***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Significance MicroRNAs ( miRNAs ) are small ∼22-nt RNAs that are important regulators of posttranscriptional gene expression . Since their initial discovery , they have been shown to be involved in many cellular processes , and their misexpression is associated with disease etiology . Currently , nearly 2,800 human miRNAs are annotated in public repositories . A key question in miRNA research is how many miRNAs are harbored by the human genome . To answer this question , we examined 1,323 short RNA sequence sample s and identified 3,707 novel miRNAs , many of which are human-specific and tissue-specific . Our findings suggest that the human genome expresses a greater number of miRNAs than has previously been appreciated and that many more miRNA molecules may play key roles in disease etiology . Two decades after the discovery of the first animal microRNA ( miRNA ) , the number of miRNAs in animal genomes remains a vexing question . Here , we report findings from analyzing 1,323 short RNA sequencing sample s ( RNA-seq ) from 13 different human tissue types . Using stringent thresholding criteria , we identified 3,707 statistically significant novel mature miRNAs at a false discovery rate of ≤0.05 arising from 3,494 novel precursors ; 91.5 % of these novel miRNAs were identified independently in 10 or more of the processed sample s. Analysis of these novel miRNAs revealed tissue-specific dependencies and a commensurate low Jaccard similarity index in intertissue comparisons . Of these novel miRNAs , 1,657 ( 45 % ) were identified in 43 data sets that were generated by cross-linking followed by Argonaute immunoprecipitation and sequencing ( Ago CLIP-seq ) and represented 3 of the 13 tissues , indicating that these miRNAs are active in the RNA interference pathway . Moreover , experimental investigation through stem-loop PCR of a r and om collection of newly discovered miRNAs in 12 cell lines representing 5 tissues confirmed their presence and tissue dependence . Among the newly identified miRNAs are many novel miRNA clusters , new members of known miRNA clusters , previously unreported products from uncharacterized arms of miRNA precursors , and previously unrecognized paralogues of functionally important miRNA families ( e.g. , miR-15/107 ) . Examination of the sequence conservation across vertebrate and invertebrate organisms showed 56.7 % of the newly discovered miRNAs to be human-specific whereas the majority ( 94.4 % ) are primate lineage-specific . Our findings suggest that the repertoire of human miRNAs is far more extensive than currently represented by public repositories and that there is a significant number of lineage- and /or tissue-specific miRNAs that are uncharacterized Neurofibrillary tangles ( NFT ) constitute one of the cardinal histopathological features of Alzheimer 's disease ( AD ) . To explore in vivo molecular processes involved in the development of NFTs , we compared gene expression profiles of NFT-bearing entorhinal cortex neurons from 19 AD patients , adjacent non-NFT-bearing entorhinal cortex neurons from the same patients , and non-NFT-bearing entorhinal cortex neurons from 14 non-demented , histopathologically normal controls ( ND ) . Of the differentially expressed genes , 225 showed progressively increased expression ( AD NFT neurons > AD non-NFT neurons > ND non-NFT neurons ) or progressively decreased expression ( AD NFT neurons < AD non-NFT neurons < ND non-NFT neurons ) , raising the possibility that they may be related to the early stages of NFT formation . Immunohistochemical studies confirmed that many of the implicated proteins are dysregulated and preferentially localized to NFTs , including apolipoprotein J , interleukin-1 receptor-associated kinase 1 , tissue inhibitor of metalloproteinase 3 , and casein kinase 2 , beta . Functional validation studies are underway to determine which c and i date genes may be causally related to NFT neuropathology , thus providing therapeutic targets for the treatment of AD Since 1992 , the amyloid cascade hypothesis has played the prominent role in explaining the etiology and pathogenesis of Alzheimer 's disease  ( AD ) . It proposes that the deposition of β-amyloid ( Aβ ) is the initial pathological event in AD leading to the formation of senile plaques ( SPs ) and then to neurofibrillary tangles ( NFTs ) , neuronal cell death , and ultimately dementia . While there is substantial evidence supporting the hypothesis , there are also limitations : ( 1 ) SP and NFT may develop independently , and ( 2 ) SPs and NFTs may be the products rather than the causes of neurodegeneration in AD . In addition , r and omized clinical trials that tested drugs or antibodies targeting components of the amyloid pathway have been inconclusive . This paper provides a critical overview of the evidence for and against the amyloid cascade hypothesis in AD and provides suggestions for future directions There has been a plausible link between human exposure to aluminum and Alzheimer 's disease for several decades . We contend that the only direct and ethically acceptable experimental test of the ' aluminum hypothesis ' , which would provide unequivocal data specific to the link , is to test the null hypothesis that a reduction in the body burden of aluminum to its lowest practical limit would have no influence upon the incidence , progression , or severity of Alzheimer 's disease . Herein we are testing the hypothesis that silicon-rich mineral waters can be used as non-invasive methods to reduce the body burden of aluminum in individuals with Alzheimer 's disease and a control group consisting of their carers and partners . We have shown that drinking up to 1 L of a silicon-rich mineral water each day for 12 weeks facilitated the removal of aluminum via the urine in both patient and control groups without any concomitant affect upon the urinary excretion of the essential metals , iron and copper . We have provided preliminary evidence that over 12 weeks of silicon-rich mineral water therapy the body burden of aluminum fell in individuals with Alzheimer 's disease and , concomitantly , cognitive performance showed clinical ly relevant improvements in at least 3 out of 15 individuals . This is a first step in a much needed rigorous test of the ' aluminum hypothesis of Alzheimer 's disease ' and a longer term study involving many more individuals is now warranted The formation of 5-hydroxymethylcytosine ( 5hmC ) , a key intermediate of DNA demethylation , is driven by the ten eleven translocation ( TET ) family of proteins that oxidize 5-methylcytosine ( 5mC ) to 5hmC. To determine whether methylation/demethylation status is altered during the progression of Alzheimer 's disease ( AD ) , levels of TET1 , 5mC and subsequent intermediates , including 5hmC , 5-formylcytosine ( 5fC ) and 5-carboxylcytosine ( 5caC ) were quantified in nuclear DNA from the hippocampus/parahippocampal gyrus ( HPG ) and the cerebellum of 5 age-matched normal controls , 5 subjects with pre clinical AD ( PCAD ) and 7 late-stage AD ( LAD ) subjects by immunochemistry . The results showed significantly ( p < 0.05 ) increased levels of TET1 , 5mC , and 5hmC in the HPG of PCAD and LAD subjects . In contrast , levels of 5fC and 5caC were significantly ( p < 0.05 ) decreased in the HPG of PCAD and LAD subjects . Overall , the data suggest altered methylation/demethylation patterns in vulnerable brain regions prior to the onset of clinical symptoms in AD suggesting a role in the pathogenesis of the disease BACKGROUND Memory declines more rapidly with age in apolipoprotein E ( APOE ) epsilon4 carriers than in APOE epsilon4 noncarriers , and APOE epsilon4 homozygotes ' cognitive performances correlate with stressors . These changes could represent presymptomatic disease in some , despite their youth . OBJECTIVE To show that presymptomatic APOE epsilon4 homozygotes experience greater psychometric decline at a younger age than APOE epsilon4 heterozygotes and noncarriers before the diagnosis of mild cognitive impairment ( MCI ) and Alzheimer disease ( AD ) . DESIGN Prospect i ve observational study SETTING Academic medical center . PARTICIPANTS A total of 43 APOE epsilon4 homozygotes , 59 APOE epsilon4 heterozygotes , and 112 APOE epsilon4 noncarriers aged 50 to 69 years were cognitively healthy and matched at entry according to age , educational level , and sex . INTERVENTION Neuropsychological battery given every 2 years . MAIN OUTCOME MEASURES Predefined test and cognitive domain decline criteria applied to consecutive epochs . RESULTS Of 214 participants , 48 showed no decline on any test , 126 showed decline on only 1 test in 1 or more domains , and 40 showed decline on 2 or more tests in 1 or more domains .  Cognitive domain decline occurred in 4 of 10 APOE epsilon4 homozygotes 60 years and older at entry ( 40.0 % ) compared with 5 of 66 APOE epsilon4 heterozygotes and noncarriers ( 7.6 % ) ( P = .02 ) and was more predictive of subsequent decline than nondomain decline ( 17 of 24 [ 70.8 % ] vs 29 of 70 [ 41.4 % ] ; P = .01 ) . Decline on any memory test was predictive of further decline ( P < .001 ) , as was memory domain decline ( P = .006 ) in all genetic subgroups . Seven participants developed MCI ( in 6 ) or AD ( in 1 ) , of whom 5 were APOE epsilon4 homozygotes ( P = .008 ) . Retrospective comparison showed that those who experienced multidomain , memory , and language domain decline had lower spatial and memory scores at entry than those who experienced no decline . CONCLUSIONS APOE epsilon4 homozygotes in their 60s have higher rates of cognitive domain decline than APOE epsilon4 heterozygotes or noncarriers before the diagnosis of MCI and AD , thus confirming and characterizing the existence of a pre-MCI state in this genetic subset We present here both linear regressions and multivariate analyses correlating three global neuropsychological tests with a number of structural and neurochemical measurements performed on a prospect i ve series of 15 patients with Alzheimer 's disease and 9 neuropathologically normal subjects . The statistical data show only weak correlations between psychometric indices and plaques and tangles , but the density of neocortical synapses measured by a new immunocytochemical/densitometric technique reveals very powerful correlations with all three psychological assays . Multivariate analysis by stepwise regression produced a model including midfrontal and inferior parietal synapse density , plus inferior parietal plaque counts with a correlation coefficient of 0.96 for Mattis 's Dementia Rating Scale . Plaque density contributed only 26 % of that strength Positional cloning studies to identify disease genes are being carried out for many human genetic diseases . Such studies often include a genome-scan linkage analysis to identify the rough chromosomal location of a disease gene , fine structure genetic mapping to define and narrow the chromosomal interval in which the disease gene may be located , and physical mapping and gene identification in the genetically defined interval to clone the disease gene . During the planning of a positional cloning study , it is important to know that , if linkage is found , the genetic interval identified is likely to be sufficiently narrow to be dissected efficiently by methods of physical mapping and gene identification . Thus , we wish to know the limits of resolution of a genetic linkage study . In this paper , I determine for Mendelian diseases the distributions and moments of three measures of linkage resolution : ( 1 ) in a set of N chromosomes , the distance between the nearest crossovers that flank a disease locus , ( 2 ) the distance between the nearest genetic markers that flank the pair of flanking crossovers after a genome scan , and ( 3 ) the distance between the nearest flanking markers after additional r and omly placed markers are generated and typed in an identified interval . These results provide explicit sample -size guidelines for future positional cloning studies of Mendelian diseases and make possible a more objective evaluation of whether a proposed positional cloning study is likely to be successful . I also briefly discuss the more difficult problem of linkage resolution for complex genetic diseases BACKGROUND Imaging with amyloid-β PET can potentially aid the early and accurate diagnosis of Alzheimer 's disease .  Florbetaben ( ¹⁸F ) is a promising ¹⁸F-labelled amyloid-β-targeted PET tracer in clinical development . We aim ed to assess the sensitivity and specificity of florbetaben ( ¹⁸F ) PET in discriminating between patients with probable Alzheimer 's disease and elderly healthy controls . METHODS We did a multicentre , open-label , non-r and omised phase 2 study in 18 centres in Australia , Germany , Switzerl and , and the USA . Imaging with florbetaben ( ¹⁸F ) PET was done on patients with probable Alzheimer 's disease ( age 55 years or older , mini-mental state examination [ MMSE ] score=18 - 26 , clinical dementia rating [CDR]=0·5 - 2·0 ) and age-matched healthy controls ( MMSE ≥ 28 , CDR=0 ) . Our primary objective was to establish the diagnostic efficacy of the scans in differentiating between patients with probable disease and age-matched health 
    Output:
    
The promising newer approaches may provide reliable means of early and more specific diagnosis and help identify therapeutic interventions for LOAD