Molecular Epidemiology of HIV-1 Subtypes in India: Origin and Evolutionary History of the Predominant Subtype C

This thesis describes the translational genomics of HIV-1subtype C in India from its origin to therapeutic response with the aim to improve our knowledge for better therapeutic and preventive strategies to combat HIV/AIDS. In a systemic approach, we identified the molecular phylogeny of HIV-1 subtypes circulating in India and the time to most recent common ancestors (tMRCA) of predominant HIV-1 subtype C strains. Additionally, this thesis also studied drug resistance mutations in children, adolescents and adults, the role of host factors in evolution of drug resistance, and population dynamics of viremia and viral co-receptor tropism in perinatal transmission. Finally, the long term therapeutic responses on Indian national first-line antiretroviral therapy were also studied. In Paper I, we reported an increase in the HIV-1 recombinant forms in the HIV-1 epidemiology using a robust subtyping methodology. While the study confirmed HIV- 1 subtype C as a dominant subtype, its origin was dated back to the early 1970s from a single or few genetically related strains from South Africa, whereafter, it has evolved independently. In Paper II, the lethal hypermutations due to the activity of human apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (hA3G) was significantly associated with antiretroviral therapy (ART) failure in Indian HIV-1 subtype C patients. The presence of M184I and M230I mutations were observed due to the editing of hA3G in the proviral compartment but stop codons were also found in the open reading frames and the same drug resistance mutations were absent in plasma virus. Therefore, it is unlikely that the viral variants which exhibit hypermutated sequences and M184I and/or M230I will mature and expand in vivo and hence are unlikely to have any clinical significance. The high concordance of drug resistance genotyping in the plasma and proviral compartments in therapy-naïve patients, gives weight to the idea of using whole blood for surveillance of drug resistance mutations which precludes logistic challenges of cold chain transport. In Papers III and IV, we identified a substantial proportion of HIV-1 subtype C perinatally-infected older children who had a high burden of plasma viremia but also had high CD4+ T-cell counts. In addition, older children with HIV-1 subtype C infection presented a high prevalence of predicted X4 and R5/X4 tropic strains which indicates that HIV-1 subtype C strains required longer duration of infection and greater disease progression to co-receptor transition from R5- to X4-tropic strains (IV). Our studies also indicate that transmitted drug resistance is low among Indian HIV-1 infected children, adolescents (III) and adults (II). In Paper V, in a longitudinal cohort study, a good long-term response to the Indian national first-line therapy for a median of nearly four years with 2.8% viral failure, indicating the overall success of the Indian ART program. Our study also showed that three immunologically well patients with virological rebound and major viral drug resistance mutations (M184V, K103N and Y181C) during one study visit had undetectable viral load at their next visit. These findings suggest that use of multiple parameters like patients’ immunological (CD4+ T-cell count), virological (viral load) and drug resistance data should all be used to optimize the treatment switch to second line therapy. In conclusion, this translational genomics study enhances our knowledge about the HIV-1 subtype C strains circulating in India which are genetically distinct from prototype African subtype C strains. Considerably more research using appropriate models need to be performed to understand the phenotypic and biological characteristics of these strains to guide efficient disease intervention and management strategies

Vacuum-ultraviolet photoabsorption imaging system for laser plasma plume diagnostics

We describe a recently designed and constructed system based on a 1 m normal incidence vacuum monochromator with corrected (toroidal) optics that produces a wavelength tuneable and collimated vacuum-ultraviolet (VUV) (λ=30–100 nm) beam. The VUV continuum source is a laser-generated gold plasma. The primary function of the system is the measurement of time resolved “images” or spatial distributions of photoabsorption/photoionization in expanding laser plasma plumes. This is achieved by passing the beam through the sample of interest (in our case a second synchronised plasma) and recording the “footprint” of the attenuated beam on a charge coupled device. Using this VUV photoabsorption imaging or “shadowgraphy” technique we track and extract column density distributions in expanding plasma plumes. We can also measure the plume front velocity. We have characterized the system, particularly in relation to spectral and spatial resolution and the experimental results meet very well the expectations from ray tracing done at the design phase. We present first photoabsorption images and column density distributions of laser produced Ca plumes from the system

Absolute photoionization cross section measurements of the Kr I-isoelectronic sequence

Photoionization spectra have been recorded in the 4s, 4p and 3d resonance regions for the Kr Iisoelectronic sequence using both the dual laser produced plasma technique (at DCU) to produce photoabsorption spectra, and the merged ion beam and synchrotron radiation technique (at ASTRID) to measure absolute photoionization cross sections. Profile parameters are compared for the 4s − np resonances of Rb+ and Sr2+. Many new 4p " ns, md transitions are identified with the aid of Hartree-Fock calculations, and consistent quantum defects are observed for the various ns and md Rydberg series. Absolute single and double photoionization cross sections recorded in the 3d region for Rb+ and Sr2+ ions show preferential decay via double photoionization. This is only the second report where both the DLP technique and the merged beam technique have been used simultaneously to record photoionization spectra, and the advantages of both techniques (i.e. better resolution in the case of DLP and values for absolute photoionization cross sections in the case of the merged beam technique) are highlighted

Development of the American College of Rheumatology Electronic Clinical Quality Measures for Gout

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143639/1/acr23500.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143639/2/acr23500-sup-0001-AppendixS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143639/3/acr23500_am.pd

Simulation of dimensionality effects in thermal transport

The discovery of nanostructures and the development of growth and fabrication techniques of one- and two-dimensional materials provide the possibility to probe experimentally heat transport in low-dimensional systems. Nevertheless measuring the thermal conductivity of these systems is extremely challenging and subject to large uncertainties, thus hindering the chance for a direct comparison between experiments and statistical physics models. Atomistic simulations of realistic nanostructures provide the ideal bridge between abstract models and experiments. After briefly introducing the state of the art of heat transport measurement in nanostructures, and numerical techniques to simulate realistic systems at atomistic level, we review the contribution of lattice dynamics and molecular dynamics simulation to understanding nanoscale thermal transport in systems with reduced dimensionality. We focus on the effect of dimensionality in determining the phononic properties of carbon and semiconducting nanostructures, specifically considering the cases of carbon nanotubes, graphene and of silicon nanowires and ultra-thin membranes, underlying analogies and differences with abstract lattice models.Comment: 30 pages, 21 figures. Review paper, to appear in the Springer Lecture Notes in Physics volume "Thermal transport in low dimensions: from statistical physics to nanoscale heat transfer" (S. Lepri ed.

Acute Flares of Knee Osteoarthritis (the ACT-FLARE Study): Protocol for a Web-Based Case-Crossover Study in Community-Dwelling Adults.

BACKGROUND The cardinal feature of osteoarthritis (OA) is pain. Although heterogeneity in pain and function have been demonstrated in the long-term course of OA, the more proximate determinants of acute flare-ups remain less clear. How short-term intermittent or transient exposures trigger acute flare-ups has important implications for effective and sustainable self-management strategies. OBJECTIVE The primary objective of this study is to identify potential triggers of acute flares in knee OA. Secondary objectives are to determine their course and consequences and describe high-risk participant profiles. METHODS We carried out a Web-based case-crossover study. This study aims to recruit 620 community-dwelling adults aged ≥40 years, resident in England, and who have knee pain, with or without a recorded diagnosis of knee OA, and no preexisting diagnosis of inflammatory arthropathy. Participants will be recruited via 3 routes: (1) general practice registers, (2) offline community advertisement, and (3) online social media advertisement. By using questionnaires comparing periods before participants' self-reported flare-up episodes (hazard periods) with periods during the study when their knee OA symptoms are stable (control periods), triggers preceding flare-ups will be identified and examined using conditional logistic regression. Time-to-resolution of flare-up will be examined by monitoring people's daily pain, bothersomeness, and medication usage until the participant reports when their flare-up episode ends. Rates of flare-ups will be examined across different participant and flare characteristics using regression models to identify high-risk participant profiles. A study-specific Patient Advisory Group (PAG) is providing suggestion, input, and ongoing support for all stages of the research process. RESULTS Participant recruitment opened in July 2018 and is anticipated to continue for 6 months. The study results will be disseminated through a number of channels, including relevant national or international conferences and peer-reviewed publication in a medical journal, via advocacy or charity organizations, such as Versus Arthritis and across social media. Findings will be fed back to members of our PAG, study participants, and clinicians from participating primary care general practices. The PAG will also take an active role in the overall dissemination strategy. CONCLUSIONS This study will provide empirical evidence to help patients identify common knee OA flare triggers and provide health care professionals with questions to identify patients at most risk of frequent flare-ups. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/13428

A System for Information Management in BioMedical Studies—SIMBioMS

Summary: SIMBioMS is a web-based open source software system for managing data and information in biomedical studies. It provides a solution for the collection, storage, management and retrieval of information about research subjects and biomedical samples, as well as experimental data obtained using a range of high-throughput technologies, including gene expression, genotyping, proteomics and metabonomics. The system can easily be customized and has proven to be successful in several large-scale multi-site collaborative projects. It is compatible with emerging functional genomics data standards and provides data import and export in accepted standard formats. Protocols for transferring data to durable archives at the European Bioinformatics Institute have been implemented