Inhibition of Pore Formation by Blocking the Assembly of Staphylococcus aureus α-Hemolysin Through a Novel Peptide Inhibitor: an In Silco Approach

Staphylococcus aureus self-assembling α-hemolysin heptamer is an acute virulence factor that determines the severity of S. aureus infections. Hence, inhibiting the heptamer formation is of considerable interest. However, both natural and chemical inhibitors reported so far has difficulties related to toxicity, bioavailability, and solubility, which necessitate in identifying some alternatives. Hence, in this study, potential peptides for α-hemolysin inhibition was developed using in silico based approach. Haddock server was used to understand the residues involved in complex formation. Based on the key residues involved in the interaction, 20 peptides were designed and docked with the α-hemolysin monomer (Chain A). Further, the best scored Chain A-peptide complex was chosen and docked with Chain B to identify the ability of dimer formation in the presence of designed peptide. The stability of the Chain A–B dimer, Chain A-peptide and Chain A-peptide-Chain B complex was studied by performing molecular dynamic simulation over 3,000 ps. The peptide IYGSKANRQTDK was found to be binding efficiently with Chain A of α-hemolysin with highest binding energy and also revealed that the designed peptide disturbed the dimer formation, which provided useful information in developing promising lead for inhibiting α-hemolysin assembly in the future.     

Pathological implications of Gymnoascaceae

Summary The Gymnoascaceae have long been regarded by many as the perfect stages of certain imperfect dermatophytic fungi. In recent years increasing numbers of reports have been published in which the Gymnosacaceae have been isolated from pathological conditions and have often been regarded as at least potential pathogens. This paper reviews previous reports and presents certain new isolation data which should lead to a better understanding and appreciation of the role of these fungi in clinical investigations. Evidence supporting pathogencity of the Gymnoascaceae is suggestive but inconclusive.

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Zusammenfassung Manche Verfasser haben die Gymnoascaceae schon lange als die perfekten Formen von gewissen imperfekten Dermatophyten betrachtet. In den letzten Jahren ist eine wachsende Anzahl von Berichten veröffentlich worden bezüglich Gymnoascaceae, die vom pathologischen Material gezüchtet und mindestens als bedingt pathogen betrachtet worden sind. Dieser Bericht gibt eine Übersicht von früheren Befunden und bringt manche neuen Tatsachen von neuen Isolationen. Sie sollen zu einem besseren Verständnis und zu einer besseren Auswertung der Rolle dieser Hyphomyceten in der klinischen Untersuchung führen. Die Beweise betreffs der Pathogenität der Gymnoascaceae sind lediglich mutmasslich und nicht konklusiv.

     

Trefoil Factor 2 Negatively Regulates Type 1 Immunity against Toxoplasma gondii

IL-12-mediated type 1 inflammation confers host protection against the parasitic protozoan Toxoplasma gondii. However, production of IFN-γ, another type 1 inflammatory cytokine, also drives lethality from excessive injury to the intestinal epithelium. As mechanisms that restore epithelial barrier function following infection remain poorly understood, this study investigated the role of trefoil factor 2 (TFF2), a well-established regulator of mucosal tissue repair. Paradoxically, TFF2 antagonized IL-12 release from dendritic cells (DCs) and macrophages, which protected TFF2-deficient (TFF2(-/-)) mice from T. gondii pathogenesis. Dysregulated intestinal homeostasis in naive TFF2(-/-) mice correlated with increased IL-12/23p40 levels and enhanced T cell recruitment at baseline. Infected TFF2(-/-) mice displayed low rates of parasite replication and reduced gut immunopathology, whereas wild-type (WT) mice experienced disseminated infection and lethal ileitis. p38 MAPK activation and IL-12p70 production was more robust from TFF2(-/-)CD8(+) DC compared with WT CD8(+) DC and treatment of WT DC with rTFF2 suppressed TLR-induced IL-12/23p40 production. Neutralization of IFN-γ and IL-12 in TFF2(-/-) animals abrogated resistance shown by enhanced parasite replication and infection-induced morbidity. Hence, TFF2 regulated intestinal barrier function and type 1 cytokine release from myeloid phagocytes, which dictated the outcome of oral T. gondii infection in mice.     

Genomic structures and population histories of linguistically distinct tribal groups of India

There are various conflicting hypotheses regarding the origins of the tribal groups of India, who belong to three major language groups--Austro-Asiatic, Dravidian and Tibeto-Burman. To test some of the major hypotheses we designed a genetic study in which we sampled tribal populations belonging to all the three language groups. We used a set of autosomal DNA markers, mtDNA restriction-site polymorphisms (RSPs) and mtDNA hypervariable segment-1 (HVS-1) sequence polymorphisms in this study. Using the unlinked autosomal markers we found that there is a fair correspondence between linguistic and genomic affinities among the Indian tribal groups. We reconstructed mtDNA RSP haplotypes and found that there is extensive haplotype sharing among all tribal populations. However, there is very little sharing of mtDNA HVS-1 sequences across populations, and none across language groups. Haplogroup M is ubiquitous, and the subcluster U2i of haplogroup U occurs in a high frequency. Our analyses of haplogroup and HVS-1 sequence data provides evidence in support of the hypothesis that the Austro-Asiatic speakers are the most ancient inhabitants of India. Our data also support the earlier finding that some of the western Eurasian haplogroups found in India may have been present in India prior to the entry of Aryan speakers. However, we do not find compelling evidence to support the theory that haplogroup M was brought into India on an "out of Africa" wave of migration through a southern exit route from Ethiopia. On the contrary, our data raise the possibility that this haplogroup arose in India and was later carried to East Africa from India.