In silico designing of peptide inhibitors against pregnane X receptor: the novel candidates to control drug metabolism

Drug-induced pregnane X receptor (PXR) activation may be unavoidable with some treatments. Besides, drug-induced PXR activation may lead to drug interactions with a number of treatments. Human PXR antagonists represent a means to counteract such interactions. Indeed, the ideal small molecule would have good drug-like properties, but be devoid of nonspecific cell-target effects and ability to induce cytotoxicity. Researchers assess on the possibility of deriving inhibitory peptides, which are derived from interfaces of “protein–protein interactions” (PPIs) could inhibit interactions of their origin domain by mimicking its mode of binding to cognate partners. Such peptides could serve as promising leads for rational design of inhibitory drugs. In this study, In silico designing of peptide inhibitors and peptidomimetics against PPIs was done to prevent unwanted drug metabolisms caused by PXR activation. In sum, no designed peptides had considerable higher energy of interactions and more H-bonds with the receptor compared to the SRC-1 peptides. Hence, none of the designed peptides are predicted to be more active against the target receptor. However, compared to the SRC-1 peptide, a designed peptidomimetic (mimetic3) had considerable higher energy of interactions with the receptor. It formed five H-bonds with PXR that was equal to the number of H-bonds that SRC-1 formed with the receptor. Therefore, by designing such mimetics, it would be probable to have a realistic chance of achieving peptides with improved binding affinity compared to SRC-1 and consequently prevent the unwanted drug metabolisms caused by PXR activation.     

Computational modeling of the effective Young’s modulus values of fullerene molecules: a combined molecular dynamics simulation and continuum shell model

Estimating the Young’s modulus of a structure in the nanometer size range is a difficult task. The reliable determination of this parameter is, however, important in both basic and applied research. In this study, by combining molecular dynamics (MD) simulations and continuum shell theory, we designed a new approach to determining the Young’s modulus values of different spherical fullerenes. The results indicate that the Young’s modulus values of fullerene molecules decrease nonlinearly with increasing molecule size and understandably tend to the Young’s modulus of an ideal flat graphene sheet at large molecular radii. To the best of our knowledge, this is first time that a combined atomistic–continuum method which can predict the Young’s modulus values of fullerene molecules with high precision has been reported.     

Variation of DAT1 VNTR alleles and genotypes among old ethnic groups in Mesopotamia to the Oxus region

Variation of a VNTR in the DAT1 gene in seven ethnic groups of the Middle East was used to infer the history and affinities of these groups. The populations consisted of Assyrian, Jewish, Zoroastrian, Armenian, Turkmen, and Arab peoples of Iran, Iraq, and Kuwait. Three hundred forty subjects from these seven ethnic groups were screened for DAT1. DAT1 VNTR genotyping showed 3, 6, 7, 8, 9, 10, 11, and 12 alleles in the samples. Analysis of these data revealed differentiation and relationship among the populations. In this region, which covers an area of 2-2.5 million km2, the influence of geography and especially of linguistic characteristics has had potentially major effects on differentiation. Religion also has played a major role in imposing restrictions on some ethnic groups, who as a consequence have maintained their community. Overall, these ethnic groups showed greater heterogeneity compared to other populations.     

Novel O-[11C]methylated derivatives of candesartan as angiotensin II AT1 receptor imaging ligands: Radiosynthesis and ex vivo evaluation in rats

[¹¹C]Methyl-candesartan and its desethyl derivative ([¹¹C]TH4) were developed as potential radiotracers for imaging angiotensin II (Ang II) type 1 (AT₁) receptors. These compounds were synthesized via methylation of tetrazole-protected candesartan using [¹¹C]methyl iodide followed by deprotection through HCl hydrolysis at 65 °C to produce [¹¹C]methyl-candesartan, and 90 °C for [¹¹C]TH4. Ex vivo biodistribution and competition studies were carried out for both [¹¹C]methyl-candesartan and [¹¹C]TH4 to assess tissue retention time course and binding selectivity. Besides the liver, [¹¹C]methyl-candesartan and [¹¹C]TH4 displayed highest tissue retention in the AT₁ receptor-rich renal cortex and outer medulla. At tracer doses 15 min post-injection, [¹¹C]methyl-candesartan demonstrated higher specific binding proportion for AT₁ receptors, and selectivity for AT₁ over Ang II AT₂, Mas, β-adrenergic, and α₂-adrenergic receptors in rat kidneys compared to [¹¹C]TH4. This study indicates that [¹¹C]methyl-candesartan has potential for in vivo imaging renal AT₁ receptors selectively using positron emission tomography.     

Measurement of opsonophagocytic activity of antibodies specific toNeisseria meningitidis serogroup A capsular polysaccharide-serogroup B outer membrane vesicle conjugate in animal model

Neisseria meningitidis is efficiently phagocytosed by polymorphonuclear leukocytes (PMNS) following opsonization with opsonic antibodies; opsonophagocytosis is the primary mechanism for clearance of meningococci from the host. Thus, in testing meningococcal vaccines, the level of opsonophagocytic antibodies appears to correlate with vaccine-induced protection. Our previous studies demonstrated that the conjugation ofN. meningitidis serogroup A capsular polysaccharide (CPSA) to serogroup B outer membrane vesicle (OMV) could induce a high level of bactericidal antibody response against serogroup A meningococci in animals. The purpose of this study was to evaluate opsonophagocytic activity of the conjugate of CPSA to OMV (CPSA-OMV). In order to evaluate the potential efficacy of CPSA-OMV a flow cytometric opsonophagocytic assay was used. The conjugate and controls were injected intramuscularly into four groups of rabbits with boosters on days 14, 28 and 42 following primary immunization. The rabbits were bled prior to injection and two weeks after each injection. Opsonophagocytic activity of antibodies in hyperimmune sera through rabbit PMNS were measured with flow cytometer, using dihydrorhodamine-123 as a probe. The results indicated that our conjugate could induce a highly significant level of opsonophagocytic activity against serogroup A meningococci after 56 days compared to the control groups (P<0.05). We conclude that this conjugate represents a vaccine candidate against serogroups A and B meningococci after further investigation.     

Enhancement of Anaerobic Digestion Using Particulate Growth Systems

Attached media reactors are used for enhancement of wastewater treatment processes including anaerobic condition. Selection of a suitable biofilm carrier is a compelling method to improve anaerobic digestion systems. This study investigates the performance of four fibrous biofilms installed in batch biogas reactors for treatment of cow manure. BioCords HS1, HS2, LS1, and LS2 are manufactured by Bishop Water Technologies, ON, Canada. Effluents and attached growth media were analyzed after batch experiment; methane production, methane yield, transfer efficiencies, organic and solid removal efficiencies, pH, and attached volatile suspended solid (VSS) were measured; VSS attached to biofilms mainly correlated with the specific surface area of each biofilm. Additionally, SEM (scanning electron microscopy) was used for further understanding of biofilm formation process for BioCords and the dissimilarity in their performance. The results indicated that BioCord LS2 had positive impact on achieving higher methane production and removal efficiencies compared to other support media utilized in batch reactors. It was also demonstrated from the experiment that BioCord LS2 potentially could generate higher methane production than conventional batch bioreactor.     

High-intensity interval training lowers blood pressure and improves apelin and NOx plasma levels in older treated hypertensive individuals

Hypertension is the major risk factor for cardiovascular diseases and is one of the primary causes of morbidity and mortality worldwide. Apelin levels and NO bioavailability are impaired in older hypertensive patients. Exercise is an effective intervention for treating hypertension. Our purpose was to evaluate the effect of high-intensity interval training on blood pressure, apelin, and NOx plasma levels in older treated hypertensive individuals. Thirty treated hypertensive subjects (61.70?±?5.78 years, 17 males, 13 females) were randomly divided into 6 weeks of high-intensity interval training (n?=?15) and control (n?=?15). The exercise training was conducted for three 35-min sessions a week (1.5-min interval at 85–90% of heart rate reserve [HRR] and 2 min active phase at 50–55% of HRR). Assessment of plasma apelin, nitrite/nitrate (NOx), and endothelin-1 (ET-1) was performed before and after the intervention. At the end of the study, apelin, and NOx plasma levels increased significantly in the high-intensity interval training (HIIT) group (P?=?0.021, P?=?0.003, respectively). Conversely, ET-1 plasma levels significantly decreased in the training group after the intervention (P?=?0.015). Moreover, there was a positive correlation between the change of plasma apelin and change of plasma NOx (r?=?0. 771, P?=?0.0008). In addition, there was a negative correlation between the change of plasma ET-1, change of plasma apelin (r?=???0.595, P?=?0.019), and variation of NOx (r?=???0.572, P?=?0.025). This study indicates that, by increasing of apelin and NOx plasma levels, HIIT may be effective in reducing blood pressure.     

A Series of Pyrene‐Substituted Silicon Phthalocyanines as Near‐IR Sensitizers in Organic Ternary Solar Cells

An attractive method to broaden the absorption bandwidth of polymer/fullerene‐based bulk heterojunction (BHJ) solar cells is to blend near infrared (near‐IR) sensitizers into the host system. Axial substitution of silicon phthalocyanines (Pcs) opens a possibility to modify the chemical, thermodynamic, electronic, and optical properties. Different axial substitutions are already designed to modify the thermodynamic properties of Pcs, but the impact of extending the π‐conjugation of the axial ligand on the opto‐electronic properties, as a function of the length of the alkyl spacer, has not been investigated yet. For this purpose, a novel series of pyrene‐substituted silicon phthalocyanines (SiPc‐Pys) with varying lengths of alkyl chain tethers are synthesized. The UV–vis and external quantum efficiency (EQE) results exhibit an efficient near IR sensitization up to 800 nm, clearly establishing the impact of the pyrene substitution. This yields an increase of over 20% in the short circuit current density (J _SC) and over 50% in the power conversion efficiency (PCE) for the dye‐sensitized ternary device. Charge generation, transport properties, and microstructure are studied using different advanced technologies. Remarkably, these results provide guidance for the diverse and judicious selection of dye sensitizers to overcome the absorption limitation and achieve high efficiency ternary solar cells.