Epitope enhancement of a CD4 HIV epitope toward the development of the next generation HIV vaccine

Virus-specific CD4+ T cell help and CD8+ cytotoxic T cell responses are critical for maintenance of effective immunity in chronic viral infections. The importance of CD4+ T cells has been documented in HIV infection. To investigate whether a stronger CD4+ T cell response can be induced by modifications to enhance the T1 epitope, the first CD4+ T cell epitope discovered in HIV-1-gp120, we developed a T1-specific CD4+ T cell line from a healthy volunteer immunized with a canarypox vector expressing gp120 and boosted with recombinant gp120. This T1-specific CD4+ T cell line was restricted to DR13, which is common in U.S. Caucasians and African-Americans and very frequent in Africans. Peptides with certain amino acid substitutions in key positions induced enhanced specific CD4+ T cell proliferative responses at lower peptide concentration than the original epitope. This relatively conserved CD4 epitope improved by the epitope enhancement strategy could be a component of a more effective second generation vaccine construct for HIV infection

Navigating the dilemmas of climate policy in Europe: evidence from policy evaluation studies

Climate change is widely recognised as a �wicked� policy problem. Agreeing and implementing governance responses is proving extremely difficult. Policy makers in many jurisdictions now emphasise their ambition to govern using the best available evidence. One obvious source of such evidence is the evaluations of the performance of existing policies. But to what extent do these evaluations provide insights into the difficult dilemmas that governors typically encounter? We address this question by reviewing the content of 262 evaluation studies of European climate policies in the light of six kinds of dilemma found in the governance literature. We are interested in what these studies say about the performance of European climate policies and in their capacity to inform evidence-based policy-making. We find that the evaluations do arrive at common findings: that climate change is framed as a problem of market and/or state failure; that voluntary measures tend to be ineffective; that market-based instruments tend to be regressive; that EU-level policies have driven climate policies in the latecomer EU Member States; and that lack of monitoring and weak enforcement are major obstacles to effective policy implementation. However, we also conclude that the evidence base these studies represent is surprisingly weak for such a high profile area. There is too little systematic climate policy evaluation work in the EU to support systematic evidence-based policy making. This reduces the scope for sound policy making in the short run and is a constraint to policy learning in the longer term.JRC.H.2 - Climate chang

Comparing Balance Performance on Force Platform Measures in Individuals with Parkinson\u27s Disease and Healthy Adults

Introduction. Postural instability is a known contributing factor to balance dysfunction and increased fall risk in those with Parkinson’s disease (PD). Computerized posturography employing a force platform system provides objective, quantitative as- sessments of postural control impairments. This study examines balance performance as measured by force platform (FP) tests in persons with PD compared to age-matched healthy adults. Secondarily, we examine if these FP measures provide diagnostic and clinically meaningful information about the underlying balance impairments in the PD population. Methods. Participants—42 individuals with PD (Hoehn and Yahr stage 2.33 0.77) and 55 age-matched healthy adults—were assessed on three standardized balance measures on a computerized force platform system. Between groups, comparisons of FP performance were analyzed using independent t-test. Within the group, comparisons for the PD cohort were analyzed using ANOVA for comparing disease stage and Mann–Whitney U test for PD subtypes. Results. The PD cohort demonstrated significantly greater postural instability on the sensory organization test (SOT) measures (P 0.013, CI-95% 1.286 to 10.37) and slower movement velocity on the limits of stability (LOS) test (P 0.001, CI-95% 0.597 to 1.595) than the healthy cohort, suggesting that these tests were sensitive to detect sensory integration and voluntary postural control deficits in the PD cohort. Within the PD group, the SOT differentiated between H&Y stages 1–3. The motor control test (MCT) detected changes in reactive postural control mainly in later disease stages. All three FP tests distinguished between PD subtypes, with the Posture Gait Instability subtype demonstrating poorer balance performance than Tremor Dominant subtype. Conclusion. These findings suggest FP measures provide clinically meaningful, diagnostic information in the examination of balance impairments in individuals with PD. FP measures may inform clinicians regard sic balance deficits and guide them in designing targeted balance interventions to reduce fall risk in persons with PD

The future of the CDM: same same, but differentiated?

Policy-makers and scientists have raised concerns about the functioning of the Clean Development Mechanism (CDM), in particular regarding its low contribution to sustainable development, unbalanced regional and sectoral distribution of projects, and its limited contribution to global emission reductions. Differentiation between countries or project types has been proposed as a possible way forward to address these problems. An overview is provided of the different ways in which CDM differentiation could be implemented. The implications for the actors involved in the CDM are analysed, along with a quantitative assessment of the impacts on the carbon market, using bottom-up marginal abatement cost curves. The discounting of CDM credits, quota systems, or differentiated eligibility of countries could help to address several of the concerns raised. Preferential treatment may also make a limited contribution to achieving the aims of CDM differentiation by increasing opportunities for under-represented host countries. The impact on the carbon market appears to be limited for most options

Frontotemporal dementia and its subtypes: a genome-wide association study

SummaryBackground Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with {FTD} and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with {FTD} and 4308 controls), we did separate association analyses for each {FTD} subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and {FTD} overlapping with motor neuron disease FTD-MND), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, \{HLA\} locus (immune system), for rs9268877 (p=1·05 × 10−8; odds ratio=1·204 95% \{CI\} 1·11–1·30), rs9268856 (p=5·51 × 10−9; 0·809 0·76–0·86) and rs1980493 (p value=1·57 × 10−8, 0·775 0·69–0·86) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural \{FTD\} subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10−7; 0·814 0·71–0·92). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center

Calcium Carbonate and Water Pyrolysis Measurements Suggest Minor Adjustment to the VPDB and VSMOW-SLAP δ¹⁸O Scale Relation

Rationale: Measurements of the oxygen isotopic composition of materials are widely used in many fields. These oxygen isotopic compositions are expressed using different scales. These scales are only linked indirectly, because water and calcium carbonate reference materials, used to establish these oxygen isotope delta scales, have to be converted to CO2 first, and the isotopic fractionation of these conversions has only been measured a few times in the past. The anchoring of the two oxygen isotope delta scales is therefore currently suboptimal. Methods: Primary reference materials, both waters and calcium carbonates, were pyrolyzed within a single measurement sequence in a high-temperature elemental analyzer–pyrolysis system connected to an isotope ratio mass spectrometer in continuous-flow mode. As calcium carbonate is difficult to pyrolyze completely, additives were added to reach a 100% yield. The δ18O of the calcium carbonates were normalized on the VSMOW-SLAP scale using VSMOW2 and in-house water references. Results: The average results of 6 international calcites references measured in five independent sequences of pyrolysis measurements showed a difference of 0.07 to 0.09‰ with the presently described relationship in literature between the δ18O VPDB and δ18O VSMOW-SLAP scale. Conclusions: The outcome of the study made the direct comparison of the two different 18O scales possible. Our results demonstrate a small discrepancy in the presently recommended relation between the two oxygen isotope delta scales.</p

Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations

Mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) are major genetic causes of early-onset Alzheimer's disease (EOAD). Clinical heterogeneity is frequently observed in patients with PSEN1 and PSEN2 mutations. Using whole exome sequencing, we screened a Dutch cohort of 68 patients with EOAD for rare variants in Mendelian Alzheimer's disease, frontotemporal dementia, and prion disease genes. We identified 3 PSEN1 and 2 PSEN2 variants. Three variants, 1 in PSEN1 (p.H21Profs*2) and both PSEN2 (p.A415S and p.M174I), were novel and absent in control exomes. These novel variants can be classified as probable pathogenic, except for PSEN1 (p.H21Profs*2) in which the pathogenicity is uncertain. The initial clinical symptoms between mutation carriers varied from behavioral problems to memory impairment. Our findings extend the mutation spectrum of EOAD and underline the clinical heterogeneity among PSEN1 and PSEN2 mutation carriers. Screening for Alzheimer's disease–causing genes is indicated in presenile dementia with an overlapping clinical diagnosis

Acute kidney injury in a patient with nontuberculous mycobacterial infections: a case report

Nontuberculous mycobacterial infections are an increasingly recognized cause of chronic lung disease in both immunocompromised and immunocompetent patients. Pre-existing lung disease, alcohol abuse, diabetes mellitus, malignancy, and smoking have been identified as important risk factors in nontuberculous mycobacterial infections, with only few cases of Nontuberculous mycobacterial infection in renal failure patients, mostly on peritoneal dialysis. However, acute kidney injury associated with atypical mycobacterial infection is a very rare clinical event. To our knowledge, the present patient is the first case of acute kidney injury in a patient with documented nontuberculous mycobacterial infection. Our case is also a first report of Mycobacteria avium complex and Mycobacteria gordonae isolated simultaneously from individual patient with nontuberculous mycobacterial disease