Minimum information about a microarray experiment (MIAME)-toward standards for microarray data.

Microarray analysis has become a widely used tool for the generation of gene expression data on a genomic scale. Although many significant results have been derived from microarray studies, one limitation has been the lack of standards for presenting and exchanging such data. Here we present a proposal, the Minimum Information About a Microarray Experiment (MIAME), that describes the minimum information required to ensure that microarray data can be easily interpreted and that results derived from its analysis can be independently verified. The ultimate goal of this work is to establish a standard for recording and reporting microarray-based gene expression data, which will in turn facilitate the establishment of databases and public repositories and enable the development of data analysis tools. With respect to MIAME, we concentrate on defining the content and structure of the necessary information rather than the technical format for capturing it.     

Cadmium is a mutagen that acts by inhibiting mismatch repair

Most errors that arise during DNA replication can be corrected by DNA polymerase proofreading or by post-replication mismatch repair (MMR). Inactivation of both mutation-avoidance systems results in extremely high mutability that can lead to error catastrophe. High mutability and the likelihood of cancer can be caused by mutations and epigenetic changes that reduce MMR. Hypermutability can also be caused by external factors that directly inhibit MMR. Identifying such factors has important implications for understanding the role of the environment in genome stability. We found that chronic exposure of yeast to environmentally relevant concentrations of cadmium, a known human carcinogen, can result in extreme hypermutability. The mutation specificity along with responses in proofreading-deficient and MMR-deficient mutants indicate that cadmium reduces the capacity for MMR of small misalignments and base-base mismatches. In extracts of human cells, cadmium inhibited at least one step leading to mismatch removal. Together, our data show that a high level of genetic instability can result from environmental impediment of a mutation-avoidance system.     

Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration

We defined the genetic landscape of balanced chromosomal rearrangements at nucleotide resolution by sequencing 141 breakpoints from cytogenetically interpreted translocations and inversions. We confirm that the recently described phenomenon of 'chromothripsis' (massive chromosomal shattering and reorganization) is not unique to cancer cells but also occurs in the germline, where it can resolve to a relatively balanced state with frequent inversions. We detected a high incidence of complex rearrangements (19.2%) and substantially less reliance on microhomology (31%) than previously observed in benign copy-number variants (CNVs). We compared these results to experimentally generated DNA breakage-repair by sequencing seven transgenic animals, revealing extensive rearrangement of the transgene and host genome with similar complexity to human germline alterations. Inversion was the most common rearrangement, suggesting that a combined mechanism involving template switching and non-homologous repair mediates the formation of balanced complex rearrangements that are viable, stably replicated and transmitted unaltered to subsequent generations.     

Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy

Auditory neuropathy is a particular type of hearing impairment in which neural transmission of the auditory signal is impaired, while cochlear outer hair cells remain functional. Here we report on DFNB59, a newly identified gene on chromosome 2q31.1-q31.3 mutated in four families segregating autosomal recessive auditory neuropathy. DFNB59 encodes pejvakin, a 352-residue protein. Pejvakin is a paralog of DFNA5, a protein of unknown function also involved in deafness. By immunohistofluorescence, pejvakin is detected in the cell bodies of neurons of the afferent auditory pathway. Furthermore, Dfnb59 knock-in mice, homozygous for the R183W variant identified in one DFNB59 family, show abnormal auditory brainstem responses indicative of neuronal dysfunction along the auditory pathway. Unlike previously described sensorineural deafness genes, all of which underlie cochlear cell pathologies, DFNB59 is the first human gene implicated in nonsyndromic deafness due to a neuronal defect.     

乳腺癌血清多肽图研究

乳腺癌一直是全世界范围内威胁妇女健康的恶性疾病, 尽管人们已经进行了大量的研究以减少乳腺癌对人类的危害, 但是乳腺癌仍然是目前导致死亡的恶性肿瘤之一. 乳腺癌的早期发现对于患者的愈后与生存意义重大, 可以明显提高病人生存时间、降低病人的死亡率. 据统计, 在过去的5年里, 早期诊断每年可减少3.2%因乳腺癌死亡的患者. 然而研究表明, 目前常用的乳腺癌诊断技术, 如乳腺X射线摄影和乳房检查均无法诊断出40%的早期乳癌患者和大多数年轻女性的乳腺肿瘤. 因此在乳腺癌临床治疗中, 急需发展新型的高效诊断技术.     

Extraction of a weak climatic signal by an ecosystem

The complexity of ecosystems can cause subtle and chaotic responses to changes in external forcing. Although ecosystems may not normally behave chaotically, sensitivity to external influences associated with nonlinearity can lead to amplification of climatic signals. Strong correlations between an El Ni?o index and rainfall and maize yield in Zimbabwe have been demonstrated; the correlation with maize yield was stronger than that with rainfall. A second example is the 100,000-year ice-age cycle, which may arise from a weak cycle in radiation through its influence on the concentration of atmospheric CO2 (ref. 5). Such integration of a weak climatic signal has yet to be demonstrated in a realistic theoretical system. Here we use a particular climatic phenomenon-the observed association between plankton populations around the UK and the position of the Gulf Stream-as a probe to demonstrate how a detailed marine ecosystem model extracts a weak signal that is spread across different meteorological variables. Biological systems may therefore respond to climatic signals other than those that dominate the driving variables.     

The p53 tumour suppressor gene

The cell cycle is composed of a series of steps which can be negatively or positively regulated by various factors. Chief among the negative regulators is the p53 protein. Alteration or inactivation of p53 by mutation, or by its interactions with oncogene products of DNA tumour viruses, can lead to cancer. These mutations seem to be the most common genetic change in human cancers.