Alien Registration- Mcknight, Samuel D. (Gardiner, Kennebec County)

https://digitalmaine.com/alien_docs/29184/thumbnail.jp

Interferon-Alpha Mediates Restriction of Human Immunodeficiency Virus Type-1 Replication in Primary Human Macrophages at an Early Stage of Replication

Type I interferons (IFNα and β) are induced directly in response to viral infection, resulting in an antiviral state for the cell. In vitro studies have shown that IFNα is a potent inhibitor of viral replication; however, its role in HIV-1 infection is incompletely understood. In this study we describe the ability of IFNα to restrict HIV-1 infection in primary human macrophages in contrast to peripheral blood mononuclear cells and monocyte-derived dendritic cells. Inhibition to HIV-1 replication in cells pretreated with IFNα occurred at an early stage in the virus life cycle. Late viral events such as budding and subsequent rounds of infection were not affected by IFNα treatment. Analysis of early and late HIV-1 reverse transcripts and integrated proviral DNA confirmed an early post entry role for IFNα. First strand cDNA synthesis was slightly reduced but late and integrated products were severely depleted, suggesting that initiation or the nucleic acid intermediates of reverse transcription are targeted. The depletion of integrated provirus is disproportionally greater than that of viral cDNA synthesis suggesting the possibility of a least an additional later target. A role for either cellular protein APOBEC3G or tetherin in this IFNα mediated restriction has been excluded. Vpu, previously shown by others to rescue a viral budding restriction by tetherin, could not overcome this IFNα induced effect. Determining both the viral determinants and cellular proteins involved may lead to novel therapeutic approaches. Our results add to the understanding of HIV-1 restriction by IFNα

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Alien Registration- Mcknight, Samuel D. (Gardiner, Kennebec County)

https://digitalmaine.com/alien_docs/29184/thumbnail.jp

The need to embrace molecular profiling of tumor cells in prostate and bladder cancer

Purpose: Current treatment strategies for urological cancer are still based on empirical formulae as opposed to treatment tailored for each cancer patient. To individualize treatment, the multiple molecular abnormalities within tumor cell populations needs to be mapped out. The aim of this article is to explain molecular profiling (MP) and its associated techniques so that the process is not purely seen as a research tool but as a future adjunctive measure in patient diagnosis and treatment. Experimental Design: A Medline search of publications relating to MP of prostate and bladder cancer was carried out. A review article was written combining the relevant published literature along with the clinical and scientific experience of both centers. Results: The advent of MP now provides a strategy by which these molecular abnormalities can be assessed. As well as being of diagnostic and prognostic use, these molecular profiles will identify putative molecular abnormalities within tumor cells that may be appropriate for therapeutic modulation. Conclusions: In prostate and bladder cancer, mapping out the molecular abnormalities could be translated into a valuable tool to help solve difficult issues regarding patient management decisions.SCOPUS: sh.jinfo:eu-repo/semantics/publishe

Mitogenomics reveals low variation within a trigeneric complex of black corals from the North Pacific Ocean

A 2013 study revealed that three morphologically distinct antipatharian genera (Dendrobathypathes, Lillipathes, Parantipathes) from the eastern North Pacific (ENP) are genetically indistinguishable using three mitochondrial and four nuclear markers (7,203 bp). To investigate whether this lack of molecular variability extends beyond three mitochondrial genes, we sequenced the complete mitogenome of a single representative within each genus. Dendrobathypathes was the only specimen from the 2013 study containing high molecular weight (HMW) DNA. In terms of geographic proximity to the ENP, the closest Lillipathes and Parantipathes yielding HMW DNA were from the central North Pacific near Hawai'i. Based on cox3-IGR-cox1, Lillipathes and Parantipathes each contained two variable sites and thus were not equivalent substitutes for specimens from the ENP. Nonetheless, variation was extremely low when comparing the mitogenomes, with 32 variable positions across 17,687 bp. Pairwise comparisons revealed 18 (Dendrobathypathes and Parantipathes) and 23 (Lillipathes and Parantipathes;Lillipathes and Dendrobathypathes) variable sites. An ML-based phylogenetic reconstruction using 13 protein-coding genes and two rRNAs revealed that the three North Pacific genera grouped in a clade with Atlantic Dendrobathypathes, while Atlantic Parantipathes spp. formed a sister clade. Previous research hypothesized that hybridization with subsequent introgression was responsible for the lack of variability among genera. Due to uniparental inheritance and lack of recombination, mtDNA cannot identify hybrids; however, finding Pacific Parantipathes grouping with Dendrobathypathes and Lillipathes rather than Atlantic Parantipathes suggests that the trigeneric complex has a unique evolutionary history. If high-resolution nuclear markers support hybridization, it will be important to elucidate the molecular mechanism that maintains three distinct morphological forms occurring in sympatry