Precise Synthesis of Diastereomers of Spiro-oxindole Derivatives through Dynamic Covalent Transformation.

In this study, [1+2+2] cyclization of tryptamine-derived isocyanides with 3-ylideneoxindoles was systematically investigated. A series of structurally complex spiro-oxindole derivatives were obtained. Characteristic dynamic covalent chemistry was observed and confirmed by experiments and density functional theory calculation. Through the regulation of the solvent, temperature, and time, the precise and stereodivergent synthesis of spiro-oxindoles was achieved.

The antihyperuricemia activity of Astragali Radix through regulating the expression of uric acid transporters via PI3K/Akt signalling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Astragali Radix (AR) is the dry root of the leguminous plants Astragalus membranaceus (Fisch) Beg. var. mongholicus (Beg) Hsiao, and Astragalus membranaceus (Fisch) Bge., being used as a medicinal and edible resource. AR is used in traditional Chinese medicine prescriptions to treat hyperuricemia, but this particular effect is rarely reported, and the associated mechanism of action is still need to be elucidated. AIM OF THE STUDY: To research the uric acid (UA)-lowering activity and mechanism of AR and the representative compounds through the constructed hyperuricemia mouse and cellular models. MATERIALS AND METHODS: In our study, the chemical profile of AR was analysed by UHPLC-QE-MS, as well as the mechanism of action of AR and the representative compounds on hyperuricemia was studied through the constructed hyperuricemia mouse and cellular models. RESULTS: The main compounds in AR were terpenoids, flavonoids and alkaloids. Mice group treated with the highest AR dosage showed significantly lower (p < 0.0001) serum uric acid (208 ± 9 µmol/L) than the control group (317 ± 11 µmol/L). Furthermore, UA increased in a dose-dependence manner in urine and faeces. Serum creatinine and blood urea nitrogen standards, as well as xanthine oxidase in mice liver, decreased (p < 0.05) in all cases, indicating that AR could relieve acute hyperuricemia. UA reabsorption protein (URAT1 and GLUT9) was down-regulated in AR administration groups, while the secretory protein (ABCG2) was up-regulated, indicating that AR could promote the excretion of UA by regulating UA transporters via PI3K/Akt signalling pathway. CONCLUSION: This study validated the activity, and revealed the mechanism of AR in reducing UA, which provided experimental and clinical basis for the treatment of hyperuricemia with it.

Sub-shot-noise-limited phase estimation via single-mode inputs.

In 1981, Caves pointed out that the phase sensitivity of a Mach-Zehnder interferometer with single-mode inputs is bounded by the shot-noise limit. The quantum Fisher information analysis shows that this statement holds true for the scenario where two antisymmetric phase shifts occur in two arms, but it is invalid for the scenario where an unknown phase is embedded in one of two arms. In this paper, we focus on the phase sensitivity directed against the latter scenario. The optimal single-mode input is discussed by analyzing common states, including displaced squeezed states, displaced number states, squeezed number states, Schrödinger cat states and completely mixed states. We find that the best choice is a squeezed vacuum state and show the specific measurement scheme which is capable of saturating the corresponding phase sensitivity limit. In addition, we study the effects of several realistic factors-anti-squeezing noise, photon loss and dark counts-on the phase sensitivity. Our results suggest that sub-shot-noise-limited phase sensitivity is attainable with low noise or loss, which paves the way for practical metrology.

Tumor-Associated Inflammation: The Tumor-Promoting Immunity in the Early Stages of Tumorigenesis.

Tumorigenesis is a multistage progressive oncogenic process caused by alterations in the structure and expression level of multiple genes. Normal cells are continuously endowed with new capabilities in this evolution, leading to subsequent tumor formation. Immune cells are the most important components of inflammation, which is closely associated with tumorigenesis. There is a broad consensus in cancer research that inflammation and immune response facilitate tumor progression, infiltration, and metastasis via different mechanisms; however, their protumor effects are equally important in tumorigenesis at earlier stages. Previous studies have demonstrated that during the early stages of tumorigenesis, certain immune cells can promote the formation and proliferation of premalignant cells by inducing DNA damage and repair inhibition, releasing trophic/supporting signals, promoting immune escape, and activating inflammasomes, as well as enhance the characteristics of cancer stem cells. In this review, we focus on the potential mechanisms by which immune cells can promote tumor initiation and promotion in the early stages of tumorigenesis; furthermore, we discuss the interaction of the inflammatory environment and protumor immune cells with premalignant cells and cancer stem cells, as well as the possibility of early intervention in tumor formation by targeting these cellular mechanisms.

A promising Prognostic risk model for advanced renal cell carcinoma (RCC) with immune-related genes.

BACKGROUND: Renal cell carcinoma (RCC) is a third most common tumor of the urinary system. Nowadays, Immunotherapy is a hot topic in the treatment of solid tumors, especially for those tumors with pre-activated immune state. METHODS: In this study, we downloaded genomic and clinical data of RCC samples from The Cancer Genome Atlas (TCGA) database. Four immune-related genetic signatures were used to predict the prognosis of RCC by Cox regression analysis. Then we established a prognostic risk model consisting of the genes most related to prognosis from four signatures to value prognosis of the RCC samples via Kaplan-Meier (KM) survival analysis. An independent data from International Cancer Genome Consortium (ICGC) database were used to test the predictive stability of the model. Furthermore, we performed landscape analysis to assess the difference of gene mutant in the RCC samples from TCGA. Finally, we explored the correlation between the selected genes and the level of tumor immune infiltration via Tumor Immune Estimation Resource (TIMER) platform. RESULTS: We used four genetic signatures to construct prognostic risk models respectively and found that each of the models could divide the RCC samples into high- and low-risk groups with significantly different prognosis, especially in advanced RCC. A comprehensive prognostic risk model was constructed by 8 candidate genes from four signatures (HLA-B, HLA-A, HLA-DRA, IDO1, TAGAP, CIITA, PRF1 and CD8B) dividing the advanced RCC samples from TCGA database into high-risk and low-risk groups with a significant difference in cancer-specific survival (CSS). The stability of the model was verified by independent data from ICGC database. And the classification efficiency of the model was stable for the samples from different subgroups. Landscape analysis showed that mutation ratios of some genes were different between two risk groups. In addition, the expression levels of the selected genes were significantly correlated with the infiltration degree of immune cells in the advanced RCC. CONCLUSIONS: Sum up, eight immune-related genes were screened in our study to construct prognostic risk model with great predictive value for the prognosis of advanced RCC, and the genes were associated with infiltrating immune cells in tumors which have potential to conduct personalized treatment for advanced RCC.

Syn-Stereoselective C3-Spirocyclization and C2-Amination of 3-(2-Isocyanoethyl)indole Using C,N-Cyclic Azomethine Imines.

By utilizing an underexplored reaction mode of C,N-cyclic azomethine imines, a catalyst-free [1+2+3] cycloaddition/N-N bond cleavage sequential reaction for accessing spiroindolines with syn-stereoselectivity was developed. On the basis of experimental results and DFT calculations, peroxide and ethereal solvent were identified to trigger the hydrogen abstraction of the unstable [1+2+3] cycloaddition adducts, followed by homolytic cleavage of the N-N bond and hydrogen absorption.

CERS6-AS1 promotes cell proliferation and represses cell apoptosis in pancreatic cancer via miR-195-5p/WIPI2 axis.

Pancreatic cancer (PC) is a lethal malignancy that threatens human health. Long noncoding RNAs (lncRNAs) act as important mediators in PC development. Our study aimed to investigate the function and mechanism of lncRNA ceramide synthase 6 antisense RNA 1 (CERS6-AS1) in PC. As shown by RT-qPCR, CERS6-AS1 was significantly upregulated in PC cells and tissues. Silencing CERS6-AS1 suppressed PC cell viability and proliferation while enhancing cell apoptosis according to colony formation assays, EdU assays, and flow cytometry analyses. Mechanistically, CERS6-AS1 interacted with miR-195-5p to elevate the expression level of the WD repeat domain phosphoinositide interacting 2 (WIPI2), which is a downstream target gene of miR-195-5p in PC. Moreover, miR-195-5p expression was negatively associated with CERS6-AS1 expression (or WIPI2 expression) in PC tissues. Rescue assays revealed that WIPI2 overexpression rescued the effects of CERS6-AS1 deficiency on cell viability, proliferation, and apoptosis. In summary, CERS6-AS1 facilitates PC cell proliferation while inhibiting PC cell apoptosis by upregulating WIPI2 via miR-195-5p. This study might provide promising insight into the role of CERS6-AS1 in PC development.

Identification and expression analysis of cobia (Rachycentron canadum) liver-related miRNAs under hypoxia stress.

At present, due to the influence of global warming, seasonal change, diurnal variation, and eutrophication of the water body, hypoxia has become one of the major factors limiting the stable development of cobia (Rachycentron canadum) culture. In this study, the miRNAs involved in hypoxia stress were screened, and the target genes of miRNAs were annotated and analyzed. The results showed that a total of 184 conservative microRNA (miRNA) and 121 newly predicted miRNA were obtained by sequencing the liver of control (C) and hypoxic (dissolved oxygen, DO (2.64 ± 0.25) mg/L; 3 h) (S) groups. The pathways involved in energy metabolism included starch and sucrose metabolism (ko00500), glycosaminoglycan degradation (ko00531), and galactose metabolism (ko00052). The results indicate that the body maintains physiological activities by regulating some important pathways at the transcriptional level under hypoxia stress, such as the conversion of aerobic metabolism and anaerobic metabolism, the reduction of energy consumption, and the promotion of red blood cell proliferation to maintain the homeostasis of the body.

Bacteriological and molecular typing of Clostridium perfringens strains isolated in retail beef in Beijing, China.

Clostridium perfringens is an important zoonotic pathogen. This study was designed to explore the prevalence and toxin types of C. perfringens in retail beef collected from Beijing, China. Among 221 beef samples collected, 53 samples were positive for C. perfringens, resulting in the average prevalence as 23.98%. By toxin gene-based typing, the most C. perfringens strains belong to type A (96.23%, 51/53), only 2 strains were identified as type D. By a multi-locus sequence typing (MLST)-based analysis, a total of 36 sequence types (STs) were detected, and the most STs (n=30) represented just a single strain. These finding suggested that the prevalence of C. perfringens in retail beef in Beijing was considerably high and these bacteria displayed extreme diversity in genetics.

Cloning of Mn-SOD gene and its mRNA expression difference and antioxidant enzyme activities under hypoxia stress of cobia Rachycentron canadum.

BACKGROUND: Environmental hypoxia affects the survival and development of organisms. It is also an important environmental factor that leads to oxidative damage. Hypoxia is a condition in which tissues are deprived of oxygen; reoxygenation is the phenomenon in which hypoxic tissues are exposed to oxygen. Hypoxia-reoxygenation is vital in pathogenesis, where the production of reactive oxygen species and antioxidant disparity significantly contribute to disease progression, and it is one of the most common physiological stressors in the aquaculture industry. METHODS AND RESULTS: In this study, the full length of complementary DNA (cDNA) of the manganese superoxide dismutase (Mn-SOD) gene of healthy cobia Rachycentron canadum was analysed using rapid amplification of cDNA ends. The real-time quantitative Polymerase Chain Reaction was used to measure the expression levels of Mn-SOD mRNAs in various tissues (heart, muscle, brain, liver, kidney, gill, intestine, and spleen). The 2-ΔΔCT method was used to performed the expression analysis. The experimental data were analysed using SPSS ver. 19.0 ( https://spss.software.informer.com/19.0/ ). P < 0.05 and P < 0.01 were set as significant differences. The values were articulated as mean ± standard deviation. The Mn-SOD gene cDNA sequence was 1209 bp long, including a 684 bp open reading frame, 42 bp 5'UTR and 483 bp 3'UTR, encoding 227 amino acids. Under hypoxia-reoxygen stress, the expression of Mn-SOD in brain tissue was significantly lower than in the control group after 8 h of reoxygenation and higher than the control group after 24 h. Hypoxia and subsequent reoxygenation triggered a disturbance in antioxidant homeostasis, displayed in the modification of GPx expression/activity in the liver: GPx was improved. CONCLUSIONS: These results provide valuable information on the role of Mn-SOD regulation in oxidative stress caused by hypoxia.

Neck circumference and waist circumference associated with cardiovascular events in type 2 diabetes (Beijing Community Diabetes Study 23).

Obesity increases the risk of developing cardiovascular disease and other metabolic diseases. We intended to compare three different anthropometric indicators of obesity, in predicting the incidence of cardiovascular events in Chinese type 2 diabetes. Beijing Community Diabetes Study was a prospective multi-center study conducted in Beijing community health centers. Type 2 diabetes patients from fourteen community health centers were enrolled at baseline. The primary endpoint was cardiovascular events. The upper quartile of neck circumference (NC) was set as greater NC. A total of 3299 diabetes patients were enrolled. In which, 941 (28.52%) had cardiovascular disease at baseline. Logistic analysis showed that central obesity (waist circumference (WC) above 90 cm in men and 85 cm in women) and greater NC were all related to baseline cardiovascular disease (adjusted OR = 1.49, and 1.55). After 10-year follow-up, 340 (10.31%) had cardiovascular events. Compared with patients without cardiovascular events, those having cardiovascular events had higher BMI, larger WC and NC. Cox regression analysis showed that greater WC and NC were all associated with the occurrence of cardiovascular events (adjusted HR = 1.41, and 1.38). A higher NC and WC might increase the risk of cardiovascular events by about 40% in type 2 diabetes patients in Beijing communities.

The effects of acarbose therapy on reductions of myocardial infarction and all-cause death in T2DM during 10-year multifactorial interventions (The Beijing Community Diabetes Study 24).

To investigate the potential benefits of acarbose therapy on cardiovascular events (CVD) in Type 2 diabetes (T2DM) in an urban community over 10-year follow-up. The study population of Beijing Community Diabetes Study (BCDS) were type 2 diabetes (T2DM) living in 21 communities in Beijing. All patients received comprehensive intervention in accordance with the Chinese guidelines for the prevention and treatment of diabetes. Professors in endocrinology from top tier hospitals regularly visited the communities for consultations, which was a feature of this study. A total of 1797 T2DM in BCDS study had complete screening data, including blood glucose, blood pressure, lipid profiles and acarbose continuous therapy. After 10-year follow-up, the risks of CVD outcomes were assessed according to whether patients had received acarbose therapy or not. All patients were followed-up to assess the long-term effects of the multifactorial interventions. At baseline, compared with the acarbose therapy free in T2DM, there was no significant difference in achieving the joint target control in patients with acarbose therapy. From the beginning of 8th year follow-up, the joint target control rate in patients with acarbose therapy was significantly higher than that of acarbose therapy free. During the 10-year follow-up, a total of 446 endpoint events occurred, including all-cause death, cardiovascular events, cerebrovascular events. The incidences of myocardial infarction (from the 4th year of follow-up) and all-cause death (from the 2nd year of follow-up) in patients who received acarbose therapy were significantly lower than that of acarbose therapy free respectively. In Cox multivariate analyses, there were significant differences in incidences of myocardial infarction and all-cause death between afore two groups during the 10-year follow-up, and the adjusted HRs were 0.50 and 0.52, respectively. After multifactorial interventions, T2DM with acarbose therapy revealed significant reductions of myocardial infarction and all-cause death. The long-term effects of with acarbose therapy on improving joint target control might be one of the main reasons of myocardial infarction and all-cause death reduction.Trial Registration: ChiCTR-TRC-13003978, ChiCTR-OOC-15006090.

Photocatalyst- and Transition-Metal-Free Visible-Light-Promoted Intramolecular C(sp2)-S Formation.

A photocatalyst- and transition-metal-free visible-light-induced cyclization of ortho-halothiobenzanilides has been developed. Upon irradiation with visible light, substrates undergo dehalogenative cyclization to 2-aryl benzothiazoles with high efficiency and selectivity. This photocyclization exhibits a high tolerance to various functional groups, is applicable for the synthesis of 2-alkyl benzothiazoles, and is easy to set up for gram-scale reaction.

Kinetic Study on the Crystal Transformation of Fe-Doped TiO2 via In Situ High-Temperature X-ray Diffraction and Transmission Electron Microscopy.

Titanium dioxide (TiO2) is widely used in various major industries owing to its different crystal forms and functions. Therefore, fabricating suitable crystalline TiO2 through reasonable processes is necessary. In this study, Fe-doped TiO2 precursors were prepared via hydrolysis. Further, in situ high-temperature X-ray diffraction and transmission electron microscopy were used to transform the synthesized precursor in its crystal form. The Rietveld full-spectrum fitting method could accurately yield two different crystal forms at instant temperatures. Additionally, the rate relation between the crystal form transformation and reaction conditions was obtained. Results showed that the addition of Fe increased the temperature of phase transition of TiO2 anatase to rutile and accelerated the anatase → rutile transformation process. Further, crystal phase transition kinetic analysis showed that the phase transition kinetic model of Fe-doped TiO2 matched the Johnson-Mehl-Avrami-Kohnogorov (JMAK) model and that its phase transition was affected by crystal defects. Finally, Fe3+ in Fe-doped TiO2 was reduced to Fe2+ to generate oxygen vacancies, thus promoting the rate of transformation from titanium ore to rutile.

The association between abnormal serum magnesium levels and prognosis of elderly patients with community-acquired pneumonia.

To investigate the association between abnormal serum magnesium levels and the prognosis of elderly patients with community-acquired pneumonia (CAP). Methods: A retrospective study was conducted on 1381 elderly patients with CAP in the First Hospital of Qinhuangdao between January 2015 and December 2018. Serum magnesium concentrations in the range of 0.75-1.25 mmol/L were defined as normal. Patients were assigned into normal, hypomagnesemia, and hypermagnesemia groups. The primary outcome was in-hospital mortality, indicating whether a patient died at the time of discharge from the hospital. The percentages of respiratory failure and mechanical ventilation were 18.6% and 10.6 % in the normal group, 29% and 16.5 % in the hypomagnesemia, and 42.9% and 35.7% in the hypermagnesemia groups. The occurrence of shock was 8.5% and 4.5% in the hypomagnesemia group and the normal group. The percentages of the length of stay at ICU were 14.9%, 18.8%, and 57.1% in the hypomagnesemia, normal, and hypermagnesemia groups. The in-hospital mortality rate was 5.3%, 9.1%, and 35.7% in the normal, hypomagnesemia, and hypermagnesemia groups, respectively. The results of univariate analysis showed that the in-hospital mortality in the hypomagnesemia group was 1.790 (95% confidence interval (CI): 1.009∼3.176, P=0.046) times higher than that in the normal group; in the hypermagnesemia group, it was 9.947 (95% CI: 3.238-30.556, P<0.001) times higher than that in the normal group. The results of multivariate logistic regression analysis showed that after adjusting for gender, age, diabetes, heart failure, cerebrovascular disease, cancer, estimated glomerular filtration rate (eGFR), glucose, and CURB-65 score, in the hypomagnesemia group, the in-hospital mortality was 1.746 (95% confidence interval (CI): 0.956∼3.186, P=0.070) times higher than that in the normal group, and 5.689 (95% CI: 1.583- 20.446, P=0.008) times higher in the hypermagnesemia group than that in the normal group. Abnormal serum magnesium levels are strongly associated with in-hospital mortality in elderly patients with CAP. The measurement of serum magnesium levels in elderly patients with CAP at admission may assist clinicians to determine the prognosis of such patients.

Enantioselective Cascade Biocatalysis for Deracemization of Racemic ß-Amino Alcohols to Enantiopure (S)-ß-Amino Alcohols by Employing Cyclohexylamine Oxidase and ω-Transaminase.

Optically active ß-amino alcohols are very useful chiral intermediates frequently used in the preparation of pharmaceutically active substances. Here, a novel cyclohexylamine oxidase (ArCHAO) was identified from the genome sequence of Arthrobacter sp. TYUT010-15 with the R-stereoselective deamination activity of ß-amino alcohol. ArCHAO was cloned and successfully expressed in E. coli BL21, purified and characterized. Substrate-specific analysis revealed that ArCHAO has high activity (4.15 to 6.34 U mg-1 protein) and excellent enantioselectivity toward the tested ß-amino alcohols. By using purified ArCHAO, a wide range of racemic ß-amino alcohols were resolved, (S)-ß-amino alcohols were obtained in >99 % ee. Deracemization of racemic ß-amino alcohols was conducted by ArCHAO-catalyzed enantioselective deamination and transaminase-catalyzed enantioselective amination to afford (S)-ß-amino alcohols in excellent conversion (78-94 %) and enantiomeric excess (>99 %). Preparative-scale deracemization was carried out with 50 mM (6.859 g L-1 ) racemic 2-amino-2-phenylethanol, (S)-2-amino-2-phenylethanol was obtained in 75 % isolated yield and >99 % ee.

Super-resolved angular displacement estimation based upon a Sagnac interferometer and parity measurement.

Super-resolved angular displacement estimation is of crucial significance to the field of quantum information processing. Here we report an estimation protocol based on a Sagnac interferometer fed by a coherent state carrying orbital angular momentum. In a lossless scenario, through the use of parity measurement, our protocol can achieve a 4ℓ-fold super-resolved output with quantum number ℓ; meanwhile, a shot-noise-limited sensitivity saturating the quantum Cramér-Rao bound is reachable. We also consider the effects of several realistic factors, including nonideal state preparation, photon loss, and inefficient measurement. Finally, with mean photon number N¯=2.297 and ℓ = 1 taken, we experimentally demonstrate a super-resolved effect of angular displacement with a factor of 7.88.

High throughput solid-phase screening of bacteria with cyclic amino alcohol deamination activity for enantioselective synthesis of chiral cyclic ß-amino alcohols.

OBJECTIVES: To screening of bacteria with cyclic amino alcohol deamination activity for enantioselective synthesis of chiral cyclic ß-amino alcohols. RESULTS: A new strain named Arthrobacter sp. TYUT010-15 with the (R)-selective deamination activity of cyclic ß-amino alcohol has been isolated from nature via a high throughput solid-phase screening method. The reaction conditions of TYUT010-15 were optimized. Using the resting cell of TYUT010-15 as the catalyst, kinetic resolution of trans-2-aminocyclopentanol, trans-2-aminocyclohexanol and cis-1-amino-2-indanol was carried out to afford (1S, 2S)-trans-2-aminocyclopentanol, (1S, 2S)-trans-2-aminocyclohexanol and (1R, 2S)-cis-1-amino-2-indanol in > 99% ee and 49.6-50% conversion. Four aromatic ß-amino alcohols and two amines were also resolved, (S)-ß-amino alcohols and (R)-amines were obtained in > 99% ee. Preparation experiment was conducted with 200 mM (23.2 g L-1) racemic trans-2-aminocyclohexanol, yielding the desired (1S, 2S)-trans-2-aminocyclohexanol in 40% isolated yield, > 99% ee and 5.8 g L-1 d-1 space time yields. CONCLUSIONS: This study provides a high throughput solid-phase method for screening of bacteria with cyclic amino alcohol deamination activity and a first example for practical preparation of chiral cyclic ß-amino alcohol by Arthrobacter sp. TYUT010-15.