The Antarctic dry valley lakes: Relevance to Mars

The similarity of the early environments of Mars and Earth, and the biological evolution which occurred on early Earth, motivates exobiologists to seriously consider the possiblity of an early Martian biota. Environments are being identified which could contain Martian life and areas which may presently contain evidence of this former life. Sediments which were thought to be deposited in large ice-covered lakes are present on Mars. Such localities were identified within some of the canyons of the Valles Marineris and more recently in the ancient terrain in the Southern Hemisphere. Perennially ice-covered Antarctic lakes are being studied in order to develop quantitative models that relate environmental factors to the nature of the biological community and sediment forming processes. These models will be applied to the Martian paleolakes to establish the scientific rationale for the exobiological study of ancient Martian sediments

Rheumatoid arthritis-associated polymorphisms are not protective against Alzheimer\u27s disease

BACKGROUND: Rheumatoid arthritis (RA) and Alzheimer\u27s disease (AD) are inversely associated. To test the hypothesis that genetic elements associated with increased RA risk are associated with decreased AD risk, we evaluated RA genetic risk factors recently identified in genome-wide association studies (GWAS) for their association with AD in a two-stage, case-control analysis. RESULTS: In our Stage 1 analysis of ~800 AD and ~1,200 non-AD individuals, three of seventeen RA-associated SNPs were nominally associated with AD (p \u3c 0.05) with one SNP, rs2837960, retaining significance after correction for multiple testing (p = 0.03). The rs2837960_G (minor) allele, which is associated with increased RA risk, was associated with increased AD risk. Analysis of these three SNPs in a Stage 2 population, consisting of ~1,100 AD and ~2,600 non-AD individuals, did not confirm their association with AD. Analysis of Stage 1 and 2 combined suggested that rs2837960 shows a trend for association with AD. When the Stage 2 population was age-matched for the Stage 1 population, rs2837960 exhibited a non-significant trend with AD. Combined analysis of Stage 1 and the age-matched Stage 2 subset showed a significant association of rs2837960 with AD (p = 0.002, OR 1.24) that retained significance following correction for age, sex and APOE (p = 0.02, OR = 1.20). Rs2837960 is near BACE2, which encodes an aspartic protease capable of processing the AD-associated amyloid precursor protein. Testing for an association between rs2837960 and the expression of BACE2 isoforms in human brain, we observed a trend between rs2837960 and the total expression of BACE2 and the expression of a BACE2 transcript lacking exon 7 (p = 0.07 and 0.10, respectively). CONCLUSIONS: RA-associated SNPs are generally not associated with AD. Moreover, rs2837960_G is associated with increased risk of both RA and, in individuals less than 80 years of age, with AD. Overall, these results contest the hypothesis that genetic variants associated with RA confer protection against AD. Further investigation of rs2837960 is necessary to elucidate the mechanism by which rs2837960 contributes to both AD and RA risk, likely via modulation of BACE2 expression

Evaluation of the global association between cholesterol-associated polymorphisms and Alzheimer\u27s disease suggests a role for rs3846662 and \u3cem\u3eHMGCR\u3c/em\u3e splicing in disease risk

BACKGROUND: Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP)s that are essentially unequivocally associated with peripheral cholesterol. Since the alleles of the APOE gene, which modulate peripheral cholesterol metabolism, and midlife plasma cholesterol are both associated with Alzheimer\u27s disease (AD) risk, we have evaluated the hypothesis that SNPs associated with plasma cholesterol are also associated with AD. RESULTS: Seventeen non-APOE SNPs reproducibly associated with cholesterol per GWAS were tested for association with AD in ~2,000 AD and ~4,000 non-AD subjects. As a group, these SNPs are associated with AD. Two SNPs in particular, rs3846662 and rs1532085, are associated with AD risk and age-of-onset. Additionally, rs3846662 was associated with HMGCR exon 13 splicing in human liver but not brain, possibly obscured by CNS cell-type heterogeneity. However, rs3846662 was associated with HMGCR exon 13 splicing in liver- and brain-derived cell lines. CONCLUSIONS: Cholesterol-associated SNPs outside of APOE confer a global risk for AD. Rs3846662 and rs1532085 are associated with both AD risk and age-of-onset. Rs3846662 is associated with HMGCR exon 13 inclusion. Since rs3846662 affects AD risk and age-of-onset as well as statin responsiveness, this SNP may confound clinical trials evaluating the protective effects of statins on AD

Evaluation of the global association between cholesterol-associated polymorphisms and Alzheimer's disease suggests a role for rs3846662 and HMGCR splicing in disease risk

<p>Abstract</p> <p>Background</p> <p>Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP)s that are essentially unequivocally associated with peripheral cholesterol. Since the alleles of the <it>APOE </it>gene, which modulate peripheral cholesterol metabolism, and midlife plasma cholesterol are both associated with Alzheimer's disease (AD) risk, we have evaluated the hypothesis that SNPs associated with plasma cholesterol are also associated with AD.</p> <p>Results</p> <p>Seventeen non-<it>APOE </it>SNPs reproducibly associated with cholesterol per GWAS were tested for association with AD in ~2,000 AD and ~4,000 non-AD subjects. As a group, these SNPs are associated with AD. Two SNPs in particular, rs3846662 and rs1532085, are associated with AD risk and age-of-onset. Additionally, rs3846662 was associated with <it>HMGCR </it>exon 13 splicing in human liver but not brain, possibly obscured by CNS cell-type heterogeneity. However, rs3846662 was associated with <it>HMGCR </it>exon 13 splicing in liver- and brain-derived cell lines.</p> <p>Conclusions</p> <p>Cholesterol-associated SNPs outside of <it>APOE </it>confer a global risk for AD. Rs3846662 and rs1532085 are associated with both AD risk and age-of-onset. Rs3846662 is associated with <it>HMGCR </it>exon 13 inclusion. Since rs3846662 affects AD risk and age-of-onset as well as statin responsiveness, this SNP may confound clinical trials evaluating the protective effects of statins on AD.</p

Rheumatoid arthritis-associated polymorphisms are not protective against Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Rheumatoid arthritis (RA) and Alzheimer's disease (AD) are inversely associated. To test the hypothesis that genetic elements associated with increased RA risk are associated with decreased AD risk, we evaluated RA genetic risk factors recently identified in genome-wide association studies (GWAS) for their association with AD in a two-stage, case-control analysis.</p> <p>Results</p> <p>In our Stage 1 analysis of ~800 AD and ~1,200 non-AD individuals, three of seventeen RA-associated SNPs were nominally associated with AD (p < 0.05) with one SNP, rs2837960, retaining significance after correction for multiple testing (p = 0.03). The rs2837960_G (minor) allele, which is associated with increased RA risk, was associated with increased AD risk. Analysis of these three SNPs in a Stage 2 population, consisting of ~1,100 AD and ~2,600 non-AD individuals, did not confirm their association with AD. Analysis of Stage 1 and 2 combined suggested that rs2837960 shows a trend for association with AD. When the Stage 2 population was age-matched for the Stage 1 population, rs2837960 exhibited a non-significant trend with AD. Combined analysis of Stage 1 and the age-matched Stage 2 subset showed a significant association of rs2837960 with AD (p = 0.002, OR 1.24) that retained significance following correction for age, sex and APOE (p = 0.02, OR = 1.20). Rs2837960 is near <it>BACE2</it>, which encodes an aspartic protease capable of processing the AD-associated amyloid precursor protein. Testing for an association between rs2837960 and the expression of <it>BACE2 </it>isoforms in human brain, we observed a trend between rs2837960 and the total expression of <it>BACE2 </it>and the expression of a <it>BACE2 </it>transcript lacking exon 7 (p = 0.07 and 0.10, respectively).</p> <p>Conclusions</p> <p>RA-associated SNPs are generally not associated with AD. Moreover, rs2837960_G is associated with increased risk of both RA and, in individuals less than 80 years of age, with AD. Overall, these results contest the hypothesis that genetic variants associated with RA confer protection against AD. Further investigation of rs2837960 is necessary to elucidate the mechanism by which rs2837960 contributes to both AD and RA risk, likely via modulation of <it>BACE2 </it>expression.</p

The marine terraces of Santa Cruz Island, California: Implications for glacial isostatic adjustment models of last-interglacial sea-level history

Glacial isostatic adjustment (GIA) models hypothesize that along coastal California, last interglacial (LIG, broadly from ~130 to ~115 ka) sea level could have been as high as +11 m to +13 m, relative to present, substantially higher than the commonly estimated elevation of +6 m. Areas with low uplift rates can test whether such models are valid. Marine terraces on Santa Cruz Island have previously been reported to occur at low (\u3c10 m) elevations, but ages of many such localities are not known. Using lidar imagery as a base, marine terraces on Santa Cruz Island were newly mapped, elevations were measured, fossils were collected for U-series dating (corals), strontium isotope compositions and amino acid geochronology (mollusks), and paleozoogeography (all taxa). Sr isotope compositions of mollusks from the highest of three marine terraces give ages of ~2.5 Ma to 1.9 Ma, along with Pliocene ages, fromshells interpreted to be reworked. U-series ages of corals fromthewestern part of the island indicate that low-elevation terraces north of the Santa Cruz Island fault correlate to the LIG. Where corals are lacking, amino acid ratios and faunal aspects support terrace correlation to the LIG high stand of sea. Elevations of most terrace localities north of the east-west trending Santa Cruz Island fault, in both thewestern and eastern parts of the island, range from5.75mto 8mabove sea level, well belowthe modeled paleo-sealevel range. Subsidence is ruled out as a mechanism for explaining the lower-than-modeled elevations, because higher-elevation terraces are present alongmuch of the Santa Cruz Island coast north of the fault, indicating longterm tectonic uplift. The low elevations of the LIG terrace fragments are, however, consistent with a low rate of uplift derived from the higher, ~2.5–1.9 Ma terrace. A number of other localities on the Pacific Coast, also dated to the LIG, have marine terrace elevations below the modeled level. GIA models may have overestimated last interglacial sea level by a substantial amount and need to be revised if used for forecasts for future sea-level rise

Succession of physiological stages hallmarks the transcriptomic response of the&nbsp;fungus Aspergillus niger to lignocellulose.

BackgroundUnderstanding how fungi degrade lignocellulose is a cornerstone of improving renewables-based biotechnology, in particular for the production of hydrolytic enzymes. Considerable progress has been made in investigating fungal degradation during time-points where CAZyme expression peaks. However, a robust understanding of the fungal survival strategies over its life time on lignocellulose is thereby missed. Here we aimed to uncover the physiological responses of the biotechnological workhorse and enzyme producer Aspergillus niger over its life time to six substrates important for biofuel production.ResultsWe analysed the response of A. niger to the feedstock Miscanthus and compared it with our previous study on wheat straw, alone or in combination with hydrothermal or ionic liquid feedstock pretreatments. Conserved (substrate-independent) metabolic responses as well as those affected by pretreatment and feedstock were identified via multivariate analysis of genome-wide transcriptomics combined with targeted transcript and protein analyses and mapping to a metabolic model. Initial exposure to all substrates increased fatty acid beta-oxidation and lipid metabolism transcripts. In a strain carrying a deletion of the ortholog of the Aspergillus nidulans fatty acid beta-oxidation transcriptional regulator farA, there was a reduction in expression of selected lignocellulose degradative CAZyme-encoding genes suggesting that beta-oxidation contributes to adaptation to lignocellulose. Mannan degradation expression was wheat straw feedstock-dependent and pectin degradation was higher on the untreated substrates. In the later life stages, known and novel secondary metabolite gene clusters were activated, which are of high interest due to their potential to synthesize bioactive compounds.ConclusionIn this study, which includes the first transcriptional response of Aspergilli to Miscanthus, we highlighted that life time as well as substrate composition and structure (via variations in pretreatment and feedstock) influence the fungal responses to lignocellulose. We also demonstrated that the fungal response contains physiological stages that are conserved across substrates and are typically found outside of the conditions with high CAZyme expression, as exemplified by the stages that are dominated by lipid and secondary metabolism

Expression of SORL1 and a novel SORL1 splice variant in normal and Alzheimers disease brain

<p>Abstract</p> <p>Background</p> <p>Variations in sortilin-related receptor (SORL1) expression and function have been implicated in Alzheimers Disease (AD). Here, to gain insights into SORL1, we evaluated SORL1 expression and splicing as a function of AD and AD neuropathology, neural gene expression and a candidate single nucleotide polymorphism (SNP).</p> <p>Results</p> <p>To identify SORL1 splice variants, we scanned each of the 46 internal SORL1 exons in human brain RNA samples and readily found SORL1 isoforms that lack exon 2 or exon 19. Quantification in a case-control series of the more abundant isoform lacking exon 2 (delta-2-SORL1), as well as the "full-length" SORL1 (FL-SORL1) isoform containing exon 2 showed that expression of FL-SORL1 was reduced in AD individuals. Moreover, FL-SORL1 was reduced in cognitively intact individuals with significant AD-like neuropathology. In contrast, the expression of the delta-2-SORL1 isoform was similar in AD and non-AD brains. The expression of FL-SORL1 was significantly associated with synaptophysin expression while delta-2-SORL1 was modestly enriched in white matter. Lastly, FL-SORL1 expression was associated with rs661057, a SORL1 intron one SNP that has been associated with AD risk. A linear regression analysis found that rs661057, synaptophysin expression and AD neuropathology were each associated with FL-SORL1 expression.</p> <p>Conclusion</p> <p>These results confirm that FL-SORL1 expression declines in AD and with AD-associated neuropathology, suggest that FL-SORL1 declines in cognitively-intact individuals with AD-associated neuropathology, identify a novel SORL1 splice variant that is expressed similarly in AD and non-AD individuals, and provide evidence that an AD-associated SNP is associated with SORL1 expression. Overall, these results contribute to our understanding of SORL1 expression in the human brain.</p