The formidable challenges of controlling site-selectivity, enantioselectivity, and product chemoselectivity make asymmetric C–H oxidation a generally unsolved problem for nonenzymatic systems. ...Discrimination between the two enantiotopic C–H bonds of an unactivated methylenic group is particularly demanding and so far unprecedented, given the similarity between their environments and the facile overoxidation of the initially formed hydroxylation product. Here we show that a Mn-catalyzed C–H oxidation directed by carboxylic acids can overcome these challenges to yield γ-lactones in high enantiomeric excess (up to 99%) using hydrogen peroxide as oxidant and a Brønsted acid additive under mild conditions and short reaction times. Coordination of the carboxylic acid group to the bulky Mn complex ensures the rigidity needed for high enantioselectivity and dictates the outstanding γ site-selectivity. When the substrate contains nonequivalent γ-methylenes, the site-selectivity for lactonization can be rationally predicted on the basis of simple C–H activation/deactivation effects exerted by proximal substituents. In addition, discrimination of diastereotopic C–H bonds can be modulated by catalyst design, with no erosion of enantiomeric excess. The potential of this reaction is illustrated in the concise synthesis of a tetrahydroxylated bicyclo3.3.1nonane enabled by two key, sequential γ-C–H lactonizations, with the latter that fixes the chirality of five stereogenic centers in one step with 96% ee.
This paper presents an algorithm based on mathematical morphology and curvature evaluation for the detection of vessel-like patterns in a noisy environment. Such patterns are very common in medical ...images. Vessel detection is interesting for the computation of parameters related to blood flow. Its tree-like geometry makes it a usable feature for registration between images that can be of a different nature. In order to define vessel-like patterns, segmentation is performed with respect to a precise model. We define a vessel as a bright pattern, piece-wise connected, and locally linear, mathematical morphology is very well adapted to this description, however other patterns fit such a morphological description. In order to differentiate vessels from analogous background patterns, a cross-curvature evaluation is performed. They are separated out as they have a specific Gaussian-like profile whose curvature varies smoothly along the vessel. The detection algorithm that derives directly from this modeling is based on four steps: (1) noise reduction; (2) linear pattern with Gaussian-like profile improvement; (3) cross-curvature evaluation; (4) linear filtering. We present its theoretical background and illustrate it on real images of various natures, then evaluate its robustness and its accuracy with respect to noise.
A variety of machine learning methods such as naive Bayesian, support vector machines and more recently deep neural networks are demonstrating their utility for drug discovery and development. These ...leverage the generally bigger datasets created from high-throughput screening data and allow prediction of bioactivities for targets and molecular properties with increased levels of accuracy. We have only just begun to exploit the potential of these techniques but they may already be fundamentally changing the research process for identifying new molecules and/or repurposing old drugs. The integrated application of such machine learning models for end-to-end (E2E) application is broadly relevant and has considerable implications for developing future therapies and their targeting.
Group 2 innate lymphoid cells (ILC2s; also called nuocytes, innate helper cells, or natural helper cells) provide protective immunity during helminth infection and play an important role in ...influenza-induced and allergic airway hyperreactivity. Whereas the transcription factor GATA binding protein 3 (Gata3) is important for the production of IL-5 and -13 by ILC2s in response to IL-33 or -25 stimulation, it is not known whether Gata3 is required for ILC2 development from hematopoietic stem cells. Here, we show that chimeric mice generated with Gata3 -deficient fetal liver hematopoietic stem cells fail to develop systemically dispersed ILC2s. In these chimeric mice, in vivo administration of IL-33 or -25 fails to expand ILC2 numbers or to induce characteristic ILC2-dependent IL-5 or -13 production. Moreover, cell-intrinsic Gata3 expression is required for ILC2 development in vitro and in vivo. Using mutant and transgenic mice in which Gata3 gene copy number is altered, we show that ILC2 generation from common lymphoid progenitors, as well as ILC2 homeostasis and cytokine production, is regulated by Gata3 expression levels in a dose-dependent fashion. Collectively, these results identify Gata3 as a critical early regulator of ILC2 development, thereby extending the paradigm of Gata3 -dependent control of type 2 immunity to include both innate and adaptive lymphocytes.
Coronary calcification hinders stent delivery and expansion and is associated with adverse outcomes. Intravascular lithotripsy (IVL) delivers acoustic pressure waves to modify calcium, enhancing ...vessel compliance and optimizing stent deployment.
The purpose of this study was to assess the safety and effectiveness of IVL in severely calcified de novo coronary lesions.
Disrupt CAD III (NCT03595176) was a prospective, single-arm multicenter study designed for regulatory approval of coronary IVL. The primary safety endpoint was freedom from major adverse cardiovascular events (cardiac death, myocardial infarction, or target vessel revascularization) at 30 days. The primary effectiveness endpoint was procedural success. Both endpoints were compared with a pre-specified performance goal (PG). The mechanism of calcium modification was assessed in an optical coherence tomography (OCT) substudy.
Patients (n = 431) were enrolled at 47 sites in 4 countries. The primary safety endpoint of the 30-day freedom from major adverse cardiovascular events was 92.2%; the lower bound of the 95% confidence interval was 89.9%, which exceeded the PG of 84.4% (p < 0.0001). The primary effectiveness endpoint of procedural success was 92.4%; the lower bound of the 95% confidence interval was 90.2%, which exceeded the PG of 83.4% (p < 0.0001). Mean calcified segment length was 47.9 ± 18.8 mm, calcium angle was 292.5 ± 76.5°, and calcium thickness was 0.96 ± 0.25 mm at the site of maximum calcification. OCT demonstrated multiplane and longitudinal calcium fractures after IVL in 67.4% of lesions. Minimum stent area was 6.5 ± 2.1 mm2 and was similar regardless of demonstrable fractures on OCT.
Coronary IVL safely and effectively facilitated stent implantation in severely calcified lesions.
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Conservation outcomes are principally achieved through the protection of intact habitat or the restoration of degraded habitat. Restoration is generally considered a lower priority action than ...protection because protection is thought to provide superior outcomes, at lower costs, without the time delay required for restoration. Yet while it is broadly accepted that protected intact habitat safeguards more biodiversity and generates greater ecosystem services per unit area than restored habitat, conservation lacks a theory that can coherently compare the relative outcomes of the two actions. We use a dynamic landscape model to integrate these two actions into a unified conservation theory of protection and restoration. Using nonlinear benefit functions, we show that both actions are crucial components of a conservation strategy that seeks to optimise either biodiversity conservation or ecosystem services provision. In contrast to conservation orthodoxy, in some circumstances, restoration should be strongly preferred to protection. The relative priority of protection and restoration depends on their costs and also on the different time lags that are inherent to both protection and restoration. We derive a simple and easy-to-interpret heuristic that integrates these factors into a single equation that applies equally to biodiversity conservation and ecosystem service objectives. We use two examples to illustrate the theory: bird conservation in tropical rainforests and coastal defence provided by mangrove forests.
Abstract
Quantum light sources in solid-state systems are of major interest as a basic ingredient for integrated quantum photonic technologies. The ability to tailor quantum emitters via ...site-selective defect engineering is essential for realizing scalable architectures. However, a major difficulty is that defects need to be controllably positioned within the material. Here, we overcome this challenge by controllably irradiating monolayer MoS
2
using a sub-nm focused helium ion beam to deterministically create defects. Subsequent encapsulation of the ion exposed MoS
2
flake with high-quality hBN reveals spectrally narrow emission lines that produce photons in the visible spectral range. Based on ab-initio calculations we interpret these emission lines as stemming from the recombination of highly localized electron–hole complexes at defect states generated by the local helium ion exposure. Our approach to deterministically write optically active defect states in a single transition metal dichalcogenide layer provides a platform for realizing exotic many-body systems, including coupled single-photon sources and interacting exciton lattices that may allow the exploration of Hubbard physics.
Purpose
The EUPHRATES trial examined the impact of polymyxin B hemoperfusion (PMX) on mortality in patients with septic shock and endotoxemia, defined as EAA ≥ 0.60. No difference was found in 28-day ...all-cause mortality. However, the trial showed that in some patients with septic shock the burden of endotoxin activity was extreme (EAA ≥ 0.9). In a post hoc analysis, we evaluated the impact of PMX use in patients with septic shock and endotoxin activity measured between 0.6–0.89.
Methods
Post-hoc analysis of the EUPHRATES trial for the 194 patients with EAA ≥ 0.6–0.89 who completed two treatments (PMX or sham). The primary end point was mortality at 28 days adjusted for APACHE II score and baseline mean arterial pressure (MAP). Additional end points included changes in MAP, cumulative vasopressor index (CVI), median EAA reduction, ventilator-free days (VFD), dialysis-free days (DFD) and hospital length of stay. Subpopulations analyzed were site and type of infection and those with norepinephrine dose > 0.1 mcg/kg/min at baseline.
Results
At 28 days, 23 patients of 88 (26.1%) in the PMX group died versus 39 of 106 (36.8%) in the sham group risk difference 10.7%, OR 0.52, 95% CI (0.27, 0.99),
P
= 0.047. When unadjusted for baseline variables,
P
= 0.11. The 28-day survival time in the PMX group was longer than for the sham group HR 0.56 (95% CI 0.33, 0.95)
P
= 0.03. PMX treatment compared with sham showed greater change in MAP median (IQR) 8 mmHg (− 0.5, 19.5) vs. 4 mmHg (− 4.0, 11)
P
= 0.04 and VFD median (IQR) 20 days (0.5, 23.5) vs. 6 days (0, 20),
P
= 0.004. There were no significant differences in other end points. There was a significant difference in mortality in PMX-treated patients with no bacterial growth on culture PMX, 6/30 (20%) vs. sham, 13/31 (41.9%),
P
= 0.005. The median EAA change in the population was − 12.9% (range: increase 49.2%–reduction 86.3%). The mortality in the above median EAA change group was PMX: 6/38 (15.7%) vs. sham 15/49 (30.6%),
P
= 0.08.
Conclusions
These hypothesis-generating results, based on an exploratory post hoc analysis of the EUPHRATES trial, suggest measurable responses in patients with septic shock and an EAA ≥ 0.6 to 0.89 on changes in mean arterial pressure, ventilator-free days and mortality.
Trial registration
Clinicaltrials.gov Identifier: NCT01046669. Funding Spectral Medical Incorporated.
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