Mapping the genetic architecture of gene expression in human liver

Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits. Therefore, identifying the molecular phenotypes that vary in response to changes in DNA and that also associate with changes in disease traits has the potential to provide the functional information required to not only identify and validate the susceptibility genes that are directly affected by changes in DNA, but also to understand the molecular networks in which such genes operate and how changes in these networks lead to changes in disease traits. Toward that end, we profiled more than 39,000 transcripts and we genotyped 782,476 unique single nucleotide polymorphisms (SNPs) in more than 400 human liver samples to characterize the genetic architecture of gene expression in the human liver, a metabolically active tissue that is important in a number of common human diseases, including obesity, diabetes, and atherosclerosis. This genome-wide association study of gene expression resulted in the detection of more than 6,000 associations between SNP genotypes and liver gene expression traits, where many of the corresponding genes identified have already been implicated in a number of human diseases. The utility of these data for elucidating the causes of common human diseases is demonstrated by integrating them with genotypic and expression data from other human and mouse populations. This provides much-needed functional support for the candidate susceptibility genes being identified at a growing number of genetic loci that have been identified as key drivers of disease from genome-wide association studies of disease. By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large-scale, genome-wide association study. We also identify SORT1 and CELSR2 as candidate susceptibility genes for a locus recently associated with coronary artery disease and plasma low-density lipoprotein cholesterol levels in the process. © 2008 Schadt et al

Potential of a suite of robot/computer-assisted motivating systems for personalized, home-based, stroke rehabilitation

BACKGROUND: There is a need to improve semi-autonomous stroke therapy in home environments often characterized by low supervision of clinical experts and low extrinsic motivation. Our distributed device approach to this problem consists of an integrated suite of low-cost robotic/computer-assistive technologies driven by a novel universal access software framework called UniTherapy. Our design strategy for personalizing the therapy, providing extrinsic motivation and outcome assessment is presented and evaluated. METHODS: Three studies were conducted to evaluate the potential of the suite. A conventional force-reflecting joystick, a modified joystick therapy platform (TheraJoy), and a steering wheel platform (TheraDrive) were tested separately with the UniTherapy software. Stroke subjects with hemiparesis and able-bodied subjects completed tracking activities with the devices in different positions. We quantify motor performance across subject groups and across device platforms and muscle activation across devices at two positions in the arm workspace. RESULTS: Trends in the assessment metrics were consistent across devices with able-bodied and high functioning strokes subjects being significantly more accurate and quicker in their motor performance than low functioning subjects. Muscle activation patterns were different for shoulder and elbow across different devices and locations. CONCLUSION: The Robot/CAMR suite has potential for stroke rehabilitation. By manipulating hardware and software variables, we can create personalized therapy environments that engage patients, address their therapy need, and track their progress. A larger longitudinal study is still needed to evaluate these systems in under-supervised environments such as the home

Experimental long-lived entanglement of two macroscopic objects

Entanglement is considered to be one of the most profound features of quantum mechanics. An entangled state of a system consisting of two subsystems cannot be described as a product of the quantum states of the two subsystems. In this sense the entangled system is considered inseparable and nonlocal. It is generally believed that entanglement manifests itself mostly in systems consisting of a small number of microscopic particles. Here we demonstrate experimentally the entanglement of two objects, each consisting of about 10^12 atoms. Entanglement is generated via interaction of the two objects - more precisely, two gas samples of cesium atoms - with a pulse of light, which performs a non-local Bell measurement on collective spins of the samples. The entangled spin state can be maintained for 0.5 millisecond. Besides being of fundamental interest, the robust, long-lived entanglement of material objects demonstrated here is expected to be useful in quantum information processing, including teleportation of quantum states of matter and quantum memory.Comment: Submitted to Nature, June 9, 2001, 11 pages, 3 figures. Contents changed following referees' suggestion

BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs

Background: BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene located on chromosome 3p21. Germline BAP1 mutations have been recently associated with an increased risk of malignant mesothelioma, atypical melanocytic tumors and other neoplasms. To answer the question if different germline BAP1 mutations may predispose to a single syndrome with a wide phenotypic range or to distinct syndromes, we investigated the presence of melanocytic tumors in two unrelated families (L and W) with germline BAP1 mutations and increased risk of malignant mesothelioma.Methods: Suspicious cutaneous lesions were clinically and pathologically characterized and compared to those present in other families carrying BAP1 mutations. We then conducted a meta-analysis of all the studies reporting BAP1-mutated families to survey cancer risk related to the germline BAP1 mutation (means were compared using t-test and proportions were compared with Pearson χ2 test or two-tailed Fisher's exact test).Results: Melanocytic tumors: of the five members of the L family studied, four (80%) carried a germline BAP1 mutation (p.Gln684*) and also presented one or more atypical melanocytic tumors; of the seven members of W family studied, all carried a germline BAP1 mutation (p.Pro147fs*48) and four of them (57%) presented one or more atypical melanocytic tumors, that we propose to call " melanocytic BAP1-mutated atypical intradermal tumors" (MBAITs). Meta-analysis: 118 individuals from seven unrelated families were selected and divided into a BAP1-mutated cohort and a BAP1-non-mutated cohort. Malignant mesothelioma, uveal melanoma, cutaneous melanoma, and MBAITs prevalence was significantly higher in the BAP1-mutated cohort (p ≤ 0.001).Conclusions: Germline BAP1 mutations are associated with a novel cancer syndrome characterized by malignant mesothelioma, uveal melanoma, cutaneous melanoma and MBAITs, and possibly by other cancers. MBAITs provide physicians with a marker to identify individuals who may carry germline BAP1 mutations and thus are at high risk of developing associated cancers. © 2012 Carbone et al.; licensee BioMed Central Ltd

Advanced development of the spectrum sciences Model 5005-TF, single-event test fixture

This report summarizes the advanced development of the Spectrum Sciences Model 5005-TF, Single-Event Test Fixture. The Model 5005-TF uses a Californium-252 (Cf-252) fission-fragment source to test integrated circuits and other devices for the effects of single-event phenomena. Particle identification methods commonly used in high-energy physics research and nuclear engineering have been incorporated into the Model 5005-TF for estimating the particle charge, mass, and energy parameters. All single-event phenomena observed in a device under test (DUT) are correlated with an identified fission fragment, and its linear energy transfer (LET) and range in the semiconductor material of the DUT

A mammalian functional-genetic approach to characterizing cancer therapeutics

Supplementary information is available online at http://www.nature.com/naturechemicalbiology/. Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/.Identifying mechanisms of drug action remains a fundamental impediment to the development and effective use of chemotherapeutics. Here we describe an RNA interference (RNAi)–based strategy to characterize small-molecule function in mammalian cells. By examining the response of cells expressing short hairpin RNAs (shRNAs) to a diverse selection of chemotherapeutics, we could generate a functional shRNA signature that was able to accurately group drugs into established biochemical modes of action. This, in turn, provided a diversely sampled reference set for high-resolution prediction of mechanisms of action for poorly characterized small molecules. We could further reduce the predictive shRNA target set to as few as eight genes and, by using a newly derived probability-based nearest-neighbors approach, could extend the predictive power of this shRNA set to characterize additional drug categories. Thus, a focused shRNA phenotypic signature can provide a highly sensitive and tractable approach for characterizing new anticancer drugs.National Institute of Mental Health (U.S.) (grant RO1 CA128803-03)American Association for Cancer ResearchMassachusetts Institute of Technology. Dept. of BiologyNational Cancer Institute (U.S.). Integrative Cancer Biology Program (grant 1-U54-CA112967

Genetic and Proteomic Approaches to Identify Cancer Drug Targets

While target-based small-molecule discovery has taken centre-stage in the pharmaceutical industry, there are many cancer-promoting proteins not easily addressed with a traditional target-based screening approach. In order to address this problem, as well as to identify modulators of biological states in the absence of knowing the protein target of the state switch, alternative phenotypic screening approaches, such as gene expression-based and high-content imaging, have been developed. With this renewed interest in phenotypic screening, however, comes the challenge of identifying the binding protein target(s) of small-molecule hits. Emerging technologies have the potential to improve the process of target identification. In this review, we discuss the application of genomic (gene expression-based), genetic (short hairpin RNA and open reading frame screening), and proteomic approaches to protein target identification

Caspase Inhibition Blocks Cell Death and Enhances Mitophagy but Fails to Promote T-Cell Lymphoma

Caspase-9 is a component of the apoptosome that mediates cell death following release of cytochrome c from mitochondria. Inhibition of Caspase-9 with a dominant negative construct (Casp9DN) blocks apoptosome function, promotes viability and has been implicated in carcinogenesis. Inhibition of the apoptosome in vitro impairs mitochondrial function and promotes mitophagy. To examine whether inhibition of the apoptosome would enhance mitophagy and promote oncogenesis in vivo, transgenic mice were generated that express Casp9DN in the T cell lineage. The effects of Casp9DN on thymocyte viability, mitophagy and thymic tumor formation were examined. In primary thymocytes, Casp9DN delayed dexamethasone (Dex)-induced cell death, altered mitochondrial structure, and decreased oxidant production. Transmission electron microscopy (TEM) revealed that inhibition of the apoptosome resulted in structurally abnormal mitochondria that in some cases were engulfed by double-membrane structures resembling autophagosomes. Consistent with mitochondria being engulfed by autophagosomes (mitophagy), confocal microscopy showed colocalization of LC3-GFP and mitochondria. However, Casp9DN did not significantly accelerate T-cell lymphoma alone, or in combination with Lck-Bax38/1, or with Beclin 1+/− mice, two tumor-prone strains in which altered mitochondrial function has been implicated in promoting tumor development. In addition, heterozygous disruption of Beclin 1 had no effect on T-cell lymphoma formation in Lck-Bax38/1 mice. Further studies showed that Beclin 1 levels had no effect on Casp9DN-induced loss of mitochondrial function. These results demonstrate that neither inhibition of apoptosome function nor Beclin 1 haploinsufficiency accelerate T-cell lymphoma development in mice

Melanesian mtDNA Complexity

Melanesian populations are known for their diversity, but it has been hard to grasp the pattern of the variation or its underlying dynamic. Using 1,223 mitochondrial DNA (mtDNA) sequences from hypervariable regions 1 and 2 (HVR1 and HVR2) from 32 populations, we found the among-group variation is structured by island, island size, and also by language affiliation. The more isolated inland Papuan-speaking groups on the largest islands have the greatest distinctions, while shore dwelling populations are considerably less diverse (at the same time, within-group haplotype diversity is less in the most isolated groups). Persistent differences between shore and inland groups in effective population sizes and marital migration rates probably cause these differences. We also add 16 whole sequences to the Melanesian mtDNA phylogenies. We identify the likely origins of a number of the haplogroups and ancient branches in specific islands, point to some ancient mtDNA connections between Near Oceania and Australia, and show additional Holocene connections between Island Southeast Asia/Taiwan and Island Melanesia with branches of haplogroup E. Coalescence estimates based on synonymous transitions in the coding region suggest an initial settlement and expansion in the region at ∼30–50,000 years before present (YBP), and a second important expansion from Island Southeast Asia/Taiwan during the interval ∼3,500–8,000 YBP. However, there are some important variance components in molecular dating that have been overlooked, and the specific nature of ancestral (maternal) Austronesian influence in this region remains unresolved