Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates

Knowledge of the molecular networks controlling the proliferation and fate of hematopoietic stem cells (HSC) is essential to understand their function in maintaining blood cell production during normal hematopoiesis and upon clinical transplantation. Using highly purified stem and progenitor cell populations, we define the proliferation index and status of the cell cycle machinery at discrete stages of hematopoietic differentiation and during cytokine-mediated HSC mobilization. We identify distinct sets of cell cycle proteins that specifically associate with differentiation, self-renewal, and maintenance of quiescence in HSC and progenitor cells. Moreover, we describe a striking inequality of function among in vivo cycling and quiescent HSC by demonstrating that their long-term engraftment potential resides predominantly in the G0 fraction. These data provide a direct link between HSC proliferation and function and identify discrete molecular targets in regulating HSC cell fate decisions that could have implications for both the therapeutic use of HSC and the understanding of leukemic transformation

Using Co-creation Focus Groups to Customise a Remote Multidomain Programme Designed to Increase Dementia Literacy

Objectives To adapt the content and functionalities of Brain Health PRO, a web-based multidomain program designed to increase dementia literacy, to the context and needs of users, providers and community organisations across Québec, Canada. Design Five consecutive qualitative co-creation focus group sessions 30–90 min in duration each, exploring potential barriers and facilitators to usability, accessibility, comprehensibility, participant recruitment and retention. Setting Virtual meetings. Participants A 15-member team based in Québec and Ontario, Canada, consisting of 9 researchers (including a graduate student and the project coordinator), representing occupational therapy, sensory rehabilitation, neuropsychology, psychology, health science and research methods, 3 informal caregivers of older adults living with cognitive decline and 3 members of the Federation of Quebec Alzheimer Societies. Data analysis Session recordings were summarised through both qualitative description and thematic analysis. Results The synthesised recommendations included adjustments around diversity, the complexity and presentation styles of the materials, suggestions on refining the web interface and the measurement approaches; it influenced aspects of participant recruitment, retention efforts and engagement with the content of Brain Health PRO. Conclusions Co-creation in dementia prevention research is important because it involves collaboration between researchers, community support and service providers, and persons with lived experience as care providers, in the design and implementation of clinical studies. This approach helps to ensure that the content and presentation of educational material is relevant and meaningful to the target population and those involved in its delivery, and it leads to a greater understanding of their needs and perspectives

CD5 levels reveal distinct basal T-cell receptor signals in T cells from non-obese diabetic mice

Type 1 diabetes in non-obese diabetic (NOD) mice occurs when autoreactive T cells eliminate insulin producing pancreatic β cells. While extensively studied in T-cell receptor (TCR) transgenic mice, the contribution of alterations in thymic selection to the polyclonal T-cell pool in NOD mice is not yet resolved. The magnitude of signals downstream of TCR engagement with self-peptide directs the development of a functional T-cell pool, in part by ensuring tolerance to self. TCR interactions with self-peptide are also necessary for T-cell homeostasis in the peripheral lymphoid organs. To identify differences in TCR signal strength that accompany thymic selection and peripheral T-cell maintenance, we compared CD5 levels, a marker of basal TCR signal strength, on immature and mature T cells from autoimmune diabetes-prone NOD and -resistant B6 mice. The data suggest that there is no preferential selection of NOD thymocytes that perceive stronger TCR signals from self-peptide engagement. Instead, NOD mice have an MHC-dependent increase in CD4+ thymocytes and mature T cells that express lower levels of CD5. In contrast, T cell-intrinsic mechanisms lead to higher levels of CD5 on peripheral CD8+ T cells from NOD relative to B6 mice, suggesting that peripheral CD8+ T cells with higher basal TCR signals may have survival advantages in NOD mice. These differences in the T-cell pool in NOD mice may contribute to the development or progression of autoimmune diabetes

Presence of autism, hyperserotonemia, and severe expressive language impairment in Williams-Beuren syndrome.

International audienceBACKGROUND: Deletion of the Williams-Beuren syndrome (WBS) critical region (WBSCR), at 7q11.23, causes a developmental disorder commonly characterized by hypersociability and excessive talkativeness and often considered the opposite behavioral phenotype to autism. Duplication of the WBSCR leads to severe delay in expressive language. Gene-dosage effects on language development at 7q11.23 have been hypothesized. METHODS: Molecular characterization of the WBSCR was performed by fluorescence in situ hybridization and high-resolution single-nucleotide polymorphism array in two individuals with severe autism enrolled in a genetic study of autism who showed typical WBS facial dysmorphism on systematic clinical genetic examination. The serotonin transporter promoter polymorphism (5-HTTLPR, locus SLC6A4) was genotyped. Platelet serotonin levels and urinary 6-sulfatoxymelatonin excretion were measured. Behavioral and cognitive phenotypes were examined. RESULTS: The two patients had common WBSCR deletions between proximal and medial low copy repeat clusters, met diagnostic criteria for autism and displayed severe impairment in communication, including a total absence of expressive speech. Both patients carried the 5-HTTLPR ss genotype and exhibited platelet hyperserotonemia and low melatonin production. CONCLUSIONS: Our observations indicate that behaviors and neurochemical phenotypes typically associated with autism can occur in patients with common WBSCR deletions. The results raise intriguing questions about phenotypic heterogeneity in WBS and regarding genetic and/or environmental factors interacting with specific genes at 7q11.23 sensitive to dosage alterations that can influence the development of social communication skills. Thus, the influence of WBSCR genes on social communication expression might be dramatically modified by other genes, such as 5-HTTLPR, known to influence the severity of social communication impairments in autism, or by environmental factors, such as hyperserotonemia, given that hyperserotonemia is found in WBS associated with autism but not in WBS without autism. In this regard, WBS provides a potentially fruitful model with which to develop integrated genetic, cognitive, behavioral and neurochemical approaches to study genotype-phenotype correlations, possible gene-environment interactions and genetic background effects. The results underscore the importance of considering careful clinical and molecular genetic examination of individuals diagnosed with autism

Linear quadratic power control for CDMA systems, Journal of Telecommunications and Information Technology, 2003, nr 2

In this paper, we present a robust decentralized method for jointly performing channel estimation and closed loop power control for the reverse link of CDMA networks. Our method, based on linear quadratic Gaussian (LQG) control systems theory and Kalman filtering, does not require any training symbols for channel or signal to interference ratio (SIR) estimation. The main interest of this new scheme is that it improves the performance of current SIR based power control techniques while avoiding the problem of power escalation, which is often observed in current systems

CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome.

Multiple genome-wide studies have identified associations between outcome of human immunodeficiency virus (HIV) infection and polymorphisms in and around the gene encoding the HIV co-receptor CCR5, but the functional basis for the strongest of these associations, rs1015164A/G, is unknown. We found that rs1015164 marks variation in an activating transcription factor 1 binding site that controls expression of the antisense long noncoding RNA (lncRNA) CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4+ T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3' untranslated region, protecting CCR5 messenger RNA from Raly-mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4+ T cells with CCR5-tropic HIV in vitro. These data represent a rare determination of the functional importance of a genome-wide disease association where expression of a lncRNA affects HIV infection and disease progression

New Evidence on Variations of Human Body Burden of Methylmercury from Fish Consumption

Epidemiologic studies commonly use mercury (Hg) level in hair as a valid proxy to estimate human exposure to methylmercury (MeHg) through fish consumption. This study presents the results yielded by a complete data set on fish consumption habits, Hg levels in edible fish resources, and corresponding Hg accumulation in hair, gathered in three distinct communities of eastern Canada. For one of these communities, the average hair Hg concentration was 14 times less than the expected value based on calculated daily oral exposure and current knowledge of MeHg metabolism. This finding could be explained by differences in specific genetic characteristics and/or interactive effects of other dietary components

Ideal and actual involvement of community pharmacists in health promotion and prevention: a cross-sectional study in Quebec, Canada

<p>Abstract</p> <p>Background</p> <p>An increased interest is observed in broadening community pharmacists' role in public health. To date, little information has been gathered in Canada on community pharmacists' perceptions of their role in health promotion and prevention; however, such data are essential to the development of public-health programs in community pharmacy. A cross-sectional study was therefore conducted to explore the perceptions of community pharmacists in urban and semi-urban areas regarding their ideal and actual levels of involvement in providing health-promotion and prevention services and the barriers to such involvement.</p> <p>Methods</p> <p>Using a five-step modified Dillman's tailored design method, a questionnaire with 28 multiple-choice or open-ended questions (11 pages plus a cover letter) was mailed to a random sample of 1,250 pharmacists out of 1,887 community pharmacists practicing in Montreal (Quebec, Canada) and surrounding areas. It included questions on pharmacists' ideal level of involvement in providing health-promotion and preventive services; which services were actually offered in their pharmacy, the employees involved, the frequency, and duration of the services; the barriers to the provision of these services in community pharmacy; their opinion regarding the most appropriate health professionals to provide them; and the characteristics of pharmacists, pharmacies and their clientele.</p> <p>Results</p> <p>In all, 571 out of 1,234 (46.3%) eligible community pharmacists completed and returned the questionnaire. Most believed they should be very involved in health promotion and prevention, particularly in smoking cessation (84.3%); screening for hypertension (81.8%), diabetes (76.0%) and dyslipidemia (56.9%); and sexual health (61.7% to 89.1%); however, fewer respondents reported actually being very involved in providing such services (5.7% [lifestyle, including smoking cessation], 44.5%, 34.8%, 6.5% and 19.3%, respectively). The main barriers to the provision of these services in current practice were lack of: time (86.1%), coordination with other health care professionals (61.1%), staff or resources (57.2%), financial compensation (50.8%), and clinical tools (45.5%).</p> <p>Conclusions</p> <p>Although community pharmacists think they should play a significant role in health promotion and prevention, they recognize a wide gap between their ideal and actual levels of involvement. The efficient integration of primary-care pharmacists and pharmacies into public health cannot be envisioned without addressing important organizational barriers.</p

Executive functioning in children with autism and Tourette syndrome

The main aims of this study were to investigate if children with high-functioning autism (HFA) and children with Tourette syndrome (TS) can be differentiated in their executive functioning (EF) profile compared to normal controls (NCs) and compared to each other and to investigate whether children with HFA or children with TS and a comorbid group of children with both disorders are distinct conditions in terms of EF. Four groups of children participated in this study: HFA, TS, comorbid HFA + TS, and a NC group. All children were in the age range of 6 to 13 years. The groups were compared on five major domains of EF: inhibition, visual working memory, planning, cognitive flexibility, and verbal fluency. Children with HFA scored lower than NC children on all the EFs measured. Children with TS and NC children showed the same EF profile. The HFA group scored lower than the TS group for inhibition of a prepotent response and cognitive flexibility. Children with HFA performed poorer than children with comorbid HFA + TS on all functions, with the exception of inhibiting an ongoing response, interference control, and verbal fluency. Children with TS and children with comorbid HFA + TS could not be differentiated from one another in terms of EF. This study indicates that EF deficits are highly characteristic of children with HFA in comparison to children with TS and NC. The results suggest that for the comparison between HFA and TS groups, it is important to take into account comorbidity. A reevaluation of the EF hypothesis in children with TS is suggested. Copyright © 2005 Cambridge University Press