NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth

Mitochondria are emerging as important players in the transformation process of cells, maintaining the biosynthetic and energetic capacities of cancer cells and serving as one of the primary sites of apoptosis and autophagy regulation. Although several avenues of cancer therapy have focused on mitochondria, progress in developing mitochondria-targeting anticancer drugs nonetheless has been slow, owing to the limited number of known mitochondrial target proteins that link metabolism with autophagy or cell death. Recent studies have demonstrated that two members of the newly discovered family of NEET proteins, NAF-1 (CISD2) and mitoNEET (mNT; CISD1), could play such a role in cancer cells. NAF-1 was shown to be a key player in regulating autophagy, and mNT was proposed to mediate iron and reactive oxygen homeostasis in mitochondria. Here we show that the protein levels of NAF-1 and mNT are elevated in human epithelial breast cancer cells, and that suppressing the level of these proteins using shRNA results in significantly reduced cell proliferation and tumor growth, decreased mitochondrial performance, uncontrolled accumulation of iron and reactive oxygen in mitochondria, and activation of autophagy. Our findings highlight NEET proteins as promising mitochondrial targets for cancer therapy

The Structure and Regulation of Human Muscle α-Actinin

SummaryThe spectrin superfamily of proteins plays key roles in assembling the actin cytoskeleton in various cell types, crosslinks actin filaments, and acts as scaffolds for the assembly of large protein complexes involved in structural integrity and mechanosensation, as well as cell signaling. α-actinins in particular are the major actin crosslinkers in muscle Z-disks, focal adhesions, and actin stress fibers. We report a complete high-resolution structure of the 200 kDa α-actinin-2 dimer from striated muscle and explore its functional implications on the biochemical and cellular level. The structure provides insight into the phosphoinositide-based mechanism controlling its interaction with sarcomeric proteins such as titin, lays a foundation for studying the impact of pathogenic mutations at molecular resolution, and is likely to be broadly relevant for the regulation of spectrin-like proteins

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

How useful are volunteers for visual biodiversity surveys? An evaluation of skill level and group size during a conservation expedition

The ability of volunteers to undertake different tasks and accurately collect data is critical for the success of many conservation projects. In this study, a simulated herpetofauna visual encounter survey was used to compare the detection and distance estimation accuracy of volunteers and more experienced observers. Experience had a positive effect on individual detection accuracy. However, lower detection performance of less experienced volunteers was not found in the group data, with larger groups being more successful overall, suggesting that working in groups facilitates detection accuracy of those with less experience. This study supports the idea that by optimizing survey protocols according to the available resources (time and volunteer numbers), the sampling efficiency of monitoring programs can be improved and that non-expert volunteers can provide valuable contributions to visual encounter-based biodiversity surveys. Recommendations are made for the improvement of survey methodology involving non-expert volunteers

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Risk factors for failure to return to the pre-fracture place of residence after hip fracture: a prospective longitudinal study of 444 patients

Introduction: Long-term place of residence after hip fracture is not often described in literature. The goal of this study was to identify risk factors, known at admission, for failure to return to the pre-fracture place of residence of hip fracture patients in the Wrst year after a hip fracture. Methods: This is a prospective longitudinal study of 444 consecutive admissions of hip fracture patients aged ≥65 years. Place of residence prior to admission, at discharge, after 3 and 12 months was registered. Patients admitted from a nursing home (n = 49) were excluded from statistical analysis. Multivariable logistic regression analysis was performed, using age, gender, presence of a partner, ASAscore, dementia, anaemia at admission, type of fracture, pre-fracture level of mobility and level of activities of daily living (ADL) as possible risk factors. Results: Two hundred eighty-nine patients lived in their own home, 31.8% returned at discharge, 72.9% at 3 months and 72.8% at 12 months. Age, absence of a partner, dementia, and a lower pre-fracture level of ADL or mobility were independent contributors to failure to return to their own home at discharge, 3 or 12 months. 106 patients lived in a residential home; 33.3% returned at discharge, 68.4% at 3 months and 64.4% at 12 months. Age was an independent contributor to failure to return to a residential home. Conclusions: Age, dementia and a lower pre-fracture level of ADL were the main signiWcant risk factors for failure to return to the pre-fracture residence. As the 3- and 12-month return-rates were similar, 3-month follow-up might be used as an endpoint in future research

Autonomic Management of Large Clusters and Their Integration into the Grid

We present a framework for the co-ordinated, autonomic management of multiple clusters in a compute center and their integration into a Grid environment. Site autonomy and the automation of administrative tasks are prime aspects in this framework. The system behavior is continuously monitored in a steering cycle and appropriate actions are taken to resolve any problems. All presented components have been implemented in the course of the EU project DataGrid: The Lemon monitoring components, the FT fault-tolerance mechanism, the quattor system for software installation and configuration, the RMS job and resource management system, and the Gridification scheme that integrates clusters into the Grid

現地観測に基づく河川流の乱流特性に関する研究

博士（工学）神戸大