Synergistic Catalysis Involving Palladium for Stereodivergent Csp3-Csp3 Coupling Reactions.

ConspectusTransition-metal-catalyzed coupling reactions of dienes (such as 1,3-dienes, alkoxyallenes, and aminoallenes) with carbon nucleophiles have proven to be a highly effective method for creating Csp3-Csp3 bonds. These reactions have perfect atom economy and typically occur under mild reaction conditions. By using chiral metal complexes as catalysts, it is possible to create enantioenriched molecules bearing allylic stereocenters with high enantioselectivities. However, challenges arise when Csp3-Csp3 bonds bearing two vicinal stereocenters are constructed through this type of coupling reaction. Due to the inherent diastereoselectivities, only the kinetically favored diastereoisomers (either the syn- or anti-product) are usually obtained through the transition-metal catalyst system. Achieving complementary stereoisomers with high selectivity, which require complete control of both absolute and relative configurations of multiple chiral centers in a single chemical transformation, is usually impossible.Over the past decade, significant advancements have been made in stereodivergent synthesis. Notably, iridium-related synergistic catalysis has been rapidly developed for stereodivergent allylic alkylation reactions. However, these systems were limited to using allylic alcohol derivatives as electrophilic partners. Finding ways to extend the use of synergistic catalysis to other types of stereodivergent reactions is a crucial issue that needs to be addressed.In 2019, we reported the first palladium-mediated synergistic system for the stereodivergent Csp3-Csp3 coupling between 1,3-dienes and aldimine esters. Lately, this strategy has proven successful in accessing stereodivergent coupling with diverse substrate patterns. In this Account, we will summarize our laboratory's efforts in developing a range of palladium-involved synergistic catalysis systems for the stereodivergent Csp3-Csp3 coupling reactions of dienes. We discovered several synergistic catalysis systems, including Pd/Cu(Ag), Pd/amine, Pd/Lewis base, and Pd/PTC. Additionally, we developed diverse dienes, such as 1,3-dienes, alkoxyallenes, and aminoallenes, to serve as suitable coupling partners for stereodivergent coupling. These processes provide an efficient method for constructing a range of chiral scaffolds bearing vicinal stereocenters. Density functional theory (DFT) calculations have been performed to elucidate the reaction mechanism and to rationalize the origins of the stereochemistry for some of the synergistic catalyst systems. Finally, the synthetic application of these methods has been demonstrated in the concise total synthesis of a number of natural products and bioactive molecules. It is anticipated that an increasing number of chemists will join in the research on stereodivergent Csp3-Csp3 coupling reactions and contribute to more elegant examples in this area. We believe future development will further push the boundary of asymmetric catalysis and find more innovative applications soon for synthesizing complex chiral molecules.

Machine learning methods, databases and tools for drug combination prediction.

Combination therapy has shown an obvious efficacy on complex diseases and can greatly reduce the development of drug resistance. However, even with high-throughput screens, experimental methods are insufficient to explore novel drug combinations. In order to reduce the search space of drug combinations, there is an urgent need to develop more efficient computational methods to predict novel drug combinations. In recent decades, more and more machine learning (ML) algorithms have been applied to improve the predictive performance. The object of this study is to introduce and discuss the recent applications of ML methods and the widely used databases in drug combination prediction. In this study, we first describe the concept and controversy of synergism between drug combinations. Then, we investigate various publicly available data resources and tools for prediction tasks. Next, ML methods including classic ML and deep learning methods applied in drug combination prediction are introduced. Finally, we summarize the challenges to ML methods in prediction tasks and provide a discussion on future work.

Computational methods, databases and tools for synthetic lethality prediction.

Synthetic lethality (SL) occurs between two genes when the inactivation of either gene alone has no effect on cell survival but the inactivation of both genes results in cell death. SL-based therapy has become one of the most promising targeted cancer therapies in the last decade as PARP inhibitors achieve great success in the clinic. The key point to exploiting SL-based cancer therapy is the identification of robust SL pairs. Although many wet-lab-based methods have been developed to screen SL pairs, known SL pairs are less than 0.1% of all potential pairs due to large number of human gene combinations. Computational prediction methods complement wet-lab-based methods to effectively reduce the search space of SL pairs. In this paper, we review the recent applications of computational methods and commonly used databases for SL prediction. First, we introduce the concept of SL and its screening methods. Second, various SL-related data resources are summarized. Then, computational methods including statistical-based methods, network-based methods, classical machine learning methods and deep learning methods for SL prediction are summarized. In particular, we elaborate on the negative sampling methods applied in these models. Next, representative tools for SL prediction are introduced. Finally, the challenges and future work for SL prediction are discussed.

Construction and implementation of a laparoscopic skill training course based on a smartphone application and virtual reality.

BACKGROUND: To develop a laparoscopic training course that combines a smartphone application (APP) and virtual reality (VR), and initially evaluate the feasibility and effectiveness of its implementation. METHODS: The Exploring Laparoscopy (Ex-Lap) app was developed to meet training demands. The course was designed by integrating the app with a VR simulator (LapSim®) and animal organ perfusion simulators. From January 2021 to December 2023, 91 participants were enrolled in the study and then divided into 5 separate batches to undergo the first stage of the course. The performance of the participants was evaluated by rating scale, the overall Training and Assessment of Basic Laparoscopic Techniques (TABLT) scores, and pass rates. Statistical analyses were conducted using SPSS 26.0, employing Kruskal-Wallis tests, Chi-squared analysis, and Fisher's exact test, depending on the data type. RESULTS: The Staged Training and Assessment of Laparoscopic Skills (STALS) course was developed, consisting of three stages. The overall pass rates for the first stage across the five batches ranged from 85 to 100%, with no significant difference (P = 0.387). No significant differences were found in the scale scores or TABLT scores for the training tasks among students from different batches (all P > 0.05). CONCLUSIONS: The STALS course is applicable in residency training, demonstrating satisfactory teaching effectiveness and replicability.

Enantioselective Three-Component Photochemical 1,4-Bisalkylation of 1,3-Butadiene with Pd/Cu Catalysis.

Catalysis by excited-state palladium has emerged as an active area of research, but controlling the enantioselectivity remains a challenge. Herein, we report the use of synergistic Pd/Cu catalysis to accomplish the first three-component photochemical 1,4-bisalkylation reactions of 1,3-butadiene. Consequently, α-amino acid esters bearing quaternary stereocenters were expeditiously synthesized from three simple starting materials: an alkyl bromide, butadiene, and an aldimine ester. Experimental and computational investigation of the reaction mechanism confirmed a radical pathway involving catalysis by an excited-state palladium species. The stereochemistry is mainly controlled by the chiral Cu catalyst.

Diastereodivergent Aldol-Type Coupling of Alkoxyallenes with Pentafluorophenyl Esters Enabled by Synergistic Palladium/Chiral Lewis Base Catalysis.

As a fundamental and synthetically useful C-C bond formation reaction, the aldol reaction is one of the most versatile transformations in organic synthesis. However, despite extensive research on asymmetric versions of the reaction, a unified method for stereoselective access to the complementary syn and anti diastereomeric products remains to be developed. In this study, we developed a synergistic palladium/chiral Lewis base system that overcomes the inherent diastereoselectivity bias of aldol reactions and, as a result, allowed us to achieve the first diastereodivergent coupling reactions of alkoxyallenes with pentafluorophenol esters. Computational studies suggest a mechanism involving an intermolecular protonative hydropalladation pathway rather than a palladium-hydride migratory insertion pathway. The origin of the stereochemistry for this synergistic catalysis system is rationalized by DFT calculations.

Acrosomal vesicle protein in predicting progression of pancreatitis in Chinese patients with acute pancreatitis.

The present preliminary investigation was designed to identify biomarkers in the progression of pancreatitis in Chinese patients with acute pancreatitis. Chinese patients aged <60 years with a confirmed diagnosis of acute pancreatitis were enrolled. A saliva sample was collected using salimetrics oral swab in precooled polypropylene tubes to prevent degradation of sensitive peptides. All samples were then centrifuged at 700 × g for 15 min at 4°C to remove debris. The supernatant of each sample was fractionated into 100µL aliquots and frozen at -70°C until analyses using affymetrix HG U133 Plus 2.0 array technique. Bedside index for severity acute pancreatitis (BISAP) score and CT severity index were recorded for each enrolled patient to assess the progression and severity of acute pancreatitis. Data from a total of 210 patients (105 patients in each group) were analyzed. Among identified biomarkers, acrosomal vesicle protein 1 was significantly higher in patients with disease progression as compared to patient without disease progression. Logistic regression model showed that acrosomal vesicle protein 1 (ACRV1) were positively correlated with the progression of diseases. The present reports showed that a mRNA salivary biomarker (ACRV1) are associated with progression of pancreatitis in patients with early stage of pancreatitis. This study suggest that mRNA salivary biomarker (ACRV1) is a predictor of pancreatitis progression.

Synergistic Pd/Amine-Catalyzed Stereodivergent Hydroalkylation of 1,3-Dienes with Aldehydes: Reaction Development, Mechanism, and Stereochemical Origins.

Metal-hydride-catalyzed hydroalkylation of 1,3-dienes with enolizable carbonyl compounds is an atom- and step-economical method for preparing chiral molecules with allylic stereocenters. Although high diastereo- and enantioselectivities have been achieved for many coupling partners, aldehydes have not yet been used for this purpose because they are less stable than other carbonyl compounds under basic conditions and they have the potential to rapidly epimerize at the α-position. Moreover, stereodivergent hydroalkylation reactions of 1,3-dienes to access complementary diastereomers with vicinal stereocenters is challenging. Herein, we describe a synergistic palladium/amine catalyst system that allowed us to achieve the first stereodivergent hydroalkylation reactions of 1,3-dienes with aldehydes. By choosing an appropriate combination of chiral palladium and amine catalysts, we could obtain either syn or anti coupling products, and this method therefore provides highly diastereo- and enantioselective access to complementary diastereomers of chiral aldehydes with α,ß-vicinal stereocenters. Density functional theory calculations revealed a mechanism involving PdH formation and migratory insertion into the alkene, followed by C-C bond formation. The origin of the stereoselectivities was investigated by means of distortion/interaction analysis.

Diastereodivergent Synthesis of ß-Amino Alcohols by Dual-Metal-Catalyzed Coupling of Alkoxyallenes with Aldimine Esters.

Both syn- and anti-ß-amino alcohols are common structural motifs in natural products, drug molecules, chiral ligands and catalysts. However, the currently available methods for synthesizing these motifs are limited to generate only one diastereoisomer. Therefore, development of a unified method for stereoselective access to complementary diastereomers would be highly desirable. Herein, we report a method for dual-metal-catalyzed diastereodivergent coupling of alkoxyallenes with aldimine esters. By carefully selecting the two metals and appropriate chiral ligands, we could synthesize both syn- and anti-ß-amino alcohol motifs with high enantioselectivity and diastereoselectivity from the same set of starting materials. Furthermore, stereodivergent syntheses of all four stereoisomers of ß-amino alcohols could be achieved. We demonstrated the synthetic utility of this method by concisely synthesizing two ß-amino alcohol natural products, mycestericins F and G.

Palladium-Catalyzed Regio- and Enantioselective Hydrosulfonylation of 1,3-Dienes with Sulfinic Acids: Scope, Mechanism, and Origin of Selectivity.

Chiral sulfones are important structural motifs in organic synthesis because of their widespread use in pharmaceutical chemistry. In particular, chiral allylic sulfones have drawn particular interest because of their synthetic utility. However, enantioselective synthesis of 1,3-disubstituted unsymmetrical chiral allylic sulfones remains a challenge. In this article, we report a protocol for (R)-DTBM-Segphos/Pd-catalyzed regio- and enantioselective hydrosulfonylation of 1,3-dienes with sulfinic acids, which provides atom- and step-economical access to 1,3-disubstituted chiral allylic sulfones. The reaction occurs under mild conditions and has a broad substrate scope. Combined experimental and computational studies suggest that the reaction is initiated by a ligand-to-ligand hydrogen transfer followed by a C-S bond reductive elimination via a six-membered transition state. Steric repulsion between the olefinic C-H of the substrate and the tert-butyl group of (R)-DTBM-Segphos was found to be a key factor in the enantiocontrol.

Stereodivergent Coupling of 1,3-Dienes with Aldimine Esters Enabled by Synergistic Pd and Cu Catalysis.

Herein we describe the use of synergistic Pd and Cu catalysis for stereodivergent coupling reactions between 1,3-dienes and aldimine esters. By using different enantiomers of the two metal catalysts, all four stereoisomers of the coupling products, which have two vicinal stereocenters, could be accessed with high diastereo- and enantioselectivity. This atom-economical cross-coupling reaction has a wide substrate scope and good functional group tolerance. Our work highlights the power of synergistic catalysis for asymmetric coupling reactions involving Pd-hydride catalysts.

Phosphine-catalyzed intramolecular Rauhut-Currier reaction: enantioselective synthesis of hydro-2H-indole derivatives.

A highly enantioselective intramolecular Rauhut-Currier reaction catalyzed by a multifunctional chiral aminophosphine catalyst was reported. A series of hydro-2H-indole derivatives that bear an all-carbon quaternary center were obtained in high yields (up to 94%), and excellent diastereo- and enantioselectivities (up to >20 : 1 dr and >99% ee). And this reaction could be performed on a gram scale using 2 mol% catalyst loading.

A Facile Strategy to Fabricate Multishape Memory Polymers with Controllable Mechanical Properties.

A facile blending strategy to fabricate multishape memory polymers (SMPs) with only one sort of phase transition material has been reported. In this work, olefin block copolymer (OBC) and styrene-b-(ethylene-co-butylene)-b-styrene (SEBS), which are both physically crosslinked, are blended with crystalline paraffin together. Due to the different interactions between polymer matrices and paraffin, the paraffin penetrated in OBC and SEBS exhibit separated melting transitions. It is quite interesting that merely paraffin distributed in OBC also shows two distinct melting transitions with enough OBC content in composites. Therefore, excellent quadruple shape memory effect can be achieved with a maximum of three melting transitions. Furthermore, through adjusting the polymer species and content, the mechanical and rheological properties can be conveniently tuned to a great extent. Compared with the reported strategies, this simple and controllable method sheds light on rapid design of multi-SMPs using inexpensive raw materials, which greatly paves the way for multi-SMPs from laboratory to factory.

Relaxation behavior of shear-induced crystallization precursors in isotactic polypropylene containing sorbitol-based nucleating agents with different nucleating abilities.

The nature of shear-induced crystallization precursors, especially their relaxation behaviour, is an important issue in polymer chemical physics. In our work, relaxation behavior of shear-induced crystallization precursors in isotactic polypropylene containing various sorbitol-based nucleating agents (NAs) with different nucleating abilities was investigated by using both rheological and in situ small angle X-ray scattering (SAXS) methods. Rheological crystallization kinetics results showed that the amount of shear-induced precursors, calculated separately from the total nuclei, decayed exponentially with relaxation time in both pure and nucleated iPP. By fitting the decay of shear-induced precursors with relaxation time, the relaxation rate of precursors in nucleated iPP was found to be slower than that in pure iPP. Interestingly, it further decreased with the increase in the nucleating ability of sorbitol-based NAs. Meanwhile, the life-time of precursors was prolonged in nucleated iPP with increasing nucleating ability. Similar results were also testified by in situ SAXS measurements. By investigating the life-times at different temperatures, the activation energy for the relaxation of precursors was calculated and found to increase with stronger nucleating abilities. Our results demonstrated that sorbitol-based NAs could stabilize the iPP precursors and the effect of stabilization enhanced with the increase in nucleating ability. We believe that our work can not only help better reveal the relaxation behavior of shear-induced precursors but also provides a new perspective for understanding the role of NAs in real processing.

Tuning the crystalline and mesophase structure of olefin block copolymer through self-nucleation and annealing treatments.

As a type of novel semi-crystalline block copolymers, the final properties of olefin block copolymers (OBCs) greatly depend on the crystalline and phase-separated structures. In the present work, we systematically investigated the influence of self-nucleation and annealing on the lamellar and mesophase-separated structure of OBCs. According to the crystalline and melting behavior after self-nucleation and annealing treatments, four different regimes can be recognized with the self-seeding temperature Ts varying from 125 to 109 °C. In regime A, only self-nucleation occurs, while it coexists with lamellar thickening in regime B. In regime C, there is only lamellar thickening behavior. The lamellar thickening induced inconsecutive lamellar crystals observed revealed that the rearrangement of the hard blocks, which are next to the soft blocks and trapped in the intermediate regime between crystalline and amorphous phases, into neighboring lamellar crystals should be the mechanism for the lamellar thickening of the OBCs. Surprisingly, no lamellar thickening occurs and a new small melting peak appears at lower temperatures in regime D. Considering the block dispersity of OBCs, the emergence of a small melting peak at lower temperatures can be attributed to the crystallization of the ethylene sequence with relatively weaker crystallization abilities, which are not able to crystallize in a standard crystalline state. Based on these findings, we gained some new understandings on lamellar thickening behavior of OBCs and established the self-nucleation and annealing process as a powerful tool for tuning the crystalline and phase-separated structures of OBCs.

Controllable detection threshold achieved through the toehold switch system in a mercury ion whole-cell biosensor.

Due to the toxicity of mercury and its harmful effects on human health, it is essential to establish a low-cost, highly sensitive and highly specific monitoring method with a wide detection range, ideally with a simple visual readout. In this study, a whole-cell biosensor with adjustable detection limits was developed for the detection of mercury ions in water samples, allowing controllable threshold detection with an expanded detection range. Gene circuits were constructed by combining the toehold switch system with lactose operon, mercury-ion-specific operon, and inducible red fluorescent protein gene. Using MATLAB for design and selection, a total of eleven dual-input single-output sensing logic circuits were obtained based on the basic logic of gene circuit construction. Then, biosensor DTS-3 was selected based on its fluorescence response at different isopropyl ß-D-Thiogalactoside (IPTG) concentrations, exhibiting the controllable detection threshold. At 5-20 µM IPTG, DTS-3 can achieve variable threshold detection in the range of 0.005-0.0075, 0.06-0.08, 1-2, and 4-6 µM mercury ion concentrations, respectively. Specificity experiments demonstrated that DTS-3 exhibits good specificity, not showing fluorescence response changes compared with other metal ions. Furthermore spiked sample experiments demonstrated its good resistance to interference, allowing it to distinguish mercury ion concentrations as low as 7.5 nM by the naked eye and 5 nM using a microplate reader. This study confirms the feasibility and performance of biosensor with controllable detection threshold, providing a new detection method and new ideas for expanding the detection range of biosensors while ensuring rapid and convenient measurements without compromising sensitivity.

Offshore habitats of endangered large mobile species in the western Yellow Sea: Quality status under shipping pressure.

Increasing shipping pressure (SP) deteriorates offshore habitats of large mobile species (LMS) and invalidates marine conservation systems, while the threat of SP to the survival of LMS is not well understood. Here, for the 16 endangered LMS in the western Yellow Sea, we quantified their habitat quality in specific sea areas and conservation capacity of marine protected areas (MPAs) under SP, based on AIS (Automatic Identification System) data and an overlay analysis method for SP surfaces and LMS habitats. Results indicate that three specific sea areas have partially lost habitat function, and their MPA networks have also lost 66.7 %, 59.1 %, and 9.2 % of conservation capacity, respectively. To prevent the continued degradation and extinction of endangered LMS, urgent rescue efforts are needed. This study highlights the importance of monitoring offshore shipping pressure and LMS habitat quality, and the findings contribute to the adjustment of marine spatial planning and LMS protection strategies.

Diphenylamino-Modified Neutral Pt(II) Complexes: Their Aggregation-Induced Phosphorescent Emission and Picric Acid-Sensing Properties.

Three neutral Pt(II) complexes with diphenylamino-modified 2-phenylpyridine derivatives as cyclometalating ligands and acetylacetone as the ancillary ligand exhibit aggregation-induced phosphorescent emission (AIPE) properties in THF/H2O. The crystal structures of the complexes highlight the contributions of non-covalent Pt···Pt interactions and hydrogen bonds to the AIPE properties. These AIPE-active Pt(II) complexes 1-3 have been successfully applied to detect picric acid (PA) in aqueous media, affording the lowest limit of detection at 70 nM. Furthermore, three Pt(II) complexes are able to detect PA in common water samples. The quenching of luminescence in the detection can be attributed to photo-induced electron transfer.

Graph based recurrent network for context specific synthetic lethality prediction.

The concept of synthetic lethality (SL) has been successfully used for targeted therapies. To further explore SL for cancer therapy, identifying more SL interactions with therapeutic potential are essential. Recently, graph neural network-based deep learning methods have been proposed for SL prediction, which reduce the SL search space of wet-lab based methods. However, these methods ignore that most SL interactions depend strongly on genetic context, which limits the application of the predicted results. In this study, we proposed a graph recurrent network-based model for specific context-dependent SL prediction (SLGRN). In particular, we introduced a Graph Recurrent Network-based encoder to acquire a context-specific, low-dimensional feature representation for each node, facilitating the prediction of novel SL. SLGRN leveraged gate recurrent unit (GRU) and it incorporated a context-dependent-level state to effectively integrate information from all nodes. As a result, SLGRN outperforms the state-of-the-arts models for SL prediction. We subsequently validate novel SL interactions under different contexts based on combination therapy or patient survival analysis. Through in vitro experiments and retrospective clinical analysis, we emphasize the potential clinical significance of this context-specific SL prediction model.

Refining prediction of stroke in sinus node dysfunction patients without atrial fibrillation using a P-combined score: a multi-centre study.

AIMS: Isolated sinus node dysfunction (ISND) is a sinus node dysfunction without atrial fibrillation. A high risk of ischaemic stroke (IS) has been reported in ISND populations. However, current guidelines do not recommend anticoagulation in ISND management. P-wave indicates ISND-related atrial remodelling. P-wave indices and the CHA2DS2-VASc score may contribute to risk stratification for ISND-related IS. METHODS AND RESULTS: In this multi-centre longitudinal cohort, ISND patients were divided into development (n = 1185) and external validation (n = 988) cohorts. Ischaemic stroke prediction capacity of the P-combined score was assessed with regard to discrimination, calibration, and clinical effectiveness. The cut-off value of the score was confirmed by using a restricted cubic spline curve. One hundred and twenty-four (10.46%) ISND patients developed IS [1.63%/year; 95% confidence interval (CI): 1.49-1.78%/year] after a median 3.02-year follow-up in the development cohort. The P-wave terminal force in electrocardiogram-lead V1 (PTFV1) was the only significantly abnormal P-wave index (adjusted hazard ratio: 2.56; 95% CI: 1.72-3.80). Therefore, we incorporated the PTFV1 with the CHA2DS2-VASc score to generate a P-combined score. For a 5-year IS risk, the P-combined score improved Harrell's C-statistic (95% CI) from 0.678 (0.618-0.738) to 0.716 (0.657-0.774) and 0.747 (0.677-0.816) to 0.808 (0.747-0.868) in the development and validation cohorts, respectively, along with calibration and decision curve analyses. The cut-off value of the score was 3 in the development cohort and well-discriminated in the validation cohort. CONCLUSION: Chinese ISND patients have a higher IS risk than the general population. Compared with the CHA2DS2-VASc score, the PTFV1-combined CHA2DS2-VASc score shows a better risk-stratification capacity for ISND-related IS.

By screening the risk factors of ischaemic stroke for isolated sinus node dysfunction (sinus node dysfunction without atrial fibrillation), we developed and validated a new scoring system­P-combined score, which is a combination of an abnormal P-wave terminal force in electrocardiogram-lead V1 (PTFV1) and the CHA2DS2-VASc score. We constructed the P-combined score in the following way: abnormal PTFV1 (2 points), age (1 point for 65­74 years and 2 points for ≥75 years), sex (1 point for female), congestive heart failure (1 point), hypertension (1 point), diabetes mellitus (1 point), vascular disease (1 point), and thrombotic event (2 points). Based on our analysis, we found that the P-combined score showed a strong performance (with a C-statistic of 0.716 for 5 years), which was better than the CHA2DS2-VASc score (C-statistic of 0.678 for 5 years). We also found that the performance of the P-combined score was rigorous in an independent cohort from two external centres (with a C-statistic of 0.808 for 5 years) and outperformed the CHA2DS2-VASc score (C-statistic of 0.747 for 5 years).