Using peripheral measurement devices, 82% of postmenopausal women with fractures had T scores better than -2.5. A strategy to reduce overall fracture incidence will likely require lifestyle changes and a targeted effort to identify and develop treatment protocols for women with less severe low bone mass who are nonetheless at increased risk for future fractures.

Purpose: Epidermal growth factor receptor (EGFR) mutations related to gefitinib responsiveness in non-small cell lung cancer have been found recently. Detection of EGFR mutations has become an important issue for therapeutic decision-making in non-small cell lung cancer.Experimental Design: Mutational analysis of the kinase domain of EGFR coding sequence was done on 101 fresh frozen tumor tissues from patients without prior gefitinib treatment and 16 paraffin-embedded tumor tissues from patients treated with gefitinib. Detection of phosphorylated EGFR by immunoblot was also done on frozen tumor tissues.Results: The 101 non-small cell lung cancer tumor specimens include 69 adenocarcinomas, 24 squamous cell carcinomas, and 8 other types of non-small cell lung cancers. Mutation(s) in the kinase domain (exon 18 to exon 21) of the EGFR gene were identified in 39 patients. All of the mutations occurred in adenocarcinoma, except one that was in an adenosquamous carcinoma. The mutation rate in adenocarcinoma was 55% (38 of 69). For the 16 patients treated with gefitinib, 7 of the 9 responders had EGFR mutations, and only 1 of the 7 nonresponders had mutations, which included a nonsense mutation. The mutations seem to be complex in that altogether 23 different mutations were observed, and 9 tumors carried 2 mutations.Conclusions: Data from our study would predict a higher gefitinib response rate in lung adenocarcinoma patients in Chinese and, possibly, other East Asian populations. The tight association with adenocarcinoma and the high frequency of mutations raise the possibility that EGFR mutations play an important role in the tumorigenesis of adenocarcinoma of lung, especially in East Asians.

CISD2, the causative gene for Wolfram syndrome 2 (WFS2), is a previously uncharacterized novel gene. Significantly, the CISD2 gene is located on human chromosome 4q, where a genetic component for longevity maps. Here we show for the first time that CISD2 is involved in mammalian life-span control. Cisd2 deficiency in mice causes mitochondrial breakdown and dysfunction accompanied by autophagic cell death, and these events precede the two earliest manifestations of nerve and muscle degeneration; together, they lead to a panel of phenotypic features suggestive of premature aging. Our study also reveals that Cisd2 is primarily localized in the mitochondria and that mitochondrial degeneration appears to have a direct phenotypic consequence that triggers the accelerated aging process in Cisd2 knockout mice; furthermore, mitochondrial degeneration exacerbates with age, and the autophagy increases in parallel to the development of the premature aging phenotype. Additionally, our Cisd2 knockout mouse work provides strong evidence supporting an earlier clinical hypothesis that WFS is in part a mitochondria-mediated disorder; specifically, we propose that mutation of CISD2 causes the mitochondriamediated disorder WFS2 in humans. Thus, this mutant mouse provides an animal model for mechanistic investigation of Cisd2 protein function and help with a pathophysiological understanding of WFS2.[Keywords: Cisd2; Wolfram syndrome 2; autophagy; knockout mice; mitochondria; premature aging] Supplemental material is available at http://www.genesdev.org.

Several recent studies have shown the presence of genes for the key enzyme associated with archaeal methane/alkane metabolism, methyl-coenzyme M reductase (Mcr), in metagenome-assembled genomes (MAGs) divergent to existing archaeal lineages. Here, we study the mcr-containing archaeal MAGs from several hot springs, which reveal further expansion in the diversity of archaeal organisms performing methane/alkane metabolism. Significantly, an MAG basal to organisms from the phylum Thaumarchaeota that contains mcr genes, but not those for ammonia oxidation or aerobic metabolism, is identified. Together, our phylogenetic analyses and ancestral state reconstructions suggest a mostly vertical evolution of mcrABG genes among methanogens and methanotrophs, along with frequent horizontal gene transfer of mcr genes between alkanotrophs. Analysis of all mcr-containing archaeal MAGs/genomes suggests a hydrothermal origin for these microorganisms based on optimal growth temperature predictions. These results also suggest methane/alkane oxidation or methanogenesis at high temperature likely existed in a common archaeal ancestor.

No abstract

Vaccinia H1-related phosphatase (VHR) is classified as a dual specificity phosphatase. Unlike typical dual specificity phosphatases, VHR lacks the MAPK-binding domain and shows poor activity against MAPKs. We found that EGF receptor (EGFR) was a direct substrate of VHR and that overexpression of VHR down-regulated EGFR phosphorylation, particularly at Tyr-992 residue. Expression of VHR inhibited the activation of phospholipase C␥ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR. Decreasing VHR expression by RNA interference caused higher EGFR phosphorylation at Tyr-992. In addition to EGFR, VHR also directly dephosphorylated ErbB2. Consistent with these results, suppression of VHR augmented the foci formation ability of H1299 non-small cell lung cancer (NSCLC) cells, whereas overexpression of VHR suppressed cell growth in both two-and three-dimensional cultures. Expression of VHR also suppressed tumor formation in a mouse xenograft model. Furthermore, VHR expression was significantly lower in NSCLC tissues in comparison to that in normal lung tissues. Collectively, this study shows that down-regulation of VHR expression enhances the signaling of ErbB receptors and may be involved in NSCLC pathogenesis.Among protein modifications, tyrosine phosphorylation is extensively used only in multicellular, eukaryotic organisms. Protein-tyrosine phosphorylation plays an important role in signaling transduction pathways that are involved in embryogenesis, development, and homeostasis. Disorders in proteintyrosine phosphorylation are found in many human diseases from cancer to immune disorders. Although protein phosphorylation is a balanced action of protein kinases and phosphatases, the experimental data of protein phosphatases is proportionally much less than that of protein kinases. Dual specificity phosphatases (DUSPs) 3 are structurally related to protein-tyrosine phosphatases (PTP) and are initially implicated in the down-regulation of MAPKs (1). Distinct from PTPs, which have a deep catalytic cleft; DUSPs have shallow catalytic sites, which permit the less stringent phospho-amino acid specificity of DUSPs (2-4). Several DUSPs including MAPK phosphatases (MKP)-1 to -7, M3/6 (also called VH5), and VHR have been shown to inactivate one or several MAPKs (5-12). The expression of certain DUSPs is increased by mitogenic signaling (5, 13-15). Both ERK and JNK pathways induce the expression of MKPs (15-17). The induction of MKP expression by MAPK signaling may, in turn, lead to the down-regulation of MAPK activities. Recently, many newly identified DUSPs were found to have little or no phosphatase activity against MAPKs, indicating that MAPK inactivation is not the sole function of DUSPs (18 -21). These novel DUSPs are smaller in size compared with MKPs and lack the MAPK-binding domain. These groups of DUSPs have been classified as atypical DUSPs (1). Others' and our recent studies reveal that atypical DUSPs may play a critical role in the regulation of signaling triggered by protein tyrosine...

A green and sustainable strategy synthesizes clinical medicine warfarin anticoagulant by using lipase-supported metal-organic framework (MOF) bioreactors (see scheme). These findings may be beneficial for future studies in the industrial production of chemical, pharmaceutical, and agrochemical precursors.

No abstract