Iron-catalyzed stereoselective C-H alkylation for simultaneous construction of C-N axial and C-central chirality.

The assembly of chiral molecules with multiple stereogenic elements is challenging, and, despite of indisputable advances, largely limited to toxic, cost-intensive and precious metal catalysts. In sharp contrast, we herein disclose a versatile C-H alkylation using a non-toxic, low-cost iron catalyst for the synthesis of substituted indoles with two chiral elements. The key for achieving excellent diastereo- and enantioselectivity was substitution on a chiral N-heterocyclic carbene ligand providing steric hindrance and extra represented by noncovalent interaction for the concomitant generation of C-N axial chirality and C-stereogenic center. Experimental and computational mechanistic studies have unraveled the origin of the catalytic efficacy and stereoselectivity.

Nickel-Catalyzed Atroposelective C-H Alkylation Enabled by Bimetallic Catalysis with Air-Stable Heteroatom-Substituted Secondary Phosphine Oxide Preligands.

The catalytic asymmetric construction of axially chiral C-N atropisomers remains a formidable challenge due to their low rotational barriers and is largely reliant on toxic, cost-intensive, and precious metal catalysts. In sharp contrast, we herein describe the first nickel-catalyzed atroposelective C-H alkylation for the construction of C-N axially chiral compounds with the aid of a chiral heteroatom-substituted secondary phosphine oxide (HASPO)-ligated Ni-Al bimetallic catalyst. A wide range of alkenes, including terminal and internal alkenes, were well compatible with the reaction, providing a variety of benzimidazole derivatives in high yields and enantioselectivities (up to 97:3 e.r.). The key to success was the identification of novel HASPOs as highly effective chiral preligands. Mechanistic studies revealed the catalyst mode of action, and in-depth data science analysis elucidated the key features of the responsible chiral preligands in controlling the enantioselectivity.

Immp2l Mutation Induces Mitochondrial Membrane Depolarization and Complex III Activity Suppression after Middle Cerebral Artery Occlusion in Mice.

OBJECTIVE: We previously reported that mutations in inner mitochondrial membrane peptidase 2-like (Immp2l) increase infarct volume, enhance superoxide production, and suppress mitochondrial respiration after transient cerebral focal ischemia and reperfusion injury. The present study investigated the impact of heterozygous Immp2l mutation on mitochondria function after ischemia and reperfusion injury in mice. METHODS: Mice were subjected to middle cerebral artery occlusion for 1 h followed by 0, 1, 5, and 24 h of reperfusion. The effects of Immp2l+/- on mitochondrial membrane potential, mitochondrial respiratory complex III activity, caspase-3, and apoptosis-inducing factor (AIF) translocation were examined. RESULTS: Immp2l+/- increased ischemic brain damage and the number of TUNEL-positive cells compared with wild-type mice. Immp2l+/- led to mitochondrial damage, mitochondrial membrane potential depolarization, mitochondrial respiratory complex III activity suppression, caspase-3 activation, and AIF nuclear translocation. CONCLUSION: The adverse impact of Immp2l+/- on the brain after ischemia and reperfusion might be related to mitochondrial damage that involves depolarization of the mitochondrial membrane potential, inhibition of the mitochondrial respiratory complex III, and activation of mitochondria-mediated cell death pathways. These results suggest that patients with stroke carrying Immp2l+/- might have worse and more severe infarcts, followed by a worse prognosis than those without Immp2l mutations.

Data-driven design of new chiral carboxylic acid for construction of indoles with C-central and C-N axial chirality via cobalt catalysis.

Challenging enantio- and diastereoselective cobalt-catalyzed C-H alkylation has been realized by an innovative data-driven knowledge transfer strategy. Harnessing the statistics of a related transformation as the knowledge source, the designed machine learning (ML) model took advantage of delta learning and enabled accurate and extrapolative enantioselectivity predictions. Powered by the knowledge transfer model, the virtual screening of a broad scope of 360 chiral carboxylic acids led to the discovery of a new catalyst featuring an intriguing furyl moiety. Further experiments verified that the predicted chiral carboxylic acid can achieve excellent stereochemical control for the target C-H alkylation, which supported the expedient synthesis for a large library of substituted indoles with C-central and C-N axial chirality. The reported machine learning approach provides a powerful data engine to accelerate the discovery of molecular catalysis by harnessing the hidden value of the available structure-performance statistics.

Close-Shell Reductive Elimination versus Open-Shell Radical Coupling for Site-Selective Ruthenium-Catalyzed C-H Activations by Computation and Experiments.

Ruthenium-catalyzed σ-bond activation-assisted meta-C-H functionalization has emerged as a useful tool to forge distal C-C bonds. However, given the limited number of mechanistic studies, a clear understanding of the origin of the site-selectivity and the complete reaction pattern is not available. Here, we present systematic computational studies on ruthenium-catalyzed C-H functionalization with primary, secondary, tertiary alkyl bromides and aryl bromides. The C-H scission and the C-C formation were carefully examined. Monocyclometalated ruthenium(II) complexes were identified as the active species, which then underwent inner-sphere single electron transfer (ISET) to activate the organic bromides. The site-selectivity results from the competition between the close-shell reductive elimination and the open-shell radical coupling. Based on this mechanistic understanding, a multilinear regression model was built to predict the site-selectivity, which was further validated by experiments.

Association between copy number variation of SERPINA3-1 gene and growth traits in Chinese cattle.

Serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3 (SERPINA3) belongs to the serine protease inhibitor family A subtype, and contains 8 genes from SERPINA3-1 to SERPINA3-8. Although the regulatory effects of these 8 genes have been revealed one by one in recent years, the related effects of SERPINA3-1 gene on cattle growth is still unclear. This study used quantitative Real time PCR (qPCR) to detect the type of copy number variation (CNV) of SERPINA3-1 gene in a total of 542 Chinese cattle, and expression of SERPINA3-1 gene in different tissues of Qinchuan cattles (adult) on mRNA level. Then association analysis was conducted between the detection results and cattle growth traits. The results showed that the Duplication type in SERPINA3-1 gene performed better on the growth traits and the CNV was significantly correlated with multiple growth traits (p < 0.05). In addition, SERPINA3-1 gene has different expression conditions in different tissues, results showed that SERPINA3-1 gene has a low expression in muscle. In conclusion, we speculate that the SERPINA3-1 gene can be used as a molecular marker and the result of this study could be a basic material for candidate functional genes for beef cattle growth and development.

In order to detect the gene expression diversification of the SERPINA3-1 gene, blood samples were collected from five Chinese cattle breeds, we detected related signal and made an associated analyze with cattle growth traits. We determined the copy number variation distribution of the SERPINA3-1 gene in cattle populations and found that the SERPINA3-1 gene has a certain promoting effect on the growth and development of Chinese cattle. For example, Pinan cattle with Duplication type copy number have a better performance on growth traits. This study has enriched the candidate genes of Chinese cattle molecular breeding and provided basic data for Chinese cattle breeding.

Bumblebees with the socially transmitted microbiome: A novel model organism for gut microbiota research.

Eusocial bumble and honey bees are important pollinators for global ecology and the agricultural economy. Although both the bumble and honey bees possess similar and host-restricted gut microbiota, they differ in aspects of morphology, autonomy, physiology, behavior, and life cycle. The social bee gut bacteria exhibit host specificity that is likely a result of long-term co-evolution. The unique life cycle of bumblebees is key for the acquisition and development of their gut microbiota, and affects the strain-level diversity of the core bacterial species. Studies on bumblebee gut bacteria show that they retain less functional capacity for carbohydrate metabolism compared with that of the honeybee. We discuss the potential roles of the bumblebee gut microbiota against pathogenic threats and the application of host-specific probiotics for bumblebees. Given the advantages of the bumblebee microbiome, including the simple structure and host specificity, and the ease of manipulating bumblebee colonies, we propose that bumblebees may provide a valuable system for understanding the general principles of host-microbe interactions, gut-brain axis, and vertical transmission.

Stereodivergent propargylic alkylation of enals via cooperative NHC and copper catalysis.

Despite that asymmetric stereodivergent synthesis has experienced great success to provide unusual processes for the creation of chirality complexity, concepts appliable to asymmetric stereodivergent catalysis are still limited. The dependence on the unusual capacity of each catalyst to precisely control the reactive site planar in the region poses unparalleled constraints on this field. Here, we first demonstrate that the chiral Cu-allenylidene species can participate in the stereodivergent propargylic alkylation of enals, in concert with chiral N-heterocyclic carbenes (NHCs). Thus, all four stereoisomers were obtained with excellent enantioselectivity and diastereoselectivity (up to >99% e.e. and >95:5 d.r.) from the same starting materials by simply altering chiral Cu-Pybox complex and NHC combinations. The rich chemistry workable in the products enables the structurally diverse synthesis of chiral functional molecules and holds great potential in alkaloid synthesis, as showcased by the preparation of the key building block to access (-)-perophoramidine.

Electrochemical Cage Activation of Carboranes.

Carboranes are boron-carbon molecular clusters that possess unique properties, such as their icosahedron geometry, high boron content, and delocalized three-dimensional aromaticity. These features render carboranes valuable building blocks for applications in supramolecular design, nanomaterials, optoelectronics, organometallic coordination chemistry, and as boron neutron capture therapy (BNCT) agents. Despite tremendous progress in this field, stoichiometric chemical redox reagents are largely required for the oxidative activation of carborane cages. In this context, electrosyntheses represent an alternative strategy for more sustainable molecular syntheses. It is only in recent few years that considerable progress has been made in electrochemical cage functionalization of carboranes, which are summarized in this Minireview. We anticipate that electrocatalysis will serve as an increasingly powerful stimulus within the current renaissance of carborane electrochemistry.

Acupoint Injection Decreases Anesthetic Cosumption during Combined Spinal-Epidural and Patient-Controlled Epidural Labor Analgesia.

OBJECTIVE: To explore if acupoint injection can improve analgesic effects or delivery outcomes in parturients who received combined spinal-epidural analgesia (CSEA) and patient-controlled epidural analgesia (PCEA) for labor analgesia. METHODS: A total of 307 participants were prospectively collected from July 2017 to December 2019. The participants were randomized into the combined acupoint injection with CSEA plus PCEA group (AICP group, n=168) and CSEA plus PCEA group (CP group, n=139) for labor analgesia using a random number table. Both groups received CSEA plus PCEA at cervical dilation 3 cm during labor process, and parturients of the AICP group were implemented acupoint injection for which bilateral acupoint of Zusanli (ST 36) and Sanyinjiao (SP 6) were selected in addition. The primary outcome was Visual Analogue Scale (VAS) score, and the secondary outcomes were obstetric outcomes and requirement of anesthetics doses. Safety evaluations were performed after intervention. RESULTS: The VAS scores were significantly lower in the AICP group than in the CP group at 10, 30, 60, and 120 min after labor analgesia (all P<0.05). The latent phase of the AICP group was shorter than that of the CP group (P<0.05). There were less additional anesthetics consumption, lower incidences of uterine atony, fever, pruritus and urinary retention in the AICP group than those in the CP group (all P<0.05). CONCLUSION: Acupoint injection combined CSEA plus PCEA for labor analgesia can decrease the anesthetic consumption, improve analgesic quality, and reduce adverse reactions in the parturients. (Registration No. ChiMCTR-2000003120).

Diversity and functional analysis of Chinese bumblebee gut microbiota reveal the metabolic niche and antibiotic resistance variation of Gilliamella.

Bumblebees play an important role in maintaining the balance of natural and agricultural ecosystems, and the characteristic gut microbiota of bumblebees exhibit significant mutualistic functions. China has the highest diversity of bumblebees; however, gut microbiota of Chinese bumblebees have mostly been investigated through culture-independent studies. Here, we analyzed the gut communities of bumblebees from Sichuan, Yunnan, and Shaanxi provinces in China through 16S ribosomal RNA amplicon sequencing and bacterial isolation. It revealed that the bumblebees examined in this study harbored two gut enterotypes as previously reported: one is dominated by Gilliamella and Snodgrassella, and the other is distinguished by prevalent environmental species. The gut compositions obviously varied among different individual bees. We then isolated 325 bacterial strains and the comparative genomic analysis of Gilliamella strains revealed that galactose and pectin digestion pathways were conserved in strains from bumblebees, while genes for the utilization of arabinose, mannose, xylose, and rhamnose were mostly lost. Only two strains from the Chinese bumblebees possess the multidrug-resistant gene emrB, which is phylogenetically closely related to that from the symbionts of soil entomopathogenic nematode. In contrast, tetracycline-resistant genes were uniquely present in three strains from the USA. Our results illustrate the prevalence of strain-level variations in the metabolic potentials and the distributions of antibiotic-resistant genes in Chinese bumblebee gut bacteria.

Kinetic Resolution of Aziridines Enabled by N-Heterocyclic Carbene/Copper Cooperative Catalysis: Carbene Dose-Controlled Chemo-Switchability.

Catalytic kinetic resolution (KR) and dynamic kinetic asymmetric transformation (DyKAT) are alternative and complementary avenues to access chiral stereoisomers of both starting materials and reaction products. The development of highly efficient chiral catalytic systems for kinetically controlled processes has therefore been one of the linchpins in asymmetric synthesis. N-heterocyclic carbene (NHC)/copper cooperative catalysis has enabled highly efficient KR and DyKAT of racemic N-tosylaziridines by [3+3] annulation with isatin-derived enals, leading to highly enantioenriched N-tosylaziridine derivatives (up to >99 % ee) and a large library of spirooxindole derivatives with high structural diversity and stereoselectivity (up to >95:5 d.r., >99 % ee). Mechanistic studies suggest that the NHC can bind reversibly to the copper catalyst without compromising its catalytic activity and regulate the catalytic activity of the copper complex to switch the chemoselection between KR and DyKAT.

Autophagy Contributes to Oxidative Stress-Induced Apoptosis in Porcine Granulosa Cells.

Oxidative stress-induced granulosa cell (GC) death is a major cause of follicular atresia. As the major types of programmed cell death, autophagy and apoptosis have been observed in response to H2O2-mediated oxidative stress and have been demonstrated to be responsible for porcine GC death. To date, however, the cellular reactions linking autophagy to the apoptosis of porcine GC under oxidative stress are still poorly understood. Porcine GC were treated with H2O2, and autophagic flux was examined by western blotting. Cell viability and cell death assays were performed after cotreatment of porcine GC with autophagy activator (rapamycin) or inhibitor (3-methyladenine, 3-MA) together with H2O2. We revealed that short exposure (1-3 h) of porcine GC to H2O2 dramatically increased autophagic flux (1.8- to 2.5-fold over that in the control), whereas 6-12 h prolonged treatment decreased autophagy but elevated the caspase-3 activity and GC apoptotic rate. Furthermore, we showed that pretreatment with rapamycin exacerbated H2O2-mediated cytotoxicity and caspase-3 activation but that 3-MA or siRNAs specific for Beclin 1 and Atg7 genes ameliorated H2O2-mediated GC apoptosis. Together, our results indicate that autophagy plays a pivotal role in H2O2-mediated porcine GC apoptosis. Importantly, we show that the early induction of autophagic flux contributes to oxidative stress-induced apoptosis in porcine GC. The results also suggest that regulating the autophagy response in porcine GC under oxidative stress might be a new strategy for abnormal follicular atresia.

Interaction of Cyclooxygenase-2 with Helicobacter pylori Induces Gastric Chronic Nonresolving Inflammation and the Formation of Syndrome of Internal Block of Static Blood in Helicobacter pylori-Related Gastric Diseases.

Cyclooxygenase-2 (COX-2) is an inducible enzyme stimulated by various inflammatory factors (IFs). Chronic gastritis is a classic model of "inflammation-cancer transformation" and Helicobacter pylori-related gastric diseases (HPGD) are specific ones of this model. Traditional Chinese Medicine (TCM) syndromes could play a predictive role in gastric histopathological evolution. To search for early warning evidence about "inflammation-cancer transformation," this study is about to explore interaction of COX-2 with Helicobacter pylori (Hp) in HPGD with different TCM syndromes. All included subjects underwent endoscopy and biopsy. Hp infection was detected by rapid urease test and methylene blue staining. Histopathological characteristics and COX-2 expression in gastric mucosa (GM) were, respectively, observed by hematoxylin-eosin and Elivision™ plus. SPSS 18.0 and Stata 11.0 statistical software packages were used for statistical analysis. Results of immunohistochemical staining in this study showed COX-2 expression in Hp-positive patients was stronger than that in Hp-negative ones. Spearman' analysis indicated that degrees of both Hp infection and COX-2 expression were positively correlated with those of gastric inflammation and inflammatory activity. Compared with the relative normal group, both severe dysplasia group and gastric carcinoma group had more severe Hp infection and COX-2 expression. Compared with the nonsyndrome, syndrome of internal block of static blood (IBSB) had higher scores in semiquantitative analysis of COX-2 protein expression among TCM groups. Moreover, multivariate logistics regression analysis suggested that patients with Hp infection could increase the risk of IBSB. These results indicated that COX-2 interacting with Hp could play an important role in transforming gastric chronic nonresolving inflammation into carcinoma in subjects with HPGD, as well as inducing the formation of IBSB. HPGD together with IBSB could be an early warning evidence for GM with histopathological evolution from benign to malignant.

[Influence of warming needling technique on gastrointestinal reaction after hyperthermic intrape-ritoneal chemotherapy in patients with postoperation of colon cancer].

OBJECTIVE: To observe the effect of warming needling therapy on gastrointestinal reaction after hyperthermic intraperitoneal chemotherapy (HIPEC) in patients of spleen and stomach deficiency syndrome after colon cancer surgery. METHODS: A total of 120 cases of HIPEC were randomized into observation group and control group, 60 cases in each. The patients of the two groups all received HIPEC. In the observation group, 1 h before HIPEC, warming needling technique was applied to Zusanli (ST36), Sanyinjiao (SP6) and Yinlingquan (SP9) and the even-needing technique of acupuncture was applied to Neiguan (PC6) for 30 min, and then the intravenous injection with Ondansetron was given 30 min before HIPEC. In the control group, The intravenous injection with Ondansetron was given 30 min before HIPEC. In the two groups, the changes in nausea, vomiting, abdominal distention, diarrhea, total bilirubin (TB), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and KPS score, as well as the average hospitalization length of stay were observed. RESULTS: The total effective rates in the treatment of nausea, vomiting, abdominal distention and diarrhea were 91.67%(55/60), 93.33%(56/60), 80.00%(48/60) and 88.33%(53/60) in the observation group and were 78.33%(47/60), 78.33%(47/60), 63.33%(38/60) and 70.00%(42/60) in the control group respectively, and the total effective rate in the treatment of gastrointestinal reaction of HIPEC in the observation group was obviously higher than that in the control group(P<0.05). The KPS score and curative effect in the observation group was obviously higher than those of the control group(P<0.05), and the average hospitalization length of stay in the observation group was obviously reduced as compared with the control group (P<0.05). There were no significant differences in serum TB, ALT and ALP contents between the two groups after treatment (P>0.05). CONCLUSION: The warming needling technique of acupuncture and moxibustion alleviates the gastrointestinal reaction, improves KPS score and reduces the hospitalization length of stay in HIPEC patients after the surgery of colon cancer and differentiated as the spleen and stomach deficiency in traditional Chinese medicine.

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.

Update on urine as a biomarker in cancer: a necessary review of an old story.

Introduction: Cancer causes thousands of deaths worldwide each year. Therefore, monitoring of health status and the early diagnosis of cancer using noninvasive assays, such as the analysis of molecular biomarkers in urine, is essential. However, effective biomarkers for early diagnosis of cancer have not been established in many types of cancer.Areas covered: In this review, we discuss recent findings with regard to the use of urine composition as a biomarker in eleven types of cancer. We also highlight the use of urine biomarkers for improving early diagnosis.Expert opinion: Urinary biomarkers have been applied for clinical application of early diagnosis. The main limitation is a lack of integrated approaches for identification of new biomarkers in most cancer. The utilization of urinary biomarker detection will be promoted by improved detection methods and new data from different types of cancers. With the development of precision medicine, urinary biomarkers will play an increasingly important clinical role. Future early diagnosis would benefit from changes in the utilization of urinary biomarkers.

Determination of genetic effects of SERPINA3 on important growth traits in beef cattle.

Serine protease inhibitor protein 3 (serpin peptidase inhibitor, clade A, member 3, SERPINA3) is a member of the serpin superfamily, probably related to the yield and quality of muscle. This study focuses on the relationship between SERPINA3 gene polymorphism and growth traits in beef cattle. The study first uses sequencing pooled DNA samples (Pool-Seq), PCR-RFLP and Tetra-primer ARMS-PCR techniques to determine the genetic polymorphisms of SERPINA3 in 765 beef cattle. Then, the polymorphic loci were correlated with the growth characters of cattle. Five SNPs (SNP1:A-648G, SNP2:T6496A, SNP3:G2495A, SNP4:T2595A, SNP5:A2615G) were found, located in the promoter, introns 5 and SNP 3, 4, 5 were in exons 2, respectively. The observed He was from 0.44 to 0.5, Ne were approaching 2 (1.78 to 2.00). The maximum and minimum PIC (polymorphism information content) values were 0.37 and 0.34, respectively. The association analysis results showed that the SNPs had a significant height in the chest girth and body length. (p < 0.05 or p < 0.01). This will provide important information for the rapid breeding of Chinese yellow cattle and the establishment of a molecular genetic marker database.

Copy number variation of MYLK4 gene and its growth traits of Capra hircus (goat).

Copy number variation (CNV) is a form of genetic variation caused by genome rearrangement, with abnormal fragments ranging from 50 bp to Mb. And, CNV is closely related to disease, growth and reproductive shape of livestock. As a member of myosin light chain kinase (MYLK) family with serine/threonine specificity, MYLK4 belongs to an enzyme encoded by MYLK4 gene. Although MYLK4 is a recognized kinase, its function has yet to be revealed in subsequent studies. This study aims to analyze CNV and genetic effects of MYLK4 gene in goats. We used qPCR to detect CNV of MYLK4 gene in African Nubian goat (n = 32), Guizhou black goat (n = 196) and Guizhou white goat (n = 95), respectively, and correlated CNV data of MYLK4 gene with goat growth traits in Chinese goats. The results showed that the effect of MYLK4 gene CNV on body weight, body length and body height of goats had significantly different (p < 0.05, Q < 0.05), in which CNV showed better growth traits in type of deletion. Therefore, CNV of MYLK4 gene can be used as a molecular marker for assisted selection of goat growth traits, which provides a theoretical basis for the genetic improvement of goat breeds in China.

miR-181a promotes porcine granulosa cell apoptosis by targeting TGFBR1 via the activin signaling pathway.

Activin/Smad3 signaling plays a pivotal role in follicle development and atresia. However, the precise mechanisms underlying this process are not yet fully understood. Herein, we identified miR-181a as a central component of activin/Smad3-mediated follicle atresia. miR-181a was strikingly upregulated in porcine atretic follicles, which induced the apoptosis of porcine granulosa cells (GCs) in vitro. Furthermore, the transforming growth factor-ß type 1 receptor (TGFBR1) was confirmed as a direct target of miR-181a by bioinformatics analysis and luciferase assays. Transfection with an miR-181a agomir repressed the TGFBR1 mRNA and protein levels. In addition, TGFBR1 overexpression repressed GC apoptosis, whereas TGFBR1 inhibition promoted GC apoptosis. miR-181a overexpression downregulated the phosphorylation of Smad3 and blocked the activation of TGF-ß signaling. Moreover, activin A downregulated miR-181a expression and upregulated the TGFBR1 and p-Smad3 protein levels. Collectively, these data suggest that miR-181a regulates porcine GC apoptosis by targeting TGFBR1 via the activin signaling pathway.