Natural Host Genetic Resistance to Lentiviral CNS Disease: A Neuroprotective MHC Class I Allele in SIV-Infected Macaques

Human immunodeficiency virus (HIV) infection frequently causes neurologic disease even with anti-retroviral treatment. Although associations between MHC class I alleles and acquired immunodeficiency syndrome (AIDS) have been reported, the role MHC class I alleles play in restricting development of HIV-induced organ-specific diseases, including neurologic disease, has not been characterized. This study examined the relationship between expression of the MHC class I allele Mane-A*10 and development of lentiviral-induced central nervous system (CNS) disease using a well-characterized simian immunodeficiency (SIV)/pigtailed macaque model. The risk of developing CNS disease (SIV encephalitis) was 2.5 times higher for animals that did not express the MHC class I allele Mane-A*10 (P = 0.002; RR = 2.5). Animals expressing the Mane-A*10 allele had significantly lower amounts of activated macrophages, SIV RNA, and neuronal dysfunction in the CNS than Mane-A*10 negative animals (P<0.001). Mane-A*10 positive animals with the highest CNS viral burdens contained SIV gag escape mutants at the Mane-A*10-restricted KP9 epitope in the CNS whereas wild type KP9 sequences dominated in the brain of Mane-A*10 negative animals with comparable CNS viral burdens. These concordant findings demonstrate that particular MHC class I alleles play major neuroprotective roles in lentiviral-induced CNS disease

Payers' views of the changes arising through the possible adoption of adaptive pathways

Payers are a major stakeholder in any considerations and initiatives concerning adaptive licensing of new medicinal products, also referred to as Medicines Adaptive Pathways to patients (MAPPs). Firstly, the scope and necessity of MAPPs need further scrutiny, especially with regard to the definition of unmet need. Conditional approval pathways already exist for new medicines for seriously debilitating or life-threatening diseases and only a limited number of new medicines are innovative. Secondly, MAPPs will result in new medicines on the market with limited evidence about their effectiveness and safety. Additional data are to be collected after approval. Consequently, adaptive pathways may increase the risk of exposing patients to ineffective or unsafe medicines. We have already seen medicines approved conventionally that subsequently proved ineffective or unsafe amongst a wider, more co-morbid population as well as medicines that could have been considered for approval under MAPPs but subsequently proved ineffective or unsafe in Phase III trials and were never licensed. Thirdly, MAPPs also put high demands on payers. Routine collection of patient level data is difficult with high transaction costs. It is not clear who will fund these. Other challenges for payers include shifts in the risk governance framework, implications for evaluation and HTA, increased complexity of setting prices, difficulty with ensuring equity in the allocation of resources, definition of responsibility and liability and implementation of stratified use. Exit strategies also need to be agreed in advance, including price reductions, rebates, or reimbursement withdrawals when price premiums are not justified. These issues and concerns will be discussed in detail including potential ways forward

Situating language register across the ages, languages, modalities, and cultural aspects: Evidence from complementary methods

In the present review paper by members of the collaborative research center “Register: Language Users' Knowledge of Situational-Functional Variation” (CRC 1412), we assess the pervasiveness of register phenomena across different time periods, languages, modalities, and cultures. We define “register” as recurring variation in language use depending on the function of language and on the social situation. Informed by rich data, we aim to better understand and model the knowledge involved in situation- and function-based use of language register. In order to achieve this goal, we are using complementary methods and measures. In the review, we start by clarifying the concept of “register”, by reviewing the state of the art, and by setting out our methods and modeling goals. Against this background, we discuss three key challenges, two at the methodological level and one at the theoretical level: (1) To better uncover registers in text and spoken corpora, we propose changes to established analytical approaches. (2) To tease apart between-subject variability from the linguistic variability at issue (intra-individual situation-based register variability), we use within-subject designs and the modeling of individuals' social, language, and educational background. (3) We highlight a gap in cognitive modeling, viz. modeling the mental representations of register (processing), and present our first attempts at filling this gap. We argue that the targeted use of multiple complementary methods and measures supports investigating the pervasiveness of register phenomena and yields comprehensive insights into the cross-methodological robustness of register-related language variability. These comprehensive insights in turn provide a solid foundation for associated cognitive modeling.Peer Reviewe

Copy Number Variation of CCL3-like Genes Affects Rate of Progression to Simian-AIDS in Rhesus Macaques (Macaca mulatta)

Variation in genes underlying host immunity can lead to marked differences in susceptibility to HIV infection among humans. Despite heavy reliance on non-human primates as models for HIV/AIDS, little is known about which host factors are shared and which are unique to a given primate lineage. Here, we investigate whether copy number variation (CNV) at CCL3-like genes (CCL3L), a key genetic host factor for HIV/AIDS susceptibility and cell-mediated immune response in humans, is also a determinant of time until onset of simian-AIDS in rhesus macaques. Using a retrospective study of 57 rhesus macaques experimentally infected with SIVmac, we find that CCL3L CNV explains approximately 18% of the variance in time to simian-AIDS (p<0.001) with lower CCL3L copy number associating with more rapid disease course. We also find that CCL3L copy number varies significantly (p<10−6) among rhesus subpopulations, with Indian-origin macaques having, on average, half as many CCL3L gene copies as Chinese-origin macaques. Lastly, we confirm that CCL3L shows variable copy number in humans and chimpanzees and report on CCL3L CNV within and among three additional primate species. On the basis of our findings we suggest that (1) the difference in population level copy number may explain previously reported observations of longer post-infection survivorship of Chinese-origin rhesus macaques, (2) stratification by CCL3L copy number in rhesus SIV vaccine trials will increase power and reduce noise due to non-vaccine-related differences in survival, and (3) CCL3L CNV is an ancestral component of the primate immune response and, therefore, copy number variation has not been driven by HIV or SIV per se

Long-Term Programming of Antigen-Specific Immunity from Gene Expression Signatures in the PBMC of Rhesus Macaques Immunized with an SIV DNA Vaccine

While HIV-1-specific cellular immunity is thought to be critical for the suppression of viral replication, the correlates of protection have not yet been determined. Rhesus macaques (RM) are an important animal model for the study and development of vaccines against HIV/AIDS. Our laboratory has helped to develop and study DNA-based vaccines in which recent technological advances, including genetic optimization and in vivo electroporation (EP), have helped to dramatically boost their immunogenicity. In this study, RMs were immunized with a DNA vaccine including individual plasmids encoding SIV gag, env, and pol alone, or in combination with a molecular adjuvant, plasmid DNA expressing the chemokine ligand 5 (RANTES), followed by EP. Along with standard immunological assays, flow-based activation analysis without ex vivo restimulation and high-throughput gene expression analysis was performed. Strong cellular immunity was induced by vaccination which was supported by all assays including PBMC microarray analysis that identified the up-regulation of 563 gene sequences including those involved in interferon signaling. Furthermore, 699 gene sequences were differentially regulated in these groups at peak viremia following SIVmac251 challenge. We observed that the RANTES-adjuvanted animals were significantly better at suppressing viral replication during chronic infection and exhibited a distinct pattern of gene expression which included immune cell-trafficking and cell cycle genes. Furthermore, a greater percentage of vaccine-induced central memory CD8+ T-cells capable of an activated phenotype were detected in these animals as measured by activation analysis. Thus, co-immunization with the RANTES molecular adjuvant followed by EP led to the generation of cellular immunity that was transcriptionally distinct and had a greater protective efficacy than its DNA alone counterpart. Furthermore, activation analysis and high-throughput gene expression data may provide better insight into mechanisms of viral control than may be observed using standard immunological assays

What Stimulates Researchers to Make Their Research Usable? Towards an Openness Approach

Ambiguity surrounding the effect of external engagement on academic research has raised questions about what motivates researchers to collaborate with third parties. We argue that what matters for society is research that can be absorbed by users. We define openness as a willingness by researchers to make research more usable by external partners by responding to external influences in their own research practices. We ask what kinds of characteristics define those researchers who are more open to creating usable knowledge. Our empirical study analyses a sample of 1583 researchers working at the Spanish Council for Scientific Research (CSIC). Results demonstrate that it is personal factors (academic identity and past experience) that determine which researchers have open behaviours. The paper concludes that policies to encourage external engagement should focus on experiences which legitimate and validate knowledge produced through user encounters, both at the academic formation career stage as well as through providing ongoing opportunities to engage with third parties.The data used for this study comes from the IMPACTO project funded by the Spanish Council for Scientific Research - CSIC (Ref. 200410E639). The work also benefited from a mobility grant awarded by Eu-Spri Forum to Julia Olmos Penuela & Paul Benneworth for her visiting research to the Center of Higher Education Policy Studies. Finally, Julia Olmos Penuela also benefited from a post-doctoral grant funded by the Generalitat Valenciana (APOSTD-2014-A-006).Olmos-Peñuela, J.; Benneworth, P.; Castro-Martínez, E. (2015). What Stimulates Researchers to Make Their Research Usable? Towards an Openness Approach. 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Scale-dependent perspectives on the geomorphology and evolution of beachdune systems

Despite widespread recognition that landforms are complex Earth systems with process-response linkages that span temporal scales from seconds to millennia and spatial scales from sand grains to landscapes, research that integrates knowledge across these scales is fairly uncommon. As a result, understanding of geomorphic systems is often scale-constrained due to a host of methodological, logistical, and theoretical factors that limit the scope of how Earth scientists study landforms and broader landscapes. This paper reviews recent advances in understanding of the geomorphology of beach-dune systems derived from over a decade of collaborative research from Prince Edward Island (PEI), Canada. A comprehensive summary of key findings is provided from short-term experiments embedded within a decade-long monitoring program and a multi-decadal reconstruction of coastal landscape change. Specific attention is paid to the challenges of scale integration and the contextual limitations research at specific spatial and/or temporal scales imposes. A conceptual framework is presented that integrates across key scales of investigation in geomorphology and is grounded in classic ideas in Earth surface sciences on the effectiveness of formative events at different scales. The paper uses this framework to organize the review of this body of research in a 'scale aware' way and, thereby, identifies many new advances in knowledge on the form and function of subaerial beach-dune systems. Finally, the paper offers a synopsis of how greater understanding of the complexities at different scales can be used to inform the development of predictive models, especially those at a temporal scale of decades to centuries, which are most relevant to coastal management issues. Models at this (landform) scale require an understanding of controls that exist at both ‘landscape’ and ‘plot’ scales. Landscape scale controls such as sea level change, regional climate, and the underlying geologic framework essentially provide bounding conditions for independent variables such as winds, waves, water levels, and littoral sediment supply. Similarly, an holistic understanding of the range of processes, feedbacks, and linkages at the finer plot scale is required to inform and verify the assumptions that underly the physical modelling of beach-dune interaction at the landform scale

Corrigendum to "Utilisation trend of long-acting insulin analogues including biosimilars across Europe: findings and implications"

In the article titled "Utilisation Trend of Long-Acting Insulin Analogues including Biosimilars across Europe: Findings and Implications" [1], the captions of Figures 3 and 4 were incorrect. The corrected captions for Figures 3 and 4 appear below