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The persistence of HIV-1 proviruses in latently infected cells allows viremia to resume upon treatment cessation. To characterize the resulting immune response, we compare plasma proteomics and single-cell transcriptomics of peripheral blood mononuclear cells (PBMCs) before, during, and after detectable plasma viremia. We observe unique transcriptional signatures prior to viral rebound including a significant increase in CD16 monocytes with increased anti-viral gene expression. Inflammatory proteins were identified in plasma after detectable rebound. Identifying early signals of imminent viral rebound after treatment cessation will aid in the development of strategies to prolong time to viral rebound and cure HIV-1.

Broadly neutralizing antibodies (bNAbs) show promise for HIV treatment and prevention, but are vulnerable to resistance evolution. Comprehensively understanding viral escape from individual bNAbs is necessary to design bNAb combinations that will provide durable responses. We characterize viral escape from two such bNAbs, 10-1074 and 3BNC117, using deep, longitudinal sequencing of full length HIV envelope ( ) genes from study participants treated with bNAb monotherapy. Improved sequencing depth and computational evolutionary analyses permit us to identify routes and parallelism underlying HIV escape from each bNAb, providing new insights into this evolutionary process: 10-1074 escape is restricted to a small number of previously documented pathways, but these escape mutations 1) pre-exist in intra-host viral populations before therapy, 2) are not all equally preferred, and 3) emerge with a high degree of genetic parallelism within and across viral populations. In contrast, 3BNC117 escape follows background-specific patterns in which specific escape mutations present in one population rarely emerge or spread in other populations, but often still exhibit parallel evolutionary responses within their host. That bNAbs elicit starkly different escape profiles depending on their Env target exposes the limitations of generalizing escape patterns across therapies and highlights the substantial challenges in predicting a viral population's bNAb susceptibility from genetic diversity alone.

Sustained viral suppression following antiretroviral treatment (ART) cessation is a major goal of HIV cure research . Rare individuals mount immune responses able to control viral rebound without intervention , however, the earliest moments in which these responses form remain poorly defined. We performed an intensively sampled, prospective analytical treatment interruption (ATI) to study the initial immune response to rebound and to understand its role in defining subsequent virus control. Profiling of peripheral blood mononuclear cells and plasma revealed consistent immune activation prior to systemic rebound, including upregulation of antiviral transcriptional pathways, expansion of CD16 non-classical monocytes, and increases of inflammatory and antiviral soluble plasma proteins. Individuals with prior viral control (controllers) diverged from non-controllers with a slower slope of rebound, a longer period of immune activity prior to rebound, and engagement of a multifaceted immune program with less systemic inflammation. An intermediate immune signature emerged in a separate ATI cohort of individuals who experienced delayed rebound after receiving broadly neutralizing antibodies , suggesting that immunotherapy can induce a potentially protective pre-rebound immune response. Together, these data resolve the earliest systemic host immune responses to HIV rebound and demonstrate broad immune differences associated with HIV control phenotypes.

Broadly neutralizing antibodies (bNAbs) show promise for HIV treatment and prevention, but are vulnerable to resistance evolution. Comprehensively understanding in vivo viral escape from individual bNAbs is necessary to design bNAb combinations that will provide durable responses. We characterize viral escape from two such bNAbs, 10-1074 and 3BNC117, using deep, longitudinal sequencing of full length HIV envelope (env) genes from study participants treated with bNAb monotherapy. Improved sequencing depth and computational evolutionary analyses permit us to identify in vivo routes and parallelism underlying HIV escape from each bNAb, providing new insights into this evolutionary process. We find that 10-1074 escape is restricted to a small number of previously documented pathways seen across participants, but these escape mutations 1) emerge via extensively recurrent mutation, 2) are not equally preferred, and 3) can pre-exist at low frequency in intra-host viral populations before therapy, although their detection does not predict rebound timing. In contrast, 3BNC117 escape follows background-specific patterns in which specific escape mutations present in one intra-host population rarely emerge or spread in other populations, except among highly related viruses. Despite this, 3BNC117 escape mutations often still emerge recurrently within their host. Our findings map longitudinal in vivo antibody escape across 20 diverse clade B HIV intra-host populations and reveal clinically relevant resistance dynamics that highlight how combination bNAb therapies will need to contend with extensively recurring escape mutations and dependence on genetic background.Competing Interest StatementThis independent research was supported by the Gilead Sciences Research Scholars Program in HIV. The funder had no role in study design, data collection or analysis.Footnotes* This version of the manuscript has been revised for clarity and to further outline the novel contributions of our work to the field, particularly in regard to other studies of 10-1074 and 3BNC117.Funder Information DeclaredNational Institute of Allergy and Infectious Diseases, https://ror.org/043z4tv69, UM1AI64565, U01AI169385Pew Research Center, https://ror.org/02tvvdy44National Cancer Institute, 1DP2CA280623-01, P30 CA01570Gilead Sciences (United States), https://ror.org/056546b03

In the pharmaceutical manufacturing, drug release behavior development is remained as one of the main challenges to improve the drug effectiveness. Recently, more focus has been done on using mesoporous silica materials as drug carriers for prolonged and superior control of drug release in human body. In this study, release behavior of paracetamol is developed using drug-loaded KCC-1-NH 2 mesoporous silica, based on direct compaction method for preparation of tablets. The purpose of this study is to investigate the utilizing of pure KCC-1 mesoporous silica (KCC-1) and amino functionalized KCC-1 (KCC-1-NH 2 ) as drug carriers in oral solid dosage formulations compared to common excipient, microcrystalline cellulose (MCC), to improve the control of drug release rate by manipulating surface chemistry of the carrier. Different formulations of KCC-1 and KCC-NH 2 are designed to investigate the effect of functionalized mesoporous silica as carrier on drug controlled-release rate. The results displayed the remarkable effect of KCC-1-NH 2 on drug controlled-release in comparison with the formulation containing pure KCC-1 and formulation including MCC as reference materials. The pure KCC-1 and KCC-1-NH 2 are characterized using different evaluation methods such as FTIR, SEM, TEM and N 2 adsorption analysis.

Current agricultural production depends on very limited species grown as monocultures that are highly vulnerable to climate change, presenting a threat to the sustainability of agri-food systems. However, many hundreds of neglected crop species have the potential to cater to the challenges of climate change by means of resilience to adverse climate conditions. Proso millet ( Panicum miliaceum L.), one of the underutilised minor millets grown as a rainfed subsistence crop, was selected in this study as an exemplary climate-resilient crop. Using a previously calibrated version of the Agricultural Production Systems Simulator (APSIM), the sensitivity of the crop to changes in temperature and precipitation was studied using the protocol of the Coordinated Climate Crop Modelling Project (C3MP). The future (2040–2069) production was simulated using bias-corrected climate data from 20 general circulation models of the Coupled Model Intercomparison Project (CMIP5) under RCP4.5 and 8.5 scenarios. According to the C3MP analysis, we found a 1°C increment of temperature decreased the yield by 5–10% at zero rainfall change. However, Proso millet yields increased by 5% within a restricted climate change space of up to 2°C of warming with increased rainfall. Simulated future climate yields were lower than the simulated yields under the baseline climate of the 1980–2009 period (mean 1707 kg ha –1 ) under both RCP4.5 (–7.3%) and RCP8.5 (–16.6%) though these changes were not significantly (p > 0.05) different from the baseline yields. Proso millet is currently cultivated in limited areas of Sri Lanka, but our yield mapping shows the potential for expansion of the crop to new areas under both current and future climates. The results of the study, indicating minor impacts from projected climate change, reveal that Proso millet is an excellent candidate for low-input farming systems under changing climate. More generally, through this study, a framework that can be used to assess the climate sensitivity of underutilized crops was also developed.

Bullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral corticosteroids. We did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3–9, 10–30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (<30 g per week) were permitted during weeks 1–3. The non-inferiority primary effectiveness outcome was the proportion of participants with three or fewer blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of non-inferiority. The primary safety outcome was the proportion with severe, life-threatening, or fatal (grade 3–5) treatment-related adverse events by 52 weeks. Analysis (modified intention to treat [mITT] for the superiority safety analysis and mITT and per protocol for non-inferiority effectiveness analysis) used a regression model adjusting for baseline disease severity, age, and Karnofsky score, with missing data imputed. The trial is registered at ISRCTN, number ISRCTN13704604. Between March 1, 2009, and Oct 31, 2013, 132 patients were randomly assigned to doxycycline and 121 to prednisolone from 54 UK and seven German dermatology centres. Mean age was 77·7 years (SD 9·7) and 173 (68%) of 253 patients had moderate-to-severe baseline disease. For those starting doxycycline, 83 (74%) of 112 patients had three or fewer blisters at 6 weeks compared with 92 (91%) of 101 patients on prednisolone, an adjusted difference of 18·6% (90% CI 11·1–26·1) favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening, and fatal events at 52 weeks were 18% (22 of 121) for those starting doxycycline and 36% (41 of 113) for prednisolone (mITT), an adjusted difference of 19·0% (95% CI 7·9–30·1), p=0·001. Starting patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control in bullous pemphigoid and significantly safer in the long-term. NIHR Health Technology Assessment Programme.

Background The human exposome is composed of diverse metabolites and small chemical compounds originated from endogenous and exogenous sources, respectively. Genetic and environmental factors influence metabolite levels, while the extent of genetic contributions across metabolic pathways is not yet known. Untargeted profiling of human metabolome using high-resolution mass spectrometry (HRMS) combined with genome-wide genotyping allows comprehensive identification of genetically influenced metabolites. As such previous studies of adults discovered and replicated genotype–metabotype associations. However, these associations have not been characterized in children. Results We conducted the largest genome by metabolome-wide association study to date of children ( N  = 441) using 619,688 common genetic variants and 14,342 features measured by HRMS. Narrow-sense heritability ( h 2 ) estimates of plasma metabolite concentrations using genomic relatedness matrix restricted maximum likelihood (GREML) method showed a bimodal distribution with high h 2 (> 0.8) for 15.9% of features and low h 2 (< 0.2) for most of features (62.0%). The features with high h 2 were enriched for amino acid and nucleic acid metabolism, while carbohydrate and lipid concentrations showed low h 2 . For each feature, a metabolite quantitative trait loci (mQTL) analysis was performed to identify genetic variants that were potentially associated with plasma levels. Fifty-four associations among 29 features and 43 genetic variants were identified at a genome-wide significance threshold p  < 3.5 × 10 –12 (= 5 × 10 –8 /14,342 features). Previously reported associations such as UGT1A1 and bilirubin; PYROXD2 and methyl lysine; and ACADS and butyrylcarnitine were successfully replicated in our pediatric cohort. We found potential candidates for novel associations including CSMD1 and a monostearyl alcohol triglyceride ( m/z 781.7483, retention time (RT) 89.3 s); CALN1 and Tridecanol ( m/z 283.2741, RT 27.6). A gene-level enrichment analysis using MAGMA revealed highly interconnected modules for dADP biosynthesis, sterol synthesis, and long-chain fatty acid transport in the gene-feature network. Conclusion Comprehensive profiling of plasma metabolome across age groups combined with genome-wide genotyping revealed a wide range of genetic influence on diverse chemical species and metabolic pathways. The developmental trajectory of a biological system is shaped by gene–environment interaction especially in early life. Therefore, continuous efforts on generating metabolomics data in diverse human tissue types across age groups are required to understand gene–environment interaction toward healthy aging trajectories.

The compositions of phyllosilicates, with a focus on fluid-mobile elements, were evaluated as a means to fingerprint the Middle Ordovician metamorphosed (greenschist facies) volcanogenic massive sulfide deposits of the Bathurst Mining Camp (BMC), Canada. Ninety-five drill-core samples from six of the major deposits of the Bathurst Mining Camp (Brunswick No. 12, Heath Steele B zone, Halfmile Lake Deep zone, Key Anacon East zone, Louvicourt, and Restigouche) were analyzed using electron microprobe and laser ablation inductively coupled plasma-mass spectrometry. Typically, phyllosilicates (chlorite, white mica, and to a lesser extent biotite) are ubiquitous phases in the host rocks of the massive sulfide deposits of the BMC. Electron microprobe analysis results show a wide compositional variation in chlorite and white mica. Laser ablation inductively coupled plasma-mass spectrometry (LA-ICP-MS) analysis was performed to measure fluid-mobile elements, showing that Tl is distinctly enriched in all white mica (up to 719 ppm) relative to chlorite (up to 50.1 ppm). Chlorite hosts Sn (up to 4600 ppm), Hg (up to 7.3 ppm), Sb (up to 35.4 ppm), As (up to 1320 ppm), In (up to 307 ppm), Cd (up to 83.2 ppm), and Se (up to 606 ppm). White mica hosts Sn (up to 1316 ppm), Hg (up to 93 ppm), Sb (up to 1630 ppm), As (up to 14,800 ppm), In (up to 1186 ppm), Cd (up to 98 ppm), and Se (up to 38.8 ppm). Limited LA-ICP-MS analysis on biotite indicates a higher overall concentration of Tl (mean = 14.6 ppm) relative to co-existing white mica (mean = 2.18 ppm). On average, biotite is also more enriched in Hg, Sn, and Ba relative to chlorite and white mica. Laser Ablation ICP-MS profiles of chlorite, white mica, and biotite demonstrate smooth time-dependent variations diagnostic of structural substitution of these elements. Compositional variation of chlorite-white mica pairs presented in the current study shows systematic variations as a function of distance from the mineralized horizons. This highlights the potential to use trace-element signatures in these phyllosilicate pairs to identify proximal (chlorite) and distal (white mica) footprints for volcanogenic massive sulfides exploration.

Satellite data records of stratospheric water vapour have been compared to balloon-borne frost point hygrometer (FP) profiles that are coincident in space and time. The satellite data records of 15 different instruments cover water vapour data available from January 2000 through December 2016. The hygrometer data are from 27 stations all over the world in the same period. For the comparison, real or constructed averaging kernels have been applied to the hygrometer profiles to adjust them to the measurement characteristics of the satellite instruments. For bias evaluation, we have compared satellite profiles averaged over the available temporal coverage to the means of coincident FP profiles for individual stations. For drift determinations, we analysed time series of relative differences between spatiotemporally coincident satellite and hygrometer profiles at individual stations. In a synopsis we have also calculated the mean biases and drifts (and their respective uncertainties) for each satellite record over all applicable hygrometer stations in three altitude ranges (10–30 hPa, 30–100 hPa, and 100 hPa to tropopause). Most of the satellite data have biases <10 % and average drifts <1 % yr−1 in at least one of the respective altitude ranges. Virtually all biases are significant in the sense that their uncertainty range in terms of twice the standard error of the mean does not include zero. Statistically significant drifts (95 % confidence) are detected for 35 % of the ≈ 1200 time series of relative differences between satellites and hygrometers.