RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry.

The NKG2D stimulatory receptor expressed by natural killer cells and T cell subsets recognizes cell surface ligands that are induced on transformed and infected cells and facilitate immune rejection of tumor cells. We demonstrate that expression of retinoic acid early inducible gene 1 (RAE-1) family NKG2D ligands in cancer cell lines and proliferating normal cells is coupled directly to cell cycle regulation. Raet1 genes are directly transcriptionally activated by E2F family transcription factors, which play a central role in regulating cell cycle entry. Induction of RAE-1 occurred in primary cell cultures, embryonic brain cells in vivo, and cells in healing skin wounds and, accordingly, wound healing was delayed in mice lacking NKG2D. Transcriptional activation by E2Fs is likely coordinated with posttranscriptional regulation by other stress responses. These findings suggest that cellular proliferation, as occurs in cancer cells but also other pathological conditions, is a key signal tied to immune reactions mediated by NKG2D-bearing lymphocytes

The development of a program analysis environment for Ada

A unit level, Ada software module testing system, called Query Utility Environment for Software Testing of Ada (QUEST/Ada), is described. The project calls for the design and development of a prototype system. QUEST/Ada design began with a definition of the overall system structure and a description of component dependencies. The project team was divided into three groups to resolve the preliminary designs of the parser/scanner: the test data generator, and the test coverage analyzer. The Phase 1 report is a working document from which the system documentation will evolve. It provides history, a guide to report sections, a literature review, the definition of the system structure and high level interfaces, descriptions of the prototype scope, the three major components, and the plan for the remainder of the project. The appendices include specifications, statistics, two papers derived from the current research, a preliminary users' manual, and the proposal and work plan for Phase 2

Internal versus external motivation in referral of primary care patients with depression to an internet support group: randomized controlled trial

BACKGROUND: Depressive disorders and symptoms affect more than one-third of primary care patients, many of whom do not receive or do not complete treatment. Internet-based social support from peers could sustain depression treatment engagement and adherence. We do not know whether primary care patients will accept referral to such websites nor do we know which methods of referral would be most effective. OBJECTIVE: We conducted a randomized clinical trial to determine whether (1) a simple generic referral card (control), (2) a patient-oriented brochure that provided examples of online postings and experience (internal motivation), or (3) a physician letter of recommendation (external motivation) would generate the greatest participation in a primary care Internet depression treatment support portal focused around an Internet support group (ISG). METHODS: We used 3 offline methods to identify potential participants who had not used an ISG in the past 6 months. Eligibility was determined in part by a brief structured psychiatric interview based on the Patient Health Questionnaire-9 (PHQ-9). After consent and enrollment, participants were randomly assigned to 1 of 3 groups (control, internal motivation, or external motivation). We constructed a portal to connect primary care patients to both fact-based information and an established ISG (Psycho-Babble). The ISG allowed participants to view messages and then decide if they actually wished to register there. Participation in the portal and the ISG was assessed via automated activity tracking. RESULTS: Fifty participants were assigned to the 3 groups: a motivation-neutral control group (n=18), an internal motivation group (n=19), and an external motivation group (n=13). Of these participants, 31 (62%) visited the portal; 27 (54%) visited the ISG itself. The internal motivation group showed significantly greater participation than the control group on several measures. The external motivation group spent significantly less time logged onto the portal than the control group. The internal motivation group showed significantly greater participation than the external motivation group on several measures. CONCLUSIONS: Referral of primary care patients with depressive disorders and symptoms to an ISG is feasible even if they have never previously used one. This may best be accomplished by enhancing their internal motivation. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00886730; http://clinicaltrials.gov/show/NCT00886730 (Archived by WebCite at http://www.webcitation.org/6F4981fDN)

A comparative epidemiologic analysis of SARS in Hong Kong, Beijing and Taiwan

<p>Abstract</p> <p>Background</p> <p>The 2002-2003 Severe Acute Respiratory Syndrome (SARS) outbreak infected 8,422 individuals leading to 916 deaths around the world. However, there have been few epidemiological studies of SARS comparing epidemiologic features across regions. The aim of this study is to identify similarities and differences in SARS epidemiology in three populations with similar host and viral genotype.</p> <p>Methods</p> <p>We present a comparative epidemiologic analysis of SARS, based on an integrated dataset with 3,336 SARS patients from Hong Kong, Beijing and Taiwan, epidemiological and clinical characteristics such as incubation, onset-to-admission, onset-to-discharge and onset-to-death periods, case fatality ratios (CFRs) and presenting symptoms are described and compared between regions. We further explored the influence of demographic and clinical variables on the apparently large differences in CFRs between the three regions.</p> <p>Results</p> <p>All three regions showed similar incubation periods and progressive shortening of the onset-to-admission interval through the epidemic. Adjusted for sex, health care worker status and nosocomial setting, older age was associated with a higher fatality, with adjusted odds ratio (AOR): 2.10 (95% confidence interval: 1.45, 3.04) for those aged 51-60; AOR: 4.57 (95% confidence interval: 3.32, 7.30) for those aged above 60 compared to those aged 41-50 years. Presence of pre-existing comorbid conditions was also associated with greater mortality (AOR: 1.74; 95% confidence interval: 1.36, 2.21).</p> <p>Conclusion</p> <p>The large discrepancy in crude fatality ratios across the three regions can only be partly explained by epidemiological and clinical heterogeneities. Our findings underline the importance of a common data collection platform, especially in an emerging epidemic, in order to identify and explain consistencies and differences in the eventual clinical and public health outcomes of infectious disease outbreaks, which is becoming increasingly important in our highly interconnected world.</p

Comparison of Pittsburgh compound B and florbetapir in cross-sectional and longitudinal studies.

IntroductionQuantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B-based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design.MethodsPittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally.ResultsGlobal amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers.DiscussionAlthough the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers

PCYT1A Regulates Phosphatidylcholine Homeostasis from the Inner Nuclear Membrane in Response to Membrane Stored Curvature Elastic Stress.

Cell and organelle membranes consist of a complex mixture of phospholipids (PLs) that determine their size, shape, and function. Phosphatidylcholine (PC) is the most abundant phospholipid in eukaryotic membranes, yet how cells sense and regulate its levels in vivo remains unclear. Here we show that PCYT1A, the rate-limiting enzyme of PC synthesis, is intranuclear and re-locates to the nuclear membrane in response to the need for membrane PL synthesis in yeast, fly, and mammalian cells. By aligning imaging with lipidomic analysis and data-driven modeling, we demonstrate that yeast PCYT1A membrane association correlates with membrane stored curvature elastic stress estimates. Furthermore, this process occurs inside the nucleus, although nuclear localization signal mutants can compensate for the loss of endogenous PCYT1A in yeast and in fly photoreceptors. These data suggest an ancient mechanism by which nucleoplasmic PCYT1A senses surface PL packing defects on the inner nuclear membrane to control PC homeostasis

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P &lt; 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

A community effort towards a knowledge-base and mathematical model of the human pathogen Salmonella Typhimurium LT2

<p>Abstract</p> <p>Background</p> <p>Metabolic reconstructions (MRs) are common denominators in systems biology and represent biochemical, genetic, and genomic (BiGG) knowledge-bases for target organisms by capturing currently available information in a consistent, structured manner. <it>Salmonella enterica </it>subspecies I serovar Typhimurium is a human pathogen, causes various diseases and its increasing antibiotic resistance poses a public health problem.</p> <p>Results</p> <p>Here, we describe a community-driven effort, in which more than 20 experts in <it>S</it>. Typhimurium biology and systems biology collaborated to reconcile and expand the <it>S</it>. Typhimurium BiGG knowledge-base. The consensus MR was obtained starting from two independently developed MRs for <it>S</it>. Typhimurium. Key results of this reconstruction jamboree include i) development and implementation of a community-based workflow for MR annotation and reconciliation; ii) incorporation of thermodynamic information; and iii) use of the consensus MR to identify potential multi-target drug therapy approaches.</p> <p>Conclusion</p> <p>Taken together, with the growing number of parallel MRs a structured, community-driven approach will be necessary to maximize quality while increasing adoption of MRs in experimental design and interpretation.</p

Evolution of the patellar sesamoid bone in mammals

The patella is a sesamoid bone located in the major extensor tendon of the knee joint, in the hindlimb of many tetrapods. Although numerous aspects of knee morphology are ancient and conserved among most tetrapods, the evolutionary occurrence of an ossified patella is highly variable. Among extant (crown clade) groups it is found in most birds, most lizards, the monotreme mammals and almost all placental mammals, but it is absent in most marsupial mammals as well as many reptiles. Here, we integrate data from the literature and first-hand studies of fossil and recent skeletal remains to reconstruct the evolution of the mammalian patella. We infer that bony patellae most likely evolved between four and six times in crown group Mammalia: in monotremes, in the extinct multituberculates, in one or more stem-mammal genera outside of therian or eutherian mammals and up to three times in therian mammals. Furthermore, an ossified patella was lost several times in mammals, not including those with absent hindlimbs: once or more in marsupials (with some re-acquisition) and at least once in bats. Our inferences about patellar evolution in mammals are reciprocally informed by the existence of several human genetic conditions in which the patella is either absent or severely reduced. Clearly, development of the patella is under close genomic control, although its responsiveness to its mechanical environment is also important (and perhaps variable among taxa). Where a bony patella is present it plays an important role in hindlimb function, especially in resisting gravity by providing an enhanced lever system for the knee joint. Yet the evolutionary origins, persistence and modifications of a patella in diverse groups with widely varying habits and habitats—from digging to running to aquatic, small or large body sizes, bipeds or quadrupeds—remain complex and perplexing, impeding a conclusive synthesis of form, function, development and genetics across mammalian evolution. This meta-analysis takes an initial step toward such a synthesis by collating available data and elucidating areas of promising future inquiry