Amide-Directed, Rhodium-Catalyzed Regio- and Enantioselective Hydroacylation of Internal Alkenes with Unfunctionalized Aldehydes.

Despite the current progress achieved in asymmetric hydroacylations, highly enantioselective catalytic addition of unfunctionalized aldehydes to internal alkenes remains an unsolved challenge. Here, using a coordination-assisted strategy, we developed a rhodium-catalyzed regio- and enantioselective addition of unfunctionalized aldehydes to internal alkenes such as enamides and ß,γ-unsaturated amides. Valuable α-amino ketones and 1,4-dicarbonyl compounds were directly obtained with high enantioselectivity from readily available materials.

Rhodium-Catalyzed Highly Enantioselective Hydroboration of Acyclic Tetrasubstituted Alkenes Directed by an Amide.

Although progress has been made in enantioselective hydroboration of di- and trisubstituted alkenes over the past decades, enantioselective hydroboration of tetrasubstituted alkenes with high diastereo- and enantioselectivities continues as an unmet challenge since the 1950s due to its extremely low reactivity and the difficulties to simultaneously control the regio- and stereoselectivity of a tetrasubstituted alkene. Here, we report highly regio-, diastereo-, and enantioselective catalytic hydroboration of diverse acyclic tetrasubstituted alkenes. The delicate interplay of an electron-rich rhodium complex and coordination-assistance forms a highly adaptive catalyst that effectively overcomes the low reactivity and controls the stereoselectivity. The generality of the catalyst system is exemplified by its efficacy across various tetrasubstituted alkenes with diverse steric and electronic properties.

One-Step Electrochemical Ethylene-to-Ethylene Glycol Conversion over a Multitasking Molecular Catalyst.

Ethylene glycol is an essential commodity chemical with high demand, which is conventionally produced via thermocatalytic oxidation of ethylene with huge fossil fuel consumption and CO2 emission. The one-step electrochemical approach offers a sustainable route but suffers from reliance on noble metal catalysts, low activity, and mediocre selectivity. Herein, we report a one-step electrochemical oxidation of ethylene to ethylene glycol over an earth-abundant metal-based molecular catalyst, a cobalt phthalocyanine supported on a carbon nanotube (CoPc/CNT). The catalyst delivers ethylene glycol with 100% selectivity and 1.78 min-1 turnover frequency at room temperature and ambient pressure, more competitive than those obtained over palladium catalysts. Experimental data demonstrate that the catalyst orchestrates multiple tasks in sequence, involving electrochemical water activation to generate high-valence Co-oxo species, ethylene epoxidation to afford an ethylene oxide intermediate via oxygen transfer, and eventually ring-opening of ethylene oxide to ethylene glycol facilitated by in situ formed Lewis acid site. This work offers a great opportunity for commodity chemicals synthesis based on a one-step, earth-abundant metal-catalyzed, and renewable electricity-driven route.

Coordination Assistance: A Powerful Strategy for Metal-Catalyzed Regio- and Enantioselective Hydroalkynylation of Internal Alkenes.

ConspectusAlkenes are versatile compounds that are readily available on a large scale from industry or through organic synthesis. The widespread occurrence of alkenes provides the continuous impetus for the development of catalytic asymmetric alkene hydrofunctionalizations, which enables expeditious construction of complex chiral molecules from readily available starting materials. Catalytic asymmetric hydrofunctionalization of internal alkenes presents a notable challenge, due to their low reactivity, many potential side reactions, and the simultaneous control of the regio-, diastereo-, and enantioselectivities.Dehydroamino acids and enamides are among the first substrates that provide notable enantioselectivities in catalytic asymmetric hydrogenation. The crucial importance of an amide coordinating group is established by a series of classical mechanistic studies. This initial success greatly stimulated further development for catalytic hydrogenation and hydrofunctionalization. Building on these pioneering works in asymmetric hydrogenation as well as related hydrofunctionalizations, we have adopted coordination assistance as a powerful tool to address the challenges associated with the asymmetric hydrofunctionalization of internal alkenes. Using a functional group on the alkene substrate as a native coordinating group, a two-point binding mode of the substrate to the metal center effectively enhances the reactivity and facilitates the control of regio-, diastereo- and enantioselectivities. Through this strategy, we have developed a number of alkene hydrofunctionalization methods with excellent regio-, diastereo-, and enantiocontrols.In this Account, we summarize the recent advance in our lab using coordination assistance as a key element to achieve regio- and enantioselective hydroalkynylation of internal alkenes. First, we describe our early work aimed at controlling the regio- and enantioselectivity of hydroalkynylation using disubstituted enamide as the substrate. Both α- and ß-alkynylation were achieved by channeling the reaction pathway into a Chalk-Harrod or modified Chalk-Harrod mechanism. Next, we discuss the further development of catalysts to achieve regiodivergent and enantioselective hydroalkynylation of trisubstituted enamide to access vicinal stereocenters and quaternary carbon stereocenters. We also discuss the hydroalkynylation of α,ß-unsaturated amides to achieve unconventional site-selectivity through a combination of alkene isomerization and regioselective hydroalkynylation. This provides the basis for the construction of a remote quaternary carbon stereocenter through catalytic hydroalkynylation of trisubstituted ß,γ-unsaturated amides. We further show that this controlling principle is applicable to terminal alkene with a coordinating group as well. A ligand-controlled mechanism shift is discussed for the enantioselective alkynylation at the terminal and internal position of 1,1,-disubstituted alkenes. Finally, we briefly mention the application of coordination assistance to other hydrofunctionalizations such as hydroboration and hydrosilylation, where previously inaccessible reactivity and selectivity were achieved. Collectively, these catalytic methods demonstrate the power of coordination assistance for enantioselective hydrofunctionalizations. We anticipate that this strategy will create a platform to enable diverse enantioselective alkene transformations.

Visible-Light-Driven Germyl Radical Generation via EDA-Catalyzed ET-HAT Process.

We have established a facile and efficient protocol for the generation of germyl radicals by employing photo-excited electron transfer (ET) in an electron donor-acceptor (EDA) complex to drive hydrogen-atom transfer (HAT) from germyl hydride (R3GeH). Using a catalytic amount of EDA complex of commercially available thiol and benzophenone derivatives, the ET-HAT cycle smoothly proceeds simply upon blue-light irradiation without any transition metal or photocatalyst. This protocol also affords silyl radical from silyl hydride.

Reasons for Silicone Breast Implant Removal After Long-Term Implantation in Chinese Patients Without Complications: A Questionnaire-Based Study.

BACKGROUND: There are few studies of Chinese patients who request silicone breast implant removal after at least 10 years of implantation without any complications. This study aimed to study the characteristics of these patients, explore their reasons for breast implant removal and associate factors that affect their choice, so as to provide valuable information on clinical decision making. METHODS: A total of 55 eligible female patients (110 breasts) were enrolled from 2016 to 2022. A preoperative questionnaire survey before removal surgery and a telephone follow-up 1 year after removal surgery were conducted to collect data. RESULTS: The mean age of the patients was 40.6±8.8 years with the average time from breast augmentation to implant removal or replacement ranged from 10 to 15 years. Concerns about the aging of silicone gel-filled breast implant and the adverse effects of its long-term placement on body health were the top two reasons for breast implant removal. 63% of patients refused implant replacement, who were nearly 10 years older than those accepted implant replacement (p<0.05). Older age at implant removal (OR=0.67; 95%CI: 0.44-0.89) and a history of basic diseases (OR=0.02; 95%CI: 0.00-0.39) were statistically associated with lower rate of implant replacement. CONCLUSIONS: Concerns about the aging of silicone gel-filled breast implant were the main reason for uncomplicated patients to remove their breast implants. A comprehensive analysis based on patient's subjective choice and physical condition was suggested when an uncomplicated patient asks for implant removal. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Chin Augmentation and Treatment of Chin Retrusion with a Flexible Hyaluronic Acid Filler in Asian Subjects: A Randomized, Controlled, Evaluator-Blinded Study.

BACKGROUND: Aesthetic improvement of the chin is increasingly requested by patients, including those of Chinese origin. METHODS: A randomized, evaluator-blinded, no-treatment controlled study evaluated the effectiveness and safety of a flexible hyaluronic acid (HA) filler, Restylane® DefyneTM (HADEF), in the correction of chin retrusion in a Chinese adult population over 12 months after treatment. On Day 1, subjects were randomized 3:1 into two groups, HADEF or delayed-treatment controls, and those in the HADEF group were administered treatment. An optional touch-up treatment was administered 1 month after treatment to obtain optimal chin augmentation. The initially untreated control group was offered delayed-treatment after 6 months (including 1-month touch-up). RESULTS: HADEF was superior to no-treatment in improving chin retrusion according to the blinded evaluator at 6 months [Galderma Chin Retrusion Scale (GCRS) responder rate (≥ 1-point improvement from baseline) of 81% vs. 5% for untreated controls; p < 0.001, meeting the primary effectiveness objective. A majority of subjects maintained improvement at 12 months (61% in the HADEF group). All subjects reported satisfaction with results at 6 months after treatment with HADEF and aesthetic improvement rates per the global aesthetic improvement scale (GAIS) were high for 12 months following treatment, with an acceptable safety profile. CONCLUSIONS: These results demonstrated HADEF to be effective and safe for the correction of mild-to-moderate chin retrusion in Chinese subjects, confirming findings previously observed in a western population. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Directing Group Repositioning Strategy Enabled Site- and Enantioselective Addition of Heteroaromatic C-H Bonds to Acyclic Internal Alkenes.

Despite the notable advances achieved in the Murai-type hydroarylations, highly enantioselective catalytic addition of native (hetero)arenes to internal alkenes remains a prominent challenge. Herein, we report a directing group repositioning strategy, which enables the iridium-catalyzed enantioselective addition of heteroarenes including furan, benzofuran, and thiophene to internal enamides. The C-H bond at the C2 position of the heteroarene is site-selectively cleaved and added regioselectively to the ß-position of an enamide, affording a valuable ß-heteroaryl amide with high enantioselectivity. Mechanistic studies indicate that the rate and the enantioselectivity are determined by separate elementary steps.

Defect Detection for Metal Shaft Surfaces Based on an Improved YOLOv5 Algorithm and Transfer Learning.

To address the problem of low efficiency for manual detection in the defect detection field for metal shafts, we propose a deep learning defect detection method based on the improved YOLOv5 algorithm. First, we add a Convolutional Block Attention Module (CBAM) mechanism layer to the last layer of the backbone network to improve the feature extraction capability. Second, the neck network introduces the Bi-directional Feature Pyramid Network (BiFPN) module to replace the original Path-Aggregation Network (PAN) structure and enhance the multi-scale feature fusion. Finally, we use transfer learning to pre-train the model and improve the generalization ability of the model. The experimental results show that the method achieves an average accuracy of 93.6% mAP and a detection speed of 16.7 FPS for defect detection on the dataset, which can identify metal shaft surface defects quickly and accurately, and is of reference significance for practical industrial applications.

Enantioselective Hydrosilylation of ß,ß-Disubstituted Enamides to Construct α-Aminosilanes with Vicinal Stereocenters.

Despite the advances in the area of catalytic alkene hydrosilylation, the enantioselective hydrosilylation of alkenes bearing a heteroatom substituent is scarce. Here we report a rhodium-catalyzed hydrosilylation of ß,ß-disubstituted enamides to directly afford valuable α-aminosilanes in a highly regio-, diastereo-, and enantioselective manner. Stereodivergent synthesis could be achieved by regulating substrate geometry and ligand configuration to generate all the possible stereoisomers in high enantio-purity.

[Efficacy and safety of rituximab in children and adolescents with mature B-cell non-Hodgkin's lymphoma: a Meta analysis]. / 利妥昔单抗治疗儿童及青少年成熟Bç»†èƒžéžéœå¥‡é‡‘æ·‹å·´ç˜¤ç–—æ•ˆåŠå®‰å ¨æ€§çš„Meta分析.

OBJECTIVES: To study the efficacy and safety of rituximab combined with chemotherapy in the treatment of children and adolescents with mature B-cell non-Hodgkin's lymphoma (B-NHL) through a Meta analysis. METHODS: The databases including PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, Web of Science, China National Knowledge Infrastructure, Wanfang Data, and Weipu were searched to obtain 10 articles on rituximab in the treatment of mature B-NHL in children and adolescents published up to June 2022, with 886 children in total. With 3-year event-free survival (EFS) rate, 3-year overall survival (OS) rate, complete remission rate, mortality rate, and incidence rate of adverse reactions as outcome measures, RevMan 5.4 software was used for Meta analysis, subgroup analysis, sensitivity analysis, and publication bias analysis. RESULTS: The rituximab+chemotherapy group showed significant increases in the 3-year EFS rate (HR=0.38, 95%CI: 0.25-0.59, P<0.001), 3-year OS rate (HR=0.29, 95%CI: 0.14-0.61, P=0.001), and complete remission rate (OR=3.72, 95%CI: 1.89-7.33, P<0.001) as well as a significant reduction in the mortality rate (OR=0.31, 95%CI: 0.17-0.57, P<0.001), as compared with the chemotherapy group without rituximab. There was no significant difference in the incidence rate of adverse reactions between the two groups (OR=1.28, 95%CI: 0.85-1.92, P=0.24). CONCLUSIONS: The addition of rituximab to the treatment regimen for children and adolescents with mature B-cell non-Hodgkin's lymphoma can bring significant survival benefits without increasing the incidence of adverse reactions.

Iridium-Catalyzed Branch-Selective and Enantioselective Hydroalkenylation of α-Olefins through C-H Cleavage of Enamides.

Catalytic branch-selective hydrofunctionalization of feedstock α-olefins to form enantioenriched chiral compounds is a particularly attractive yet challenging transformation in asymmetric catalysis. Herein we report an iridium-catalyzed asymmetric hydroalkenylation of α-olefins through directed C-H cleavage of enamides. This atom-economical addition process is highly branch-selective and enantioselective, delivering trisubstituted alkenes with an allylic stereocenter. DFT calculations reveal the origin of regio- and enantioselectivity.

Remote Stereocenter through Amide-Directed, Rhodium-Catalyzed Enantioselective Hydroboration of Unactivated Internal Alkenes.

Despite the frequent occurrence of γ-branched amines in bioactive molecules, the direct catalytic asymmetric synthesis of this structural motif containing a remote stereocenter remains an important synthetic challenge. Here, we report an amide-directed, rhodium-catalyzed highly diastereo- and enantioselective hydroboration of unactivated internal alkenes. This method provided facile access to enantioenriched amines containing ß,γ-vicinal stereocenters. The application of this strategy to the synthesis of bioactive molecules was demonstrated. Computational studies indicated that migratory insertion of the alkene into rhodium hydride controls the enantioselectivity.

Population Pharmacokinetics of Intranasal Dexmedetomidine in Infants and Young Children.

BACKGROUND: Intranasal dexmedetomidine provides noninvasive, effective procedural sedation for pediatric patients, and has been widely used in clinical practice. However, the dosage applied has varied fourfold in pediatric clinical studies. To validate an appropriate dosing regimen, this study investigated the pharmacokinetics of intranasal dexmedetomidine in Chinese children under 3 yr old. METHODS: Intranasal dexmedetomidine 2 µg · kg-1 was administered to children with simple vascular malformations undergoing interventional radiological procedures. A population pharmacokinetic analysis with data from an optimized sparse-sampling design was performed using nonlinear mixed-effects modeling. Clearance was modeled using allometric scaling and a sigmoid postmenstrual age maturation model. Monte Carlo simulations were performed to assess the different dosing regimens. RESULTS: A total of 586 samples from 137 children aged 3 to 36 months were included in the trial. The data were adequately described by a two-compartment model with first-order elimination. Body weight with allometric scaling and maturation function were significant covariates of dexmedetomidine clearance. The pharmacokinetic parameters for the median subjects (weight 10 kg and postmenstrual age 101 weeks) in the authors' study were apparent central volume of distribution 7.55 l, apparent clearance of central compartment 9.92 l · h-1, apparent peripheral volume of distribution 7.80 l, and apparent intercompartmental clearance 61.7 l · h-1. The simulation indicated that at the dose of 2 µg · kg-1, 95% of simulated individuals could achieve a target therapeutic concentration of 0.3 ng · ml-1 within 20 min, and the average peak concentration of 0.563 ng · ml-1 could be attained at 61 min. CONCLUSIONS: The pharmacokinetic characteristics of intranasal dexmedetomidine were evaluated in Chinese pediatric patients aged between 3 and 36 months. An evidence-based dosing regimen at 2 µg · kg-1 could achieve a preset therapeutic threshold of mild to moderate sedation that lasted for up to 2 h.

Novel organization of mitochondrial minicircles and guide RNAs in the zoonotic pathogen Trypanosoma lewisi.

Kinetoplastid flagellates are known for several unusual features, one of which is their complex mitochondrial genome, known as kinetoplast (k) DNA, composed of mutually catenated maxi- and minicircles. Trypanosoma lewisi is a member of the Stercorarian group of trypanosomes which is, based on human infections and experimental data, now considered a zoonotic pathogen. By assembling a total of 58 minicircle classes, which fall into two distinct categories, we describe a novel type of kDNA organization in T. lewisi. RNA-seq approaches allowed us to map the details of uridine insertion and deletion editing events upon the kDNA transcriptome. Moreover, sequencing of small RNA molecules enabled the identification of 169 unique guide (g) RNA genes, with two differently organized minicircle categories both encoding essential gRNAs. The unprecedented organization of minicircles and gRNAs in T. lewisi broadens our knowledge of the structure and expression of the mitochondrial genomes of these human and animal pathogens. Finally, a scenario describing the evolution of minicircles is presented.

Latissimus dorsi muscle flap transfer through endoscopic approach combined with the implant after tissue expansion for breast reconstruction of mastectomy patients.

BACKGROUND: Implant-based breast reconstruction is easy to be performed but has flaws that an unnatural appearance might be presented when no sufficient coverage existing. While autologous tissue reconstruction also has disadvantages like donor site scar and skin patch effect. There is a demand for a new method to obtain natural and aesthetic appearance while surmounting drawbacks of conventional breast reconstruction surgery. METHODS: A retrospective review of thirty-one patients undergoing tissue expander (TE)/implant two-stage breast reconstruction with latissimus dorsi muscle flap (LDMF) transfer through endoscopic approach in Peking University Third Hospital from April 2016 to August 2020 was performed. The LDMF harvest time, drain time, and complications were reviewed. The 3D volume was obtained to assess the volume symmetry of bilateral breasts. The BREAST-Q reconstruction module was used to evaluate the satisfaction. RESULTS: The mean endoscopic LDMF harvest time was 90.4 min. In the mean follow-up of 11.2 months, there were no severe capsular contracture happened. The reconstructed side achieved good volume symmetry to the contralateral side (P = 0.256). Based on the evaluation of the BREAST-Q scores, the outcome of Satisfaction with Breasts was excellent or good in 87.1% of the cases. CONCLUSIONS: The novel type of two-stage breast reconstruction protocol, which includes tissue expansion followed by implant insertion with endoscopy-assisted LDMF transfer, could effectively reduce visible scars, avoid the patch effect, while require short time for LDMF harvest and present low incidence of complications. It is a promising method for breast reconstruction because it achieves good outcomes in the mastectomy patients.

Iridium-Catalyzed Regiodivergent and Enantioselective Hydroalkynylation of Unactivated 1,1-Disubstituted Alkenes.

Catalytic enantioselective functionalization of unactivated 1,1-disubstituted alkenes is challenging due to the difficulty to discriminate the enantiotopic faces. Enantioselective hydrofunctionalization of unactivated 1,1-disubstituted alkenes with tunable Markovnikov and anti-Markovnikov selectivity remains elusive. We report here an amide-directed, regiodivergent and enantioselective hydroalkynylation of unactivated alkenes. The regioselectivity can be readily tuned by the choice of a proper ligand. Catalytic alkynylations occurred with tunable Markovnikov and anti-Markovnikov selectivity to afford products containing acyclic tertiary or quaternary stereocenters ß to an amide. Combining a sequence of alkene isomerization and regioselective hydroalkynylation, we further realized an iridium-catalyzed formal asymmetric conjugated alkynylation of ß,ß-disubstituted α,ß-unsaturated amides. Computational studies suggest that the regioselectivity is dictated by the ligand structures.

Stereodefined Skipped Dienes through Iridium-Catalyzed Formal Addition of Tertiary Allylic C-H Bonds to Alkynes.

Preparation of skipped dienes with a quaternary carbon center at the C-3 position remains a synthetic challenge. We report here an iridium-catalyzed formal addition of tertiary sp3 C-H bond to alkyne for the facile preparation of skipped dienes. The tertiary allylic C-H bond is cleaved regioselectively, at the site of which a new C-C bond is formed. Enantioselective construction of acyclic quaternary carbon stereocenters is also demonstrated.

Ir-Catalyzed Regio- and Enantioselective Hydroalkynylation of Trisubstituted Alkene to Access All-Carbon Quaternary Stereocenters.

The stereoselective construction of all-carbon quaternary stereocenters, especially acyclic ones, represents an important challenge in organic synthesis. In particular, homopropargyl amides with a quaternary stereocenter ß to a nitrogen atom are valuable synthetic intermediates, which could be transformed to diverse chiral structures through alkyne transformations. However, highly enantioselective synthetic methods for homopropargyl amides with a ß quaternary stereocenter are extremely rare. We report here unprecedented substrate-directed, iridium-catalyzed enantioselective hydroalkynylations of trisubstituted alkenes to form an acyclic all-carbon quaternary stereocenter ß to a nitrogen atom. The hydroalkynylation of enamide occurred with unconventional selectivity, favoring the more hindered reaction site. Homopropargyl amides with ß-stereocenters were prepared in high regio- and enantioselectivities. Combined experimental and computational studies revealed the origin of the regio- and enantioselectivities.

Prognostic significance of immune landscape in tumour microenvironment of endometrial cancer.

Tumour microenvironment (TME) is crucial to tumorigenesis. This study aimed to uncover the differences in immune phenotypes of TME in endometrial cancer (EC) using Uterine Corpus Endometrial Carcinoma (UCEC) cohort and explore the prognostic significance. We employed GVSA enrichment analysis to cluster The Cancer Genome Atlas (TCGA) EC samples into immune signature cluster modelling, evaluated immune cell profiling in UCEC cohort (n = 538) and defined four immune subtypes of EC. Next, we analysed the correlation between immune subtypes and clinical data including patient prognosis. Furthermore, we analysed the expression of immunomodulators and DNA methylation modification. The profiles of immune infiltration in TCGA UCEC cohort showed significant difference among four immune subtypes of EC. Among each immune subtype, natural killer T cells (NKT), dendritic cells (DCs) and CD8+ T cells were significantly associated with EC patients survival. Each immune subtype exhibited specific molecular classification, immune cell characterization and immunomodulators expression. Moreover, the expression immunomodulators were significantly related to DNA methylation level. In conclusion, the identification of immune subtypes in EC tissues could reveal unique immune microenvironments in EC and predict the prognosis of EC patients.