Rectal Microbiome Composition Correlates with Humoral Immunity to HIV-1 in Vaccinated Rhesus Macaques.

The microbiome is an integral and dynamic component of the host and is emerging as a critical determinant of immune responses; however, its influence on vaccine immunogenicity is largely not well understood. Here, we examined the pivotal relationship between the mucosal microbiome and vaccine-induced immune responses by assessing longitudinal changes in vaginal and rectal microbiome profiles after intradermal immunization with a human immunodeficiency virus type 1 (HIV-1) DNA vaccine in adult rhesus macaques that received two prior DNA primes. We report that both vaginal and rectal microbiomes were dominated by Firmicutes but were composed of distinct genera, denoting microbiome specialization across mucosal tissues. Following immunization, the vaginal microbiome was resilient, except for a transient decrease in Streptococcus In contrast, the rectal microbiome was far more responsive to vaccination, exhibiting an increase in the ratio of Firmicutes to Bacteroidetes Within Bacteroidetes, multiple genera were significantly decreased, including Prevotella, Alloprevotella, Bacteroides, Acetobacteroides, Falsiporphyromonas, and Anaerocella. Decreased abundance of Prevotella correlated with induction of gut-homing α4β7 + effector CD4 T cells. Prevotella abundance also negatively correlated with rectal HIV-1 specific IgG levels. While rectal Lactobacillus was unaltered following DNA vaccination, baseline Lactobacillus abundance showed strong associations with higher rectal HIV-1 gp140 IgA induced following a protein boost. Similarly, the abundance of Clostridium in cluster IV was associated with higher rectal HIV-1 gp140 IgG responses. Collectively, these data reveal that the temporal stability of bacterial communities following DNA immunization is site dependent and highlight the importance of host-microbiome interactions in shaping HIV-1 vaccine responses. Our findings have significant implications for microbial manipulation as a strategy to enhance HIV vaccine-induced mucosal immunity.IMPORTANCE There is considerable effort directed toward evaluating HIV-1 vaccine platforms to select the most promising candidates for enhancing mucosal HIV-1 antibody. The most successful thus far, the RV144 trial provided partial protection due to waning HIV-1 antibody titers. In order to develop an effective HIV vaccine, it may therefore be important to understand how biological factors, such as the microbiome, modulate host immune responses. Furthermore, as intestinal microbiota antigens may generate antibodies cross-reactive to the HIV-1 envelope glycoprotein, understanding the relationship between gut microbiota composition and HIV-1 envelope antibody responses after vaccination is important. Here, we demonstrate for the first time in rhesus macaques that the rectal microbiome composition can influence HIV-1 vaccine immunogenicity, and we report temporal changes in the mucosal microbiome profile following HIV-1 vaccination. Our results could inform findings from the HIV Vaccine Trials Network (HVTN) vaccine studies and contribute to an understanding of how the microbiome influences HIV-1 antibody responses

SMG-1 and mTORC1 Act Antagonistically to Regulate Response to Injury and Growth in Planarians

Planarian flatworms are able to both regenerate their whole bodies and continuously adapt their size to nutrient status. Tight control of stem cell proliferation and differentiation during these processes is the key feature of planarian biology. Here we show that the planarian homolog of the phosphoinositide 3-kinase-related kinase (PIKK) family member SMG-1 and mTOR complex 1 components are required for this tight control. Loss of smg-1 results in a hyper-responsiveness to injury and growth and the formation of regenerative blastemas that remain undifferentiated and that lead to lethal ectopic outgrowths. Invasive stem cell hyper-proliferation, hyperplasia, hypertrophy, and differentiation defects are hallmarks of this uncontrolled growth. These data imply a previously unappreciated and novel physiological function for this PIKK family member. In contrast we found that planarian members of the mTOR complex 1, tor and raptor, are required for the initial response to injury and blastema formation. Double smg-1 RNAi experiments with tor or raptor show that abnormal growth requires mTOR signalling. We also found that the macrolide rapamycin, a natural compound inhibitor of mTORC1, is able to increase the survival rate of smg-1 RNAi animals by decreasing cell proliferation. Our findings support a model where Smg-1 acts as a novel regulator of both the response to injury and growth control mechanisms. Our data suggest the possibility that this may be by suppressing mTOR signalling. Characterisation of both the planarian mTORC1 signalling components and another PIKK family member as key regulators of regeneration and growth will influence future work on regeneration, growth control, and the development of anti-cancer therapies that target mTOR signalling

The First Data Release of the Sloan Digital Sky Survey

The Sloan Digital Sky Survey has validated and made publicly available its First Data Release. This consists of 2099 square degrees of five-band (u, g, r, i, z) imaging data, 186,240 spectra of galaxies, quasars, stars and calibrating blank sky patches selected over 1360 square degrees of this area, and tables of measured parameters from these data. The imaging data go to a depth of r ~ 22.6 and are photometrically and astrometrically calibrated to 2% rms and 100 milli-arcsec rms per coordinate, respectively. The spectra cover the range 3800--9200 A, with a resolution of 1800--2100. Further characteristics of the data are described, as are the data products themselves.Comment: Submitted to The Astronomical Journal. 16 pages. For associated documentation, see http://www.sdss.org/dr

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

The Lincoln Near-Earth Asteroid

technology to detect, characterize, and catalog satellites for more than forty years. Recent advances in highly sensitive, large-format charge-coupled devices (CCDs) allow this technology to be applied to detecting and cataloging asteroids, including near-Earth objects (NEOs). When equipped with a new Lincoln Laboratory focal-plane camera and signal processing technology, the 1-m U.S. Air Force ground-based electro-optical deep-space surveillance (GEODSS) telescopes can conduct sensitive large-coverage searches for Earthcrossing and main-belt asteroids. Field measurements indicate that these enhanced telescopes can achieve a limiting magnitude of 22 over a 2-deg 2 field of view with less than 100 sec of integration. This sensitivity rivals that of much larger telescopes equipped with commercial cameras. Working two years under U.S. Air Force sponsorship, we have developed technology for asteroid search operations at the Lincoln Laboratory Experimental Test Site near Socorro, New Mexico. By using a new large-format 2560 × 1960-pixel frame-transfer CCD camera, we have discovered over 10,00

Rectal Microbiome Composition Correlates with Humoral Immunity to HIV-1 in Vaccinated Rhesus Macaques.

The microbiome is an integral and dynamic component of the host and is emerging as a critical determinant of immune responses; however, its influence on vaccine immunogenicity is largely not well understood. Here, we examined the pivotal relationship between the mucosal microbiome and vaccine-induced immune responses by assessing longitudinal changes in vaginal and rectal microbiome profiles after intradermal immunization with a human immunodeficiency virus type 1 (HIV-1) DNA vaccine in adult rhesus macaques that received two prior DNA primes. We report that both vaginal and rectal microbiomes were dominated by Firmicutes but were composed of distinct genera, denoting microbiome specialization across mucosal tissues. Following immunization, the vaginal microbiome was resilient, except for a transient decrease in Streptococcus In contrast, the rectal microbiome was far more responsive to vaccination, exhibiting an increase in the ratio of Firmicutes to Bacteroidetes Within Bacteroidetes, multiple genera were significantly decreased, including Prevotella, Alloprevotella, Bacteroides, Acetobacteroides, Falsiporphyromonas, and Anaerocella. Decreased abundance of Prevotella correlated with induction of gut-homing α4β7+ effector CD4 T cells. Prevotella abundance also negatively correlated with rectal HIV-1 specific IgG levels. While rectal Lactobacillus was unaltered following DNA vaccination, baseline Lactobacillus abundance showed strong associations with higher rectal HIV-1 gp140 IgA induced following a protein boost. Similarly, the abundance of Clostridium in cluster IV was associated with higher rectal HIV-1 gp140 IgG responses. Collectively, these data reveal that the temporal stability of bacterial communities following DNA immunization is site dependent and highlight the importance of host-microbiome interactions in shaping HIV-1 vaccine responses. Our findings have significant implications for microbial manipulation as a strategy to enhance HIV vaccine-induced mucosal immunity.IMPORTANCE There is considerable effort directed toward evaluating HIV-1 vaccine platforms to select the most promising candidates for enhancing mucosal HIV-1 antibody. The most successful thus far, the RV144 trial provided partial protection due to waning HIV-1 antibody titers. In order to develop an effective HIV vaccine, it may therefore be important to understand how biological factors, such as the microbiome, modulate host immune responses. Furthermore, as intestinal microbiota antigens may generate antibodies cross-reactive to the HIV-1 envelope glycoprotein, understanding the relationship between gut microbiota composition and HIV-1 envelope antibody responses after vaccination is important. Here, we demonstrate for the first time in rhesus macaques that the rectal microbiome composition can influence HIV-1 vaccine immunogenicity, and we report temporal changes in the mucosal microbiome profile following HIV-1 vaccination. Our results could inform findings from the HIV Vaccine Trials Network (HVTN) vaccine studies and contribute to an understanding of how the microbiome influences HIV-1 antibody responses

The Secreted Protease PrtA Controls Cell Growth, Biofilm Formation and Pathogenicity in Xylella fastidiosa.

Pierce's disease (PD) is a deadly disease of grapevines caused by the Gram-negative bacterium Xylella fastidiosa. Though disease symptoms were formerly attributed to bacteria blocking the plant xylem, this hypothesis is at best overly simplistic. Recently, we used a proteomic approach to characterize the secretome of X. fastidiosa, both in vitro and in planta, and identified LesA as one of the pathogenicity factors of X. fastidiosa in grapevines that leads to leaf scorching and chlorosis. Herein, we characterize another such factor encoded by PD0956, designated as an antivirulence secreted protease "PrtA" that displays a central role in controlling in vitro cell proliferation, length, motility, biofilm formation, and in planta virulence. The mutant in X. fastidiosa exhibited reduced cell length, hypermotility (and subsequent lack of biofilm formation) and hypervirulence in grapevines. These findings are supported by transcriptomic and proteomic analyses with corresponding plant infection data. Of particular interest, is the hypervirulent response in grapevines observed when X. fastidiosa is disrupted for production of PrtA, and that PD-model tobacco plants transformed to express PrtA exhibited decreased symptoms after infection by X. fastidiosa