Activation of PPARa ameliorates hepatic insulin resistance and steatosis in high fructose-fed mice despite increased ER stress

Endoplasmic reticulum (ER) stress is suggested to cause hepatic insulin resistance by increasing de novo lipogenesis (DNL) and/or directly interfering with insulin signaling via activation of the JNK and IKK pathway. The present study interrogated these two proposed mechanisms in a mouse model of hepatic insulin resistance induced by a high fructose (HFru) diet with the treatment of fenofibrate (FB, 100 mg/kg/day), a PPARa agonist known to reduce lipid accumulation while maintaining elevated DNL in the liver. FB administration completely corrected HFru-induced glucose intolerance, hepatic steatosis and the impaired hepatic insulin signaling (pAkt and pGSK3ß). Intriguingly, both IRE1/XBP1 and PERK/eIF2a arms of the UPR signaling were activated. While retaining the elevated DNL (indicated by the upregulation of SREBP1c, ACC, FAS and SCD1 and 3H2O incorporation into lipids), FB treatment markedly increased FA oxidation (indicated by induction of ACOX1, pACC, ß-HAD activity and 14C-palmitate oxidation) and eliminated the accumulation of diacylglycerols (DAGs) which is known to impact on insulin signaling. Despite the marked activation of UPR signaling, neither JNK nor IKK appeared to be activated. These findings suggest that lipid accumulation (mainly DAGs), rather than the activation of JNK or IKK is pivotal for ER stress to cause hepatic insulin resistance. Therefore, by reducing the accumulation of deleterious lipids, activation of PPARa is able to ameliorate hepatic insulin resistance against increased ER stress

Rapid analysis of risk assessment using developed simulation of chemical industrial accidents software package.

The environmental consequences are defined as consequences of accidental release of hazardous substances to the natural environment. This release can lead to many hazards depending on the material stored. The consequences of these hazards to the environment are widespread and have significant importance to human communities living in the surroundings. The mathematical models are extremely useful tools to predict the impacts of chemical process accidents. The objective of this paper is to develop a software package for accident simulation and damage potential estimation. The software is coded in visual basic and is compatible with windows working environments. The software is called simulation of chemical industrial accident. This application is a comprehensive software package which can be integrated with geographical information system to predict and display the consequence of chemical hazards. The software is a user-friendly and effective tool for evaluating the consequences of major chemical accidents, process decision making for land-use planning, namely locating suitable hazardous installations, hazardous waste disposal areas and emergency response plan

Constraint of B_{d,s}-bar{B}_{d,s} mixing on warped extra-dimension model

Recent CDF measurement of the Bs-Bs oscillation frequency, at the Tevatron imposes significant constraint on various models for new physics. A warped extra-dimension model with custodial isospin symmetry accommodates the Bd-Bd mixing at tree level mainly through the Kaluza-Klein gluons. This is due to the misalignment between the bulk gauge eigenstates and the localized Yukawa eigenstates of the bulk fermions. We adopt the universal 5D Yukawa coupling model where all Yukawa couplings are of order one. The SM fermion mass spectra and mixings are controlled by the bulk Dirac mass parameters. With two versions of the hadronic parameter values, we investigate the implication of the observed BB mixings on this model. The CP-violating effects on the Bd system is shown to provide very strong constraint: The first Kaluza-Klein mass of a gluon has its lower bound about 3.7 TeV with 1 sigma uncertainty.Comment: published version in JHEP, CP-violating effects include

Patient and clinician characteristics and preferences for increasing participation in placebo surgery trials: a scoping review of attributes to inform a discrete choice experiment

Background: Orthopaedic surgeries include some of the highest volume surgical interventions globally; however, studies have shown that a significant proportion of patients report no clinically meaningful improvement in pain or function after certain procedures. As a result, there is increasing interest in conducting randomised placebo-controlled trials in orthopaedic surgery. However, these frequently fail to reach recruitment targets suggesting a need to improve trial design to encourage participation. The objective of this study was to systematically scope the available evidence on patient and clinician values and preferences which may influence the decision to participate in placebo surgery trial. Methods: A systematic review was conducted via a literature search in the MEDLINE, Embase, PsycInfo, CINAHL, and EconLit databases as of 19 July 2021, for studies of any design (except commentaries or opinion pieces) based on two key concepts: patient and clinician characteristics, values and preferences, and placebo surgery trials. Results: Of 3424 initial articles, we retained 18 eligible studies. Characteristics, preferences, values, and attitudes of patients (including levels of pain/function, risk/benefit perception, and altruism) and of clinicians (including concerns regarding patient deception associated with placebo, and experience/training in research) influenced their decisions to participate in placebo-controlled trials. Furthermore, some aspects of trial design, including randomisation procedures, availability of the procedure outside of the trial, and the information and consent procedures used, also influenced decisions to participate. Conclusion: Participant recruitment is a significant challenge in placebo surgery trials, and individual decisions to participate appear to be sensitive to preferences around treatment. Understanding and quantifying the role patient and clinician preferences may play in surgical trials may contribute to the optimisation of the design and implementation of clinical trials in surgery

Directed evolution of nucleotide-based libraries using lambda exonuclease

Directed evolution of nucleotide libraries using recombination or mutagenesis is an important technique for customizing catalytic or biophysical traits of proteins. Conventional directed evolution methods, however, suffer from cumbersome digestion and ligation steps. Here, we describe a simple method to increase nucleotide diversity using single-stranded DNA (ssDNA) as a starting template. An initial PCR amplification using phosphorylated primers with overlapping regions followed by treatment with lambda exonuclease generates ssDNA templates that can then be annealed via the overlap regions. Double-stranded DNA (dsDNA) is then generated through extension with Klenow fragment. To demonstrate the applicability of this methodology for directed evolution of nucleotide libraries, we generated both gene shuffled and regional mutagenesis synthetic antibody libraries with titers of 2x108 and 6x107, respectively. We conclude that our method is an efficient and convenient approach to generate diversity in nucleic acid based libraries, especially recombinant antibody libraries

Strong Spin-Phonon Coupling Mediated by Single Ion Anisotropy in the All-In-All-Out Pyrochlore Magnet Cd2Os2 O7

Spin-phonon coupling mediated by single ion anisotropy was investigated using optical spectroscopy and first-principles calculations in the all-in-all-out pyrochlore magnet Cd2Os2O7. Clear anomalies were observed in both the phonon frequencies and linewidths at the magnetic ordering temperature. The renormalization of the phonon modes was exceptionally large, signifying the presence of an unconventional magnetoelastic term from large spin-orbit coupling. In addition, the relative phonon frequency shifts show a strong correlation with the modulation of noncubic crystal field by the corresponding lattice distortion. Our observation establishes a new type of spin-phonon coupling through single ion anisotropy, a second-order spin-orbit coupling term, in Cd2Os2O7. © 2017 American Physical Society4

Association of PCK1 with Body Mass Index and Other Metabolic Features in Patients With Psychotropic Treatments.

Weight gain is a major health problem among psychiatric populations. It implicates several receptors and hormones involved in energy balance and metabolism. Phosphoenolpyruvate carboxykinase 1 is a rate-controlling enzyme involved in gluconeogenesis, glyceroneogenesis and cataplerosis and has been related to obesity and diabetes phenotypes in animals and humans. The aim of this study was to investigate the association of phosphoenolpyruvate carboxykinase 1 polymorphisms with metabolic traits in psychiatric patients treated with psychotropic drugs inducing weight gain and in general population samples. One polymorphism (rs11552145G > A) significantly associated with body mass index in the psychiatric discovery sample (n = 478) was replicated in 2 other psychiatric samples (n1 = 168, n2 = 188), with AA-genotype carriers having lower body mass index as compared to G-allele carriers. Stronger associations were found among women younger than 45 years carrying AA-genotype as compared to G-allele carriers (-2.25 kg/m, n = 151, P = 0.009) and in the discovery sample (-2.20 kg/m, n = 423, P = 0.0004). In the discovery sample for which metabolic parameters were available, AA-genotype showed lower waist circumference (-6.86 cm, P = 0.008) and triglycerides levels (-5.58 mg/100 mL, P < 0.002) when compared to G-allele carriers. Finally, waist-to-hip ratio was associated with rs6070157 (proxy of rs11552145, r = 0.99) in a population-based sample (N = 123,865, P = 0.022). Our results suggest an association of rs11552145G > A polymorphism with metabolic-related traits, especially in psychiatric populations and in women younger than 45 years

Influence of MCHR2 and MCHR2-AS1 Genetic Polymorphisms on Body Mass Index in Psychiatric Patients and In Population-Based Subjects with Present or Past Atypical Depression.

Obesity development during psychotropic treatments represents a major health issue in psychiatry. Melanin-concentrating hormone receptor 2 (MCHR2) is a central receptor involved in energy homeostasis. MCHR2 shares its promoter region with MCHR2-AS1, a long antisense non-coding RNA. The aim of this study was to determine whether tagging single nucleotide polymorphisms (tSNPs) of MCHR2 and MCHR2-AS1 are associated with the body mass index (BMI) in the psychiatric and in the general population. The influence of MCHR2 and MCHR2-AS1 tSNPs on BMI was firstly investigated in a discovery psychiatric sample (n1 = 474). Positive results were tested for replication in two other psychiatric samples (n2 = 164, n3 = 178) and in two population-based samples (CoLaus, n4 = 5409; GIANT, n5 = 113809). In the discovery sample, TT carriers of rs7754794C>T had 1.08 kg/m2 (p = 0.04) lower BMI as compared to C-allele carriers. This observation was replicated in an independent psychiatric sample (-2.18 kg/m2; p = 0.009). The association of rs7754794C>T and BMI seemed stronger in subjects younger than 45 years (median of age). In the population-based sample, a moderate association was observed (-0.17 kg/m2; p = 0.02) among younger individuals (<45y). Interestingly, this association was totally driven by patients meeting lifetime criteria for atypical depression, i.e. major depressive episodes characterized by symptoms such as an increased appetite. Indeed, patients with atypical depression carrying rs7754794-TT had 1.17 kg/m2 (p = 0.04) lower BMI values as compared to C-allele carriers, the effect being stronger in younger individuals (-2.50 kg/m2; p = 0.03; interaction between rs7754794 and age: p-value = 0.08). This study provides new insights on the possible influence of MCHR2 and/or MCHR2-AS1 on obesity in psychiatric patients and on the pathophysiology of atypical depression