Evaluation of the therapeutic potential effect of Fas receptor gene knockdown in experimental model of non-alcoholic steatohepatitis

Aim: Stimulation of Fas death receptor is introduced as a major cause of non-alcoholic steatohepatitis (NASH) progression through suppression of cell viability. Therefore, the blocking of death pathways is hypothesised to be express new approaches to NASH therapy. For this purpose, current experiment applied synthetic small interference RNA (SiRNA) to trigger Fas death receptor and to show its potential therapeutic role in designed NASH model.

Methods: Male mice were placed on a western diet (WD) for 8 weeks and exposed to cigarette smoke during the last 4 weeks of feeding to induce NASH model. In the next step, Fas SiRNA was injected to mice aiming to examine specific Fas gene silencing, after 8 weeks. As a control, mice received scrambled SiRNA. Reversible possibility of disease was examined by 3 weeks of recovery.

Results: Analysis of data is accompanied with the significant histopathological changes (steatosis, ballooning and inflammation), increased lipid profile and hepatic enzyme activities (AST, ALT, ALP) plus TBARS as well as decreased antioxidants levels in NASH model. Upon Fas-SiRNA injection, almost all measured parameters of NASH such as overexpression of Fas receptor, caspase3, NF-kB genes and marked increase of hepatic TNF-α were significantly restored and were remained nearly unchanged following recovery liking as scrambled groups.

Conclusions: The suppression of Fas receptor signalling subsequent RNAi therapy may represent an applicable strategy to decline hepatocyte damages and so NASH progression in mice.     

Efficient and Stable TiO2:Pt–Cu(In,Ga)Se2 Composite Photoelectrodes for Visible Light Driven Hydrogen Evolution

Novel thin film composite photocathodes based on device‐grade Cu(In,Ga)Se₂ chalcopyrite thin film absorbers and transparent conductive oxide Pt‐implemented TiO₂ layers on top are presented for an efficient and stable solar‐driven hydrogen evolution. Thin films of phase‐pure anatase TiO₂ are implemented with varying Pt‐concentrations in order to optimize simultaneously i) conductivity of the films, ii) electrocatalytic activity, and iii) light‐guidance toward the chalcopyrite. Thereby, high incident‐photon‐to‐current‐efficiencies of more than 80% can be achieved over the full visible light range. In acidic electrolyte (pH 0.3), the most efficient Pt‐implemented TiO₂–Cu(In,Ga)Se₂ composite electrodes reveal i) photocurrent densities up to 38 mA cm^?2 in the saturation region (?0.4 V RHE, reversible hydrogen electrode), ii) 15 mA cm^?2 at the thermodynamic potential for H₂‐evolution (0 V RHE), and iii) an anodic onset potential shift for the hydrogen evolution (+0.23 V RHE). It is shown that the gradual increase of the Pt‐concentration within the TiO₂ layers passes through an efficiency‐ and stability‐maximum of the device (5 vol% of Pt precursor solution). At this maximum, optimized light‐incoupling into the device‐grade chalcopyrite light‐absorber as well as electron conductance properties within the surface layer are achieved while no degradation are observed over more than 24 h of operation.     

Stable isotope-resolved metabolomic analysis of lithium effects on glial-neuronal metabolism and interactions

Despite the long-established therapeutic efficacy of lithium in the treatment of bipolar disorder (BPD), its molecular mechanism of action remains elusive. Newly developed stable isotope-resolved metabolomics (SIRM) is a powerful approach that can be used to elucidate systematically how lithium impacts glial and neuronal metabolic pathways and activities, leading ultimately to deciphering its molecular mechanism of action. The effect of lithium on the metabolism of three different ¹³C-labeled precursors ([U-¹³C]-glucose, ¹³C-3-lactate or ¹³C-2,3-alanine) was analyzed in cultured rat astrocytes and neurons by nuclear magnetic resonance (NMR) spectroscopy and gas chromatography mass spectrometry (GC-MS). Using [U-¹³C]-glucose, lithium was shown to enhance glycolytic activity and part of the Krebs cycle activity in both astrocytes and neurons, particularly the anaplerotic pyruvate carboxylation (PC). The PC pathway was previously thought to be active in astrocytes but absent in neurons. Lithium also stimulated the extracellular release of ¹³C labeled-lactate, -alanine (Ala), -citrate, and -glutamine (Gln) by astrocytes. Interrogation of neuronal pathways using ¹³C-3-lactate or ¹³C-2,3-Ala as tracers indicated a high capacity of neurons to utilize lactate and Ala in the Krebs cycle, particularly in the production of labeled Asp and Glu via PC and normal cycle activity. Prolonged lithium treatment enhanced lactate metabolism via PC but inhibited lactate oxidation via the normal Krebs cycle in neurons. Such lithium modulation of glycolytic, PC and Krebs cycle activity in astrocytes and neurons as well as release of fuel substrates by astrocytes should help replenish Krebs cycle substrates for Glu synthesis while meeting neuronal demands for energy. Further investigations into the molecular regulation of these metabolic traits should provide new insights into the pathophysiology of mood disorders and early diagnostic markers, as well as new target(s) for effective therapies.     

Common Premotor Regions for the Perception and Production of Prosody and Correlations with Empathy and Prosodic Ability

Background

Prosody, the melody and intonation of speech, involves the rhythm, rate, pitch and voice quality to relay linguistic and emotional information from one individual to another. A significant component of human social communication depends upon interpreting and responding to another person''s prosodic tone as well as one''s own ability to produce prosodic speech. However there has been little work on whether the perception and production of prosody share common neural processes, and if so, how these might correlate with individual differences in social ability.

Methods

The aim of the present study was to determine the degree to which perception and production of prosody rely on shared neural systems. Using fMRI, neural activity during perception and production of a meaningless phrase in different prosodic intonations was measured. Regions of overlap for production and perception of prosody were found in premotor regions, in particular the left inferior frontal gyrus (IFG). Activity in these regions was further found to correlate with how high an individual scored on two different measures of affective empathy as well as a measure on prosodic production ability.

Conclusions

These data indicate, for the first time, that areas that are important for prosody production may also be utilized for prosody perception, as well as other aspects of social communication and social understanding, such as aspects of empathy and prosodic ability.     

Predictive Validity of the Suicide Trigger Scale (STS-3) for Post-Discharge Suicide Attempt in High-Risk Psychiatric Inpatients

Background

The greatly increased risk of suicide after psychiatric hospitalization is a critical problem, yet we are unable to identify individuals who would attempt suicide upon discharge. The Suicide Trigger Scale v.3 (STS-3), was designed to measure the construct of an affective ‘suicide trigger state’ hypothesized to precede a suicide attempt (SA). This study aims to test the predictive validity of the STS-3 for post-discharge SA on a high-risk psychiatric-inpatient sample.

Methods

The STS-3, and a psychological test battery measuring suicidality, mood, impulsivity, trauma history, and attachment style were administered to 161 adult psychiatric patients hospitalized following suicidal ideation (SI) or SA. Receiver Operator Characteristic and logistic regression analyses were used to assess prediction of SA in the 6-month period following discharge from hospitalization.

Results

STS-3 scores for the patients who made post-discharge SA followed a bimodal distribution skewed to high and low scores, thus a distance from median transform was applied to the scores. The transformed score was a significant predictor of post-discharge SA (AUC 0.731), and a subset of six STS-3 scale items was identified that produced improved prediction of post-discharge SA (AUC 0.814). Scores on C-SSRS and BSS were not predictive. Patients with ultra-high (90^th percentile) STS-3 scores differed significantly from ultra-low (10^th percentile) scorers on measures of affective intensity, depression, impulsiveness, abuse history, and attachment security.

Conclusion

STS-3 transformed scores at admission to the psychiatric hospital predict suicide attempts following discharge among the high-risk group of suicidal inpatients. Patients with high transformed scores appear to comprise two clinically distinct groups; an impulsive, affectively intense, fearfully attached group with high raw STS-3 scores and a low-impulsivity, low affect and low trauma-reporting group with low raw STS-3 scores. These groups may correspond to low-plan and planned suicide attempts, respectively, but this remains to be established by future research.     

Simple benzene derivatives adsorption on defective single-walled carbon nanotubes: a first-principles van der Waals density functional study

We have investigated the interaction between open-ended zig-zag single-walled carbon nanotube (SWCNT) and a few benzene derivatives using the first-principles van der Waals density functional (vdW-DF) method, involving full geometry optimization. Such sp ²-like materials are typically investigated using conventional DFT methods, which significantly underestimate non-local dispersion forces (vdW interactions), therefore affecting interactions between respected molecules. Here, we considered the vdW forces for the interacting molecules that originate from the interacting π electrons of the two systems. The ?0.54 eV adsorption energy reveals that the interaction of benzene with the side wall of the SWCNT is typical of the strong physisorption and comparable with the experimental value for benzene adsorption onto the graphene sheet. It was found that aromatics are physisorbed on the sidewall of perfect SWCNTs, as well as at the edge site of the defective nanotube. Analysis of the electronic structures shows that no orbital hybridization between aromatics and nanotubes occurs in the adsorption process. The results are relevant in order to identify the potential applications of noncovalent functionalized systems.

Impact of pericentric inversion of Chromosome 9 [inv (9) (p11q12)] on infertility

BACKGROUND:

One of the frequent occurrences in chromosome rearrangements is pericentric inversion of the Chromosome 9; inv (9) (p11q12), which is consider to be the variant of normal karyotype. Although it seems not to correlate with abnormal phenotypes, there have been many controversial reports indicating that it may lead to abnormal clinical conditions such as infertility. The incidence is found to be about 1.98% in the general population.

MATERIALS AND METHODS:

We investigated the karyotypes of 300 infertile couples (600 individuals) being referred to our infertility clinic using standard GTG banding for karyotype preparation.

RESULTS:

The chromosomal analysis revealed a total of 15 (2.5%) inversions, among these, 14 male patients were inversion 9 carriers (4.69%) while one female patient was affected (0.33%). The incidence of inversion 9 in male patients is significantly higher than that of normal population and even than that of female patients (P< 0.05).

CONCLUSIONS:

This result suggests that inversion 9 may often cause infertility in men due to spermatogenic disturbances, which are arisen by the loops or acentric fragments formed in meiosis.