Synthesis of Chiral Endocyclic Allenes and Alkynes via Pd-Catalyzed Asymmetric Higher-Order Dipolar Cycloaddition.

A Pd-catalyzed asymmetric higher-order dipolar cycloaddition between allenyl carbonates and azadienes is achieved by exploiting novel alkylidene-π-allyl-Pd dipoles. This research provides a modular platform for the synthesis of challenging chiral endocyclic allenes bearing a medium-sized heterocyclic motif and a centrally chiral stereocenter in good yields with high enantio- and diastereoselectivities (29 examples, up to 97% yield, 97:3 er and >19:1 dr). Experimental and computational studies elucidate the possible reaction mechanism and the observed stereochemical results. Based on the mechanistic understanding, a new π-propargyl-Pd dipole was designed to further extend the success of the higher order dipolar cycloaddition strategy to the synthesis of 10-membered endocyclic alkynes from propargyl carbonates and azadienes (13 examples, up to 98% yield and 94.5:5.5 er).

Comparison of Efficacy and Safety of Different Guided Technologies Combined With Ultrathin Bronchoscopic Biopsy for Peripheral Pulmonary Lesions.

INTRODUCTION: Various bronchoscopic guidance techniques have emerged to improve the diagnostic yield of peripheral pulmonary lesions (PPLs), especially when combined with ultra-thin bronchoscopy. However, uncertainties exists in the convenience, accuracy rate, and complications of these techniques. We compared the feasibility, accuracy rate, and complication rates of transbronchial biopsy of PPLs sampled by the standard thin-layer CT navigation combined with ultrathin bronchoscopy (CTNUTB), the Lungpro virtual navigation combined with ultrathin bronchoscopy (VNUTB), and electromagnetic navigation combined with ultrathin bronchoscopy (ENUTB). METHODS: Retrospectively identified were 256 patients sampled with transbronchial biopsy of PPLs. Eligible patients referred for CTNUTB, VNUTB, and ENUTB from January 2017 to December 2021 were included. We comprehensively compared the accuracy rate, feasibility, and complication rates for each method. RESULTS: There was no significant difference in the accuracy rate of CTNUTB, VNUTB, and ENUTB (p = 0.293). The operation time via Lungpro navigation was the shortest (14.4 min, p < 0.001). The planning time via CT planning was the shortest (7.36 min, p < 0.001). There was no difference in the incidence of complications such as hemorrhage, pneumonia, and pneumothorax (p = 0.123). Besides, ENUTB costs more than $2000, while CTNUTB and VNUTB cost only about $130-230. CONCLUSION: CTNUTB is still the main bronchoscopy method we recommended, which has low cost, simple operation, and safety no less than the others. In contrast, ENUTB provides a higher accuracy rate for small diameter nodules (less than 2 cm), which has a high use value and is worth promoting in the future.

Cobalt-Catalyzed Regio-, Diastereo- and Enantioselective Reductive Coupling of 1,3-Dienes and Aldehydes.

Catalytic regio-, diastereo- and enantioselective reductive coupling of 1,3-dienes and aldehydes through regio- and enantioselective oxidative cyclization followed by regio- and diastereoselective protonation promoted by a chiral phosphine-cobalt complex is presented. Such processes represent an unprecedented reaction pathway for cobalt catalysis that enable selective transformation of the more substituted alkene in 1,3-dienes, affording a broad scope of bishomoallylic alcohols without the need of pre-formation of stoichiometric amounts of sensitive organometallic reagents in up to 98% yield, >98:2 regioselectivity, >98:2 dr and 98:2 er. Application of this method to construction of axial stereogenicity and deuterated stereogenic center provided a wide range of multifunctional chiral building blocks that are otherwise difficult to access. DFT calculations revealed the origin of regio- and stereoselectivity as well as a unique oxidative cyclization mechanism for cobalt catalysis.

Knowledge, attitudes, and practice of physicians and pharmacists regarding the prevention and treatment of cardiovascular toxicity associated with cancer treatment.

This study aimed to explore physicians' and pharmacists' knowledge, attitudes, and practice (KAP) regarding the prevention and treatment of cardiovascular toxicity associated with cancer treatment. A multicenter cross-sectional study included physicians and pharmacists between April 2023 and June 2023. The study included 918 participants (514 physicians and 404 pharmacists). The average scores of knowledge, attitudes, and practice were 11.6 ± 3.39, 24.7 ± 2.6, and 26.3 ± 6.8 points. Sufficient knowledge was significantly associated with age ≥ 41 years (odds ratio (OR) = 2.745, 95% confidence interval (CI) 1.086-6.941, P = 0.033), male (OR = 2.745, 95% CI 1.150-2.223, P = 0.005), bachelor's degree (OR = 0.084, 95% CI 0.013-0.533, P = 0.009), master's degree and above (OR = 0.096, 95% CI 0.015-0.609, P = 0.013), physician occupation (OR = 7.601, 95% CI 1.337-43.207, P = 0.022), pharmacy department (OR = 18.858, 95% CI 3.245-109.57, P = 0.001), oncology department (OR = 4.304, 95% CI 2.426-7.634, P < 0.001), cardiology department (OR = 3.001, 95% CI 1.387-6.492, P = 0.005), hospitals located in Eastern China (OR = 1.957, 95% CI 1.120-3.418, P = 0.018), and hospitals located in Western China (OR = 3.137, 95% CI 1.783-5.518, P < 0.001). Positive attitudes were significantly associated with a senior professional title (OR = 2.989, 95% CI 1.124-7.954, P = 0.028) and hospitals located in Eastern China (OR = 0.424, 95% CI 0.257-0.698, P = 0.001), Western China (OR = 0.231, 95% CI 0.136-0.394, P < 0.001), and Southern China (OR = 0.341, 95% CI 0.198-0.587, P < 0.001). Proactive practice was significantly associated with male (OR = 1.414, 95% CI 1.029-1.943, P = 0.033), senior professional title (OR = 3.838, 95% CI 1.176-12.524, P = 0.026), oncology department (OR = 3.827, 95% CI 2.336-6.272, P < 0.001), and cardiology department (OR = 2.428, 95% CI 1.263-4.669, P = 0.008). Both physicians and pharmacists had positive attitudes toward the prevention and treatment of cardiovascular toxicity associated with cancer treatment, while their knowledge and practice were not as proactive.

A bivariate fluorescence biosensor based on Janus DNA nanoarchitecture-loaded dual-emissive Ag nanoclusters as bi-responsive signaling reporters.

Constructing label-free bivariate fluorescence biosensor would be intriguing and desired for the recognizable and accurate detection of two specific DNA segments, yet the design of functional DNA structures with low overlapped interference might be challenging. Herein in this work, a double-faced Janus DNA nanoarchitecture (JDNA) with bi-responsive recognition regions on opposite sides was assembled, which consisted of two substrate strands and two template strands for loading green-/red-emissive Ag nanoclusters (gAgNC and rAgNC) as bivariate signaling reporters. Of note, the hybridized double helix in the middle rationally oriented two flank faces and stabilized the rigid conformation of JDNA, while the template sequences of bicolor clusters were blocked to minimize non-specific background leakage. Upon inputting two targets, the discernible hairpins lost their hairpin structures due to forming two dsDNA complexes. They were executed to simultaneously invade JDNA for activating two individual target-recycled strand displacement (TRSD) events, guiding signal transduction and efficient amplification. Consequently, the clustering templates were unlocked via the tailored conformation switch of JDNA, in which gAgNC and rAgNC were in situ synthesized in two diagonal positions, thereby significantly emitting bi-responsive signal without cross interference. Benefited from the logic integration of double-faced JDNA and TRSD, a label-free, sensitive and specific bivariate fluorescence approach was developed, which would open a new avenue for the potential application in biosensing and bioanalysis.

Cobalt-Catalyzed Chemo- and Stereoselective Transfer Semihydrogenation of 1,3-Dienes with Water as a Hydrogen Source.

(Z)-1,2-Disubstituted, trisubstituted, and tetrasubstituted alkenes are not only important units in medicinal chemistry, natural product synthesis, and material science but also useful intermediates in organic synthesis. Development of catalytic stereoselective transformations to access multisubstituted alkenes with various substitution patterns from easily accessible modular starting materials and readily available catalysts is a crucial goal in the field of catalysis. Water is an ideal hydrogen source for catalytic transfer hydrogenation despite of the high difficulty to activate water. Here, we report a cobalt-catalyzed protocol for regio- and stereoselective transfer semihydrogenation of 1,3-dienes to construct a broad scope of (Z)-1,2-disubstituted, (Z)-, (E)-trisubstituted, and tetrasubstituted alkenes in high stereoselectivity with H2O as the hydrogen source. Mechanistic studies revealed that the reactions proceeded through a unique Co(I)/Co(III) cycle and involved a 1,4-cobalt shift process, which is an unprecedented reaction pathway, providing a new platform for modular synthesis of multisubstituted alkenes as well as opportunities for designing novel reaction modes and pushing forward the advancement in organocobalt chemistry.

Hyperconjugation-Driven Isodesmic Reaction of Indoles and Anilines: Reaction Discovery, Mechanism Study, and Antitumor Application.

Isodesmic reactions, in which chemical bonds are redistributed between substrates and products, provide a general and powerful strategy for both biological and chemical synthesis. However, most isodesmic reactions involve either metathesis or functional-group transfer. Here, we serendipitously discovered a novel isodesmic reaction of indoles and anilines that proceeds intramolecularly under weakly acidic conditions. In this process, the five-membered ring of the indole motif is broken and a new indole motif is constructed on the aniline side, accompanied by the formation of a new aniline motif. Mechanistic studies revealed the pivotal role of σ→π* hyperconjugation on the nitrogen atom of the indole motif in driving this unusual isodesmic reaction. Furthermore, we successfully synthesized a diverse series of polycyclic indole derivatives; among quinolines, potential antitumor agents were identified using cellular and in vivo experiments, thereby demonstrating the synthetic utility of the developed methodology.

Nanoscale hyperthermia mesostructures for sustainable antimicrobial design.

Sustainability is critical in addressing global challenges posed by prolonged pandemics that impact health, economies, and the environment. Here, we introduce a molecular engineering approach for thermoregulated antimicrobial management inspired by firewalking rituals. The study uses in situ spectroscopy and multi-scale modeling to validate a hierarchical design. Efficient light-to-thermal energy conversion is achieved by engineering the molecular band structure. Rapid nanoscale hyperthermia is facilitated through thermal engineering. This approach significantly reduces the half-life of pathogens such as Escherichia coli, influenza A, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to 1.4 min while maintaining a low perceived temperature on human skin. Standard disease infection and epidemic models show this technology's potential to flatten outbreak curves and delay peak infection rates, which is crucial during the early stages of pandemics when developing vaccines and antiviral drugs takes time. The scalable manufacturing and broad antimicrobial applicability hold great promise for controlling emerging infectious diseases and diverse bioprotective applications.

Branch-convergence structure based on double-layer chip: a universal method for enhancing microfluidic mixing.

Microfluidic mixing has significant applications in various fields, including materials synthesis and biochemical analysis. In this study, we propose a universal strategy to enhance mixing efficiency in microfluidic chips. This strategy initially divides the liquid into branches, which then converge in an interdigitated manner at the beginning of the mixing segment. This branch-convergence structure reduces the flow width of each liquid, thereby decreasing the diffusion distances required for mixing. Under the conditions of this study, the mixing efficiency could be improved by approximately 10 times. Importantly, this enhancement strategy only requires changing the structure of the liquid inflow channel without changing the structure of the mixing segment. Thus, this strategy has broad applicability, any mixing section with different principles and structures can be connected downstream of the branch-convergence structure. In addition, we applied this universal mixing enhancement strategy to the continuous synthesis of lactic-co-glycolic acid nanoparticles, resulting in a higher uniformity of synthesized nanoparticles compared to unenhanced devices.

Efficient Self-cleaning and antibacterial ceramics with active sites fully exposed obtained from rare earth waste.

The utilization of rare earth polishing powder waste (RPW) to prepare antibacterial ceramics can effectively avoid problems of pollution in the recycling process and waste of rare earth resources. Herein, a novel RPW-based antibacterial ceramics was developed, which possesses the core-shell structure with ceramics as the cores and the CeO2/BiOCl as the superficial coating. The antibacterial ceramics display notable antibacterial activity, and the inactivation rates of 3.3 log under visible light irradiation in 30 min and 2.4 log under darkness in 1 h were achieved, and the zone of inhibition values was found to be 16.6 mm for E.coil. The hardness of antibacterial ceramics was measured to be 897 (±38) HV, higher than commercial porcelain's hardness (600 HV). The antibacterial mechanism was verified by the Ce ion release, reactive species, and fluorescence-based live/dead cells. This study presents a novel antibacterial ceramic structure and green economic reuse method of rare earth waste.

A General Copper-Box System for the Asymmetric Arylative Functionalization of Benzylic, Propargylic or Allenylic Radicals.

Radical-involved arylative cross-coupling reactions have recently emerged as an attractive strategy to access valuable aryl-substituted motifs. However, there still exist several challenges such as limited scope of radical precursors/acceptors, and lack of general asymmetric catalytic systems, especially regarding the multicomponent variants. Herein, we reported a general copper-Box system for asymmetric three-component arylative radical cross-coupling of vinylarenes and 1,3-enynes, with oxime carbonates and aryl boronic acids. The reactions proceed under practical conditions in the absence or presence of visible-light irradiation, affording chiral 1,1-diarylalkanes, benzylic alkynes and allenes with good enantioselectivities. Mechanistic studies imply that the copper/Box complexes play a dual role in both radical generation and ensuing asymmetric cross-coupling. In the cases of 1,3-enynes, visible-light irradiation could improve the activity of copper/Box complex toward the initial radical generation, enabling better efficiency match between radical formation and cross-coupling.

A High-Performance Pixel-Level Fully Pipelined Hardware Accelerator for Neural Networks.

The design of convolutional neural network (CNN) hardware accelerators based on a single computing engine (CE) architecture or multi-CE architecture has received widespread attention in recent years. Although this kind of hardware accelerator has advantages in hardware platform deployment flexibility and development cycle, it is still limited in resource utilization and data throughput. When processing large feature maps, the speed can usually only reach 10 frames/s, which does not meet the requirements of application scenarios, such as autonomous driving and radar detection. To solve the above problems, this article proposes a full pipeline hardware accelerator design based on pixel. By pixel-by-pixel strategy, the concept of the layer is downplayed, and the generation method of each pixel of the output feature map (Ofmap) can be optimized. To pipeline the entire computing system, we expand each layer of the neural network into hardware, eliminating the buffers between layers and maximizing the effect of complete connectivity across the entire network. This approach has yielded excellent performance. Besides that, as the pixel data stream is a fundamental paradigm in image processing, our fully pipelined hardware accelerator is universal for various CNNs (MobileNetV1, MobileNetV2 and FashionNet) in computer vision. As an example, the accelerator for MobileNetV1 achieves a speed of 4205.50 frames/s and a throughput of 4787.15 GOP/s at 211 MHz, with an output latency of 0.60 ms per image. This extremely shorts processing time and opens the door for AI's application in high-speed scenarios.

Transfer RNA­derived small RNAs: A class of potential biomarkers in multiple cancers (Review).

Transfer (t)RNA-derived small RNAs (tsRNAs) are a class of novel non-coding small RNAs that are created via precise cleavage of tRNAs or tRNA precursors by different enzymes. tsRNAs are specific biological molecules that serve essential roles in cell proliferation, apoptosis, transcriptional regulation, post-transcriptional modification and translational regulation. Additionally, tsRNAs participate in the pathogenesis of several diseases, particularly in the development of malignant tumors. At present, the process of discovering and understanding the functions of tsRNAs is still in its early stages. The present review introduces the known biological functions and mechanisms of tsRNAs, and discusses the tsRNAs progression in several types of cancers as well as the possibility of tsRNAs becoming novel tumor biomarkers. Furthermore, tsRNAs may promote and hinder tumor formation according to different mechanisms and act as oncogenic or oncostatic molecules. Therefore, tsRNAs may be future potential tumor biomarkers or therapeutic targets.

Clinical features and possible pathogenesis of multiple evanescent white dot syndrome with different retinal diseases and events: a narrative review.

Multiple evanescent white dot syndrome (MEWDS) is a rare fundus disease, characterized by acute vision loss and visual field defects. Many previous studies have explained the possible pathogenesis and clinical features of primary MEWDS. However, as the number of reported cases increases, secondary MEWDS occurs in other related retinal diseases and injuries, exhibiting some special characteristics. The associated retinal diseases include multifocal choroiditis/punctate inner choroidopathy (MFC/PIC), acute zonal occult outer retinopathy, best vitelliform macular dystrophy, pseudoxanthoma elasticum, and ocular toxoplasmosis. The related retinal injury is laser photocoagulation, surgery, and trauma. Although primary MEWDS often have a self-limiting course, secondary MEWDS may require treatment in some cases, according to the severity of concomitant diseases and complications. Notably, MEWDS secondary to MFC/PIC that is prone to forming choroidal neovascularization and focal choroidal excavation, needs positive treatment with corticosteroids. The possible underlying pathogenesis of secondary MEWDS is the exposure of choroidal antigen after the disruption of Bruch's membrane. The MEWDS-related features in secondary MEWDS are still evanescent under most circumstances. Its prognosis and treatment depend on the severity of complications. Current studies propose that the etiology is associated with immune factors, including viral infection, inflammation in choroid and Bruch's membrane, and antigen exposure caused by retinal and/or choroidal insults. More pathogenic studies should be conducted in the future. Accurate diagnosis for secondary MEWDS could benefit patients in aspects of management and prognosis.

Enantioselective synthesis of chiral α,α-dialkyl indoles and related azoles by cobalt-catalyzed hydroalkylation and regioselectivity switch.

General, catalytic and enantioselective construction of chiral α,α-dialkyl indoles represents an important yet challenging objective to be developed. Herein we describe a cobalt catalyzed enantioselective anti-Markovnikov alkene hydroalkylation via the remote stereocontrol for the synthesis of α,α-dialkyl indoles and other N-heterocycles. This asymmetric C(sp3)-C(sp3) coupling features high flexibility in introducing a diverse set of alkyl groups at the α-position of chiral N-heterocycles. The utility of this methodology has been demonstrated by late-stage functionalization of drug molecules, asymmetric synthesis of bioactive molecules, natural products and functional materials, and identification of a class of molecules exhibiting anti-apoptosis activities in UVB-irradiated HaCaT cells. Ligands play a vital role in controlling the reaction regioselectivity. Changing the ligand from bi-dentate L6 to tridentate L12 enables CoH-catalyzed Markovnikov hydroalkylation. Mechanistic studies disclose that the anti-Markovnikov hydroalkylation involves a migratory insertion process while the Markovnikov hydroalkylation involves a MHAT process.

Deciphering the pancreatic cancer microbiome in Mainland China: Impact of Exiguobacterium/Bacillus ratio on tumor progression and prognostic significance.

The existing body of research underscores the critical impact of intratumoral microbiomes on the progression of pancreatic ductal adenocarcinoma (PDAC), particularly in reshaping the tumor microenvironment and influencing gemcitabine resistance. However, peritumoral tissues' microbiome, distinct from PDAC tumors, remain understudied, and Western-centric analyses overlooking potential variations in dietary-influenced microbiomes. Our study addresses this gap by 16 S rRNA sequencing of PDAC tumors and matched peritumoral tissues from Chinese Mainland patients. Our research has uncovered that the microbiome composition within tumors and paired peritumoral tissues exhibits a high degree of similarity, albeit with certain discrepancies. Notably, Exiguobacterium is found to be more abundant within the tumor tissues. Further investigations have revealed that a lower Exiguobacterium/Bacillus ratio in both the tumor and peritumoral tissues of PDAC patients is indicative of a more favorable prognosis. Further exploration utilizing an orthotopic tumor model demonstrates that the probiotic Bacillus Coagulans impedes PDAC progression, accompanied by an increased infiltration of inflammatory neutrophils in tumors. Additionally, in the subgroup with a low Exiguobacterium/Bacillus ratio, whole-exome sequencing reveals elevated missense mutations in ABL2 and MSH2. The elevated expression of ABL2 and MSH2 has been correlated with poorer prognostic outcomes in PDAC patients. Together, these insights shed light on risk factors influencing PDAC progression and unveil potential therapeutic targets, alongside probiotic intervention strategies.

A novel tRNA-derived fragment tRF-17-18VBY9M works as a potential diagnostic biomarker for gastric cancer.

BACKGROUND: Gastric cancer (GC) is one of the most prevalent malignant tumors worldwide. The low effectiveness of common biomarkers for the detection of early GC makes it essential to seek new biomarkers to improve diagnostic efficacy. tsRNAs (transfer RNA-derived small RNAs) are related to the growth of malignant tumors. In this article, we focused on whether tsRNAs may be employed as biomarkers for GC. METHODS: tRF-17-18VBY9M was screened in the tsRFun database as a research object. The methodological efficacy of tRF-17-18VBY9M was evaluated using Sanger sequencing, agarose gel electrophoresis assays, and gradient dilution. The χ2 test was applied to assess the interaction between tRF-17-18VBY9M expression and clinicopathologic characteristics. The receiver operating characteristic (ROC) curve was utilized to investigate the clinical efficiency of tRF-17-18VBY9M in GC. RESULTS: The Chi-square test demonstrated that high-expressed tRF-17-18VBY9M was closely associated with the T stage, tumor node metastasis stage (TNM), lymph node metastasis, and neurological/vascular invasion. ROC curve analysis revealed that the diagnostic value of tRF-17-18VBY9M in GC was superior to carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), and carbohydrate antigen 724 (CA724). CONCLUSION: tRF-17-18VBY9M is up-regulated in both GC sera and tissues. Differential tRF-17-18VBY9M expression distinguishes GC patients from healthy donors and gastritis patients, which suggests tRF-17-18VBY9M could act as a diagnostic biomarker in GC.

Photoinduced Copper-Catalyzed Asymmetric Three-Component Radical 1,2-Azidooxygenation of 1,3-Dienes.

Radical-involved multicomponent difunctionalization of 1,3-dienes has recently emerged as a promising strategy for rapid synthesis of valuable allylic compounds in one-pot operation. However, the expansion of radical scope and enantiocontrol remain two major challenges. Herein, we describe an unprecedented photoinduced copper-catalyzed highly enantioselective three-component radical 1,2-azidooxygenation of 1,3-dienes with readily available azidobenziodazolone reagent and carboxylic acids. This mild protocol exhibits a broad substrate scope, high functional group tolerance, and exceptional control over chemo-, regio- and enantioselectivity, providing practical access to diverse valuable azidated chiral allylic esters. Mechanistic studies imply that the chiral copper complex is implicated as a bifunctional catalyst in both the photoredox catalyzed azidyl radical generation and enantioselective radical C-O cross-coupling.

Cobalt-Catalyzed Enantioselective Alkenylation of Aldehydes.

Catalytic enantioselective alkenylation of aldehydes with easily accessible alkenyl halides promoted by a chiral cobalt complex derived from a newly developed tridentate bisoxazolinephosphine is presented. Such processes represent an unprecedented reaction pathway for cobalt catalysis and a general approach that enable rapid construction of highly diversified enantioenriched allylic alcohols containing a 1,1-, 1,2-disubstituted and trisubstituted alkene as well as axial stereogenicity in up to 99 % yield and 99 : 1 er without the need of preformation of alkenyl-metal reagents. DFT calculations revealed the origin of enantioselectivity.

FragGrow: A Web Server for Structure-Based Drug Design by Fragment Growing within Constraints.

Fragment growing is an important ligand design strategy in drug discovery. In this study, we present FragGrow, a web server that facilitates structure-based drug design by fragment growing. FragGrow offers two working modes: one for growing molecules through the direct replacement of hydrogen atoms or substructures and the other for growing via virtual synthesis. FragGrow works by searching for suitable fragments that meet a set of constraints from an indexed 3D fragment database and using them to create new compounds in 3D space. The users can set a range of constraints when searching for their desired fragment, including the fragment's ability to interact with specific protein sites; its size, topology, and physicochemical properties; and the presence of particular heteroatoms and functional groups within the fragment. We hope that FragGrow will serve as a useful tool for medicinal chemists in ligand design. The FragGrow server is freely available to researchers and can be accessed at https://fraggrow.xundrug.cn.