Relay Annulation of Ammonium Ylides with Oxindole-Derived α,ß-Unsaturated Ketimines: Catalytic Construction of Spiro-polycyclic Oxindoles.

An ammonium ylide-based relay annulation was disclosed, which uses DABCO as the catalyst and oxindole-derived α,ß-unsaturated ketimines and γ-bromo-crotonates as the starting materials. This method enables the rapid assembly of a series of structurally novel spiro-polycyclic oxindoles containing a bicyclo[4.1.0]heptane moiety through simultaneous generation of three new bonds and two rings in one step under mild reaction conditions.

1,5-Hydrogen atom transfer of α-iminyl radical cations: a new platform for relay annulation for pyridine derivatives and axially chiral heterobiaryls.

The exploitation of new reactive species and novel transformation modes for their synthetic applications have significantly promoted the development of synthetic organic methodology, drug discovery, and advanced functional materials. α-Iminyl radical cations, a class of distonic ions, exhibit great synthetic potential for the synthesis of valuable molecules. For their generation, radical conjugate addition to α,ß-unsaturated iminium ions represents a concise yet highly challenging route, because the in situ generated species are short-lived and highly reactive and they have a high tendency to cause radical elimination (ß-scission) to regenerate the more stable iminium ions. Herein, we report a new transformation mode of the α-iminyl radical cation, that is to say, 1,5-hydrogen atom transfer (1,5-HAT). Such a strategy can generate a species bearing multiple reactive sites, which serves as a platform to realize (asymmetric) relay annulations. The present iron/secondary amine synergistic catalysis causes a modular assembly of a broad spectrum of new structurally fused pyridines including axially chiral heterobiaryls, and exhibits good functional group tolerance. A series of mechanistic experiments support the α-iminyl radical cation-induced 1,5-HAT, and the formation of several radical species in the relay annulations. Various synthetic transformations of the reaction products demonstrate the usefulness of this relay annulation protocol for the synthesis of significant molecules.

Modular Assembly of 2-Aminoaniline Derivatives by Merging Hydroxylamine-Passerini and Hetero-Cope Rearrangement.

A metal-free three-component protocol that combines a hydroxylamine-Passerini reaction and hetero-Cope rearrangement was realized, which enables the modular assembly of a wide range of structurally new and interesting 2-aminoanilines bearing an α-hydroxyamide substructure.

Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

Skeletal Transformation of Oxindoles into Quinolinones Enabled by Synergistic Copper/Iminium Catalysis.

We describe a synergistic Cu/secondary amine catalysis for skeletal transformation of an oxindole core into a quinolinone skeleton, which generates several structurally new pyridine-fused quinolinones. The synergistic reactions allow expansion of a five-membered lactam ring by radical cation-triggered C-C bond cleavage and enable a further intramolecular cyclization with the aim to construct totally distinct core skeletons.

Discovery of novel aporphine alkaloid derivative as potent TLR2 antagonist reversing macrophage polarization and neutrophil infiltration against acute inflammation

Toll-like receptor 2 (TLR2) mediated macrophages regulate the protective immune response to infectious microorganisms, but the aberrant activation of macrophages often leads to pathological inflammation, including tissue damage. In this study, we identified antagonists of TLR2 by screening 2100 natural products and subsequently identified Taspine, an aporphine alkaloid, as an excellent candidate. Furthermore, analysis of the 10 steps chemical synthesis route and structural optimization yielded the Taspine derivative SMU-Y6, which has higher activity, better solubility, and improved drug-feasible property. Mechanistic studies and seq-RNA analysis revealed that SMU-Y6 inhibited TLR2 over other TLRs, hindered the formation of TLR2/MyD88 complex, and blocked the downstream NF-κB and MAPK signaling pathway, thus suppressing the release of inflammatory cytokines. SMU-Y6 could stabilize TLR2 and bind to TLR2 protein with a Kd of 0.18 μmol/L. Additionally, SMU-Y6 could efficiently reverse the M1 phenotype macrophage polarization, reduce the production of cytokines as well as infiltration of neutrophiles and alleviate the local inflammation in mice with acute paw edema and colitis. Collectively, we reported the first aporphine alkaloid derivative that selectively inhibits TLR2 with high binding affinity and superior drug-feasible property, thus providing an urgently-needed molecular probe and potential drug candidate for inflammatory and autoimmune disease therapy.

Research progress of small molecule modulators targeting Toll-like receptor 2 / 药学学报

Toll like receptors (TLRs) are the earliest discovered natural immune pattern recognition receptors (PRRs). The abnormality of TLR signal transduction pathway is the key factor leading to chronic inflammatory, cancer, nervous system disease and cardiovascular diseases. The development of TLR agonists and inhibitors has attracted much attention. Currently known TLR2 agonists, such as lipopeptides or their derivatives, have certain limitations in drug development due to their difficult synthesis, easy hydrolysis, and triggering inflammatory cytokine storms, while inhibitors have been rarely reported. New small molecule TLR2 agonists or inhibitors with higher stability are more likely to be developed as tumor immunotherapy or anti-inflammatory drugs.

Current perspectives, future challenges and key technologies of biohydrogen production for building a carbon-neutral future: A review.

The ever-increasing quantity of greenhouse gases in the atmosphere can be attributed to the rapid increase in the world population as well as the expansion of globalization. Hence, achieving carbon neutrality by 2050 stands as a challenging task to accomplish. Global industrialization had necessitated the need to enhance the current production systems to reduce greenhouse gases emission, whilst promoting the capture of carbon dioxide from atmosphere. Hydrogen is often touted as the fuel of future via substituting fossil-based fuels. In this regard, renewable hydrogen happens to be a niche sector of novel technologies in achieving carbon neutrality. Microalgae-based biohydrogen technologies could be a sustainable and economical approach to produce hydrogen from a renewable source, while simultaneously promoting the absorption of carbon dioxide. This review highlights the current perspectives of biohydrogen production as an alternate source of energy. In addition, future challenges associated with biohydrogen production at large-scale application, storage and transportation are included. Key technologies in producing biohydrogen are finally described in building a carbon-neutral future.

Iminyl radical-triggered relay annulation for the construction of bridged aza-tetracycles bearing four contiguous stereogenic centers.

Bridged tetracyclic nitrogen scaffolds are found in numerous biologically active molecules and medicinally relevant structures. Traditional methods usually require tedious reaction steps, and/or the use of structurally specific starting materials. We report an unprecedented, iminyl radical-triggered relay annulation from oxime-derived peresters and azadienes, which shows good substrate scope and functional group compatibility, and can deliver various bridged aza-tetracyclic compounds with complex molecular topology and four contiguous stereogenic centers (dr > 19 : 1) in a single operation. This transformation represents the first example of trifunctionalization of iminyl radicals through simultaneous formation of one C-N and two C-C bonds. DFT calculation studies were conducted to obtain an in-depth insight into the reaction pathways, which revealed that the reactions involved an interesting 1,6-hydrogen atom transfer process.

Comparison of Safety of Different Vaccine Boosters Following Two-Dose Inactivated Vaccines: A Parallel Controlled Prospective Study.

A vaccine booster to maintain high antibody levels and provide effective protection against COVID-19 has been recommended. However, little is known about the safety of a booster for different vaccines. We conducted a parallel controlled prospective study to compare the safety of a booster usingfour common vaccines in China. In total, 320 eligible participants who had received two doses of an inactivated vaccine were equally allocated to receive a booster of the same vaccine (Group A), a different inactivated vaccine (Group B), an adenovirus type-5 vectored vaccine (Group C), or a protein subunit vaccine (Group D). A higher risk of adverse reactions, observed up to 28 days after injection, was found in Groups C and D, compared to Group A, with odds ratios (OR) of 11.63 (95% confidence interval (CI): 4.22-32.05) and 4.38 (1.53-12.56), respectively. Recipients in Group C were more likely to report ≥two reactions (OR = 29.18, 95% CI: 3.70-229.82), and had a higher risk of injection site pain, dizziness, and fatigue. A gender and age disparity in the risk of adverse reactions was identified. Despite the majority of reactions being mild, heterologous booster strategies do increase the risk of adverse reactions, relative to homologous boosters, in subjects who have had two doses of inactive vaccine.

Acute mushroom poisoning of Amanita pseudosychnopyramis: A case report from Fujian, China with exact species identification and descriptive study.

Mushroom poisoning is a deeply concerning food safety problem that affects the public in China every year. Although there are statistics on the number of poisonings and incidents, there is a lack of data on the types of toxic mushrooms, clinical manifestations and toxins. A case of wild mushroom poisoning occurred in Xiamen. Descriptive epidemiological investigation, toxins detection, and morphological and phylogenetic identification were immediately performed. The patients exhibited typical neurotoxic symptoms after consuming wild mushrooms, including chills, vertigo, drowsiness, salivation and coma. The average incubation period was 30 min. Treatments that were adopted included fluid infusion, gastric lavage, catharsis, and liver protection treatment. All patients recovered within 10 days. The species was identified as Amanita pseudosychnopyramis, and its contents of muscarine, muscimol and ibotenic acid were 170.3 ± 5.9 mg/kg, 835.4 ± 43.1 mg/kg and 637.9 ± 54.8 mg/kg in dry weight, respectively, as detected by ultrahigh-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). To our knowledge, this is the first report of Amanita pseudosychnopyramis poisoning worldwide.

Surface tuned polyethersulfone membrane using an iron oxide functionalized halloysite nanocomposite for enhanced humic acid removal.

Nanomodification of ultrafiltration (UF) membranes has been shown to be a simple and efficient technique for the preparation of high-performance membranes. In this work, an iron oxide functionalized halloysite nanoclay (Fe-HNC) nanocomposite was prepared and used as a nanofiller for polyethersulfone (PES) membranes. The effect of Fe-HNC concentration on the filtration performance of the membrane was investigated by varying the nanocomposite dosage (0-0.5 wt %) in the casting dope. Various characterization studies showed that the incorporation of Fe-HNC nanocomposites improved the membrane morphology and enhanced the surface properties, thermal stability, mechanical strength, hydrophilicity, and porosity. The permeability to pure water and filtration of humic acid (HA) were significantly improved by incorporating Fe-HNC into the PES membranes. The membrane with Fe-HNC loading of 0.1 wt % exhibited the highest pure water permeability (174.3 L/(m2 h bar)) and removal of HA (90.1 %), which were 1.8 times and 29 % higher, respectively than the pristine PES membrane. Moreover, fouling studies showed the enhanced antifouling ability of the Fe-HNC nanocomposites modified PES membranes, especially against irreversible fouling. Continuous membrane regeneration-based fouling removal studies from HA showed that the PES/0.1 wt % Fe-HNC membrane exhibited a high fouling recovery of 70.4 % with very low reversible and irreversible fouling resistance of 9.61 % and 14.78 %, respectively, compared to the pristine PES membrane (fouling recovery: 40.4 %; reversible fouling: 21.7 %; irreversible fouling: 20.1 %). Overall, the Fe-HNC nanocomposite proved to be an effective nanomodifier for improving the permeability of PES membranes and the antifouling ability to treat HA polluted aqueous streams.

Global Genomic Characterization of Salmonella enterica Serovar Telelkebir.

Non-typhoidal Salmonella (NTS) is a common cause for self-limiting gastroenteritis, representing a public health concern globally. NTS is one of the leading causes of foodborne illnesses in China; however, the invasive infection caused by NTS is largely underappreciated. Here, we reported an NTS invasive infection caused by an infrequently reported serovar Telelkebir (13,23:d:e,n,z15) strain FJ001 in China, which carries antimicrobial-resistant genes [fosA7 and aac(6')-Iaa] and typhoid-toxin genes (cdtB, pltA, and pltB). By conducting the whole genomic sequencing, we also investigated the relatedness of this strain with an additional 120 global contextual Salmonella enterica serovar Telelkebir (S. Telelkebir) isolates, and assessed the antimicrobial-resistant determinants and key virulence factors using the available genomic dataset. Notably, all 121 (100%) of the S. Telelkebir strains possessed the typhoid toxin genes cdtB, pltA, and pltB, and 58.67% (71/121) of S. Telelkebir harbored antimicrobial-resistant gene fosaA7. The study by core genome multilocus sequence typing (cgMLST) and core single-nucleotide polymorphism (SNP)-based phylogenomic analysis demonstrated that the S. Telelkebir isolates from different sources and locations clustered together. This suggests that regular international travels might increase the likelihood of rapid and extensive transmissions of potentially pathogenic bacteria. For the first time, our study revealed the antimicrobial resistance, virulence patterns, and genetic diversity of the serovar S. Telelkebir isolate in humans and similar isolates over the world. The present study also suggests that genomic investigation can facilitate surveillance and could offer added knowledge of a previously unknown threat with the unique combination of virulent and antimicrobial-resistant determinants.

Two newly recorded species of plants in Jiangxi province / 中国中药杂志

Based on the investigation of wild medicinal plant resources in Dexing city, Jiangxi province, and the collected plant specimens, which were identified by taxonomy, two new record species of geographical distribution were found, which are Meehania zheminensis A. Takano, Pan Li & G.-H. Xia and Corydalis huangshanensis L.Q.Huang & H.S.Peng. The voucher specimens are kept in Dexing museum of traditional Chinese medicine. In this paper, the new distribution species were reported, which provides valuable information for further enriching and supplementing the species diversity of medicinal plant resources in Jiangxi province.

Safety Evaluation and Experimental Study of a New Bionic Muscle Cable-Driven Lower Limb Rehabilitation Robot.

Safety is a significant evaluation index of rehabilitation medical devices and a significant precondition for practical application. However, the safety evaluation of cable-driven rehabilitation robots has not been reported, so this work aims to study the safety evaluation methods and evaluation index of cable-driven rehabilitation robots. A bionic muscle cable (BM cable) is proposed to construct a bionic muscle cable-driven lower limb rehabilitation robot (BM-CDLR). The working principle of the BM-CDLR is introduced. The safety performance factors are defined based on the mechanical analysis of the BM-CDLR. The structural safety evaluation index and the use safety evaluation index of the BM-CDLR are given by comprehensively considering the safety performance factors and a proposed speed influence function. The effect of the structural parameters of the elastic elements in the BM cable on the safety performance factors and safety of the BM-CDLR is analyzed and verified by numerical simulations and experimental studies. The results provide the basis for further study of the compliance control strategy and experiments of the human-machine interaction of the BM-CDLR.

Frequent Import and Multiple Sources of Dengue Fever have Changed the Epidemic Situation of the Disease in Fujian Province, China.

OBJECTIVE: The aim of this study was to update the epidemic situation of dengue fever (DF) and provide new insights for the consideration of disease control in Fujian province, China. METHODS: Details about DF cases in Fujian reported during 2004-2017 were collected and analyzed. The envelope (E) genes of isolates of dengue virus (DENV) were sequenced for phylogenetic analysis. RESULTS: The number of imported DF cases had increased dramatically since 2013, and the source regions expanded from Southeast Asia to South Asia, America, Oceania, and Africa, as well as the surrounding provinces. This resulted in local outbreaks and indigenous cases of DF that occurred more frequently, with 10 of 13 local outbreaks and 85.9% (1,252/1,458) of indigenous cases reported in 2013-2017. Compared with only two coastal cities before 2013, four coastal and one inland city in 2013-2017 experienced the local DF outbreaks. The phylogenetic analysis of E genes confirmed that the import of DENV, not only from abroad but also from the surrounding provinces, played an important role in dissemination and local outbreaks of DF in Fujian. CONCLUSIONS: The frequent import of DF cases from not only abroad but also the surrounding provinces resulted in increased incidence, frequent local outbreaks, and expansion of distribution in Fujian in recent years. There is a need for urgent measures to improve disease control in this province.

RT-nPCR Assays for Amplification and Sequencing of VP1 Genes in Human Enterovirus A-D from Clinical Specimens.

OBJECTIVE: To develop RT-nPCR assays for amplifying partial and complete VP1 genes of human enteroviruses (HEVs) from clinical samples and to contribute to etiological surveillance of HEV-related diseases. METHODS: A panel of RT-nPCR assays, consisting of published combined primer pairs for VP1 genes of HEV A-C and in-house designed primers for HEV-D, was established in this study. The sensitivity of each RT-nPCR assay was evaluated with serially diluted virus stocks of five serotypes expressed as CCID 50 per µL and copies per µL, and the newly established methods were tested in clinical specimens collected in recent years. RESULTS: The sensitivity of RT-nPCR assays for amplifying partial VP1 gene of HEVs was 0.1 CCID 50 per µL and 10 virus copies per µL, and for the complete VP1 gene was 1 CCID 50 per µL and 100 virus copies per µL, using serially-diluted virus stocks of five serotypes. As a proof-of-concept, 25 serotypes were identified and complete VP1 sequences of 23 serotypes were obtained by this system among 858 clinical specimens positive for HEVs during the past eight surveillance seasons. CONCLUSION: This RT-nPCR system is capable of amplifying the partial and complete VP1 gene of HEV A-D, providing rapid, sensitive, and reliable options for molecular typing and molecular epidemiology of HEVs in clinical specimens.

Immunotherapy for treating methamphetamine, heroin and cocaine use disorders.

Drug addiction is a serious health problem prevalent worldwide. Currently available therapies including pharmacotherapy and psychotherapy are insufficient to meet the clinical needs for treating drug abuse. Recently, immunotherapy has emerged as a promising approach to treat such drug-use disorders. Pharmacokinetic antagonists are used in immunotherapy, functioning by sequestering the drugs in the periphery but without allowing the drug to cross the blood-brain barrier. This can reduce the toxic and rewarding effects of the drugs, while preventing addiction and facilitating reduced relapse rates. Herein, we update recent developments in the immunotherapeutic strategies to treat abuse of drugs like methamphetamine, heroin and cocaine. In addition, we summarize the drug design used so far and its optimization strategies. Further, we document the efficacy of anti-drug vaccines and monoclonal antibodies, with an aim to promote development of new anti-drug immunotherapies.

Frequent Import and Multiple Sources of Dengue Fever have Changed the Epidemic Situation of the Disease in Fujian Province, China / 生物医学与环境科学（英文）

Objective@#The aim of this study was to update the epidemic situation of dengue fever (DF) and provide new insights for the consideration of disease control in Fujian province, China.@*Methods@#Details about DF cases in Fujian reported during 2004-2017 were collected and analyzed. The envelope (E) genes of isolates of dengue virus (DENV) were sequenced for phylogenetic analysis.@*Results@#The number of imported DF cases had increased dramatically since 2013, and the source regions expanded from Southeast Asia to South Asia, America, Oceania, and Africa, as well as the surrounding provinces. This resulted in local outbreaks and indigenous cases of DF that occurred more frequently, with 10 of 13 local outbreaks and 85.9% (1,252/1,458) of indigenous cases reported in 2013-2017. Compared with only two coastal cities before 2013, four coastal and one inland city in 2013-2017 experienced the local DF outbreaks. The phylogenetic analysis of E genes confirmed that the import of DENV, not only from abroad but also from the surrounding provinces, played an important role in dissemination and local outbreaks of DF in Fujian.@*Conclusions@#The frequent import of DF cases from not only abroad but also the surrounding provinces resulted in increased incidence, frequent local outbreaks, and expansion of distribution in Fujian in recent years. There is a need for urgent measures to improve disease control in this province.

RT-nPCR Assays for Amplification and Sequencing of VP1 Genes in Human Enterovirus A-D from Clinical Specimens / 生物医学与环境科学（英文）

Objective@#To develop RT-nPCR assays for amplifying partial and complete VP1 genes of human enteroviruses (HEVs) from clinical samples and to contribute to etiological surveillance of HEV-related diseases.@*Methods@#A panel of RT-nPCR assays, consisting of published combined primer pairs for VP1 genes of HEV A-C and in-house designed primers for HEV-D, was established in this study. The sensitivity of each RT-nPCR assay was evaluated with serially diluted virus stocks of five serotypes expressed as CCID @*Results@#The sensitivity of RT-nPCR assays for amplifying partial VP1 gene of HEVs was 0.1 CCID @*Conclusion@#This RT-nPCR system is capable of amplifying the partial and complete VP1 gene of HEV A-D, providing rapid, sensitive, and reliable options for molecular typing and molecular epidemiology of HEVs in clinical specimens.