Structural and Functional Impact of SRP54 Mutations Causing Severe Congenital Neutropenia

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Computational Design and Analysis of a Poly-Epitope Fusion Protein: A New Vaccine Candidate for Hepatitis and Poliovirus

International Journal of Peptide Research and Therapeutics - Infections with HCV, HBV and poliovirus are still considered to be substantial global health burdens. Vaccination is one of the most...     

Utilization of the human gamma-satellite insulator for the enhancement of anti-PCSK9 monoclonal antibody expression in Chinese hamster ovary cells

Molecular Biology Reports - Monoclonal antibodies (mAbs) are widely employed as invaluable therapeutics for a vast number of human disorders. Several approaches have been introduced for the...     

COVID-19 and male reproductive system: pathogenic features and possible mechanisms

Multiorgan dysfunction is the main characteristic of severe COVID-19 patients and the involvement of male reproductive system may occur among these patients. Although there is a limited evidence to confirm the orchitis and virus presence in the semen of patients, there are concerns about the transmission of virus through the semen. In addition, reduced fertility or infertility can be seen as consequences of severe COVID-19 in recovered subjects. In this study, we aimed to review articles related to COVID-19 and male reproductive system to find the possible underlying mechanisms of SARS-CoV-2 in affecting male fertility. The following keywords of SARS-CoV-2, COVID-19, testis, orchitis, semen, angiotensin-converting enzyme 2 (ACE2), hypothalamic–pituitary–testicular (HPT) axis, Hypothalamus, etc., were defined to find the related publications from standard search engines, e.g., PUBMED, SCOPUS, Google Scholar. According to studies, COVID-19 occurs in severe patients as respiratory disease, along with multi-organ failure. The most important mechanisms are classified as direct and indirect pathogenesis of SARS-CoV-2. The presence of ACE2 on the cell surface of various cells in testis increases the risk of direct infection by this virus. SARS-CoV-2 also affects the testis through the cytokine storm. In addition, the important role of HPT axis dysregulation through impaired Leydig cells and hypothalamus should be considered. Using antiviral and immunomodulatory therapy can be harmful for testis function. Further investigations are required to investigate potential mechanisms of male infertility in survivals of COVID-19. Since involvement of testis is essential for fertility, increasing the knowledge of health system may improve the outcomes.

     

Exact results for fixation probability of bithermal evolutionary graphs

One of the most fundamental concepts of evolutionary dynamics is the “fixation” probability, i.e. the probability that a mutant spreads through the whole population. Most natural communities are geographically structured into habitats exchanging individuals among each other and can be modeled by an evolutionary graph (EG), where directed links weight the probability for the offspring of one individual to replace another individual in the community. EGs have recently spurred huge interest, as it has been shown that some topology can amplify or suppress the effect of beneficial mutations. Very few exact analytical results however are known for EGs. In this article we show that the use of a new technique, the fixed point of probability generating function, allows us to compute the exact fixation probability for a large subset of bithermal graphs. We also show by numerical simulations that the computed solution holds for all bithermal graphs. Moreover, the analytical solution allows us to clarify the opposing consequences of birth–death versus death–birth processes as amplifier or suppressor of beneficial mutations for the same bithermal topology.     

Microsporum fulvum, an Ignored Pathogenic Dermatophyte: A New Clinical Isolation from Iran

Misidentifying with Microsporum gypseum has for a long time been accounted for less prevalence of the geophilic species, Microsporum fulvum in human dermatophytosis. We describe a new case of infection with the species in an Iranian young man. Direct examination of skin scrapings revealed a tinea corporis, and morphological study of the recovered isolate from the culture resulted in the identification of M. gypseum. However, PCR amplification of ITS1-5.8S rDNA-ITS2 region and subsequent ITS-RFLP and sequencing were indicative of M. fulvum as the true causative agent. To recognize M. fulvum in human infections and to validate the morphologically distinguished isolates of M. gypseum, the genetic-based identification is strongly recommended.     

Structure and Stability Analysis of Cytotoxic Complex of Camel α-Lactalbumin and Unsaturated Fatty Acids Produced at High Temperature

Abstract

α-Lactalbumin (α-La), together with oleic acid can be converted to a complex, which kills tumor cells selectively. Cytotoxic α-La -oleic acid and a-La -linoleic acid complexes were generated by adding fatty acid to camel holo a-La at 60°C (referred to as La-OA-60 and La-LA-60 state, respectively). Structural properties of these complexes were studied and compared to the camel α-La. The experimental results show that linoleic acid induces a-La partial unfolding but oleic acid does not change the protein structure significantly. Also the stability of La-OA-60 and La- LA-60 toward thermal denaturation was measured. The order of temperature at the transition midpoint is as follows: La-LA-60 < La-0A-60 < α-La. La-0A-60 complex inhibited tubulin polymerization in vitro. Although the structures of La-0A-60 and La-LA-60 were different, these two complexes had similar cytotoxic effect to DU145 human prostate cancer cells. Samples of La-0A-60 that have been renatured after denaturation lost the specific biological activity toward tumor cells.     

Design and synthesis of novel 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridines as small molecule BACE-1 inhibitors

Alzheimer disease (AD) is a neuronal dementia for which no treatment has been consolidated yet. Major pathologic hallmark of AD is the aggregated extracellular amyloid-β plaques in the brains of disease sufferers. Aβ-peptide is a major component of amyloid plaques and is produced from amyloid precursor protein (APP) via the proteolysis action. An aspartyl protease known as β-site amyloid precursor protein cleaving enzyme (BACE-1) is responsible for this proteolytic action. Distinctive role of BACE-1 in AD pathogenesis has made it a validated target to develop anti-Alzheimer agents. Our structure-based virtual screening method led to the synthesis of novel 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridine BACE-1 inhibitors (6a–6p; in vitro hits). Molecular docking and DFT-based ab initio studies using B3LYP functional in association with triple-ζ basis set (TZV) proposed binding mode and binding energies of ligands in the active site of the receptor. In vitro BACE-1 inhibitory activities were determined by enzymatic fluorescence resonance energy transfer (FRET) assay. Most of the synthesized dihydropyridine scaffolds were active against BACE-1 while 6d, 6k, 6n and 6a were found to be the most potent molecules with IC₅₀ values of 4.21, 4.27, 4.66 and 6.78 μM, respectively. Superior BACE-1 inhibitory activities were observed for dihydropyridine derivatives containing fused/nonfused thiazole containing groups, possibly attributing to the additional interactions with S2–S3 subpocket residues. Relatively reliable correlation between calculated binding energies and experimental BACE-1 inhibitory activities was achieved (R² = 0.51). Moreover, compounds 6d, 6k, 6n and 6a exhibited relatively no calcium channel blocking activity with regard to nifedipine suggesting them as appropriate candidates for further modification(s) to BACE-1 inhibitory scaffolds.