Host genotype and time dependent antigen presentation of viral peptides: predictions from theory

The rate of progression of HIV infected individuals to AIDS is known to vary with the genotype of the host, and is linked to their allele of human leukocyte antigen (HLA) proteins, which present protein degradation products at the cell surface to circulating T-cells. HLA alleles are associated with Gag-specific T-cell responses that are protective against progression of the disease. While Pol is the most conserved HIV sequence, its association with immune control is not as strong. To gain a more thorough quantitative understanding of the factors that contribute to immunodominance, we have constructed a model of the recognition of HIV infection by the MHC class I pathway. Our model predicts surface presentation of HIV peptides over time, demonstrates the importance of viral protein kinetics, and provides evidence of the importance of Gag peptides in the long-term control of HIV infection. Furthermore, short-term dynamics are also predicted, with simulation of virion-derived peptides suggesting that efficient processing of Gag can lead to a 50% probability of presentation within 3 hours post-infection, as observed experimentally. In conjunction with epitope prediction algorithms, this modelling approach could be used to refine experimental targets for potential T-cell vaccines, both for HIV and other viruses

Regulatory T Cells Expanded from Hiv-1-Infected Individuals Maintain Phenotype, Tcr Repertoire and Suppressive Capacity

While modulation of regulatory T cell (Treg) function and adoptive Treg transfer are being explored as therapeutic modalities in the context of autoimmune diseases, transplantation and cancer, their role in HIV-1 pathogenesis remains less well defined. Controversy persists regarding their beneficial or detrimental effects in HIV-1 disease, which warrants further detailed exploration. Our objectives were to investigate if functional CD4+ Tregs can be isolated and expanded from HIV-1-infected individuals for experimental or potential future therapeutic use and to determine phenotype and suppressive capacity of expanded Tregs from HIV-1 positive blood and tissue. Tregs and conventional T cell controls were isolated from blood and gut-associated lymphoid tissue of individuals with HIV-1 infection and healthy donors using flow-based cell-sorting. The phenotype of expanded Tregs was assessed by flow-cytometry and quantitative PCR. T-cell receptor ß-chain (TCR-β) repertoire diversity was investigated by deep sequencing. Flow-based T-cell proliferation and chromium release cytotoxicity assays were used to determine Treg suppressive function. Tregs from HIV-1 positive individuals, including infants, were successfully expanded from PBMC and GALT. Expanded Tregs expressed high levels of FOXP3, CTLA4, CD39 and HELIOS and exhibited a highly demethylated TSDR (Treg-specific demethylated region), characteristic of Treg lineage. The TCRß repertoire was maintained following Treg expansion and expanded Tregs remained highly suppressive in vitro. Our data demonstrate that Tregs can be expanded from blood and tissue compartments of HIV-1+ donors with preservation of Treg phenotype, function and TCR repertoire. These results are highly relevant for the investigation of potential future therapeutic use, as currently investigated for other disease states and hold great promise for detailed studies on the role of Tregs in HIV-1 infection.Elizabeth Glaser Pediatric AIDS Foundation (Pediatric HIV Vaccine Program Award MV-00-9-900-1429-0-00)Massachusetts General Hospital. Executive Committee on Research (MGH/ECOR Physician Scientist Development Award)National Institutes of Health (U.S.) (NIH NIAID (KO8 AI074405))National Institutes of Health (U.S.) (NIH NIAID AI074405-03S1)Massachusetts General Hospital (William F. Milton Fund)Harvard University. Center for AIDS Research (CFAR Scholar Award)Massachusetts General Hospital. Center for the Study Inflammatory Bowel Disease (P30DK043351)Harvard University. Center for AIDS Research (NIH funded program (5P30AI060354-09

Regional adaptation defines sensitivity to future ocean acidification

Physiological responses to temperature are known to be a major determinant of species distributions and can dictate the sensitivity of populations to global warming. In contrast, little is known about how other major global change drivers, such as ocean acidification (OA), will shape species distributions in the future. Here, by integrating population genetics with experimental data for growth and mineralization, physiology and metabolomics, we demonstrate that the sensitivity of populations of the gastropod Littorina littorea to future OA is shaped by regional adaptation. Individuals from populations towards the edges of the natural latitudinal range in the Northeast Atlantic exhibit greater shell dissolution and the inability to upregulate their metabolism when exposed to low pH, thus appearing most sensitive to low seawater pH. Our results suggest that future levels of OA could mediate temperature-driven shifts in species distributions, thereby influencing future biogeography and the functioning of marine ecosystems

Relationship between Tumor DNA Methylation Status and Patient Characteristics in African-American and European-American Women with Breast Cancer

Aberrant DNA methylation is critical for development and progression of breast cancer. We investigated the association of CpG island methylation in candidate genes and clinicopathological features in 65 African-American (AA) and European-American (EA) breast cancer patients. Quantitative methylation analysis was carried out on bisulfite modified genomic DNA and sequencing (pyrosequencing) for promoter CpG islands of p16, ESR1, RASSF1A, RARβ2, CDH13, HIN1, SFRP1 genes and the LINE1 repetitive element using matched paired non-cancerous and breast tumor specimen (32 AA and 33 EA women). Five of the genes, all known tumor suppressor genes (RASSF1A, RARβ2, CDH13, HIN1 and SFRP1), were found to be frequently hypermethylated in breast tumor tissues but not in the adjacent non-cancerous tissues. Significant differences in the CDH13 methylation status were observed by comparing DNA methylation between AA and EA patients, with more obvious CDH13 methylation differences between the two patient groups in the ER- disease and among young patients (age<50). In addition, we observed associations between CDH13, SFRP1, and RASSF1A methylation and breast cancer subtypes and between SFRP1 methylation and patient's age. Furthermore, tumors that received neoadjuvant therapy tended to have reduced RASSF1A methylation when compared with chemotherapy naïve tumors. Finally, Kaplan Meier survival analysis showed a significant association between methylation at 3 loci (RASSF1A, RARβ2 and CDH13) and reduced overall disease survival. In conclusion, the DNA methylation status of breast tumors was found to be significantly associated with clinicopathological features and race/ethnicity of the patients

Controlling spins in adsorbed molecules by a chemical switch

The development of chemical systems with switchable molecular spins could lead to the architecture of materials with controllable magnetic or spintronic properties. Here, we present conclusive evidence that the spin of an organometallic molecule coupled to a ferromagnetic substrate can be switched between magnetic off and on states by a chemical stimulus. This is achieved by nitric oxide (NO) functioning as an axial ligand of cobalt(II)tetraphenylporphyrin (CoTPP) ferromagnetically coupled to nickel thin-film (Ni(001)). On NO addition, the coordination sphere of Co2+ is modified and a NO–CoTPP nitrosyl complex is formed, which corresponds to an off state of the Co spin. Thermal dissociation of NO from the nitrosyl complex restores the on state of the Co spin. The NO-induced reversible off–on switching of surface-adsorbed molecular spins observed here is attributed to a spin trans effect

Epidemic of hypertension in Ghana: a systematic review

Background Hypertension is a major risk factor for many cardiovascular diseases in developing countries. A comprehensive review of the prevalence of hypertension provides crucial information for the evaluation and implementation of appropriate programmes. Methods The PubMed and Google Scholar databases were searched for published articles on the population-based prevalence of adult hypertension in Ghana between 1970 and August 2009, supplemented by a manual search of retrieved references. Fifteen unique population-based articles in non-pregnant humans were obtained. In addition, two relevant unpublished graduate student theses from one university department were identified after a search of its 1996-2008 theses. Results The age and sex composition of study populations, sampling strategy, measurement of blood pressure, definition of hypertension varied between studies. The prevalence of hypertension (BP ≥ 140/90 mmHg ± antihypertensive treatment) ranged from 19% to 48% between studies. Sex differences were generally minimal whereas urban populations tended to have higher prevalence than rural population in studies with mixed population types. Factors independently associated with hypertension included older age group, over-nutrition and alcohol consumption. Whereas there was a trend towards improved awareness, treatment and control between 1972 and 2005, less than one-third of hypertensive subjects were aware they had hypertension and less than one-tenth had their blood pressures controlled in most studies. Conclusion Hypertension is clearly an important public health problem in Ghana, even in the poorest rural communities. Emerging opportunities such as the national health insurance scheme, a new health policy emphasising health promotion and healthier lifestyles and effective treatment should help prevent and control hypertension

Low utilization of health care services following screening for hypertension in Dar es Salaam (Tanzania): a prospective population-based study

Drug therapy in high-risk individuals has been advocated as an important strategy to reduce cardiovascular disease in low income countries. We determined, in a low-income urban population, the proportion of persons who utilized health services after having been diagnosed as hypertensive and advised to seek health care for further hypertension management. A population-based survey of 9254 persons aged 25-64 years was conducted in Dar es Salaam. Among the 540 persons with high blood pressure (defined here as BP >or= 160/95 mmHg) at the initial contact, 253 (47%) had high BP on a 4th visit 45 days later. Among them, 208 were untreated and advised to attend health care in a health center of their choice for further management of their hypertension. One year later, 161 were seen again and asked about their use of health services during the interval. Among the 161 hypertensive persons advised to seek health care, 34% reported to have attended a formal health care provider during the 12-month interval (63% public facility; 30% private; 7% both). Antihypertensive treatment was taken by 34% at some point of time (suggesting poor uptake of health services) and 3% at the end of the 12-month follow-up (suggesting poor long-term compliance). Health services utilization tended to be associated with older age, previous history of high BP, being overweight and non-smoking, but not with education or wealth. Lack of symptoms and cost of treatment were the reasons reported most often for not attending health care. Low utilization of health services after hypertension screening suggests a small impact of a patient-centered screen-and-treat strategy in this low-income population. These findings emphasize the need to identify and address barriers to health care utilization for non-communicable diseases in this setting and, indirectly, the importance of public health measures for primary prevention of these diseases

Task shifting to non-physician clinicians for integrated management of hypertension and diabetes in rural Cameroon: a programme assessment at two years

<p>Abstract</p> <p>Background</p> <p>The burden of non-communicable chronic diseases, such as hypertension and diabetes, increases in sub-Saharan Africa. However, the majority of the rural population does still not have access to adequate care. The objective of this study is to examine the effectiveness of integrating care for hypertension and type 2 diabetes by task shifting to non-physician clinician (NPC) facilities in eight rural health districts in Cameroon.</p> <p>Methods</p> <p>Of the 75 NPC facilities in the area, 69 (87%) received basic equipment and training in hypertension and diabetes care. Effectiveness was assessed after two years on status of equipment, knowledge among trained NPCs, number of newly detected patients, retention of patients under care, treatment cost to patients and changes in blood pressure (BP) and fasting plasma glucose (FPG) among treated patients.</p> <p>Results</p> <p>Two years into the programme, of 54 facilities (78%) available for re-assessment, all possessed a functional sphygmomanometer and stethoscope (65% at baseline); 96% stocked antihypertensive drugs (27% at baseline); 70% possessed a functional glucose meter and 72% stocked oral anti-diabetics (15% and 12% at baseline). NPCs' performance on multiple-choice questions of the knowledge-test was significantly improved. During a period of two years, trained NPCs initiated treatment for 796 patients with hypertension and/or diabetes. The retention of treated patients at one year was 18.1%. Hypertensive and diabetic patients paid a median monthly amount of 1.4 and 0.7 Euro respectively for their medication. Among hypertensive patients with ≥ 2 documented visits (n = 493), systolic BP decreased by 22.8 mmHg (95% CI: -20.6 to -24.9; p < 0.0001) and diastolic BP by 12.4 mmHg (-10.9 to -13.9; p < 0.0001). Among diabetic patients (n = 79) FPG decreased by 3.4 mmol/l (-2.3 to -4.5; p < 0.001).</p> <p>Conclusions</p> <p>The integration of hypertension and diabetes into primary health care of NPC facilities in rural Cameroon was feasible in terms of equipment and training, accessible in terms of treatment cost and showed promising BP- and FPG-trends. However, low case-detection rates per NPC and a very high attrition among patients enrolled into care, limited the effectiveness of the programme.</p

Physcomitrella patens DCL3 Is Required for 22–24 nt siRNA Accumulation, Suppression of Retrotransposon-Derived Transcripts, and Normal Development

Endogenous 24 nt short interfering RNAs (siRNAs), derived mostly from intergenic and repetitive genomic regions, constitute a major class of endogenous small RNAs in flowering plants. Accumulation of Arabidopsis thaliana 24 nt siRNAs requires the Dicer family member DCL3, and clear homologs of DCL3 exist in both flowering and non-flowering plants. However, the absence of a conspicuous 24 nt peak in the total RNA populations of several non-flowering plants has raised the question of whether this class of siRNAs might, in contrast to the ancient 21 nt microRNAs (miRNAs) and 21–22 nt trans-acting siRNAs (tasiRNAs), be an angiosperm-specific innovation. Analysis of non-miRNA, non-tasiRNA hotspots of small RNA production within the genome of the moss Physcomitrella patens revealed multiple loci that consistently produced a mixture of 21–24 nt siRNAs with a peak at 23 nt. These Pp23SR loci were significantly enriched in transposon content, depleted in overlap with annotated genes, and typified by dense concentrations of the 5-methyl cytosine (5 mC) DNA modification. Deep sequencing of small RNAs from two independent Ppdcl3 mutants showed that the P. patens DCL3 homolog is required for the accumulation of 22–24 nt siRNAs, but not 21 nt siRNAs, at Pp23SR loci. The 21 nt component of Pp23SR-derived siRNAs was also unaffected by a mutation in the RNA-dependent RNA polymerase mutant Pprdr6. Transcriptome-wide, Ppdcl3 mutants failed to accumulate 22–24 nt small RNAs from repetitive regions while transcripts from two abundant families of long terminal repeat (LTR) retrotransposon-associated reverse transcriptases were up-regulated. Ppdcl3 mutants also displayed an acceleration of leafy gametophore production, suggesting that repetitive siRNAs may play a role in the development of P. patens. We conclude that intergenic/repeat-derived siRNAs are indeed a broadly conserved, distinct class of small regulatory RNAs within land plants