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Social isolation is a pervasive and debilitating condition that has adverse prognostic impacts. This condition often co-occurs with other geriatric syndromes, further exacerbating negative health outcomes. Given these considerations, the present study aims to elucidate the roles of social isolation in older adults with anorexia of aging and/or sarcopenia with respect to long-term mortality using a nationally representative cohort study. Data were obtained from the Taiwan Longitudinal Study on Aging (TLSA), with a sample size of 3,762 study participants aged 50 years and older. Data from 1999 (wave 4) to 2015 (wave 9) were analyzed. The TLSA questionnaire was used to define social isolation, anorexia, and sarcopenia. Logistic regressions were employed to explore the associations between social isolation, anorexia, and sarcopenia. The Cox proportional hazard model was utilized to examine the synergistic effects of social isolation and anorexia or sarcopenia on 16-year all-cause mortality. After controlling for demographic information and comorbidities, older adults with social isolation were significantly associated with anorexia (adjusted odds ratio [aOR] 1.46 [95% confidence interval: 1.00–2.12, p=0.0475]) and sarcopenia (aOR 1.35 [95% CI: 1.12–1.64, p=0.0021]). Furthermore, the synergistic effects of social isolation with anorexia (aOR 1.65 [95% CI: 1.25–2.18, p=0.0004]) or sarcopenia (aOR 1.65 [95% CI: 1.42–1.92, p<0.0001]) were both significantly associated with higher risks of all-cause mortality, while social isolation alone revealed borderline statistical significance. Our findings indicate that social isolation is closely linked to anorexia and sarcopenia among middle-aged and older adults. Additionally, social isolation significantly exacerbates the long-term mortality risk associated with anorexia of aging and sarcopenia. However, social isolation alone appears to have borderline long-term mortality risk in this cohort. These findings underscore the importance of addressing social isolation in older adults with anorexia and/or sarcopenia to optimize their health outcomes and mitigate long-term mortality risk.

Traffic emissions are a significant source of airborne particulate matter (PM) in ambient environments. These emissions contain an abundance of toxic metals and thus pose adverse effects on human health. Size-fractionated aerosol samples were collected from May to September 2013 by using micro-orifice uniform deposited impactors (MOUDIs). Sample collection was conducted simultaneously at the inlet and outlet sites of Hsuehshan Tunnel in northern Taiwan, which is the second-longest freeway tunnel (12.9 km) in Asia. This endeavor aims to characterize the chemical constituents and size distributions, as well as fingerprinting ratios of particulate metals emitted by vehicle fleets. A total of 36 metals in size-resolved aerosols were determined through inductively coupled plasma mass spectrometry. Three major groups – namely, tailpipe emissions (Zn, Pb, and V in fine mode), wear debris (Cu, Cd, Fe, Ga, Mn, Mo, Sb, and Sn), and resuspended dust (Ca, Mg, K, and Rb) – of airborne PM metals were categorized on the basis of the results of enrichment factor, correlation matrix, and principal component analysis. Size distributions of wear-originated metals resembled the pattern of crustal elements, which were predominated by super-micron particulates (PM1–10). By contrast, tailpipe exhaust elements such as Zn, Pb, and V were distributed mainly in submicron particles. By employing Cu as a tracer of wear abrasion, several inter-metal ratios – including Fe / Cu (14), Ba / Cu (1.05), Sb / Cu (0.16), Sn / Cu (0.10), and Ga / Cu (0.03) – served as fingerprints for wear debris. However, the data set collected in this work is useful for further studies on traffic emission inventory and human health effects of traffic-related PM.

Poxviruses replicate in cytoplasmic structures called factories and each factory begins as a single infecting particle. Sixty-years ago Cairns predicted that this might have effects on vaccinia virus (VACV) recombination because the factories would have to collide and mix their contents to permit recombination. We've since shown that factories collide irregularly and that even then the viroplasm mixes poorly. We've also observed that while intragenic recombination occurs frequently early in infection, intergenic recombination is less efficient and happens late in infection. Something inhibits factory fusion and viroplasm mixing but what is unclear. To study this, we've used optical and electron microscopy to track factory movement in co-infected cells and correlate these observations with virus development and recombinant formation. While the technical complexity of the experiments limited the number of cells that are amenable to extensive statistical analysis, these studies do show that intergenic recombination coincides with virion assembly and when VACV replication has declined to ≤10% of earlier levels. Along the boundaries between colliding factories, one sees ER membrane remnants and other cell constituents like mitochondria. These collisions don't always cause factory fusion, but when factories do fuse, they still entrain cell constituents like mitochondria and ER-wrapped microtubules. However, these materials wouldn't seem to pose much of a further barrier to DNA mixing and so it's likely that the viroplasm also presents an omnipresent impediment to DNA mixing. Late packaging reactions might help to disrupt the viroplasm, but packaging would sequester the DNA just as the replication and recombination machinery goes into decline and further reduce recombinant yields. Many factors thus appear to conspire to limit recombination between co-infecting poxviruses.

Background: Sorafenib is the only drug approved for the treatment of hepatocellular carcinoma (HCC). The bioenergetic propensity of cancer cells has been correlated to anticancer drug resistance, but such correlation is unclear in sorafenib resistance of HCC. Methods: Six sorafenib-naive HCC cell lines and one sorafenib-resistant HCC cell line (Huh-7R; derived from sorafenib-sensitive Huh-7) were used. The bioenergetic propensity was calculated by measurement of lactate in the presence or absence of oligomycin. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, and siRNA of hexokinase 2 (HK2) were used to target relevant pathways of cancer metabolism. Cell viability, mitochondrial membrane potential, and sub-G1 fraction were measured for in vitro efficacy. Reactive oxygen species (ROS), adenosine triphosphate (ATP) and glucose uptake were also measured. A subcutaneous xenograft mouse model was used for in vivo efficacy. Results: The bioenergetic propensity for using glycolysis correlated with decreased sorafenib sensitivity ( R 2 =0.9067, among sorafenib-naive cell lines; P =0.003, compared between Huh-7 and Huh-7 R). DCA reduced lactate production and increased ROS and ATP, indicating activation of oxidative phosphorylation (OXPHOS). DCA markedly sensitised sorafenib-resistant HCC cells to sorafenib-induced apoptosis (sub-G1 (combination vs sorafenib): Hep3B, 65.4±8.4% vs 13±2.9%; Huh-7 R, 25.3± 5.7% vs 4.3±1.5%; each P <0.0001), whereas siRNA of HK2 did not. Sorafenib (10 mg kg −1 per day) plus DCA (100 mg kg −1 per day) also resulted in superior tumour regression than sorafenib alone in mice (tumour size: −87% vs −36%, P <0.001). Conclusion: The bioenergetic propensity is a potentially useful predictive biomarker of sorafenib sensitivity, and activation of OXPHOS by PDK inhibitors may overcome sorafenib resistance of HCC.

We examine the effects of energy prices on groundwater extraction using an econometric model of a farmer's irrigation water pumping decision that accounts for both the intensive and extensive margins. Our results show that energy prices have an effect on both types of margins. Increasing energy prices would affect crop selection decisions, crop acreage allocation decisions, and farmers' demand for water. Our estimated total marginal effect, which sums the effects on the intensive and extensive margins, suggests that a $1 per million btu increase in the energy price would decrease water extraction by an individual farmer by 5.89 acre-feet per year, a decrease of 3.6 percent of the average annual extraction rate. Our estimated elasticity of water extraction with respect to energy price is -0.26.

Previously, we reported that Akt inactivation determines the sensitivity of hepatocellular carcinoma (HCC) cells to bortezomib. In this study, we report that cancerous inhibitor of protein phosphatase 2A (CIP2A), a cellular inhibitor of protein phosphatase 2A (PP2A), mediates the apoptotic effect of bortezomib in HCC. Silencing PP2A by small interference RNA (siRNA) abolishes bortezomib-induced down-regulation of phospho-Akt and apoptosis. Bortezomib increases PP2A activity in sensitive HCC cells, including Sk-Hep1, Hep3B and Huh-7, but not in resistant PLC5 cells. Bortezomib down-regulates CIP2A in a dose- and time-dependent manner in all sensitive HCC cells, whereas no alterations in CIP2A were found in resistant PLC5 cells. Knockdown of CIP2A by siRNA restored bortezomib’s effects on apoptosis and PP2A activity in PLC5 cells. Moreover, over-expression of CIP2A up-regulated phospho-Akt and protected Sk-Hep1 cells from bortezomib-induced apoptosis. It is significant that, ectopic expression of CIP2A decreased Akt-related PP2A activity, whereas silencing CIP2A increased this activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells, furthermore, our in vivo data showed that bortezomib down-regulates CIP2A and up-regulates PP2A activity in Huh-7 tumors, but not in PLC5 tumors. In conclusion, inhibition of CIP2A determines the effects of bortezomib on apoptosis and PP2A-dependent Akt inactivation in HCC.

The present research aimed to investigate the efficacy of a multifaceted intervention that included motivational interviewing (MI) and psychoeducation in improving medication adherence (MA) among patients with bipolar disorder (BD). A multicenter, cluster randomized, observer-blind, controlled, parallel-group trial was conducted in ten academic centers in Iran. Patients with BD were randomly assigned to the experimental group (EXP; n = 136) or the usual care group (UC; n = 134). The EXP group received five sessions of MI and psychoeducation together with their family members. The primary outcome measure was changes in scores on the Medication Adherence Rating Scale from baseline to 6 months post-intervention. Other outcome measures included serum levels of mood stabilizers, clinical symptoms, quality of life, as well as measures of intention, beliefs about medicine, perceived behavioral control, automaticity, action and coping planning, and adverse reactions. Medication adherence improved over time in both groups, but patients in the EXP group improved more (baseline score: 6.03; score at the sixth month: 9.55) than patients in the UC group (baseline score: 6.17; score at the sixth month: 6.67). In addition, patients in the EXP group showed greater improvement than patients in the UC group in almost all secondary outcomes 6 months following the intervention. Multifaceted interventions that include motivational-interviewing and psychoeducation can significantly improve MA and clinical and functional outcomes in patients with BD. The trial was registered with theClinicalTrials.gov database (NCT02241863) https://clinicaltrials.gov/ct2/show/NCT02241863.

In this single-arm non-comparative trial, 13 patients in an Australian hospital with severe Staphylococcus aureus infections were intravenously administered a good manufacturing practice-quality preparation of three Myoviridae bacteriophages (AB-SA01) as adjunctive therapy. AB-SA01 was intravenously administered twice daily for 14 d and the clinical, haematological and blood biochemical parameters of the recipients were monitored for 90 d. The primary outcome was the assessment of safety and tolerability (that is, pain and redness at the infusion site and systemic adverse reactions, such as fever, tachycardia, hypotension, diarrhoea or abdominal pain and the development of renal or hepatic dysfunction). No adverse reactions were reported, and our data indicate that AB-SA01 administered in this way is safe in severe S. aureus infections, including infective endocarditis and septic shock. Future controlled trials will be needed to determine the efficacy of AB-SA01 but no phage resistance evolved in vivo and the measurements of bacterial and phage kinetics in blood samples suggest that 12 h dosing of 10 9 plaque-forming units may be a rational basis for further studies. Trial Registration: Westmead Hospital Human Research Ethics Committee HREC/17/WMEAD/275; ClinicalTrials.gov: NCT03395769 ; Clinical Trials Notification (Australian Therapeutic Goods Association): CT-2018-CTN-02372-1. An observational human clinical trial using a bacteriophage preparation showed that it was well tolerated without major adverse events in human patients with Staphylococcus aureus septicaemia.

Paternal diet linked to glucose intolerance in daughters Childhood obesity and diabetes are closely related to these conditions in either parent, but how the father contributes is unclear. A study in rats shows that normal females mated with obese, glucose-intolerant fathers on a high-fat diet produce female offspring who develop glucose intolerance due to impaired insulin secretion and pancreatic function. This is the first report in any species that a father's diet can initiate progression to diabetes in his offspring. The work highlights a novel role for environmentally induced paternal factors in influencing metabolic disease in offspring and in the growing epidemics of obesity and diabetes. Here it is shown that the consumption of a high-fat diet by male rats has an intergenerational effect: it leads to the dysfunction of pancreatic β-cells in female offspring. Relative to controls, these offspring showed an early onset of impaired insulin secretion and glucose tolerance, which worsened with time. The results add to our understanding of the complex genetic and environmental factors that are leading to the global epidemic of obesity and type 2 diabetes. The global prevalence of obesity is increasing across most ages in both sexes. This is contributing to the early emergence of type 2 diabetes and its related epidemic 1 , 2 . Having either parent obese is an independent risk factor for childhood obesity 3 . Although the detrimental impacts of diet-induced maternal obesity on adiposity and metabolism in offspring are well established 4 , the extent of any contribution of obese fathers is unclear, particularly the role of non-genetic factors in the causal pathway. Here we show that paternal high-fat-diet (HFD) exposure programs β-cell ‘dysfunction’ in rat F 1 female offspring. Chronic HFD consumption in Sprague–Dawley fathers induced increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had an early onset of impaired insulin secretion and glucose tolerance that worsened with time, and normal adiposity. Paternal HFD altered the expression of 642 pancreatic islet genes in adult female offspring ( P  < 0.01); genes belonged to 13 functional clusters, including cation and ATP binding, cytoskeleton and intracellular transport. Broader pathway analysis of 2,492 genes differentially expressed ( P  < 0.05) demonstrated involvement of calcium-, MAPK- and Wnt-signalling pathways, apoptosis and the cell cycle. Hypomethylation of the Il13ra2 gene, which showed the highest fold difference in expression (1.76-fold increase), was demonstrated. This is the first report in mammals of non-genetic, intergenerational transmission of metabolic sequelae of a HFD from father to offspring.

Submicron aerosol particles (PM1) were measured in-situ using a High-Resolution Time-of-Flight Aerosol Mass Spectrometer during the summer 2009 Field Intensive Study at Queens College in New York, NY. Organic aerosol (OA) and sulfate are the two dominant species, accounting for 54% and 24%, respectively, of the total PM1 mass. The average mass-based size distribution of OA presents a small mode peaking at ~150 nm (Dva) and an accumulation mode (~550 nm) that is internally mixed with sulfate, nitrate, and ammonium. The diurnal cycles of both sulfate and OA peak between 01:00–02:00 p.m. EST due to photochemical production. The average (±σ) oxygen-to-carbon (O/C), hydrogen-to-carbon (H/C), and nitrogen-to-carbon (N/C) ratios of OA in NYC are 0.36 (±0.09), 1.49 (±0.08), and 0.012 (±0.005), respectively, corresponding to an average organic mass-to-carbon (OM/OC) ratio of 1.62 (±0.11). Positive matrix factorization (PMF) of the high resolution mass spectra identified two primary OA (POA) sources, traffic and cooking, and three secondary OA (SOA) components including a highly oxidized, regional low-volatility oxygenated OA (LV-OOA; O/C = 0.63), a less oxidized, semi-volatile SV-OOA (O/C = 0.38) and a unique nitrogen-enriched OA (NOA; N/C = 0.053) characterized with prominent CxH2x + 2N+ peaks likely from amino compounds. Our results indicate that cooking and traffic are two distinct and mass-equivalent POA sources in NYC, together contributing ~30% of the total OA mass during this study. The OA composition is dominated by secondary species, especially during high PM events. SV-OOA and LV-OOA on average account for 34% and 30%, respectively, of the total OA mass. The chemical evolution of SOA in NYC appears to progress with a continuous oxidation from SV-OOA to LV-OOA, which is further supported by a gradual increase of O/C ratio and a simultaneous decrease of H/C ratio in total OOA. Detailed analysis of NOA (5.8% of OA) presents evidence that organic nitrogen species such as amines might have played an important role in the atmospheric processing of OA in NYC, likely involving both acid-base chemistry and photochemistry. In addition, analysis of air mass trajectories and satellite imagery of aerosol optical depth (AOD) indicates that the high potential source regions of secondary sulfate and aged OA are mainly located in regions to the west and southwest of the city.