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α-Chiral alkyne is a key structural element of many bioactive compounds, chemical probes, and functional materials, and is a valuable synthon in organic synthesis. Here we report a NiH-catalysed reductive migratory hydroalkynylation of olefins with bromoalkynes that delivers the corresponding benzylic alkynylation products in high yields with excellent regioselectivities. Catalytic enantioselective hydroalkynylation of styrenes has also been realized using a simple chiral PyrOx ligand. The obtained enantioenriched benzylic alkynes are versatile synthetic intermediates and can be readily transformed into synthetically useful chiral synthons. Chiral alkyne motifs bearing an α stereocentre are often found in many bioactive compounds, chemical probes, and functional materials. Here the authors show NiH-catalysed reductive migratory hydroalkynylation of olefins with bromoalkynes that form benzylic alkynylation products in high yield and with excellent regioselectivity.

A bstract The study of the interior of hairy black holes has received significant attention recently. This paper builds upon our recent analytical approach to investigate the internal dynamics of charged black holes with scalar hair in general spacetime dimensions. The geometries of these hairy balck holes end at a spacelike singularity. We investigate the alternation of Kasner epoch at later interior times and obtain the analytic expression for two kinds of transformation, namely Kasner inversion and Kasner transition. Moreover, we classify three different types of Kasner alternations for a large class of Einstein-Maxwell-scalar theory. Our analytical results are corroborated by numerical solutions to the full equations of motion, including a top-down model from supergravity. For general interactions, more complicated behaviors beyond our analytical description are also found and discussed, including the presence of non-Kasner epochs and the random change of the amplitude of the Kasner exponent at late interior times.

A bstract We investigate the internal dynamics of hairy black holes in the Einstein-Maxwell-vector theory. The development of the charged vector hair necessarily removes the inner Cauchy horizon and results in an anisotropic black hole ending at a spacelike singularity. The far interior evolution is characterized by the chaotic alternations among different Kasner epochs. We show that those late interior time dynamics of bounces and epochs can be captured analytically. In particular, we obtain three distinct types of transformation laws for the alternation of Kasner epochs analytically, including the Kasner inversion, Kasner transition, and Kasner reflection. Our analytical approach is corroborated by numerical solutions to the full equations of motion. Moreover, we provide a clear explanation of the alternation of Kasner epochs found numerically in the literature.

Background We aimed to evaluate the epidemiology of sepsis in secondary and tertiary hospitals in Beijing, China between 2012 and 2018 using information derived from the Beijing Public Health System. Methods The Beijing Public Health System accessed hospital homepage databases and identify patients who diagnosed sepsis or associated condition according to the International Classification of Diseases, 10th Edition, Clinical Modification codes. There are 125 hospitals involved in this study, including 61 secondary hospitals, accounting for 49.2%, and 63 tertiary hospitals, accounting for 50.8%. Patients were stratified by age as minors (0–17 years old), adults (18–64 years old), seniors (65–84 years old), and the elderly (≥ 85 years old). Patient’s demographic information, treatments, outcomes, and all-cause hospitalization cost were evaluated. Results This study involved 8,597 patients. Patients treated in tertiary hospitals or received blood transfusion decreased with age, while patients who were male, received ventilation, or took Traditional Chinese Medicine, and in-hospital mortality and hospitalization cost, increased with age. There were 2,729 (31.7%) deaths in this study. A slight increase in in-hospital mortality occurred from 2012 to 2018. Median hospitalization cost for all patients was ¥29,453 (15,011, 65,237). Hospitalization cost showed no significant change from 2012 to 2016, but increased in 2017 and 2018. Conclusion Sepsis is associated with high mortality and cost. From 2012 to 2018, in-hospital mortality and hospitalization cost of sepsis in Beijing increased significantly with age, and slightly by year.

Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis. This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing and models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein. studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was -6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1. CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.

Background As the most lethal gynecologic cancer, ovarian cancer (OV) holds the potential of being immunotherapy-responsive. However, only modest therapeutic effects have been achieved by immunotherapies such as immune checkpoint blockade. This study aims to propose a generalized stroma-immune prognostic signature (SIPS) to identify OV patients who may benefit from immunotherapy. Methods The 2097 OV patients included in the study were significant with high-grade serous ovarian cancer in the III/IV stage. The 470 immune-related signatures were collected and analyzed by the Cox regression and Lasso algorithm to generalize a credible SIPS. Correlations between the SIPS signature and tumor microenvironment were further analyzed. The critical immunosuppressive role of stroma indicated by the SIPS was further validated by targeting the major suppressive stroma component (CAFs, Cancer-associated fibroblasts) in vitro and in vivo. With four machine-learning methods predicting tumor immune subtypes, the stroma-immune signature was upgraded to a 23-gene signature. Results The SIPS effectively discriminated the high-risk individuals in the training and validating cohorts, where the high SIPS succeeded in predicting worse survival in several immunotherapy cohorts. The SIPS signature was positively correlated with stroma components, especially CAFs and immunosuppressive cells in the tumor microenvironment, indicating the critical suppressive stroma-immune network. The combination of CAFs’ marker PDGFRB inhibitors and frontline PARP inhibitors substantially inhibited tumor growth and promoted the survival of OV-bearing mice. The stroma-immune signature was upgraded to a 23-gene signature to improve clinical utility. Several drug types that suppress stroma-immune signatures, such as EGFR inhibitors, could be candidates for potential immunotherapeutic combinations in ovarian cancer. Conclusions The stroma-immune signature could efficiently predict the immunotherapeutic sensitivity of OV patients. Immunotherapy and auxiliary drugs targeting stroma could enhance immunotherapeutic efficacy in ovarian cancer.

With the publication of Sepsis-3 definition, epidemiological data based on Sepsis-3 definition from middle-income countries including China are scarce, which prohibits understanding of the disease burden of this newly defined syndrome in these settings. The purpose of this study was to describe incidence and outcome of Sepsis-3 in Yuetan sub-district of Beijing and to estimate the incidence rate of Sepsis-3 in China. The medical records of all adult residents hospitalized from July 1, 2012 to June 30, 2014 in Yuetan sub-district of Beijing were reviewed. Patients with sepsis-3 and severe sepsis/septic shock were identified. The incidence rates and mortality rate of sepsis-3 and sepsis/septic shock were calculated, incidence rates and in-hospital mortality rates were normalized to the population distribution in the 2010 National Census. Population incidence rate and case fatality rate between sexes were compared with the Z test, as the data conformed to Poisson distribution. Of the 21,191 hospitalized patients, 935 patients were diagnosed with Sepsis-3, and 498 cases met severe sepsis/septic shock criteria. The crude annual incidence rate of Sepsis-3 in Yuetan sub-district was 363 cases per 100,000 population, corresponding to standardized incidence rates of 236 cases per 100,000 population per year, respectively. The overall case fatality rate of Sepsis-3 was 32.0%, the crude population mortality rates of Sepsis-3 was 116 cases per 100,000 population per year, the standardized mortality rate was 67 cases per 100,000 population per year, corresponding to a speculative extrapolation of 700,437 deaths in China. The incidence rate and mortality rate of Sepsis-3 were significantly higher in males, elderly people, and patients with more comorbidities. The 62.1% of patients with Sepsis-3 had community-acquired infections, compared with 75.3% of infected patients without Sepsis-3 (P < 0.001). The most common infection in patients with Sepsis-3 was lower respiratory tract infection. When compared with patients with Sepsis-3, patients diagnosed as severe sepsis/septic shock were more likely to have higher case fatality rate (53.4% vs. 32.0%, P < 0.001) CONCLUSIONS:: This study found the standardized incidence rate of 236 cases per 100,000 person-year for Sepsis-3, which was more common in males and elderly population. This corresponded to about 2.5 million new cases of Sepsis-3 per year, resulting in more than 700,000 deaths in China. NCT02285257, https://clinicaltrials.gov/ct2/show/record/NCT02285257.

Chiral α-aminoboronic acids and their derivatives are generally useful as bioactive compounds and some have been approved as therapeutic agents. Here we report a NiH-catalysed asymmetric hydroamidation process that with a simple amino alcohol ligand can easily produce a wide range of highly enantioenriched α-aminoboronates from alkenyl boronates and dioxazolones under mild conditions. The reaction is proposed to proceed by an enantioselective hydrometallation followed by an inner-sphere nitrenoid transfer and C–N bond forming sequence. The synthetic utility of this transformation was demonstrated by the efficient synthesis of a current pharmaceutical agent, Vaborbactam. Enantioenriched α-aminoboronic acid, a structural unit in many bioactive molecules, is also a valuable synthon in organic synthesis. Here, the authors disclose a NiH-catalysed asymmetric hydroamidation process for their direct synthesis.

The separation of Al from the silicon-rich diasporic bauxite is of great significance in alumina production. Herein, we proposed a low-temperature ammonium sulfate roasting-water leaching process to extract aluminum from silicon-rich diasporic bauxite. Parameters including roasting temperature, dosage of ammonium sulfate, roasting time, and particle size of ore were investigated. Under the condition of roasting temperature of 400 °C, roasting time of 5 h, ammonium sulfate dosage of 2.5 times of the theoretical value and ore particle size of 80–96 µm, more than 98% leaching rate of aluminum was obtained. The phase transformation and mechanism during the roasting process were revealed by using X-ray diffraction, thermogravimetric analysis, differential thermal analysis, and scanning electron microscope methods. The diaspore and kaolinite phases in the silicon-rich diasporic bauxite could react with ammonium sulfate to form corresponding sulfates (NH4)3Al(SO4)3, NH4Al(SO4)2 and Al2(SO4)3. The proposed technology could provide an effective method for the direct and separation of aluminum from silicon-rich diasporic bauxite.

Uric acid (UA) is a risk factor for endothelial dysfunction, a process in which inflammation may play an important role. UA increases high mobility group box chromosomal protein 1 (HMGB1) expression and extracellular release in endothelial cells. HMGB1 is an inflammatory cytokine that interacts with the receptor for advanced glycation end products (RAGE), inducing an oxidative stress and inflammatory response, which leads to endothelial dysfunction. In this study, human umbilical vein endothelial cells (HUVECs) were incubated with a high concentration of UA (20 mg/dL) after which endothelial function and the expression of HMGB1, RAGE, nuclear factor kappa B (NF-κB), inflammatory cytokines, and adhesion molecules were evaluated. UA inhibited endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) production in HUVECs, increased intracellular HMGB1 expression and extracellular HMGB1 secretion, and upregulated RAGE expression. UA also activated NF-κB and increased the level of inflammatory cytokines. Blocking RAGE significantly suppressed the upregulation of RAGE and HMGB1 and prevented the increase in DNA binding activity of NF-κB and the levels of inflammatory cytokines. It also blocked the decrease in eNOS expression and NO production induced by UA. Our results suggest that high concentrations of UA cause endothelial dysfunction via the HMGB1/RAGE signaling pathway.