Use of CUDA for the Continuous Space Language Model

The training phase of the Continuous Space Language Model (CSLM) was implemented in the NVIDIA hardware/software architecture Compute Unified Device Architecture (CUDA). Implementation was accomplished using a combination of CUBLAS library routines and CUDA kernel calls on three different CUDA enabled devices of varying compute capability and a time savings over the traditional CPU approach demonstrated

Action ascription and deonticity in everyday advice-giving sequences

Peer reviewe

Consensual Qualitative Research: An Update

The authors reviewed the application of consensual qualitative research (CQR) in 27 studies published since the method’s introduction to the field in 1997 by C. E. Hill, B. J. Thompson, and E. N. Williams (1997). After first describing the core components and the philosophical underpinnings of CQR, the authors examined how it has been applied in terms of the consensus process, biases, research teams, data collection, data analysis, and writing up the results and discussion sections of articles. On the basis of problems that have arisen in each of these areas, the authors made recommendations for modifications of the method. The authors concluded that CQR is a viable qualitative method and suggest several ideas for research on the method itself

Improving Estimates of Genetic Maps: A Maximum Likelihood Approach

As a result of previous large, multipoint linkage studies there is a substantial amount of existing marker data. Due to the increased sample size, genetic maps estimated from these data could be more accurate than publicly available maps. However, current methods for map estimation are restricted to data sets containing pedigrees with a small number of individuals, or cannot make full use of marker data that are observed at several loci on members of large, extended pedigrees. In this article, a maximum likelihood (ML) method for map estimation that can make full use of the marker data in a large, multipoint linkage study is described. The method is applied to replicate sets of simulated marker data involving seven linked loci, and pedigree structures based on the real multipoint linkage study of Abkevich et al. (2003, American Journal of Human Genetics 73, 1271–1281). The variance of the ML estimate is accurately estimated, and tests of both simple and composite null hypotheses are performed. An efficient procedure for combining map estimates over data sets is also suggested.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66271/1/j.1541-0420.2006.00532.x.pd

Evaluation of the Induction of Immune Memory following Infant Immunisation with Serogroup C Neisseria meningitidis Conjugate Vaccines - Exploratory Analyses within a Randomised Controlled Trial

Aim: We measured meningococcal serogroup C (MenC)-specific memory B-cell responses in infants by Enzyme-Linked Immunospot (ELISpot) following different MenC conjugate vaccine schedules to investigate the impact of priming on immune memory. Methods: Infants aged 2 months were randomised to receive 1 or 2 doses of MenC-CRM197 at 3 or 3 and 4 months, 1 dose of MenC-TT at 3 months, or no primary MenC doses. All children received a Haemophilus influenzae type b (Hib)-MenC booster at 12 months. Blood was drawn at 5, 12, 12 months +6 days and 13 months of age. Results: Results were available for 110, 103, 76 and 44 children from each group respectively. Following primary immunisations, and prior to the 12-month booster, there were no significant differences between 1- or 2-dose primed children in the number of MenC memory B-cells detected. One month following the booster, children primed with 1 dose MenC-TT had more memory B-cells than children primed with either 1-dose (p = 0.001) or 2-dose (p<0.0001) MenC-CRM197. There were no differences in MenC memory B-cells detected in children who received 1 or 2 doses of MenC-CRM197 in infancy and un-primed children. Conclusions: MenC-specific memory B-cell production may be more dependent on the type of primary vaccine used than the number of doses administered. Although the mechanistic differences between MenC-CRM197 and MenC-TT priming are unclear, it is possible that structural differences, including the carrier proteins, may underlie differential interactions with B- and T-cell populations, and thus different effects on various memory B-cell subsets. A MenC-TT/Hib-MenC-TT combination for priming/boosting may offer an advantage in inducing more persistent antibody.peer-reviewe

The role of adjuvant-induced innate immune activation in shaping vaccine responses

Adjuvants are components added to non-live vaccine formulations to enhance the effect of the vaccine by alerting the immune system to initiate a response against the vaccine. Powerful new adjuvants will be critical for the development of next generation vaccines to diseases such as tuberculosis, HIV-1/AIDS, malaria, and therapeutic cancer vaccines. My thesis work has focused on the responses induced by adjuvants targeting different immune-modulatory receptors in the innate immune system. The overall aim of the studies was to better understand the mechanisms by which adjuvants can alter innate immune activation and thereby influence the magnitude, polarization, and longevity of adaptive vaccine responses. In paper I, I investigated an adjuvant combining the toll-like receptor (TLR)3-agonist, Poly IC:LC, and an agonistic monoclonal antibody targeting CD40 (anti-CD40Ab) for the potential to induce T cell responses. We found low T cell responses in the blood, but remarkable frequencies of vaccine-specific T cells restricted to the lung and bronchoalveolar lavage after vaccination. The majority of the vaccine-specific T cells in the lung expressed CD103, representing tissue-resident memory T cells (TRM). However, we found that the anti-CD40Ab was widely disseminated after vaccination to all organs analyzed, and therefore lung-specific adjuvant activation alone could not explain the compartmentalized TRM. We consequently expanded the studies in paper II to compare the intravenous (IV) and subcutaneous (SQ) routes of administration. In contrast to IV, the CD40Ab stayed localized to the skin and the skin draining lymph nodes following SQ administration. While both groups induced equivalent vaccine-specific T cell homing to the lung, IV immunization induced a significantly higher proportion of CD103+ TRM. IV immunization induced an innate profile skewed towards IL-10 production, which strongly correlated with the proportion of TRM. By in vitro studies, we found that blood monocytes were the main producers of IL-10 and could mediate increased CD103 expression on T cells. IL-10 did not directly cause CD103 upregulation, but instead conditioned monocytes to release TGFb which in turn induced the TRM phenotype. In paper III, I compared how adjuvants targeting either TLR4, TLR7/8, or TLR9 induced different innate immune responses to polarize the adaptive vaccine responses. In a large preclinical vaccine study, the TLR-adjuvants were added to polymer-based nanoparticles encapsulating the malaria transmission-blocking vaccine antigen Pfs25, to identify correlates of immunity leading to robust, long-lived, functional Ab titers. All groups induced high Ab titers and transmission reducing activity in mosquitoes at peak responses. However, the adjuvants targeting TLR7/8 or TLR9 induced higher levels of IFNα production and type I IFN associated gene signatures than the adjuvant targeting TLR4. The IFNα signature showed strong correlations with the increased Ab half-life observed in these groups. All adjuvants generated Pfs25-specific CD4 T cell responses when combined with the nanoparticle encapsulated antigen, which correlated with increased IgG Ab avidity. In conclusion, the thesis provides increased understanding of the mechanisms by which adjuvants potentiate and regulate vaccine responses and will hopefully aid in refining future vaccine formulations