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...     

Genome-wide comparative analysis of Mg transporter gene family between Triticum turgidum and Camelina sativa

Magnesium (Mg) as a bimetal plays critical roles in biochemical processes, membrane stability, and enzyme activity. Mg transporters (MGTs) are involving in maintaining Mg homeostasis in cells. Although the MGT family members have been identified in different plant species, there is no comprehensive analysis of the other plants' MGT genes. In the current study, 62 and 41 non-redundant putative MGT proteins were recognized into the genome of Camelina sativa, and Triticum turgidum and they were compared based on physicochemical properties, protein structure, expression, and interaction. All identified MGTs were classified into three subgroups, NIPA, CorA, and MRS2/MGT, based on conserved-motifs distribution. The results showed that the secondary structure pattern in NIPA and MRS2 subfamily members in both studied plant species were highly similar. Furthermore, MGTs encompass the conserved structures and the critical sites mainly in the metal ion and Mg²⁺ binding centers as well as the catalytic sites were observed. The highest numbers of protein channels were predicted in CorA proteins in both C. sativa and T. turgidum with 24 and 17 channel numbers, respectively. The Ser, Pro, Gly, Lys, Tyr, and Arg amino acids were predicted as the binding residues in MGTs channel regions. The expression pattern of identified genes demonstrated that MGT genes have diverse tissue-specific expression and stress response expression patterns. Besides, 147 co-expressed genes with MGTs were clustered into the eight co-expression nodes involved in N-glycan biosynthesis, protein processing in the endoplasmic reticulum, carbon metabolism, biosynthesis of amino acids, and endocytosis. In the present study, all interpretations are based on in silico predictions, which can be used in further studies related to functional genomics of MGT genes.

     

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.