The impact of aging on innate and adaptive immunity in the human female genital tract

Mucosal tissues in the human female reproductive tract (FRT) are primary sites for both gynecological cancers and infections by a spectrum of sexually transmitted pathogens, including human immunodeficiency virus (HIV), that compromise women''s health. While the regulation of innate and adaptive immune protection in the FRT by hormonal cyclic changes across the menstrual cycle and pregnancy are being intensely studied, little to nothing is known about the alterations in mucosal immune protection that occur throughout the FRT as women age following menopause. The immune system in the FRT has two key functions: defense against pathogens and reproduction. After menopause, natural reproductive function ends, and therefore, two overlapping processes contribute to alterations in immune protection in aging women: menopause and immunosenescence. The goal of this review is to summarize the multiple immune changes that occur in the FRT with aging, including the impact on the function of epithelial cells, immune cells, and stromal fibroblasts. These studies indicate that major aspects of innate and adaptive immunity in the FRT are compromised in a site‐specific manner in the FRT as women age. Further, at some FRT sites, immunological compensation occurs. Overall, alterations in mucosal immune protection contribute to the increased risk of sexually transmitted infections (STI), urogenital infections, and gynecological cancers. Further studies are essential to provide a foundation for the development of novel therapeutic interventions to restore immune protection and reverse conditions that threaten women''s lives as they age.     

Declined miR‐181a‐5p expression is associated with impaired natural killer cell development and function with aging

MicroRNAs (miRNAs) regulate gene expression and thereby influence cell development and function. Numerous studies have shown the significant roles of miRNAs in regulating immune cells including natural killer (NK) cells. However, little is known about the role of miRNAs in NK cells with aging. We previously demonstrated that the aged C57BL/6 mice have significantly decreased proportion of mature (CD27⁻CD11b⁺) NK cells compared with young mice, indicating impaired maturation of NK cells with aging. Here, we performed deep sequencing of CD27⁺ NK cells from young and aged mice. Profiling of the miRNome (global miRNA expression levels) revealed that 49 miRNAs displayed a twofold or greater difference in expression between young and aged NK cells. Among these, 30 miRNAs were upregulated and 19 miRNAs were downregulated in the aged NK cells. We found that the expression level of miR‐l8la‐5p was increased with the maturation of NK cells, and significantly decreased in NK cells from the aged mice. Knockdown of miR‐181a‐5p inhibited NK cell development in vitro and in vivo. Furthermore, miR‐181a‐5p is highly conserved in mice and human. MiR‐181a‐5p promoted the production of IFN‐γ and cytotoxicity in stimulated NK cells from both mice and human. Importantly, miR‐181a‐5p level markedly decreased in NK cells from PBMC of elderly people. Thus, our results demonstrated that the miRNAs profiles in NK cells change with aging, the decreased level of miR‐181a‐5p contributes to the defective NK cell development and function with aging. This opens new strategies to preserve or restore NK cell function in the elderly.     

A DNA Damage Checkpoint Pathway Coordinates the Division of Dikaryotic Cells in the Ink Cap Mushroom Coprinopsis cinerea

The fungal fruiting body or mushroom is a multicellular structure essential for sexual reproduction. It is composed of dikaryotic cells that contain one haploid nucleus from each mating partner sharing the same cytoplasm without undergoing nuclear fusion. In the mushroom, the pileus bears the hymenium, a layer of cells that includes the specialized basidia in which nuclear fusion, meiosis, and sporulation occur. Coprinopsis cinerea is a well-known model fungus used to study developmental processes associated with the formation of the fruiting body. Here we describe that knocking down the expression of Atr1 and Chk1, two kinases shown to be involved in the response to DNA damage in a number of eukaryotic organisms, dramatically impairs the ability to develop fruiting bodies in C. cinerea, as well as other developmental decisions such as sclerotia formation. These developmental defects correlated with the impairment in silenced strains to sustain an appropriated dikaryotic cell cycle. Dikaryotic cells in which chk1 or atr1 genes were silenced displayed a higher level of asynchronous mitosis and as a consequence aberrant cells carrying an unbalanced dose of nuclei. Since fruiting body initiation is dependent on the balanced mating-type regulator doses present in the dikaryon, we believe that the observed developmental defects were a consequence of the impaired cell cycle in the dikaryon. Our results suggest a connection between the DNA damage response cascade, cell cycle regulation, and developmental processes in this fungus.     

Loss of functional MYO1C/myosin 1c,a motor protein involved in lipid raft trafficking,disrupts autophagosome-lysosome fusion

MYO1C, a single-headed class I myosin, associates with cholesterol-enriched lipid rafts and facilitates their recycling from intracellular compartments to the cell surface. Absence of functional MYO1C disturbs the cellular distribution of lipid rafts, causes the accumulation of cholesterol-enriched membranes in the perinuclear recycling compartment, and leads to enlargement of endolysosomal membranes. Several feeder pathways, including classical endocytosis but also the autophagy pathway, maintain the health of the cell by selective degradation of cargo through fusion with the lysosome. Here we show that loss of functional MYO1C leads to an increase in total cellular cholesterol and its disrupted subcellular distribution. We observe an accumulation of autophagic structures caused by a block in fusion with the lysosome and a defect in autophagic cargo degradation. Interestingly, the loss of MYO1C has no effect on degradation of endocytic cargo such as EGFR, illustrating that although the endolysosomal compartment is enlarged in size, it is functional, contains active hydrolases, and the correct pH. Our results highlight the importance of correct lipid composition in autophagosomes and lysosomes to enable them to fuse. Ablating MYO1C function causes abnormal cholesterol distribution, which has a major selective impact on the autophagy pathway.     

Two new Dematiaceous Hyphomycetes from humid tropic forest litter

Abstract

Two Dematiaceous Hyphomycetes, Beltraniella lyrata and Beltraniopsis fabularis, found on tropical forest litter in the Tai National Park in Ivory Coast are proposed as new species and described.     

Neurogenomics of speech and language disorders: the road ahead

Next-generation sequencing is set to transform the discovery of genes underlying neurodevelopmental disorders, and so offer important insights into the biological bases of spoken language. Success will depend on functional assessments in neuronal cell lines, animal models and humans themselves.     

Potential role of vaccines in elimination of Plasmodium vivax

The unique biology of Plasmodium vivax, with its ability to form latent hypnozoites in the liver stage and the early appearance of gametocytes during blood stage infection, makes it difficult to target for elimination with standard malaria control tools. Here, we use modelling studies to demonstrate that vaccines that target different stages of P. vivax could greatly assist efforts to eliminate P. vivax. Combination of vaccines that target different P. vivax life cycle stages may be required to achieve high efficacy. Our simulations demonstrate that repeated rounds of mass vaccination with multi-stage vaccines can help achieve pre-elimination levels of P. vivax in both low and high transmission settings. We review the status of global efforts to develop vaccines for P. vivax malaria. We describe the status of the leading P. vivax vaccine candidates and share some thoughts on the prospects for availability of an effective vaccine for P. vivax malaria.