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Background Thymidine analogs, namely AZT (Zidovudine or Retrovir™) and d4T (Stavudine or Zerit™) are antiretroviral drugs still employed in over 75% of first line combination antiretroviral therapy (cART) in Kampala, Uganda despite aversion to prescribing these drugs for cART in high income countries due in part to adverse events. For this study, we explored how the continued use of these thymidine analogs in cART could impact emergence of drug resistance and impact on future treatment success in Uganda, a low-income country. Methods We examined the drug resistance genotypes by Sanger sequencing of 262 HIV-infected patients failing a first line combined antiretroviral treatment containing either AZT or d4T, which represents approximately 5% of the patients at the Joint Clinical Research Center receiving a AZT or d4T containing treatment. Next generation sequencing (DEEPGEN™HIV) and multiplex oligonucleotide ligation assays (AfriPOLA) were then performed on a subset of patient samples to detect low frequency drug resistant mutations. CD4 cell counts, viral RNA loads, and treatment changes were analyzed in a cohort of treatment success and failures. Results Over 80% of patients failing first line AZT/d4T-containing cART had predicted drug resistance to 3TC (Lamivudine) and non-nucleoside RT inhibitors (NNRTIs) in the treatment regimen but only 45% had resistance AZT/d4T associated resistance mutations (TAMs). TAMs were however detected at low frequency within the patients HIV quasispecies (1–20%) in 21 of 34 individuals who were failing first-line AZT-containing cART and lacked TAMs by Sanger. Due to lack of TAMs by Sanger, AZT was typically maintained in second-line therapies and these patients had a low frequency of subsequent virologic success. Conclusions Our findings suggest that continued use of AZT and d4T in first-line treatment in low-to-middle income countries may lead to misdiagnosis of HIV-1 drug resistance and possibly enhance a succession of second- and third-line treatment failures.

Human immunodeficiency virus type 1 (HIV-1) emerged in the human population shortly after the turn of the 19th century. Distribution of HIV-1 across the globe over the past 30–35 years can be traced to founder events with primordial HIV strains from sub-Saharan Africa. Even considering the burden of HIV in Africa, our knowledge of HIV-1 disease is still largely limited to subtype B HIV-1, a strain responsible for 3 million infections in North America and Europe as compared to the 33 million that are infected with HIV-1 subtypes A, C, D, and circulating and unique recombinant forms. This dissertation analyzes data and archived samples from a cohort of HIV+ women in Uganda and Zimbabwe to assess the role of HIV-1 Group M subtype in disease progression, viral replicative fitness and cellular entry efficiency. Generalized estimating equation models are employed to calculate average rates of CD4+ T-cell loss over the course of disease, investigate circulating viral load, and compare depletion of memory T-cell subsets in CD4+ and CD8+ Tcells. Fluorescent tissue culture assays of HIV-1 entry were used to phenotypically evaluate entry efficiency and its association with replicative fitness. Ugandan and Zimbabwean women infected with HIV-1 subtype C had 2.5-fold slower rates of CD4 T-cell declines and higher frequencies of long-term non-progression than those infected with subtype A or D, a difference not associated with any other clinical parameters. Relative replicative fitness and entry efficiency of HIV-1 variants directly correlated with virulence in the patients, subtype D > A > C. These relationships were maintained in both assays evaluating HIV-induced cell-fusion rates, viral particle entry rates and CD4 receptor affinity. The primary burden of HIV infection is placed on T-cell memory populations that are focal points for progeny virion production, the latent proviral reservoir, and immune activation. All subtypes depleted effector memory T-cells preferentially, however subtype D infections lost these cells at about twice the rate of subtype C infections. Finally, subtype D was found to uniquely deplete CD8+ memory T-cells.

HIV-1 subtypes differ, among other things, in their clinical manifestations and the speed in which they spread. In particular, the frequency of subtype C is increasing relative to subtype A and D. We aim to investigate whether HIV-1 subtype A, C and D differ in their per-pathogen virulence and to what extend this can explain the difference in spread between these subtypes. We use data from the Hormonal Contraception and HIV-1 Genital Shedding and Disease Progression among Women with Primary HIV Infection (GS) Study. For each study participant, we determine the set-point viral load value, CD4+ T cell level after primary infection and CD4+ T cell decline. Based on both the CD4+ T cell count after primary infection and CD4+ T cell decline, we estimate the time until AIDS for each individual. We then obtain our newly introduced measure of virulence as the inverse of the estimated time until AIDS. This new measure of virulence has an improved correlation with the set-point viral load compared to the decline of CD4+ T cells alone. After fitting a model to the measured virulence and set-point viral load values, we tested if this relation varies per subtype. We found that subtype C has a significantly higher per-pathogen virulence than subtype A. Based on an evolutionary model, we then hypothesize that differences in the primary length of infection period cause the observed variation in the speed of spread of the subtypes. Competing Interest Statement The authors have declared no competing interest.

Many hypotheses suggest that pollinators act to maintain or change floral color morph frequencies in nature, although pollinator preferences do not always match color morph frequencies in the field. Therefore, non-pollinating agents may also be responsible for color morph frequencies. To test this hypothesis, we examined whether Raphanus sativus plants with white flowers received different amounts of florivory than plants with pink flowers, and whether florivores preferred one floral color over the other. We found that white-flowered plants received significantly more floral damage than pink-flowered plants in eight populations over 4 years in northern California. Both generalists and specialists on Brassicaceae preferred white petals in choice and short-term no choice tests. In performance tests, generalists gained more weight on white versus pink petals whereas specialists gained similar amounts of weight on pink and white morphs. Because our results suggest that florivores prefer and perform better on white versus pink flowers, these insects may have the opportunity to affect the frequency of color morphs in the field.

Abstract This article traces the contribution of the Dowson and Higginson work to numerical line contact elasto-hydrodynamic lubricated film thickness prediction and the Hamrock and Dowson contribution to the film thickness prediction in elliptical contacts. Considering the line contact work, this article shows that both the numerical pressure and film thickness results and the curve-fitted film thickness predictions are very accurate, even by today's standards. Concerning the elliptical results, the authors show that the original predictions remain surprisingly accurate but that the issue of the minimum to central film thicknesss ration Hm/ Hc is not yet completely settled. The article then continues to discuss some limitations of the current models that require additional work, mainly in the area of realistic non-Newtonian lubricant rheology for film thickness predictions and pressure spike analysis.

In October 2019, 46 scientists from around the world participated in the first National Center for Biotechnology Information (NCBI) Structural Variation (SV) Codeathon at Baylor College of Medicine. The charge of this first annual working session was to identify ongoing challenges around the topics of SV and graph genomes, and in response to design reliable methods to facilitate their study. Over three days, seven working groups each designed and developed new open-sourced methods to improve the bioinformatic analysis of genomic SVs represented in next-generation sequencing (NGS) data. The groups' approaches addressed a wide range of problems in SV detection and analysis, including quality control (QC) assessments of metagenome assemblies and population-scale VCF files, de novo copy number variation (CNV) detection based on continuous long sequence reads, the representation of sequence variation using graph genomes, and the development of an SV annotation pipeline. A summary of the questions and developments that arose during the daily discussions between groups is outlined. The new methods are publicly available at https://github.com/NCBI-Codeathons/, and demonstrate that a codeathon devoted to SV analysis can produce valuable new insights both for participants and for the broader research community.

We report the validation of multiple planets transiting the nearby (\\(d = 12.8\\) pc) K5V dwarf HD 101581 (GJ 435, TOI-6276, TIC 397362481). The system consists of at least two Earth-size planets whose orbits are near a mutual 4:3 mean-motion resonance, HD 101581 b (\\(R_{p} = 0.956_{-0.061}^{+0.063}~R_{\\oplus}\\), \\(P = 4.47\\) days) and HD 101581 c (\\(R_{p} = 0.990_{-0.070}^{+0.070}~R_{\\oplus}\\), \\(P = 6.21\\) days). Both planets were discovered in Sectors 63 and 64 TESS observations and statistically validated with supporting ground-based follow-up. We also identify a signal that probably originates from a third transiting planet, TOI-6276.03 (\\(R_{p} = 0.982_{-0.098}^{+0.114}~R_{\\oplus}\\), \\(P = 7.87\\) days). These planets are remarkably uniform in size and their orbits are evenly spaced, representing a prime example of the \"peas-in-a-pod\" architecture seen in other compact multi-planet systems. At \\(V = 7.77\\), HD 101581 is the brightest star known to host multiple transiting planets smaller than \\(1.5~R_{\\oplus}\\). HD 101581 is a promising system for atmospheric characterization and comparative planetology of small planets.