Capturing sequence diversity in metagenomes with comprehensive and scalable probe design.

Metagenomic sequencing has the potential to transform microbial detection and characterization, but new tools are needed to improve its sensitivity. Here we present CATCH, a computational method to enhance nucleic acid capture for enrichment of diverse microbial taxa. CATCH designs optimal probe sets, with a specified number of oligonucleotides, that achieve full coverage of, and scale well with, known sequence diversity. We focus on applying CATCH to capture viral genomes in complex metagenomic samples. We design, synthesize, and validate multiple probe sets, including one that targets the whole genomes of the 356 viral species known to infect humans. Capture with these probe sets enriches unique viral content on average 18-fold, allowing us to assemble genomes that could not be recovered without enrichment, and accurately preserves within-sample diversity. We also use these probe sets to recover genomes from the 2018 Lassa fever outbreak in Nigeria and to improve detection of uncharacterized viral infections in human and mosquito samples. The results demonstrate that CATCH enables more sensitive and cost-effective metagenomic sequencing

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The Use of Doublecortin to Quantify the Effects of Pharmacological Treatment on Neurogenesis and Functional Recovery after Stroke

Ischemic strokes account for 87% of all strokes and can have debilitating effects on language, sensory, and motor skills. Currently, tPA is the only medication approved by the FDA for the treatment of ischemic stroke, but the window of time to administer the drug is very small. In this thesis, we investigate the use of a simvastatin and fluoxetine drug combination (FS) as a possible treatment for ischemic stroke victims. To analyze the effects of FS on neurogenesis and functional recovery, we utilize the Montoya Staircase and quantify the amount of neurogenesis using doublecortin. Although the results of this study show that the drug treatment did not produce the significant increase in neurogenesis when comparing the control with the drug-treated animals as we had hoped for, nor did it translate to an increase in functional recovery, there was significantly more neurogenesis in the right hemisphere in the anterior and middle region of the subventricular zone (SVZ) of the FS rats than the left. This tells us that the drug treatment did produce a significant amount of neurogenesis in the SVZ, but further work need to be done to better understand how the FS drug treatment affects neurogenesis and functional recovery. There may be an optimal window of time and dosage that will lead to a greater significance in recovery and higher levels of neurogenesis. This could open the door for a better treatment option to increase the quality of life for ischemic stroke patients

Presentazione del documento

The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands centered at: 27, 39, 93, 145, 225 and 280 GHz. The initial configuration of SO will have three small-aperture 0.5-m telescopes and one large-aperture 6-m telescope, with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The small aperture telescopes will target the largest angular scales observable from Chile, mapping ≈ 10% of the sky to a white noise level of 2 μK-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, r, at a target level of σ(r)=0.003. The large aperture telescope will map ≈ 40% of the sky at arcminute angular resolution to an expected white noise level of 6 μK-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the Large Synoptic Survey Telescope sky region and partially with the Dark Energy Spectroscopic Instrument. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensor-to-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources

The Simons Observatory: Astro2020 Decadal Project Whitepaper

International audienceThe Simons Observatory (SO) is a ground-based cosmic microwave background (CMB) experiment sited on Cerro Toco in the Atacama Desert in Chile that promises to provide breakthrough discoveries in fundamental physics, cosmology, and astrophysics. Supported by the Simons Foundation, the Heising-Simons Foundation, and with contributions from collaborating institutions, SO will see first light in 2021 and start a five year survey in 2022. SO has 287 collaborators from 12 countries and 53 institutions, including 85 students and 90 postdocs. The SO experiment in its currently funded form ('SO-Nominal') consists of three 0.4 m Small Aperture Telescopes (SATs) and one 6 m Large Aperture Telescope (LAT). Optimized for minimizing systematic errors in polarization measurements at large angular scales, the SATs will perform a deep, degree-scale survey of 10% of the sky to search for the signature of primordial gravitational waves. The LAT will survey 40% of the sky with arc-minute resolution. These observations will measure (or limit) the sum of neutrino masses, search for light relics, measure the early behavior of Dark Energy, and refine our understanding of the intergalactic medium, clusters and the role of feedback in galaxy formation. With up to ten times the sensitivity and five times the angular resolution of the Planck satellite, and roughly an order of magnitude increase in mapping speed over currently operating ("Stage 3") experiments, SO will measure the CMB temperature and polarization fluctuations to exquisite precision in six frequency bands from 27 to 280 GHz. SO will rapidly advance CMB science while informing the design of future observatories such as CMB-S4

The Simons Observatory: Astro2020 Decadal Project Whitepaper

International audienceThe Simons Observatory (SO) is a ground-based cosmic microwave background (CMB) experiment sited on Cerro Toco in the Atacama Desert in Chile that promises to provide breakthrough discoveries in fundamental physics, cosmology, and astrophysics. Supported by the Simons Foundation, the Heising-Simons Foundation, and with contributions from collaborating institutions, SO will see first light in 2021 and start a five year survey in 2022. SO has 287 collaborators from 12 countries and 53 institutions, including 85 students and 90 postdocs. The SO experiment in its currently funded form ('SO-Nominal') consists of three 0.4 m Small Aperture Telescopes (SATs) and one 6 m Large Aperture Telescope (LAT). Optimized for minimizing systematic errors in polarization measurements at large angular scales, the SATs will perform a deep, degree-scale survey of 10% of the sky to search for the signature of primordial gravitational waves. The LAT will survey 40% of the sky with arc-minute resolution. These observations will measure (or limit) the sum of neutrino masses, search for light relics, measure the early behavior of Dark Energy, and refine our understanding of the intergalactic medium, clusters and the role of feedback in galaxy formation. With up to ten times the sensitivity and five times the angular resolution of the Planck satellite, and roughly an order of magnitude increase in mapping speed over currently operating ("Stage 3") experiments, SO will measure the CMB temperature and polarization fluctuations to exquisite precision in six frequency bands from 27 to 280 GHz. SO will rapidly advance CMB science while informing the design of future observatories such as CMB-S4