Immunization with HIV Gag targeted to dendritic cells followed by recombinant New York vaccinia virus induces robust T-cell immunity in nonhuman primates

Protein vaccines, if rendered immunogenic, would facilitate vaccine development against HIV and other pathogens. We compared in nonhuman primates (NHPs) immune responses to HIV Gag p24 within 3G9 antibody to DEC205 ( DEC-HIV Gag p24 ), an uptake receptor on dendritic cells, to nontargeted protein, with or without poly ICLC, a synthetic double stranded RNA, as adjuvant. Priming s.c. with 60 ?g of both HIV Gag p24 vaccines elicited potent CD4+ T cells secreting IL-2, IFN-γ, and TNF-α, which also proliferated. The responses increased with each of three immunizations and recognized multiple Gag peptides. DEC-HIV Gag p24 showed better cross-priming for CD8+ T cells, whereas the avidity of anti-Gag antibodies was ∼10-fold higher with nontargeted Gag 24 protein. For both protein vaccines, poly ICLC was essential for T- and B-cell immunity. To determine whether adaptive responses could be further enhanced, animals were boosted with New York vaccinia virus (NYVAC)-HIV Gag/Pol/Nef. Gag-specific CD4+ and CD8+ T-cell responses increased markedly after priming with both protein vaccines and poly ICLC. These data reveal qualitative differences in antibody and T-cell responses to DEC-HIV Gag p24 and Gag p24 protein and show that prime boost with protein and adjuvant followed by NYVAC elicits potent cellular immunity

Why be first if it doesn’t pay? The case of early adopters of C-TPAT supply chain security certification

Purpose The purpose of this paper is to focus on adoption of certified management standards, specifically public standards. Such standards play an increasingly important role in today’s business environment. However, to generate adoption benefits, they must be first widely accepted – a situation where they have become viewed as the de facto norms. For this state to occur early adopters play a critical role. Past research has argued that early adopters, in exchange for assuming more risk, are rewarded with higher economic returns. Yet, these findings are based on private, not public standards. With public standards, early adopters do not receive such benefits. There is evidence that public standards are becoming more important. This situation leads to a simple but important question addressed in this study – if early adopters assume the risks of embracing a new public standard without economic benefits, then what is their motivation? To resolve this question, this study draws on agency theory and prospect theory. The authors argue that early adopters embrace such standards because of their desire to minimize risk resulting from failure to support the goal at the heart of the public standards. Design/methodology/approach Data were obtained from the Customs-Trade Partnership Against Terrorism (C-TPAT) Partners Cost Benefit Survey and analyzed through structural equation modeling. Findings Early adopters of public standards are not driven by economic benefits but rather by the need to minimize their exposure to the risks associated with failing to satisfy the goals associated with a public standard. In other words, they were motivated by the need to minimize costs. In the case of C-TPAT, these costs are those of failing to provide or improve network security. Research limitations/implications This study has shed new light on the standards adoption process by clarifying the specific motivations that drive early adoption of a public standard. In addition to identifying the loss aversion motives of early adopters and economic benefit motives of later adopters, the authors have also elaborated on the notion that standards have differing levels of precedence, particularly when comparing private with public standards. Practical implications In a world characterized by increasing demands for outcomes such as improved security and where governmental funding is falling, due to growing deficits and governments that are becoming more conservative, the authors expect the use of public standards to increase. Originality/value Different from prior research on private standard, the paper focuses on the organizations involved in the adoption and diffusion of a public standard, with special attention being devoted to the early adopters. The paper provides a theoretical explanation for the actions of early adopters of a public standard through the theoretical lens of prospect theory

Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates

There is a remarkable heterogeneity in the functional profile (quality) of T cell responses. Importantly, the magnitude and/or quality of a response required for protection may be different depending on the infection. Here, we assessed the capacity of different Toll like receptor (TLR)-binding compounds to influence T helper cell (Th)1 and CD8+ T cell responses when used as adjuvants in nonhuman primates (NHP) with HIV Gag as a model antigen. NHP were immunized with HIV Gag protein emulsified in Montanide ISA 51, an oil-based adjuvant, with or without a TLR7/8 agonist, a TLR8 agonist, or the TLR9 ligand cytosine phosphate guanosine oligodeoxynucleotides (CpG ODN), and boosted 12 wk later with a replication-defective adenovirus-expressing HIV-Gag (rAD-Gag). Animals vaccinated with HIV Gag protein/Montanide and CpG ODN or the TLR7/8 agonist had higher frequencies of Th1 responses after primary immunization compared to all other vaccine groups. Although the rAD-Gag boost did not elevate the frequency of Th1 memory cytokine responses, there was a striking increase in HIV Gag-specific CD8+ T cell responses after the boost in all animals that had received a primary immunization with any of the TLR adjuvants. Importantly, the presence and type of TLR adjuvant used during primary immunization conferred stability and dramatically influenced the magnitude and quality of the Th1 and CD8+ T cell responses after the rAD-Gag boost. These data provide insights for designing prime-boost immunization regimens to optimize Th1 and CD8+ T cell responses

Aerosol influences on low-level clouds in the West African monsoon

Low-level clouds (LLC) cover a wide area of southern West Africa (SWA) during the summer monsoon months, and have an important cooling effect on the regional climate. Previous studies of these clouds have focused on modelling and remote sensing via satellite. We present the first comprehensive set of regional, in situ measurements of cloud microphysics, taken during June – July 2016, as part of the DACCIWA (Dynamics-Aerosol-Chemistry-Clouds Interactions in West Africa) campaign, assessing spatial and temporal variation in the properties of these clouds. LLC developed overnight and mean cloud cover peaked a few hundred kilometres inland around 10:00 local solar time (LST), before clouds began to dissipate and convection intensified in the afternoon. Additional sea breeze clouds developed near the coast in the late morning, reaching a maximum extent around 12:00 LST. Regional variation in LLC cover was largely determined by the modulation of the cool maritime inflow by the local orography, with peaks on the upwind side of hills and minima on the leeward sides. In the broad-scale cloud field, no lasting impacts related to anthropogenic aerosol were observed downwind of major population centres. The boundary layer cloud drop number concentration (CDNC) was locally variable inland, ranging from 200 to 840 cm−3 (10th and 90th percentiles at standard temperature and pressure), but showed no systematic regional variations. Enhancements were seen in pollution plumes from the coastal cities, but were not statistically significant across the region. The majority of accumulation mode aerosols, and therefore cloud condensation nuclei, were from ubiquitous biomass burning smoke transported from the southern hemisphere. Consequently, all clouds measured (inland and offshore) had significantly higher CDNC and lower effective radius than clouds over the remote south Atlantic from literature. A parcel model sensitivity analysis showed that doubling or halving local emissions only changed the calculated CDNC by 13–22 %, as the high background meant local emissions were a small fraction of total aerosol. As the population of SWA grows, local emissions are expected to rise. Biomass burning smoke transported from the southern hemisphere is likely to dampen any effect of these increased local emissions on cloud-aerosol interactions. An integrative analysis between local pollution and Central African biomass burning emissions must be considered when predicting anthropogenic impacts on the regional cloud field during the West African monsoon

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24 months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30 minutes spent performing activities ≥500 counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24 months), both the number of steps per day (per 500 steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500 counts per minute (per 30 minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score >10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

A deep learning approach to photo–identification demonstrates high performance on two dozen cetacean species

We thank the countless individuals who collected and/or processed the nearly 85,000 images used in this study and those who assisted, particularly those who sorted these images from the millions that did not end up in the catalogues. Additionally, we thank the other Kaggle competitors who helped develop the ideas, models and data used here, particularly those who released their datasets to the public. The graduate assistantship for Philip T. Patton was funded by the NOAA Fisheries QUEST Fellowship. This paper represents HIMB and SOEST contribution numbers 1932 and 11679, respectively. The technical support and advanced computing resources from University of Hawaii Information Technology Services—Cyberinfrastructure, funded in part by the National Science Foundation CC* awards # 2201428 and # 2232862 are gratefully acknowledged. Every photo–identification image was collected under permits according to relevant national guidelines, regulation and legislation.Peer reviewedPublisher PD

Differential Impact of Tetratricopeptide Repeat Proteins on the Steroid Hormone Receptors

Tetratricopeptide repeat (TPR) motif containing co-chaperones of the chaperone Hsp90 are considered control modules that govern activity and specificity of this central folding platform. Steroid receptors are paradigm clients of Hsp90. The influence of some TPR proteins on selected receptors has been described, but a comprehensive analysis of the effects of TPR proteins on all steroid receptors has not been accomplished yet.We compared the influence of the TPR proteins FK506 binding proteins 51 and 52, protein phosphatase-5, C-terminus of Hsp70 interacting protein, cyclophillin 40, hepatitis-virus-B X-associated protein-2, and tetratricopeptide repeat protein-2 on all six steroid hormone receptors in a homogeneous mammalian cell system. To be able to assess each cofactor's effect on the transcriptional activity of on each steroid receptor we employed transient transfection in a reporter gene assay. In addition, we evaluated the interactions of the TPR proteins with the receptors and components of the Hsp90 chaperone heterocomplex by coimmunoprecipitation. In the functional assays, corticosteroid and progesterone receptors displayed the most sensitive and distinct reaction to the TPR proteins. Androgen receptor's activity was moderately impaired by most cofactors, whereas the Estrogen receptors' activity was impaired by most cofactors only to a minor degree. Second, interaction studies revealed that the strongly receptor-interacting co-chaperones were all among the inhibitory proteins. Intriguingly, the TPR-proteins also differentially co-precipitated the heterochaperone complex components Hsp90, Hsp70, and p23, pointing to differences in their modes of action.The results of this comprehensive study provide important insight into chaperoning of diverse client proteins via the combinatorial action of (co)-chaperones. The differential effects of the TPR proteins on steroid receptors bear on all physiological processes related to steroid hormone activity

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

International Society of Sports Nutrition Position Stand: Probiotics.

Position statement: The International Society of Sports Nutrition (ISSN) provides an objective and critical review of the mechanisms and use of probiotic supplementation to optimize the health, performance, and recovery of athletes. Based on the current available literature, the conclusions of the ISSN are as follows: 1)Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (FAO/WHO).2)Probiotic administration has been linked to a multitude of health benefits, with gut and immune health being the most researched applications.3)Despite the existence of shared, core mechanisms for probiotic function, health benefits of probiotics are strain- and dose-dependent.4)Athletes have varying gut microbiota compositions that appear to reflect the activity level of the host in comparison to sedentary people, with the differences linked primarily to the volume of exercise and amount of protein consumption. Whether differences in gut microbiota composition affect probiotic efficacy is unknown.5)The main function of the gut is to digest food and absorb nutrients. In athletic populations, certain probiotics strains can increase absorption of key nutrients such as amino acids from protein, and affect the pharmacology and physiological properties of multiple food components.6)Immune depression in athletes worsens with excessive training load, psychological stress, disturbed sleep, and environmental extremes, all of which can contribute to an increased risk of respiratory tract infections. In certain situations, including exposure to crowds, foreign travel and poor hygiene at home, and training or competition venues, athletes' exposure to pathogens may be elevated leading to increased rates of infections. Approximately 70% of the immune system is located in the gut and probiotic supplementation has been shown to promote a healthy immune response. In an athletic population, specific probiotic strains can reduce the number of episodes, severity and duration of upper respiratory tract infections.7)Intense, prolonged exercise, especially in the heat, has been shown to increase gut permeability which potentially can result in systemic toxemia. Specific probiotic strains can improve the integrity of the gut-barrier function in athletes.8)Administration of selected anti-inflammatory probiotic strains have been linked to improved recovery from muscle-damaging exercise.9)The minimal effective dose and method of administration (potency per serving, single vs. split dose, delivery form) of a specific probiotic strain depends on validation studies for this particular strain. Products that contain probiotics must include the genus, species, and strain of each live microorganism on its label as well as the total estimated quantity of each probiotic strain at the end of the product's shelf life, as measured by colony forming units (CFU) or live cells.10)Preclinical and early human research has shown potential probiotic benefits relevant to an athletic population that include improved body composition and lean body mass, normalizing age-related declines in testosterone levels, reductions in cortisol levels indicating improved responses to a physical or mental stressor, reduction of exercise-induced lactate, and increased neurotransmitter synthesis, cognition and mood. However, these potential benefits require validation in more rigorous human studies and in an athletic population