Post-mining neutralization of acidic surface mine lakes

Twenty core samples and 54 surface sediment samples were taken from surface mine lakes in Missouri, Illinois, and Indiana to determine the rates of neutralization of acid mine lakes. Sediment samples were analyzed for diatom microfossils, selected chemical elements, and the radionuclide, lead-210. The surface samples showed that there were strong differences in diatom microfossils between acidic and neutral lakes but there was no strong difference in sediment chemical composition between acidic and neutral lakes. Of 20 lakes from which cores were examined, 9 showed diatom evidence of neutralization and one of acidification over time. Cores from 5 of these were dated using lead-210 analysis. Diatom microfossils showed that neutralization took from less than 3 years to 30 years to occur. Comparisons between lake sediment and water column chemistry indicated that neither sulfide deposition nor H2S outgasing is likely to play a major role in the neutralization process. Chemical analyses of lake sediment showed that the sediment is a sink for heavy metals. These metals are held as sulfides. There is also a considerable fraction of metal ions strongly bound to clays. This research demonstrates that acid lake neutralization is common, that it occurs over moderate time spans and that the rate is controlled by rates of acid supply from the watershed.U.S. Department of the InteriorU.S. Geological SurveyOpe

Exome-Sequencing Confirms DNAJC5 Mutations as Cause of Adult Neuronal Ceroid-Lipofuscinosis

We performed whole-exome sequencing in two autopsy-confirmed cases and an elderly unaffected control from a multigenerational family with autosomal dominant neuronal ceroid lipofuscinosis (ANCL). A novel single-nucleotide variation (c.344T>G) in the DNAJC5 gene was identified. Mutational screening in an independent family with autosomal dominant ANCL found an in-frame single codon deletion (c.346_348 delCTC) resulting in a deletion of p.Leu116del. These variants fulfill all genetic criteria for disease-causing mutations: they are found in unrelated families with the same disease, exhibit complete segregation between the mutation and the disease, and are absent in healthy controls. In addition, the associated amino acid substitutions are located in evolutionarily highly conserved residues and are predicted to functionally affect the encoded protein (CSPα). The mutations are located in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of CSPα. We performed a comprehensive in silico analysis of the functional and structural impact of both mutations on CSPα. We found that these mutations dramatically decrease the affinity of CSPα for the membrane. We did not identify any significant effect on palmitoylation status of CSPα. However, a reduction of CSPα membrane affinity may change its palmitoylation and affect proper intracellular sorting. We confirm that CSPα has a strong intrinsic aggregation propensity; however, it is not modified by the mutations. A complementary disease-network analysis suggests a potential interaction with other NCLs genes/pathways. This is the first replication study of the identification of DNAJC5 as the disease-causing gene for autosomal dominant ANCL. The identification of the novel gene in ANCL will allow us to gain a better understanding of the pathological mechanism of ANCLs and constitutes a great advance toward the development of new molecular diagnostic tests and may lead to the development of potential therapies

Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families

Pathogenic mutations in APP, PSEN1, PSEN2, MAPT and GRN have previously been linked to familial early onset forms of dementia. Mutation screening in these genes has been performed in either very small series or in single families with late onset AD (LOAD). Similarly, studies in single families have reported mutations in MAPT and GRN associated with clinical AD but no systematic screen of a large dataset has been performed to determine how frequently this occurs. We report sequence data for 439 probands from late-onset AD families with a history of four or more affected individuals. Sixty sequenced individuals (13.7%) carried a novel or pathogenic mutation. Eight pathogenic variants, (one each in APP and MAPT, two in PSEN1 and four in GRN) three of which are novel, were found in 14 samples. Thirteen additional variants, present in 23 families, did not segregate with disease, but the frequency of these variants is higher in AD cases than controls, indicating that these variants may also modify risk for disease. The frequency of rare variants in these genes in this series is significantly higher than in the 1,000 genome project (p = 5.09×10−5; OR = 2.21; 95%CI = 1.49–3.28) or an unselected population of 12,481 samples (p = 6.82×10−5; OR = 2.19; 95%CI = 1.347–3.26). Rare coding variants in APP, PSEN1 and PSEN2, increase risk for or cause late onset AD. The presence of variants in these genes in LOAD and early-onset AD demonstrates that factors other than the mutation can impact the age at onset and penetrance of at least some variants associated with AD. MAPT and GRN mutations can be found in clinical series of AD most likely due to misdiagnosis. This study clearly demonstrates that rare variants in these genes could explain an important proportion of genetic heritability of AD, which is not detected by GWAS

Number of rare non-synonymous and splice-site variants found in the 439 sequenced samples.

<p>*Based on our segregation analyses.</p><p>**Not present in the AD&FTD mutation database or in dbSNP.</p><p>Only the rare (MAF<0.05) non-synonymous, splice-site and nonsense sequence variants are shown.</p

Demographic data for the cohort.

<p>The mean, the standard deviation and the range for the age at onset (AAO) for the sequenced samples and the families are shown. For the families the AAO represents the mean AAO of the affected individuals of each family.</p

Pedigrees for some of the sequenced families illustrating the presence of phenocopies and low penetrance mutations or the presence of presymptomatic cases.

<p>A) Pedigree for a family with the <i>PSEN1 A79V</i> mutation. B) Pedigree for a family with the <i>GRN R493X</i> mutation. AO indicates the subject or family report of age of onset of symptoms. AE = the age of last evaluation. MCI: Mild cognitive impairment or questionable dementia by family report.+symbol indicates that the subject is positive for the indicated mutation.−symbol indicates that the subject is negative for the indicated mutation. A number inside of a diamond indicates the number of subjects with the same status. Fully shaded circles or squares indicate confirmed AD by autopsy. Three/fourths shaded symbol indicates probable AD diagnosed using NINCDS-ADRDA criteria. One/fourth shaded symbol indicates that the family reports this individual has AD.</p

Distribution of the families by the number of affected individuals in each family.

<p>The number of families with different numbers of affected individuals is shown. More than 50% of the families have 4 or 5 affected individuals. The number of sequence variants found in each group is also shown.</p

List of the pathogenic and likely pathogenic non-synonymous, splice site and nonsense sequence variants identified.

<p>List of the non-synonymous, splice and nonsense variants identified in the 439 sequenced samples. The identified variants were genotyped in all the available family samples. The number of affected carriers, non-carriers and the un-affected carriers, non-carriers, as well as the mean age at onset and the standard deviation for the affected and the age at last assessment for the unaffected individuals are shown.</p><p>The variants were classified as pathogenic, or likely pathogenic based on our segregation analyses, bioinformatic analyses, sequencing and genotyping data in additional cases and controls (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031039#pone-0031039-t005" target="_blank">table 5</a>) and previous reports.</p