interact with DNA. Overall, the data were consistent with these peptides acting as cell penetrating peptides with intracellular targets, which did not appear to be DNA. Pinholins are a family of lytic membrane proteins responsible for the lysis of the cytosolic membrane in host cells of double stranded DNA bacteriophages. Protein-lipid interactions have been shown to influence membrane protein topology as well as its function. This work investigated the interactions of pinholin with the phospholipid bilayer while in active and inactive confirmations to elucidate the different interactions the two forms have with the bilayer. Pinholin incorporated into deuterated DMPC-d54 lipid bilayers, along with 31P and 2H solid state NMR (SS-NMR) spectroscopy were used to probe the protein-lipid interactions with the phosphorus head group at the surface of the bilayer while interactions with the 2H nuclei were used to study the hydrophobic core. A comparison of the 31P chemical shift anisotropy (CSA) values of the active S2168 pinholin and inactive S21IRS pinholin indicated stronger head group interactions for the pinholin in its active form when compared to that of the inactive form supporting the model of a partially externalized peripheral transmembrane domain (TMD) of the active S2168 instead of complete externalized TMD1 as suggested by Ahammad et al.