Synthesis of Z-gem-Cl,CF3-Substituted Alkenes by Stereoselective Cross-Metathesis and the Role of Disubstituted Mo Alkylidenes.

Stereochemically defined organofluorine compounds are central to drug discovery and development. Here, we present a catalytic cross-metathesis method for the synthesis of Z-trisubstituted olefins that contain a Cl- and a CF3-bound carbon terminus. Notably, the process is stereoselective, which is in contrast to the existing stereoretentive strategies that also involve a trisubstituted olefin as starting material. Reactions are catalyzed by a Mo monoaryloxide pyrrolide alkylidene, involve a trisubstituted alkene and gem-Cl,CF3-substituted alkene, and are fully Z-selective. Catalytic cross-coupling can be used to convert the C-Cl bond of the trisubstituted olefin to C-B, C-D, and different C-C bonds. We elucidate the role of Cl,CF3-disubstituted Mo alkylidenes. Experimental and computational (DFT) data show that in some instances a disubstituted alkylidene is formed and then transformed to a more active complex. In other cases, the Cl,CF3-disubstituted alkylidene is a direct participant in a catalytic cycle. The studies described shed new light on the chemistry of high oxidation-state disubstituted alkylidenes-scarcely investigated entities likely to be pivotal to approaches for stereocontrolled synthesis of tetrasubstituted alkenes through olefin metathesis.

Taking Olefin Metathesis to the Limit: Stereocontrolled Synthesis of Trisubstituted Alkenes.

ConspectusIn this Account, we share the story of the development of catalytic olefin metathesis processes that efficiently deliver a wide range of acyclic and macrocyclic E- or Z-trisubstituted alkenes. The tale starts with us unveiling, in collaboration with Richard Schrock and his team, the blueprint in 2009 for the design of kinetically controlled Z-selective olefin metathesis reactions. This paved the way for the development of Mo-, W-, and Ru-based catalysts and strategies for synthesizing countless linear and macrocyclic Z-olefins. Six years later, in 2015, we found that abundant Z-alkene feedstocks, such as oleic acid, can be directly transformed to high-value and more difficult-to-access alkenes through a cross-metathesis reaction promoted by a Ru-catechothiolate complex that we had developed; the approach, later coined stereoretentive olefin metathesis, was extended to the synthesis of E-alkenes.It was all about disubstituted alkenes until when in 2017 we addressed the challenge of accessing stereodefined Z- and E-trisubstituted alkenes, key to medicine and materials research. These transformations can be most effectively catalyzed by Mo monoaryloxides pyrrolide (MAP) and chloride (MAC) complexes. A central aspect of the advance is the merging of olefin metathesis, which delivered trisubstituted alkenyl fluorides, chlorides, and bromides with cross-coupling. These catalytic and stereoretentive transformations can be used in various combinations, thereby enabling access to assorted Z- or E-trisubstituted alkene. Ensuing work led to the emergence of other transformations involving substrates that can be purchased with high stereoisomeric purity, notably E- and Z-trihalo alkenes. Trisubstituted olefins, Z or E, bearing a chemoselectively and stereoretentively alterable F,Cl-terminus or B(pin),Cl-terminus may, thus, be easily and reliably synthesized. Methods for stereoretentive preparation of other alkenyl bromide regioisomers and α,ß-unsaturated carboxylic and thiol esters, nitriles, and acid fluorides followed, along with stereoretentive ring-closing metathesis reactions that afford macrocyclic trisubstituted olefins. Z- and E-Macrocyclic trisubstituted olefins, including those that contain little or no entropic support for cyclization (minimally functionalized) and/or are disfavored under substrate-controlled conditions, can now be synthesized. The utility of this latest chapter in the history of olefin metathesis has been highlighted by applications to the synthesis of several biologically active compounds, as well as their analogues, such as those marked by one or more site-specifically incorporated fluorine atoms or more active but higher energy and otherwise unobtainable conformers.The investigations discussed here, which represent every stereoretentive method that has been reported thus far for preparing a trisubstituted olefin, underscore the inimitable power of Mo-based catalysts. This Account also showcases a variety of mechanistic attributes─some for the first time, and each instrumental in solving a problem. Extensive knowledge of mechanistic nuances will be needed if we are to address successfully the next challenging problem, namely, the development of catalysts and strategies that may be used to synthesize a wide range of tetrasubstituted alkenes, especially those that are readily modifiable, with high stereoisomeric purity.

Exploration of plasma biomarkers for Alzheimer's disease by targeted lipid metabolomics based on nuclear magnetic resonance (NMR) spectroscopy.

Alzheimer's disease (AD) is the most common cause of dementia, but the disease lacks convenient and cost-effective alternative biomarkers currently. We utilized targeted lipid metabolomics based on nuclear magnetic resonance (NMR) spectroscopy to identify plasma biomarkers in AD patients. Our study was a cross-sectional study that enrolled 58 AD patients and 40 matched health controls (HCs). Firstly, we identified plasma lipid metabolites that were significantly different between the two groups based on P < 0.05 and variable importance in the projection (VIP) > 1. Then we examined the correlation between the lipid metabolites and cognitive function using partial correlation analysis and assessed the diagnostic ability of the lipid metabolites using receiver operating characteristic (ROC) curves. Seventeen lipoproteins showed significant differences between AD patients and HCs among 114 lipid metabolites. All 17 lipoproteins were subtypes of low-density lipoprotein (LDL). Among them, LDL-3 particle number, LDL-3 apolipoprotein-B, LDL-3 phospholipids, LDL free cholesterol and LDL phospholipids were significantly correlated with cognitive function. The ROC curves showed that LDL-2 triglycerides (TG) and LDL-3 TG could significantly distinguish AD patients from HCs, with the area under the curve (AUC) above 0.7. In addition, we explored a strategy of combined diagnosis that significantly improved the diagnostic efficacy for AD (AUC = 0.879). Our study provides insight into the lipoprotein alterations associated with AD and potential biomarkers for its diagnosis and cognitive function assessment.

Elemental geochemical evidence for the river-derived sources of trace metals in surface sediments from Hangzhou Bay, East China Sea.

Coastal estuaries are often heavily subject to riverine influences by the inputs of sediment from terrestrial sources. Hangzhou Bay (HZB) is threatened by the riverine derived trace metals from two large rivers of Qiantang River (QTR) and Yangtze River (YZR). However, previous studies mainly focused on the incidental transport from the largest river in China (YZR) and failed to simultaneously evaluate the contributions of these two rivers, especially the directly flowing river of QTR, by their trace elemental geochemical composition and distribution. Herein, a comprehensive study identified the river-derived sources of multiple trace metals in surface sediments which transported from both of the rivers. The sampling stations were separated into three regions of YZR, HZB, and QTR based on their spatial distributions of sediment grain size and components. The significant variations for most of the trace metals concentrations, except for Cd, Th, and U, were found among three regions (χ2 ≥ 8.22, p ≤ 0.016). The highest concentrations in HZB were mainly resulted from the grain size effect (68.82% of the total variance), while the highest concentrations of Sr, Cd, and Ba in YZR and Zr and Hf in QTR were attributed to the anthropogenic source (11.90%) and mineral composition (6.21%) of river basins. After normalized the diversity of multiple trace metals concentrations and the influence of grain size by ratios of Igeo and EFLi, three regions were effectively distinguished. It was indicated that As, Cd, and Sb were enriched in the sediments of rivers by anthropogenic source (EFLi > 1.5 and/or Igeo > 1). The results evidenced that, after removing the influence of grain size, elemental geochemical composition of the surface sediments confidently identified the river-derived anthropogenic sources of the enriched trace metals from two major rivers, and largely from YZR.

Catalytic Cross-Metathesis Reactions That Afford E- and Z-Trisubstituted Alkenyl Bromides: Scope, Applications, and Mechanistic Insights.

Stereochemically defined trisubstituted alkenes with a bromide and a methyl group at a terminus can be readily and stereoretentively derivatized through catalytic cross-coupling, affording unsaturated fragments found in many bioactive natural products. A direct method for generating such entities would be by stereocontrolled catalytic cross-metathesis (CM). Such methods are scarce however. Here, we present a stereoretentive strategy for CM between tri-, Z- or E-di, or monosubstituted olefins and Z- or E-2-bromo-2-butene, affording an assortment of E- or Z-trisubstituted alkenyl bromides. The majority of the transformations were catalyzed by two Mo monoaryloxide pyrrolide (MAP) complexes, one purchasable and the other accessible by well-established protocols. Substrates, such as feedstock trisubstituted olefins, can be purchased; the alkenyl bromide reagents are commercially available or can be prepared in two steps in a multigram scale. The catalytic process can be used to generate products that contain polar moieties, such as an amine or an alcohol, or sterically hindered alkenes that are α- or ß-branched. The utility of the approach is highlighted by a brief and stereocontrolled synthesis of an unsaturated fragment of phomactin A and a concise total synthesis of ambrein. An unexpected outcome of these investigations was the discovery of a new role for the presence of a small-molecule alkene in an olefin metathesis reaction. DFT studies indicate that this additive swiftly reacts with a short-lived Mo alkylidene and probably helps circumvent the formation of catalytically inactive square pyramidal metallacyclobutanes, enhancing the efficiency of a transformation.

CircTMOD3 promotes lipopolysaccharide-induced chondrocyte apoptosis in osteoarthritis by sponging miR-27a.

INTRODUCTION: The progression of osteoarthritis (OA) requires the involvement of lipopolysaccharide (LPS)-induced inflammation, in which circTMOD3 plays an important role. We predicted that circTMOD3 could interact with miR-27a to inhibit LPS-induced chondrocyte apoptosis and explored the interaction between circTMOD3 and miR-27a in OA. MATERIALS AND METHODS: Total RNAs were isolated from cartilage tissue samples from both OA patients (n = 62) and controls (n = 62) and subjected to RT-qPCRs to determine circTMOD3 and miR-27a (mature and premature) expression. Subcellular location of circTMOD3 and its interaction with premature miR-27a were analyzed using subcellular fractionation assay and RNA-RNA pulldown assay, respectively. CircTMOD3 was overexpressed in chondrocytes to study its role in miR-27a maturation. The roles of circTMOD3 and miR-27a in LPS-induced chondrocyte apoptosis were analyzed using cell apoptosis assay. RESULTS: CircTMOD3 and premature miR-27a levels were increased while mature miR-27a level was decreased in OA. CircTMOD3 was located in both nuclear and cytoplasm fractions of chondrocytes. CircTMOD3 directly interacted with premature miR-27a and promoted LPS-induced chondrocyte apoptosis, while miR-27a inhibited LPS-induced chondrocyte apoptosis. Moreover, circTMOD3 overexpression suppressed miR-27a maturation and reduced the inhibitory effects of miR-27a on LPS-induced chondrocyte apoptosis. CONCLUSION: CircTMOD3 suppresses miR-27a maturation in OA to promote chondrocyte apoptosis induced by LPS.

Reagent-Controlled Highly Stereoselective Difluoromethylation: Efficient Access to Chiral α-Difluoromethylamines from Ketimines.

A reagent-controlled highly stereoselective reaction between (S)-difluoromethyl phenyl sulfoximine 1 and imines is reported, and this synthetic method provides a variety of enantiomerically enriched α-difluoromethyl amines. The main pros of this approach include high efficiency, high stereoselectivity, and a broad substrate scope, which is probably achieved through a non-chelating transition state.

Catalytic and Stereoselective Transformations with Easily Accessible and Purchasable Allyl and Alkenyl Fluorides.

Stereochemically defined organofluorine compounds are vital to drug discovery and many applicable catalytic strategies have been introduced for accessing these entities stereoselectively. One approach entails incorporation of a fluorine atom (C-F bond formation) or an organofluorine moiety (e.g., CF3 or CF2 H), and another exploits commercially available compounds with one or more fluorine atoms. Here, we present the state-of-the-art regarding the use of alkenyl and allylic fluorides in preparation of stereochemically defined fluoro-organic molecules. Allylic and alkenyl fluorides may be purchased or generated from a commercially available acid, carboxylate salt, ester, aldehyde hydrate, or ketone bearing several fluorine atoms next to a carbonyl group. We underscore the untapped potential of purchasable organofluorine compounds, many allylic and alkenyl fluorides, as launching points for development of stereoselective processes that are of value to therapeutic science.

From C1 to C3 : Copper-Catalyzed gem-Bis(trifluoromethyl)olefination of α-Diazo Esters with TMSCF3.

A Cu-catalyzed gem-bis(trifluoromethyl)olefination of α-diazo esters, using TMSCF3 as the only fluorocarbon source, has been developed and provides an exquisite method to access gem-bis(trifluoromethyl)alkenes. This unprecedented olefination process involves a carbene migratory insertion into "CuCF3 " to generate the α-CF3 -substituted organocopper species, which then undergoes ß-fluoride elimination and two consecutive addition-elimination processes to give the desired products. The key to this efficient one-pot C1 -to-C3 synthetic protocol lies in the controllable double (over single and triple) trifluoromethylations of the gem-difluoroalkene intermediates.

Catalytic Enantioselective Synthesis of Allylic Boronates Bearing a Trisubstituted Alkenyl Fluoride and Related Derivatives.

The first catalytic method for diastereo- and enantioselective synthesis of allylic boronates bearing a Z-trisubstituted alkenyl fluoride is disclosed. Boryl substitution is performed with either a Z- or E-allyldifluoride and is catalyzed by bisphosphine/Cu complexes, affording products in up to 99 % yield with >98:2 Z/E selectivity and 99:1 enantiomeric ratio. A variety of subsequent modifications are feasible, and notable examples are diastereoselective additions to aldehydes/aldimines to access homoallylic alcohols/amines containing a fluorosubstituted stereogenic quaternary center.

An IBeacon-Based Location System for Smart Home Control.

Indoor location and intelligent control system can bring convenience to people’s daily life. In this paper, an indoor control system is designed to achieve equipment remote control by using low-energy Bluetooth (BLE) beacon and Internet of Things (IoT) technology. The proposed system consists of five parts: web server, home gateway, smart terminal, smartphone app and BLE beacons. In the web server, fingerprint matching based on RSSI stochastic characteristic and posture recognition model based on geomagnetic sensing are used to establish a more efficient equipment control system, combined with Pedestrian Dead Reckoning (PDR) technology to improve the accuracy of location. A personalized menu of remote “one-click” control is finally offered to users in a smartphone app. This smart home control system has been implemented by hardware, and precision and stability tests have been conducted, which proved the practicability and good user experience of this solution.

Stereoselective Carbonyl Olefination with Fluorosulfoximines: Facile Access to Z or E Terminal Monofluoroalkenes.

Terminal monofluoroalkenes are important structural motifs in the design of bioactive compounds, such as homeostasis regulators and mechanism-based enzyme inhibitors. However, it is difficult to control the stereoselectivity of known carbonyl olefination reactions, and olefin metathesis is limited to disubstituted terminal monofluoroalkenes. Although sulfoximines have been used extensively in organic synthesis, reports on their use in carbonyl olefination reactions have not appeared to date. Herein, we report highly stereoselective carbonyl monofluoroolefination with a fluorosulfoximine reagent. The potential of this method is demonstrated by the synthesis of MDL 72161 and by the late-stage monofluoromethylenation of complex molecules, such as haloperidol and steroid derivatives.

Fabrication of hierarchical TiO2 coated Co20Ni80 particles with tunable core sizes as high-performance wide-band microwave absorbers.

Multifunctional composite microspheres with a Co20Ni80 core and anatase TiO2 shells (Co20Ni80@TiO2) are synthesized by combining a solvothermal reaction and a calcination process, and include a series of microspheres with different core sizes (100 nm, 500 nm and 1 µm). The mechanism of self-assembly of the primary particles has been effective in both the fabrication of the core and the process of coating. The obtained core-shell particles possess superior monodispersity, size uniformity, and tailored core sizes, and are characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Furthermore, the electromagnetic shielding performance of the microspheres is investigated in terms of the theory of transmission lines. The Co20Ni80@TiO2 core-shell particle (CoNi@TiO2) with a well-defined core size of 500 nm demonstrates a remarkable wide-band electromagnetic shielding performance of up to 6.2 GHz (10.0-16.2 GHz, <-10 dB) within 2-18 GHz, which is due to the tunable multi-component hierarchical structure of the particles and contributes to the complex permittivity and permeability and the multiple scattering loss of the microwave. The Co20Ni80@TiO2 particle with a specific core size (500 nm) is a promising candidate for the wide-band electromagnetic shielding materials, gathering increasing interest from researchers.

Nucleophilic difluoromethylation of epoxides with PhSO(NTBS)CF2H by a preorganization strategy.

Unlike the facile synthesis of ß-monofluoromethyl alcohols by nucleophilic monofluoromethylation of epoxides, the synthesis of ß-difluoromethyl alcohols by nucleophilic difluoromethylation of epoxides still remains a challenge. Herein, studies on tackling this problem with PhSO(NTBS)CF2H (2; TBS=tert-butyldimethylsilyl) are reported. The preorganization of 2 and epoxides with BF3⋅Et2O was found to be crucial for the reaction. The reaction shows excellent regioselectivity and has a broad substrate scope. The facile transformation of the ring-opened products to ß-difluoromethyl, γ-difluoromethyl, and ß-difluoromethylenyl alcohols demonstrates the synthetic utility of the reaction.

A new approach for the treatment of proximal humeral fractures using the TRIGEN proximal humeral nail.

The optimal surgical treatment for displaced proximal humeral fractures continues to be controversial. One of the new treatment options is the minimally invasive intramedullary nail. The purpose of this study was to evaluate the functional outcome of using the TRIGEN proximal humeral nail (PHN) for the treatment of displaced proximal humeral fractures in elderly patients. From January 2004 to December 2008, 64 elderly patients (age > 60 years old) with displaced proximal humeral fractures were treated using TRIGEN PHN. A complete 12-month postoperative follow-up was available for 54 patients. The study cohort included two-part (29 shoulders), three-part (22 shoulders), and four-part (3 shoulders) Neer classification fracture types. The Constant-Murley score was used to assess functional outcome. Radiological outcomes were evaluated, and all complications were recorded. All fractures were united. The Constant-Murley score data indicated that the patients experienced improvement from 6 to 12 months postoperatively. The mean absolute Constant-Murley score on the injured side increased from 71.2 ± 11.2 points at 6 months to 82.4 ± 16.4 points at 12 months (P = 0.01). The mean neck-shaft angle 1 year after surgery was 125° ± 8.1° (95°-140°). Secondary complications were minimal and observed in only 6 of 54 patients. In conclusion, the TRIGEN intramedullary humeral nail is effective for the treatment of proximal humeral fractures.

Medical Federated Model with Mixture of Personalized and Shared Components.

Although data-driven methods usually have noticeable performance on disease diagnosis and treatment, they are suspected of leakage of privacy due to collecting data for model training. Recently, federated learning provides a secure and trustable alternative to collaboratively train model without any exchange of medical data among multiple institutes. Therefore, it has draw much attention due to its natural merit on privacy protection. However, when heterogenous medical data exists between different hospitals, federated learning usually has to face with degradation of performance. In the paper, we propose a new personalized framework of federated learning to handle the problem. It successfully yields personalized models based on awareness of similarity between local data, and achieves better tradeoff between generalization and personalization than existing methods. After that, we further design a differentially sparse regularizer to improve communication efficiency during procedure of model training. Additionally, we propose an effective method to reduce the computational cost, which improves computation efficiency significantly. Furthermore, we collect five real medical datasets, including two public medical image datasets and three private multi-center clinical diagnosis datasets, and evaluate its performance by conducting nodule classification, tumor segmentation, and clinical risk prediction tasks. Comparing with 14 existing related methods, the proposed method successfully achieves the best model performance, and meanwhile up to 60% improvement of communication efficiency. Source code is public, and can be accessed at: https://github.com/ ApplicationTechnologyOfMedicalBigData/pFedNet-code.

Decadal changes of macrofauna community in a semi-enclosed Bay of Yueqing in East China Sea.

To reveal the long-term variation of macrofauna community in Yueqing Bay, an aquacultural bay famous for its shellfish culturing in the East China Sea, macrofauna samples were collected in three period from 2002 to 2003 and 2006-2007 to 2020-2021. The results show that macrofaunal community structure in this area has changed significantly (ANOSIM, p < 0.01) in nearly two decades with significant decreases in species number, biodiversity index and average biomass. Meanwhile, the taxa composition also changed significantly as the dominance of annelid increased while that of mollusks, echinoderms and vertebrates decreased. As a consequence of the variation of taxa composition and total biomass, macrofauna community showed a tendency of miniaturization as individuals with smaller body size and lower biomass dominated the community. According to the results of CCA analysis, temperature, salinity and dissolved oxygen content were the main environmental factors that restricted the species composition of macrofauna community. Further studies still needed to reveal the main reasons that cause the variation of macrofauna community. Overall, the results of this study suggest that the present status of Yueqing Bay benthic ecosystem is concerning from a macrobenthos perspective, as the biodiversity index and biomass of macrofauna decreased significantly. Effective measures should be taken in urgently to restrain the safety and function of coastal ecosystems.

Characteristic chromanone acids from Calophyllum membranaceum: Determination of C-3 configuration and anti-inflammatory activity.

One undescribed homologous furanochromanone (1) featuring a 6/6/5/3 tetracyclic skeleton and four highly oxidized pyranochromanones (2-5), along with a set of four pyranochromanone stereoisomers [(±)-6a and (±)-6b], were isolated from the leaves of Calophyllum membranaceum Gardn. Et Champ. Their structures were elucidated by using spectroscopic data, Snatzke's method, quantum-chemical calculations, and X-ray crystallographic analysis. The correlation of characteristic Cotton effects and specific chemical shifts with C-3 configuration provided a convenient approach to assign the C-3 configuration of 2,3-dimethylchromanones. The stereochemical assignments of 3-OH substituted pyranochromanones by quantum-based NMR methods following single/double MTPA derivatization were consistent with the ECD/NMR prediction, which verified the feasibility and reliability of the proposed empirical rule. The underlying mechanism was further clarified by conformational and molecular orbital analyses. Moreover, biological evaluation and binding assays demonstrated that compound 3 (KD = 0.45 µM) tightly binds to the TLR4-MD2 target, thereby inhibiting the TLR4/MyD88-dependent and -independent signal pathways. This study provides the first evidence that Calophyllum chromanones are a novel structural type of TLR4 inhibitors, exerting their anti-inflammatory effects by disrupting the binding between TLR4 and MD2.

Multiple interface coupling in ultrathin Mn-based composites for superior catalytic oxidation: Implications of interface coupling on structural defects.

Manganese oxide has been recognized as one of the most promising gaseous heterogeneous catalysts due to its low cost, environmental friendliness, and high catalytic oxidation performance. The modulation of the interfacial coupling effect of manganese oxides by chemical means is considered a critical and effective way to improve the catalytic performance. Herein, a novel one-step synthetic strategy of highly-efficient ultrathin manganese-based catalysts is proposed through optimal regulation of metal/manganese oxide multi-interfacial coupling. Carbon monoxide (CO) and propane (C3H8) oxidation are employed as probe reactions to investigate the structure-catalytic mechanism - catalytic performance relationship. The ultrathin manganese (Mn)-based catalyst exhibits superior low-temperature catalytic activity with a 90% conversion of CO/C3H8 realized at 106℃ and 350℃. Subsequently, the effect of "interfacial effect" on the intrinsic properties of manganese oxides is revealed. The ultrathin appearance of two-dimensional (2D) manganese dioxide (MnO2) nanosheets changes the binding force in the vertical direction, thus resulting in an increase in the average manganese-oxygen (Mn-O) bond length and exposing more surface defects. Besides, the introduction of Copper (Cu) species into the catalyst further weakens the Mn-O bond and promotes the generation of oxygen vacancies, which subsequently enhances the oxygen migration rate. This study provides new insights into the optimal design of transition metal oxide interfacial assemblies for efficient catalytic reactions.

Ecological risk assessment of trace metals in sediments and their effect on benthic organisms from the south coast of Zhejiang province, China.

To explore the ecological risks of trace metals in sediments and their relationship with benthic organisms, 12 trace metals were analyzed and the macrobenthos were identified in the sediments collected from the south coast of Zhejiang province which belongs to the East China Sea. Spatially, the concentrations of most trace metals were high in the estuary, except for Ba and Sr. There was no obvious enrichment for trace metals, except that the concentration of Cd slightly exceeded the coastal background. The ecological risks calculated by the concentrations of Cr, Cd, Cu, Zn, Pb, and Ni in sediments showed that the methods based on sediment quality guidelines could judge the ecological risk more intuitively than the methods based on background value (PN, PLI, RI). The significant correlations between ecological risks and benthos density and biomass revealed the negative impact of trace metals at high concentrations on macrobenthic survival in sediments.