Expeditious Synthesis of Spiroindoline Derivatives via Tandem C(sp2)-H and C(sp3)-H Bond Functionalization of N-Methyl-N-nitrosoanilines.

Presented herein is a novel synthesis of pharmaceutically privileged spiroindoline derivatives via cascade reactions of N-methyl-N-nitrosoanilines with diazo homophthalimides. A group of mechanistic studies disclosed that the formation of product involves an unusual reaction mode of N-methyl-N-nitrosoaniline featuring an initial C(sp2)-H bond activation/alkylation followed by a C(sp3)-H bond activation/spiroannulation. To our knowledge, this is the first example in which N-methyl-N-nitrosoaniline acts as a C3N1 synthon to accomplish formal [4+1] spiroannulation with the participation of the N-methyl unit rather than the previously reported C2N1 synthon to undergo formal [3+2] annulation without the participation of the N-methyl unit. In general, this newly developed synthetic protocol features simple and readily accessible starting materials, valuable products, unique reaction mechanism, high efficiency and atom-economy, excellent compatibility with diverse functional groups, and ready scalability.

Synthesis of Acyl Cyclopentaquinolinones through Simultaneous Construction of the Heterocyclic Scaffold and Introduction of the Acyl Group.

Presented herein is an effective and concise synthesis of acyl cyclopentaquinolinone derivatives via the cascade reactions of N-(o-ethynylaryl)acrylamides with α-diazo carbonyl compounds. The formation of product involves a visible light-induced radical formation from α-diazo carbonyl compound followed by its addition onto the acrylamide moiety to trigger double radical annulation, single-electron oxidation, and ß-elimination. To our knowledge, this is the first example in which the cyclopentaquinolinone scaffold was constructed along with the introduction of an acyl group under visible light irradiation conditions. Compared with literature methods for similar purpose, this newly developed protocol has advantages such as readily accessible substrates, mild reaction conditions, valuable products, concise synthetic procedure, and high sustainability. With all these merits, this method is expected to find wide applications in the construction of related acyl heterocyclic skeletons.

OsPGL3A encodes a DYW-type pentatricopeptide repeat protein involved in chloroplast RNA processing and regulated chloroplast development.

The chloroplast serves as the primary site of photosynthesis, and its development plays a crucial role in regulating plant growth and morphogenesis. The Pentatricopeptide Repeat Sequence (PPR) proteins constitute a vast protein family that function in the post-transcriptional modification of RNA within plant organelles. In this study, we characterized mutant of rice with pale green leaves (pgl3a). The chlorophyll content of pgl3a at the seedling stage was significantly reduced compared to the wild type (WT). Transmission electron microscopy (TEM) and quantitative PCR analysis revealed that pgl3a exhibited aberrant chloroplast development compared to the wild type (WT), accompanied by significant alterations in gene expression levels associated with chloroplast development and photosynthesis. The Mutmap analysis revealed that a single base deletionin the coding region of Os03g0136700 in pgl3a. By employing CRISPR/Cas9 mediated gene editing, two homozygous cr-pgl3a mutants were generated and exhibited a similar phenotype to pgl3a, thereby confirming that Os03g0136700 was responsible for pgl3a. Consequently, it was designated as OsPGL3A. OsPGL3A belongs to the DYW-type PPR protein family and is localized in chloroplasts. Furthermore, we demonstrated that the RNA editing efficiency of rps8-182 and rpoC2-4106, and the splicing efficiency of ycf3-1 were significantly decreased in pgl3a mutants compared to WT. Collectively, these results indicate that OsPGL3A plays a crucial role in chloroplast development by regulating the editing and splicing of chloroplast genes in rice. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01468-7.

Off-label use of Baricitinib improves moderate and severe atopic dermatitis in China through inhibiting MAPK and PI3K/Akt/mTOR pathway via targeting JAK-STAT signaling of CD4+ cells.

As an inflammatory disease with a disrupted immune system, cytokine disorders in atopic dermatitis (AD) are closely related to the abnormal activation of JAK-STAT signal pathway. The critical relevance of the JAK-STAT signaling pathway to the pathogenesis of AD provides a strong rationale for JAK inhibitor research. Baricitinib, a small-molecule oral JAK inhibitor, has been proven to inhibit JAK-STAT signaling in a variety of diseases, including AD. It is currently available in China for off-label use. However, its efficacy in China and its mechanism are rarely reported. In our study, we found that the immune status of patients with moderate and severe AD was hyperactive. Among the 49 known immunotherapy targets, JAK1 and JAK2 genes on lymphocytes of AD patients were significantly upregulated, which was closely related to the symptom severity in moderate and severe AD patients. Baricitinib can improve immune hyperresponsiveness and clinical symptoms in moderate and severe AD by inhibiting the activation of Th2 cell subsets and the secretion of Th2-type cytokines through MAPK, mTOR and PI3K-Akt signaling pathways, providing an important theoretical basis for clinical off-label use of Baricitinib to treat moderate and severe AD.

Analysis of related factors for neuropsychiatric comorbidities in children with epilepsy.

OBJECTIVE: To analyze the risk factors affecting psychiatric behavior and study the psychobehavioral conditions of children with epilepsy. METHOD: We randomly selected and enrolled 294 children with epilepsy who visited and were hospitalized in the pediatric clinic of Hebei General Hospital between January 2017 and January 2022, as the study participants. We comprehensively assessed their cognitive functions using the Gesell development schedule or Wechsler Intelligence Scales. The participants were divided into the study group (n = 123) with cognitive impairment and the control group (n = 171) with normal cognitive functions, for analysis. RESULTS: There were statistically significant differences between the two groups in disease course, frequency of epilepsy, status epilepticus, and the number of antiseizure medications (ASMs) used (P < 0.05), while there were no statistically significant differences in age, gender, age of onset, form of onset, interictal epileptiform discharge, history of febrile convulsion, and the time from onset to initial visit (P > 0.05). Based on multivariate logistic regression analysis, the course of disease, frequency of onset, status epilepticus and number of ASMs used were identified as high-risk factors for cognitive impairment in children with epilepsy. Similarly, early onset, long course of disease, known etiology, and combination of multiple drugs have a negative impact on behavioral problems, school education, and social adaptability. CONCLUSION: The course of disease, the frequency of onset, status epilepticus, and the number of ASMs used are high-risk factors for cognitive impairment in children with epilepsy, which can be prevented and controlled early. When selecting ASMs, their advantages and disadvantages should be weighed. Moreover, the availability of alternative treatment options must be considered. With the help of genomic technology, the causes of epilepsy should be identified as early as possible, and precision medicine and gene therapy for children with epilepsy should be actively developed.

The multi-scale structure changes of γ-ray irradiated potato starch to mitigate pasting/digestion properties.

The comprehensive understanding of multi-scale structure of starch and how the structure regulates the pasting/digestion properties remain unclear. This work investigated the effects of γ-ray irradiation with different doses on multi-scale structure and pasting/digestion properties of potato starch. Results indicated that γ-ray at lower doses (<20 kGy) had little effect on micromorphology of starch, increased mainly the amylose content and the thickness of amorphous region while decreased crystallinity, double helix content and lamellar ordering. With the increase of dose, the internal structure of large granules was destroyed, resulting in the depolymerization of starch to form more short-chains and to reduce molecular weight. Meanwhile, amylose content decreased due to the depolymerization of amylose. The enhanced double helix content, crystallinity, lamellar ordering and structural compactness manifested the formation of the thicker and denser starch structure. These structure changes resulted in the decreased viscosity, the increased stability and anti- digestibility of paste.

C-H activation-initiated spiroannulation reactions and their applications in the synthesis of spirocyclic compounds.

Spirocyclic skeletons are prevalent in natural products, pharmaceuticals and organic functional materials. Meanwhile, transition-metal-catalyzed C-H activation reactions have demonstrated unparalleled advantages such as high efficiency, excellent atom-economy, good chemoselectivity and regioselectivity for the formation of target organic molecules. In recent years, C-H activation reactions have been creatively utilized in the synthesis of spirocyclic compounds. This review summarizes the most recent progress made in C-H activation-initiated spiroannulation reactions and their applications in the construction of structurally diverse and biologically valuable spirocyclic scaffolds by using alkynes, diazo compounds, maleimides, alkenes, quinones and cyclopropenones as the coupling partners.

Synthesis of Naphtho[1',2':4,5]furo[3,2-b]pyridinones via Ir(III)-Catalyzed C6/C5 Dual C-H Functionalization of N-Pyridyl-2-pyridones with Diazonaphthalen-2(1H)-ones.

Presented herein is an unprecedented synthesis of naphtho[1',2':4,5]furo[3,2-b]pyridinones via Ir(III)-catalyzed C6/C5 dual C-H functionalization of N-pyridyl-2-pyridones with diazonaphthalen-2(1H)-ones. This protocol forms C-C and C-O bonds in one pot in which diazonaphthalen-2(1H)-ones serve as bifunctional reagents, providing both alkyl and aryloxy sources. To the best of our knowledge, this is the first example of an Ir(III)-catalyzed synthesis of the title compounds by using diazonaphthalen-2(1H)-ones as bifunctional substrates. Notably, this method features operational simplicity, good functional group tolerance, high efficiency, and high atom economy.

Synthesis of 1,7-Fused Indolines Tethered with Spiroindolinone Based on C-H Activation Strategy with Air as a Sustainable Oxidant.

Herein, we present an efficient synthesis of 1,7-fused indolines tethered with a spiroindolinonyl moiety through the cascade reaction of indolin-1-yl(aryl)methanimines with diazo oxindoles. To the best of our knowledge, this is the first example in which 1,7-fused indoline skeleton was constructed along with the simultaneous introduction of a spiro element initiated by the C-H bond activation of indoline. In forming the title product, the indoline substrate and the diazo coupling partner demonstrated an unprecedented reaction pattern in which the latter acts as a C1 synthon to participate in the construction of the spirocyclic scaffold through the reductive elimination of a key seven-membered Ru(II) species by using air as an effective and sustainable oxidant to regenerate the active catalyst. Moreover, studies on the cytotoxicity of selected products against several human cancer cell lines demonstrated their potential as lead compounds for the development of anticancer drugs. With notable features such as simple and economical substrates, pharmaceutically valuable products with sophisticated spirocyclic skeleton, mild reaction conditions, cost-free and sustainable oxidants, high efficiency, excellent compatibility with diverse functional groups, and scalability, this method is expected to find wide applications in related areas.

Inferior social hierarchy is vulnerable to anxiety-like behavior in chronic pain mice: Potential role of gut microbiota and metabolites.

Social dominance is a universal phenomenon among grouped animals that profoundly affects survival, health, and reproductive success by determining access to resources, and exerting a powerful influence on subsequent behavior. However, the understanding of pain and anxiety comorbidities in dominant or subordinate animals suffering from chronic pain is not well-defined. Here, we provide evidence that subordinate mice are more susceptible to pain-induced anxiety compared to dominant mice. We propose that the gut microbiota may play a mediating role in this mechanism. Our findings demonstrate that transplantation of fecal microbiota from subordinate mice with chronic inflammatory pain, but not dominant mice, into antibiotics-treated pseudo-germ-free mice significantly amplifies anxiety-like phenotypes, highlighting the critical involvement of gut microbiota in this behavioral response. Using chronic inflammatory pain model, we carried out 16S rRNA sequencing and untargeted metabolomic analyses to explore the relationship between microbiota and metabolites in a stable social hierarchy of mice. Interestingly, anxiety-like behaviors were directly associated with some microbial genera and metabolites, especially bile acid metabolism. Overall, we have demonstrated a close relationship between social status and anxiety susceptibility, highlighting the contributions of gut microbiota and the associated metabolites in the high-anxiety state of subordinate mice with chronic inflammatory pain.

Regulation of Microglial Activation by Wnt/ß-Catenin Signaling After Global Cerebral Ischemia in Mice.

Microglia are immunocompetent cells in the central nervous system. Following cerebral ischemia, microglia will be rapidly activated and undergo proliferation, morphological transformation, and changes in gene expression and function. At present, the regulatory mechanisms of microglial activation following ischemia remain largely unclear. In this study, we took advantage of CX3CR1GFP/+ fluorescent mice and a global cerebral ischemia-reperfusion model to investigate the mechanisms of microglial activation following different degrees of global ischemia. Our results showed that the proliferation of microglia was gated by the degree of ischemia. Marked microglial de-ramification and proliferation were observed after 60 min of ischemia but not in transient ischemia (20 min). Immunohistology, qRT-PCR, and Western blotting analysis showed that microglial activation was accompanied with a reduction in Wnt/ß-catenin signaling after cerebral ischemia. Downregulation of Wnt/ß-catenin signaling using Wnt antagonist XAV939 during 20 min ischemia promoted microglial de-ramification and proliferation. In contrast, enhancing Wnt/ß-catenin signaling using Wnt agonist LiCl during 60 min ischemia-reduced microglial de-ramification and proliferation. Importantly, we found that Wnt agonist inhibited inflammation in the ischemic brain and was conducive to animal behavioral recovery. Collectively, these data demonstrated that Wnt/ß-catenin signaling played a key role in microglial activation following cerebral ischemia, and regulating microglial activation may be a potential therapeutic strategy for the treatment of ischemic stroke.

The role of CD38 in inflammation-induced depression-like behavior and the antidepressant effect of (R)-ketamine.

CD38 is involved in immune responses, cell proliferation, and has been identified in the brain, where it is implicated in inflammation processes and psychiatric disorders. We hypothesized that dysfunctional CD38 activity in the brain may contribute to the pathogenesis of depression. To investigate the underlying mechanisms, we used a lipopolysaccharide (LPS)-induced depression-like model and conducted behavioral tests, molecular and morphological methods, along with optogenetic techniques. We microinjected adeno-associated virus into the hippocampal CA3 region with stereotaxic instrumentation. Our results showed a marked increase in CD38 expression in both the hippocampus and cortex of LPS-treated mice. Additionally, pharmacological inhibition and genetic knockout of CD38 effectively alleviated neuroinflammation, microglia activation, synaptic defects, and Sirt1/STAT3 signaling, subsequently improving depression-like behaviors. Moreover, optogenetic activation of glutamatergic neurons of hippocampal CA3 reduced the susceptibility of mice to depression-like behaviors, accompanied by reduced CD38 expression. We also found that (R)-ketamine, which displayed antidepressant effects, was linked to its anti-inflammatory properties by suppressing increased CD38 expression and reversing synaptic defects. In conclusion, hippocampal CD38 is closely linked to depression-like behaviors in an inflammation model, highlighting its potential as a therapeutic target for antidepressant development.

Adaptive characteristics of indigenous microflora in an organically contaminated high salinity groundwater.

Salinity, a critical factor, could directly or indirectly affect the microbial community structure and diversity. Changes in salinity levels act as environmental filters that influence the transformation of key microbial species. This study investigates the adaptive characteristics of indigenous microflora in groundwater in relation to external organic pollutants under high salinity stress. A highly mineralized shallow groundwater in Northwest China was conducted as the study area, and six representative sampling points were chosen to explore the response of groundwater hydrochemical parameters and microflora, as well as to identify the tolerance mechanisms of indigenous microflora to combined pollution. The results revealed that the dominant genera found in high salinity groundwater contaminated with organic pollutants possess the remarkable ability to degrade such pollutants even under challenging high salinity conditions, including Halomonas, Pseudomonas, Halothiobacillus, Sphingomonas, Lutibacter, Aquabacterium, Thiomicrospira, Aequorivita, etc. The hydrochemical factors, including total dissolved solids (TDS), sulfide, nitrite, nitrate, oxidation reduction potential (ORP), NH3-N, Na, Fe, benzene series, phenols, and halogenated hydrocarbons, demonstrated a significant influence on microflora. High levels of sulphate and sulfide in groundwater can exhibit dual effects on microflora. On one hand, these compounds can inhibit the growth and metabolism of microorganisms. On the other hand, they can also serve as effective electron donors/receptors during the microbial degradation of organic pollutants. Microorganisms exhibit resilience to the inhibitory effects of high salinity and organic pollutants via a series of tolerance mechanisms, such as strengthening the extracellular membrane barrier, enhancing the synthesis of relevant enzymes, initiating novel biochemical reactions, improving cellular self-healing capabilities, responding to unfavorable environmental conditions by migration, and enhancing the S cycle for the microbial metabolism of organic pollutants.

[Effect of recombinant human growth hormone on serum Klotho and fibroblast growth factor 23 in children with idiopathic short stature]. / é‡ç»„äººç”Ÿé•¿æ¿€ç´ æ²»ç–—å¯¹ç‰¹å‘æ€§çŸ®å°ç—‡å„¿ç«¥è¡€æ¸ Klothoå’Œæˆçº¤ç»´ç»†èƒžç”Ÿé•¿å› å­23的影响.

OBJECTIVES: To investigate the changes in the serum levels of Klotho, fibroblast growth factor 23 (FGF23), and insulin-like growth factor-1 (IGF-1) in children with idiopathic short stature (ISS) before and after recombinant human growth hormone (rhGH) treatment, as well as the correlation of Klotho and FGF23 with the growth hormone (GH)/IGF-1 growth axis in these children. METHODS: A prospective study was conducted on 33 children who were diagnosed with ISS in the Department of Pediatrics, Hebei Provincial People's Hospital, from March 10, 2021 to December 1, 2022 (ISS group). Twenty-nine healthy children, matched for age and sex, who attended the Department of Child Healthcare during the same period, were enrolled as the healthy control group. The children in the ISS group were treated with rhGH, and the serum levels of Klotho, FGF23, and IGF-1 were measured before treatment and after 3, 6, and 9 months of treatment. A correlation analysis was conducted on these indexes. RESULTS: There were no significant differences in the serum levels of IGF-1, Klotho, and FGF23 between the ISS and healthy control groups (P>0.05). The serum levels of Klotho, FGF23, and IGF-1 increased significantly in the ISS group after 3, 6, and 9 months of rhGH treatment (P<0.05). In the ISS group, Klotho and FGF23 levels were positively correlated with the phosphate level before treatment (P<0.05). Before treatment and after 3, 6, and 9 months of rhGH treatment, the Klotho level was positively correlated with the IGF-1 level (P<0.05), the FGF23 level was positively correlated with the IGF-1 level (P<0.05), and the Klotho level was positively correlated with the FGF23 level (P<0.05), while Klotho and FGF23 levels were not correlated with the height standard deviation of point (P>0.05). CONCLUSIONS: The rhGH treatment can upregulate the levels of Klotho, FGF23, and IGF-1 and realize the catch-up growth in children with ISS. Klotho and FGF23 may not directly promote the linear growth of children with ISS, but may have indirect effects through the pathways such as IGF-1 and phosphate metabolism. The consistent changes in Klotho, FGF23 and IGF-1 levels show that there is a synergistic relationship among them in regulating the linear growth of ISS children.

Metabolic Engineering of Pichia pastoris for High-Level Production of Lycopene.

Lycopene is widely used in cosmetics, food, and nutritional supplements. Microbial production of lycopene has been intensively studied. However, few metabolic engineering studies on Pichia pastoris have been aimed at achieving high-yield lycopene production. In this study, the CRISPR/Cpf1-based gene repression system was developed and the gene editing system was optimized, which were applied to improve lycopene production successfully. In addition, the sterol regulatory element-binding protein SREBP (Sre) was used for the regulation of lipid metabolic pathways to promote lycopene overproduction in P. pastoris for the first time. The final engineered strain produced lycopene at 7.24 g/L and 75.48 mg/g DCW in fed-batch fermentation, representing the highest lycopene yield in P. pastoris reported to date. These findings provide effective strategies for extended metabolic engineering assisted by the CRISPR/Cpf1 system and new insights into metabolic engineering through transcriptional regulation of related metabolic pathways to enhance carotenoid production in P. pastoris.

A biodegradable chitosan-based polymer for sustained nutrient release to stimulate groundwater hydrocarbon-degrading microflora.

Petroleum hydrocarbon-contaminated groundwater often has a low indigenous microorganism population and lacks the necessary nutrient substrates for biodegradation reaction, resulting in a weak natural remediation ability within the groundwater ecosystem. In this paper, we utilized the principle of petroleum hydrocarbon degradation by microorganisms to identify effective nutrients (NaH2PO4, K2HPO4, NH4NO3, CaCl2, MgSO4·7H2O, FeSO4·7H2O, and VB12) and optimize nutrient substrate allocation through a combination of actual surveys of petroleum hydrocarbon-contaminated sites and microcosm experiments. Building on this, combining biostimulation and controlled-release technology, we developed a biodegradable chitosan-based encapsulated targeted biostimulant (i.e., YZ-1) characterized by easy uptake, good stability, controllable slow-release migration, and longevity to stimulate indigenous microflora in groundwater to efficiently degrade petroleum hydrocarbon. Results showed that YZ-1 extended the active duration of nutrient components by 5-6 times, with a sustainable release time exceeding 2 months. Under YZ-1 stimulation, microorganisms grew rapidly, increasing the degradation rate of petroleum hydrocarbon (10 mg L-1) by indigenous microorganisms from 43.03% to 79.80% within 7 d. YZ-1 can easily adapt to varying concentrations of petroleum hydrocarbon-contaminated groundwater. Specifically, in the range of 2-20 mg L-1 of petroleum hydrocarbon, the indigenous microflora was able to degrade 71.73-80.54% of the petroleum hydrocarbon within a mere 7 d. YZ-1 injection facilitated the delivery of nutrient components into the underground environment, improved the conversion ability of inorganic electron donors/receptors in the indigenous microbial community system, and strengthened the co-metabolism mechanism among microorganisms, achieving the goal of efficient petroleum hydrocarbon degradation.

Evaluation and Improvement of Employee Performance with respect to Health, Safety, and Environment (HSE) Factors: A Case of Complex Transport Construction Project.

Risk control in complex transport construction is complicated due to the dangerous nature of high variation and unpredictability. Most of the current research analysis focuses on the health, safety, and environment (HSE) risk assessment and employee performance evaluation, which neglects the impact of HSE risks on employee performance. Consequently, this research develops a framework to evaluate employee performance and identify key factors affecting performance. The employee performance indicators and HSE indicators are established by reviewing related literature. Using data from questionnaires, an artificial neural network- (ANN-) based model of employee activity effectiveness is then developed to evaluate employee performance. Sensitivity analysis is implemented to determine the key factors affecting employee performance. The Hong Kong-Zhuhai-Macau Bridge, a large-scale cross-sea channel project, is taken as a case study for validation. The model results show that the employees are satisfied with the effect of HSE management in general, but the psychological stress they perceive becomes large. The indicators of risk control and employee participation positively impact employee performance, while job satisfaction has a negative impact on performance. These findings indicate that operators should pay more attention to employees' psychological perception of work and form a standardized process management and control plan to prevent cumbersome processes from increasing employees' workload. This study helps construction systems and managers to identify the areas of strengths and weaknesses in their HSE management. The research only focuses on the impact of HSE risks on managers' performance in the complex transport construction project. In the future, further engineering projects and employee performance in composite scenarios can be investigated to improve the overall productivity.

Gut Fungal Communities Are Influenced by Seasonality in Captive Baikal Teal (Sibirionetta formosa) and Common Teal (Anas crecca).

Understanding the dynamics of avian gut fungal communities and potentially pathogenic species across different seasons is crucial for assessing their health and ecological interactions. In this study, high-throughput sequencing was employed to examine the changes in gut fungal communities and the presence of potential pathogens between different seasons in captive Baikal teal and common teal. Between the summer and autumn seasons, both duck species showed significant differences in fungal diversity and community composition. A higher fungal diversity in both species was exhibited in the summer than in the autumn. Ascomycota and Basidiomycota were the two most common phyla, with a greater proportion of Ascomycota than Basidiomycota in both duck species in the summer. Interestingly, our study also identified animal pathogens and plant saprotrophs in the gut fungal communities. Seasonal variation had an effect on the diversity and abundance of both animal pathogens and saprotrophs. Specifically, during the summer season, the diversity and relative abundance were higher compared to the autumn season. In addition, there were differences between duck species in terms of animal pathogens, while no significant differences were observed in saprotrophs. Overall, the communities of the gut fungi, animal pathogens, and saprotrophs were found to be influenced by seasonal changes rather than host species. Therefore, seasonal variations might dominate over host genetics in shaping the gut microbiota of captive Baikal teal and common teal. This study underscores the importance of incorporating an understanding of seasonal dynamics and potential pathogens within the gut microbiota of captive ducks. Such considerations have the potential to drive progress in the development of sustainable and economically viable farming practices.

Synthesis of O-Heterocycle Spiro-Fused Cyclopentaquinolinones and Cyclopentaindenes through Visible Light-Induced Radical Cyclization Reactions.

Presented herein is an effective and sustainable synthesis of O-heterocycle spiro-fused cyclopentaquinolinone and cyclopentaindene derivatives through light-driven cascade reactions of N-(o-ethynylaryl)acrylamides or 2-(2-(phenylethynyl)benzyl)acrylate with various O-heterocycles. Experimental mechanistic studies revealed that these reactions are initiated by visible light-induced radical formation from O-heterocycle and its regioselective addition onto the acrylamide or acrylate moiety followed by 6-exo-dig and 5-endo-trig cascade radical annulation, which is terminated by single electron oxidation and proton elimination. Compared with previously reported synthetic methods for similar purposes, this newly developed protocol has advantages such as a broad substrate scope, extremely mild reaction conditions, excellent atom-economy, high efficiency, and good compatibility with diverse functional groups. With all of these merits, this method is expected to find wide applications in the related research arena.

IFITM3 restricts RABV infection through inhibiting viral entry and mTORC1- dependent autophagy.

Rabies, which caused by rabies virus (RABV), is a zoonotic and life-threatening disease with 100% mortality, and there is no effective treatment thus far due to the unclear pathogenesis and less of treatment targets. Interferon-induced transmembrane protein 3 (IFITM3) has recently been identified as an important anti-viral host effector induced by type I interferon. However, the role of IFITM3 in RABV infection has not been elucidated. In this study, we demonstrated that IFITM3 is a crucial restriction factor for RABV, the viral-induced IFITM3 significantly inhibited RABV replication, while knockdown of IFITM3 had the opposite effect. We then identified that IFNß induces the upregulation of IFITM3 in the absence or presence of RABV infection, meanwhile, IFITM3 positively regulates RABV-triggered production of IFNß in a feedback manner. In-depth research we found that IFITM3 not only inhibits the virus absorb and entry, but also inhibits viral replication through mTORC1-dependent autophagy. All these findings broaden our understanding of IFITM3 function and uncover a novel mechanism against RABV infection.