On the Interplay of Telomeres,Nevi and the Risk of Melanoma

The relationship between telomeres, nevi and melanoma is complex. Shorter telomeres have been found to be associated with many cancers and with number of nevi, a known risk factor for melanoma. However, shorter telomeres have also been found to decrease melanoma risk. We performed a systematic analysis of telomere-related genes and tagSNPs within these genes, in relation to the risk of melanoma, dysplastic nevi, and nevus count combining data from four studies conducted in Italy. In addition, we examined whether telomere length measured in peripheral blood leukocytes is related to the risk of melanoma, dysplastic nevi, number of nevi, or telomere-related SNPs. A total of 796 cases and 770 controls were genotyped for 517 SNPs in 39 telomere-related genes genotyped with a custom-made array. Replication of the top SNPs was conducted in two American populations consisting of 488 subjects from 53 melanoma-prone families and 1,086 cases and 1,024 controls from a case-control study. We estimated odds ratios for associations with SNPs and combined SNP P-values to compute gene region-specific, functional group-specific, and overall P-value using an adaptive rank-truncated product algorithm. In the Mediterranean population, we found suggestive evidence that RECQL4, a gene involved in genome stability, RTEL1, a gene regulating telomere elongation, and TERF2, a gene implicated in the protection of telomeres, were associated with melanoma, the presence of dysplastic nevi and number of nevi, respectively. However, these associations were not found in the American samples, suggesting variable melanoma susceptibility for these genes across populations or chance findings in our discovery sample. Larger studies across different populations are necessary to clarify these associations.     

Roadside Revegetation in Glacier National Park, U.S.A.: Effects of Herbicide and Seeding Treatments

From 1992 to 1995 we experimentally evaluated the effectiveness of several revegetation treatments along a segment of Going-to-the-Sun Highway in Glacier National Park, U.S.A. This segment, reconstructed during the spring and summer of 1992, is bordered by fescue prairie vegetation and is known to be susceptible to invasion by several alien species, including Centaurea maculosa (spotted knapweed) and Phleum pratense (common timothy). We used a split plot study design to evaluate the effectiveness of herbicide and seeding treatments on assisting recovery of native flora and limiting the establishment of alien species. The herbicide treatment consisted of a yearly herbicide spray application of clopyralid (3,6-dichloropicolinic acid). Five seeding treatments were evaluated, three of which included an indigenous graminoid-forb seed mix. Percent canopy coverages of four species groups—alien graminoids, native graminoids, alien forbs, and native forbs—were determined in July 1995. In addition, community-level patterns in sprayed plots and unsprayed plots were compared with a reference site of native fescue prairie. Herbicide treatments decreased mean canopy coverage of alien forbs (treated = 4.2%, untreated = 23.4%) and increased mean canopy coverage of native graminoids slightly (treated = 6.3%, untreated = 4.0%). But herbicide treatments reduced mean coverage of native forbs (treated = 3.9%, untreated = 8.9%) and likely increased coverage of alien graminoids. Treatments that included a fall 1992 seed mix increased native graminoid coverages 2.8–4.6 times, although coverages were still lower than those attained by alien graminoids. Native and alien forb coverage appeared unaffected by seeding treatments. Species composition was less diverse in sprayed plots and more dominated by alien grasses than in unsprayed plots and the reference site. Areas for additional study are suggested, including seed bank assays to determine treatment effects on recruitment of alien versus native species and the use of native graminoids to create low-diversity communities with high canopy coverages to resist establishment of alien species.     

MHC class II derived recombinant T cell receptor ligands protect DBA/1LacJ mice from collagen-induced arthritis

We previously demonstrated the therapeutic effects of MHC class II derived recombinant T cell receptor ligands (RTL), single-chain two domain complexes of the alpha1 and beta1 domains of MHC class II molecules genetically linked with an immunodominant peptide, in experimental autoimmune encephalomyelitis. In the current study, we produced a monomeric murine I-Aq-derived RTL construct covalently linked with bovine collagen type II peptide (bCII257-270) suitable for use in DBA/1LacJ mice that develop collagen-induced arthritis (CIA), an animal model of human rheumatoid arthritis, after immunization with bCII protein in CFA. In this study, we demonstrate that the I-Aq-derived RTLs reduced the incidence of the disease, suppressed the clinical and histological signs of CIA and induced long-term modulation of T cells specific for arthritogenic Ags. Our results showed that the I-Aq/bCII257-270 molecule could systemically reduce proinflammatory IL-17 and IFN-gamma production and significantly increase anti-inflammatory IL-10, IL-13, and FoxP3 gene expression in splenocytes. Moreover, I-Aq/bCII257-270 molecule could also selectively inhibit IL-1beta, IL-6, and IL-23 expression in local joint tissue. This is the first report demonstrating effective prevention of joint inflammation and clinical signs of CIA with an I-Aq-derived RTL, thus supporting the possible clinical use of this approach for treating rheumatoid arthritis in humans.     

Molecular diversity of 16S rRNA and gyrB genes in copper mines

The molecular diversities of the microbial communities from four sites impacted by acid mine drainage (AMD) at Dexing Copper Mine in Jiangxi province of China were studied using 16S rRNA sequences and gyrB sequences. Of the four sampled sites, each habitat exhibited distinct geochemical characteristics and the sites were linked geographically allowing us to correlate microbial community structure to geochemical characteristics. In the present study, we examined the molecular diversity of 16S rRNA and gyrB genes from water at these sites using a PCR-based cloning approach. We found that the microbial community appears to be composed primarily of Proteobacteria, Acidobacteria, Actinobacteria, Nitrospira, Firmicutes, Chlorella and unknown phylotypes. Of clones affiliated with Nitrospira, Leptospirillum ferrooxidans, Leptospirillum ferriphilum and Leptospirillum group III were all detected. Principal-component analysis (PCA) revealed that the distribution of the microbial communities was influenced greatly by geochemical characteristics. The overall PCA profiles showed that the sites with similar geochemical characteristics had more similar microbial community structures. Moreover, our results also indicated that gyrB sequence analysis may be very useful for differentiating very closely related species in the study of microbial communities. H. Yin and L. Cao contributed equally to this work.     

Continued feeding on <Emphasis Type="Italic">Diporeia</Emphasis> by deepwater sculpin in Lake Huron

Monitoring changes in diets of fish is essential to understanding how food web dynamics respond to changes in native prey abundances. In the Great Lakes, Diporeia, a benthic macroinvertebrate and primary food of native benthivores, declined following the introduction of invasive Dreissena mussels and these changes were reflected in fish diets. We examined the diets of deepwater sculpin Myoxocephalus thompsonii collected in bottom trawls during 2010–2014 in the main basin of Lake Huron, and compared these results to an earlier diet study (2003–2005) to assess if their diets have continued to change after a prolonged period of Dreissena mussel invasion and declined Diporeia densities. Diporeia, Mysis, Bythotrephes, and Chironomidae were consumed regularly and other diet items included ostracods, copepods, sphaerid clams, and fish eggs. The prey-specific index of relative importance calculated for each prey group indicated that Mysis importance increased at shallow (≤55 m) and mid (64–73 m) depths, while Diporeia importance increased offshore (≥82 m). The average number of Diporeia consumed per fish increased by 10.0% and Mysis decreased by 7.5%, while the frequency of occurrence of Diporeia and Mysis remained comparable between time periods. The weight of adult deepwater sculpin (80 mm and 100 mm TL bins) increased between time periods; however, the change in weight was only significant for the 80 mm TL group (p?<?0.01). Given the historical importance of Diporeia in the Great Lakes, the examination of deepwater sculpin diets provides unique insight into the trophic dynamics of the benthic community in Lake Huron.     

A conserved domain of herpes simplex virus ICP34.5 regulates protein phosphatase complex in mammalian cells

ICP34.5, encoded by herpes simplex virus 1, is a protein phosphatase 1 (PP1) regulatory subunit that mediates dephosphorylation of the alpha subunit of translation initiation factor 2 (eIF2alpha). However, the mechanism of its action remains poorly understood. Here, we show that amino acid substitutions in the arginine-rich motif have differential effects on ICP34.5 activity. The phenotypes parallel with viral protein synthesis and cytopathic effects in virus infected cells. Besides the consensus PP1 binding motif, the Arg-motif appears to enhance the interaction between ICP34.5 and PP1. These results suggest that concerted action between the PP1 binding domain and the effector domain of ICP34.5 is crucial for eIF2alpha dephosphorylation and viral protein synthesis.     

The Relationship between Dipeptidase Activity Variation and Larval Viability in Drosophila melanogaster

The enzyme dipeptidase-A (DIP-A) in Drosophila melanogaster is coded by a second chromosome locus that is polymorphic for three allozymes in natural populations. DIP-A appears to be the only enzyme in D. melanogaster capable of hydrolyzing the dipeptide glycyl-L-isoleucine, since flies homozygous for null alleles at this locus have no detectable glycyl-L-isoleucine-ase activity. DIP-A activity occurs in many tissues and throughout development, but is particularly high in the larval midgut, suggesting an important role in protein digestion. These observations suggested an experimental design for investigating the adaptive significance of genetic variation in DIP-A activity. Fitness components of DIP-A variants could be estimated and compared under two environmental conditions (defined diets under axenic conditions). In the restrictive environment, the essential amino acid L-isoleucine is provided only in the form of glycyl-L-isoleucine, whereas in the permissive environment, L-isoleucine is provided in free form. We predicted that DIP-A activity would be essential in the restrictive, but not in the permissive environment. The results reported here clearly contradict this prediction. Two stocks homozygous for DIP-A null alleles from different geographic locations are each viable on the restrictive diet. Furthermore, relative viability experiments in which null allele larvae compete with larvae having DIP-A activity provide no evidence for even a partial reduction in egg to adult survival on the restrictive diet. Apparently, the null allele larvae have some alternative mechanism for obtaining L-isoleucine from the dipeptide, even though no glycyl-L-isoleucine-ase activity can be detected in vitro. These results, along with the viability of null alleles for many other enzymes, support the idea that eukaryotes have an intricate network of alternative biochemical pathways through which the same necessary function may be achieved. Such "buffering capacity" makes it very difficult to analyze the effects of enzyme variants on fitness components.     

P2Y receptors in Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia, affecting more than 10% of people over the age of 65. Age is the greatest risk factor for AD, although a combination of genetic, lifestyle and environmental factors also contribute to disease development. Common features of AD are the formation of plaques composed of beta‐amyloid peptides (Aβ) and neuronal death in brain regions involved in learning and memory. Although Aβ is neurotoxic, the primary mechanisms by which Aβ affects AD development remain uncertain and controversial. Mouse models overexpressing amyloid precursor protein and Aβ have revealed that Aβ has potent effects on neuroinflammation and cerebral blood flow that contribute to AD progression. Therefore, it is important to consider how endogenous signalling in the brain responds to Aβ and contributes to AD pathology. In recent years, Aβ has been shown to affect ATP release from brain and blood cells and alter the expression of G protein‐coupled P2Y receptors that respond to ATP and other nucleotides. Accumulating evidence reveals a prominent role for P2Y receptors in AD pathology, including Aβ production and elimination, neuroinflammation, neuronal function and cerebral blood flow.