Organofluorine compounds are widely used in pharmaceutical, agrochemical, and materials sciences. The syntheses and applications of fluorinated organoborons facilitate the rapid and modular ...assemblies of fluorine‐containing molecules because of the versatility of C−B bonds in diverse chemical transformations. Reported herein is a migratory geminal difluorination of aryl‐substituted alkenyl N‐methyliminodiacetyl (MIDA) boronates using commercially available Py⋅HF as the fluorine source and hyperiodine as the oxidant. The protocol offers facile access to α‐ and β‐difluorinated alkylboron compounds, both of which have previously been challenging to prepare. Mild reaction conditions, broad substrate scope, good functional‐group tolerance, and moderate to good yields were observed. The utility of these products is demonstrated by further transformations of the C−B bond into other valuable functional groups.
On the move: A migratory geminal difluorination of aryl‐substituted alkenyl N‐methyliminodiacetyl (MIDA) boronates using commercially available Py⋅HF as the fluorine source is reported. The protocol offers an unprecedented opportunity for the synthesis of α‐ and β‐difluorinated alkylboron compounds. Mild reaction conditions, broad substrate scope, good functional‐group tolerance, and moderate to good yields were observed.
Exhaustion of cytotoxic effector natural killer (NK) and CD8
T cells have important functions in the establishment of persistent viral infections, but how exhaustion is induced during chronic ...hepatitis C virus (HCV) infection remains poorly defined. Here we show, using the humanized C/O
mice permissive for persistent HCV infection, that NK and CD8
T cells become sequentially exhausted shortly after their transient hepatic infiltration and activation in acute HCV infection. HCV infection upregulates Qa-1 expression in hepatocytes, which ligates NKG2A to induce NK cell exhaustion. Antibodies targeting NKG2A or Qa-1 prevents NK exhaustion and promotes NK-dependent HCV clearance. Moreover, reactivated NK cells provide sufficient IFN-γ that helps rejuvenate polyclonal HCV CD8
T cell response and clearance of HCV. Our data thus show that NKG2A serves as a critical checkpoint for HCV-induced NK exhaustion, and that NKG2A blockade sequentially boosts interdependent NK and CD8
T cell functions to prevent persistent HCV infection.
ℓ1‐penalized quantile regression (QR) is widely used for analysing high‐dimensional data with heterogeneity. It is now recognized that the ℓ1‐penalty introduces non‐negligible estimation bias, while ...a proper use of concave regularization may lead to estimators with refined convergence rates and oracle properties as the signal strengthens. Although folded concave penalized M‐estimation with strongly convex loss functions have been well studied, the extant literature on QR is relatively silent. The main difficulty is that the quantile loss is piecewise linear: it is non‐smooth and has curvature concentrated at a single point. To overcome the lack of smoothness and strong convexity, we propose and study a convolution‐type smoothed QR with iteratively reweighted ℓ1‐regularization. The resulting smoothed empirical loss is twice continuously differentiable and (provably) locally strongly convex with high probability. We show that the iteratively reweighted ℓ1‐penalized smoothed QR estimator, after a few iterations, achieves the optimal rate of convergence, and moreover, the oracle rate and the strong oracle property under an almost necessary and sufficient minimum signal strength condition. Extensive numerical studies corroborate our theoretical results.
Single molecular nanoparticles (SMNPs) integrating imaging and therapeutic capabilities exhibit unparalleled advantages in cancer theranostics, ranging from excellent biocompatibility, high ...stability, prolonged blood lifetime to abundant tumor accumulation. Herein, we synthesize a sophisticated porphyrin nanocage that is further functionalized with twelve polyethylene glycol arms to prepare SMNPs (porSMNPs). The porphyrin nanocage embedded in porSMNPs can be utilized as a theranostic platform. PET imaging allows dynamic observation of the bio‐distribution of porSMNPs, confirming their excellent circulation time and preferential accumulation at the tumor site, which is attributed to the enhanced permeability and retention effect. Moreover, the cage structure significantly promotes the photosensitizing effect of porSMNs by inhibiting the π–π stacking interactions of the photosensitizers, ablating of the tumors without relapse by taking advantage of photodynamic therapy.
Sophisticated porphyrin nanocages, which can be utilized as a functional platform to develop single molecular nanoparticles, were synthesized. The unique topological structure of the nanocages results in their excellent performance as cancer nanotheranostics, as demonstrated through applications in PET imaging and photodynamic therapy.
A novel hepatocyte-targeting near-infrared fluorescent probe named Gal-NIR is developed. Gal-NIR shows ratiometric response to ONOO- with high sensitivity and selectivity. Moreover, the probe can ...accurately target the hepatocyte, and thus is used for assessing drug-induced hepatotoxicity and its remediation by using hepatoprotective medicines in living cells and mice.
The copper‐catalyzed stereoselective defluorinative borylation and silylation of gem‐difluoroalkenes was developed. The protocol led to the exclusive formation of Z type monofluoroalkenyl borons and ...silanes in generally good efficiency with broad substrate scope. The products formed could be readily transformed to other F‐containing molecules by taking advantage of the versatile reactivities of C−B and C−Si bonds. Experimental and theoretical mechanistic studies were conducted which support an olefin insertion/syn‐planar β‐F elimination pathway.
A carbene-catalyzed reductive coupling reaction of carboxylic esters and substituted Hantzsch esters is disclosed. Key steps of this reaction include one-electron reduction of a carbene ...catalyst-bound acyl azolium intermediate to generate the corresponding radical intermediate for subsequent alkylation reactions. The reaction is promoted by irradiation with visible light without the involvement of transition-metal photocatalysts. Mechanistic studies suggest that direct photoexcitation of the in situ formed acyl azolium intermediate is likely responsible for this light-induced one-electron-reduction process. Photoexcitation converts the acyl azolium intermediate to a single-electron oxidant, enabling single-electron oxidation of Hantzsch esters to generate radical intermediates. Our reactions work well for a broad range of aryl carboxylic ester and Hantzsch ester substrates. Sophisticated structures, including those present in medicines, can be incorporated into ketone molecules using our approach via very mild conditions that tolerate various functional groups.
A novel water-soluble near-infrared fluorescent probe named QX-P with simple synthesis is developed. QX-P has high sensitivity and selectivity to ALP. Moreover, the probe can not only visualize ALP ...activity in four cell lines, but also real-time image ALP activity during the diagnosis and treatment of diabetes in mice.
Drought is a major threat to plant growth and crop productivity. Calcium-dependent protein kinases (CDPKs, CPKs) are believed to play important roles in plant responses to drought stress. Here, we ...report that Arabidopsis thaliana CPK8 functions in abscisic acid (ABA)- and Ca2+-mediated plant responses to drought stress. The cpk8 mutant was more sensitive to drought stress than wild-type plants, while the transgenic plants overexpressing CPK8 showed enhanced tolerance to drought stress compared with wild-type plants. ABA-, H2O2-, and Ca2+-induced stomatal closing were impaired in cpk8 mutants. Arabidopsis CATALASE3 (CAT3) was identified as a CPK8-interacting protein, confirmed by yeast two-hybrid, coimmunoprecipitation, and bimolecular fluorescence complementation assays. CPK8 can phosphorylate CAT3 at Ser-261 and regulate its activity. Both cpk8 and cat3 plants showed lower catalase activity and higher accumulation of H2O2 compared with wild-type plants. The cat3 mutant displayed a similar drought stress-sensitive phenotype as cpk8 mutant. Moreover, ABA and Ca2+ inhibition of inward K+ currents were diminished in guard cells of cpk8 and cat3 mutants. Together, these results demonstrated that CPK8 functions in ABA-mediated stomatal regulation in responses to drought stress through regulation of CAT3 activity.
Comparing large covariance matrices has important applications in modern genomics, where scientists are often interested in understanding whether relationships (e.g., dependencies or co-regulations) ...among a large number of genes vary between different biological states. We propose a computationally fast procedure for testing the equality of two large covariance matrices when the dimensions of the covariance matrices are much larger than the sample sizes. A distinguishing feature of the new procedure is that it imposes no structural assumptions on the unknown covariance matrices. Hence, the test is robust with respect to various complex dependence structures that frequently arise in genomics. We prove that the proposed procedure is asymptotically valid under weak moment conditions. As an interesting application, we derive a new gene clustering algorithm which shares the same nice property of avoiding restrictive structural assumptions for high-dimensional genomics data. Using an asthma gene expression dataset, we illustrate how the new test helps compare the covariance matrices of the genes across different gene sets/pathways between the disease group and the control group, and how the gene clustering algorithm provides new insights on the way gene clustering patterns differ between the two groups. The proposed methods have been implemented in an R-package HDtest and are available on CRAN.
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