AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases.

L-lactate modifies proteins through lactylation1, but how this process occurs is unclear. Here we identify the alanyl-tRNA synthetases AARS1 and AARS2 (AARS1/2) as intracellular L-lactate sensors required for L-lactate to stimulate the lysine lactylome in cells. AARS1/2 and the evolutionarily conserved Escherichia coli orthologue AlaRS bind to L-lactate with micromolar affinity and they directly catalyse L-lactate for ATP-dependent lactylation on the lysine acceptor end. In response to L-lactate, AARS2 associates with cyclic GMP-AMP synthase (cGAS) and mediates its lactylation and inactivation in cells and in mice. By establishing a genetic code expansion orthogonal system for lactyl-lysine incorporation, we demonstrate that the presence of a lactyl moiety at a specific cGAS amino-terminal site abolishes cGAS liquid-like phase separation and DNA sensing in vitro and in vivo. A lactyl mimetic knock-in inhibits cGAS, whereas a lactyl-resistant knock-in protects mice against innate immune evasion induced through high levels of L-lactate. MCT1 blockade inhibits cGAS lactylation in stressed mice and restores innate immune surveillance, which in turn antagonizes viral replication. Thus, AARS1/2 are conserved intracellular L-lactate sensors and have an essential role as lactyltransferases. Moreover, a chemical reaction process of lactylation targets and inactivates cGAS.

Legionella effector LnaB is a phosphoryl-AMPylase that impairs phosphosignalling

AMPylation is a post-translational modification in which AMP is added to the amino acid side chains of proteins1,2. Here we show that, with ATP as the ligand and actin as the host activator, the effector protein LnaB of Legionella pneumophila exhibits AMPylase activity towards the phosphoryl group of phosphoribose on PRR42-Ub that is generated by the SidE family of effectors, and deubiquitinases DupA and DupB in an E1- and E2-independent ubiquitination process3-7. The product of LnaB is further hydrolysed by an ADP-ribosylhydrolase, MavL, to Ub, thereby preventing the accumulation of PRR42-Ub and ADPRR42-Ub and protecting canonical ubiquitination in host cells. LnaB represents a large family of AMPylases that adopt a common structural fold, distinct from those of the previously known AMPylases, and LnaB homologues are found in more than 20 species of bacterial pathogens. Moreover, LnaB also exhibits robust phosphoryl AMPylase activity towards phosphorylated residues and produces unique ADPylation modifications in proteins. During infection, LnaB AMPylates the conserved phosphorylated tyrosine residues in the activation loop of the Src family of kinases8,9, which dampens downstream phosphorylation signalling in the host. Structural studies reveal the actin-dependent activation and catalytic mechanisms of the LnaB family of AMPylases. This study identifies, to our knowledge, an unprecedented molecular regulation mechanism in bacterial pathogenesis and protein phosphorylation.

MIRO-1 interacts with VDAC-1 to regulate mitochondrial membrane potential in Caenorhabditis elegans.

Precise regulation of mitochondrial fusion and fission is essential for cellular activity and animal development. Imbalances between these processes can lead to fragmentation and loss of normal membrane potential in individual mitochondria. In this study, we show that MIRO-1 is stochastically elevated in individual fragmented mitochondria and is required for maintaining mitochondrial membrane potential. We further observe a higher level of membrane potential in fragmented mitochondria in fzo-1 mutants and wounded animals. Moreover, MIRO-1 interacts with VDAC-1, a crucial mitochondrial ion channel located in the outer mitochondrial membrane, and this interaction depends on the residues E473 of MIRO-1 and K163 of VDAC-1. The E473G point mutation disrupts their interaction, resulting in a reduction of the mitochondrial membrane potential. Our findings suggest that MIRO-1 regulates membrane potential and maintains mitochondrial activity and animal health by interacting with VDAC-1. This study provides insight into the mechanisms underlying the stochastic maintenance of membrane potential in fragmented mitochondria.

Oxidative cascade cyclization of N-arylacrylamides with TMSN3.

An azido-radical-triggered cyclization of N-(o-cyanobiaryl)acrylamides with TMSN3via a C(sp3)-N/C(sp2)-C(sp3)/C(sp2)-N bond formation cascade is described. This reaction features mild conditions and high bond-forming efficiency, making it an efficient method for the construction of azide-substituted pyridophenanthridines.

TOR functions as a molecular switch connecting an iron cue with host innate defense against bacterial infection.

As both host and pathogen require iron for survival, iron is an important regulator of host-pathogen interactions. However, the molecular mechanism by which how the availability of iron modulates host innate immunity against bacterial infections remains largely unknown. Using the metazoan Caenorhabditis elegans as a model, we demonstrate that infection with a pathogenic bacterium Salmonella enterica serovar Typhimurium induces autophagy by inactivating the target of rapamycin (TOR). Although the transcripts of ftn-1 and ftn-2 encoding two H-ferritin subunits are upregulated upon S. Typhimurium infection, the ferritin protein is kept at a low level due to its degradation mediated by autophagy. Autophagy, but not ferritin, is required for defense against S. Typhimurium infection under normal circumstances. Increased abundance of iron suppresses autophagy by activating TOR, leading to an increase in the ferritin protein level. Iron sequestration, but not autophagy, becomes pivotal to protect the host from S. Typhimurium infection in the presence of exogenous iron. Our results show that TOR acts as a regulator linking iron availability with host defense against bacterial infection.

Prognostic Significance of Advanced Lung Cancer Inflammation Index, a Nutritional and Inflammation Index, in Patients With Gastrointestinal Cancers: A Meta-analysis.

Previous studies have investigated the prognostic value of the advanced lung cancer inflammation index (ALI) in gastrointestinal (GI) cancers; however, the results are controversial. This meta-analysis aimed to evaluate the prognostic and clinicopathological role of ALI in patients with GI cancers. A systematic search of electronic databases was conducted to evaluate the prognostic and clinicopathological value of ALI in GI cancers. Nine studies comprising 3,750 patients were included in this meta-analysis. The pooled results showed that a low ALI was significantly associated with worse overall survival (OS, hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.53-2.47, P < 0.001, I2 = 63.9%) and disease-free survival/relapse-free survival (DFS/RFS, HR = 1.49, 95% CI = 1.28-1.73, P < 0.001, I2 = 0%) in patients with GI cancers. In addition, decreased ALI correlated with the depth of tumor invasion and presence of distant metastasis and tended to be associated with male sex, high carcinoembryonic antigen levels, lymph node metastasis, and right-sided colon cancer. Low ALI was associated with adverse OS and DFS/RFS in patients with GI cancer. In addition, decreased ALI also correlated with clinicopathological factors, indicating higher stage of the malignancy.

Photocatalytic Intramolecular Alkene Hydroamination of N-Alkoxy Ureas: An Approach to Imidazolinones.

Imidazolinones were obtained in good yields by intramolecular hydroamination of N-alkoxy ureas in the presence of an organic photocatalyst and an inorganic base. In this reaction, the N-alkoxy urea anion generated by deprotonation undergoes photocatalyzed single-electron-transfer oxidation to generate the corresponding radical, which cyclizes to afford the imidazolinone ring. This new protocol grants access to an array of complex molecules containing a privileged imidazolinone core.

Glucose and H2O2 Dual-Responsive Nanocomplex Grafted with Insulin Prodrug for Blood Glucose Regulation.

Although "closed-loop" smart insulin delivery systems have been extensively investigated, the majority of them suffer from low insulin loading efficiency and slow glucose response. Here, we constructed a novel nanocomplex (NC), which was prepared by electrostatic interaction between negatively charged insulin prodrug nanoparticles (NPs) and positively charged polycaprolactone-polyethylenimine (PCL-PEI) micelles. The insulin prodrug was linked to acetalated dextran (AD) via borate ester bonds to form IAD NPs, and glucose oxidase (GOx) was encapsulated in PCL-PEI micelles. The NC was negatively charged with a high insulin grafting rate (0.473 mg/mg), and in vitro experiments revealed that IAD was sensitive to hyperglycemia and H2O2, whereas GOx significantly improved the response to glucose by altering the microenvironment to promote sustained insulin release. Furthermore, compared with free insulin and IAD NPs, subcutaneously injected NCs in diabetic rats had long-term hypoglycemic effects, showing excellent biocompatibility in vitro and in vivo, which had good potential in insulin self-regulation delivery.

Free Radical Cascade Carbochloromethylations of Activated Alkenes.

Free radical carbochloromethylations of ortho-cyanoarylacrylamides and N-(arylsulfonyl)acrylamides have been developed by employing simple alkyl chlorides as the chloromethyl source. The transformations are characterized by wide functional group compatibility and utilizing readily available reagents, thus providing efficient methods for constructing polychloromethyl-substituted quinoline-2,4-diones and α-aryl-ß-polychloromethylated amides.

Radical borylation of vinyl azides with NHC-boranes: divergent synthesis of α-boryl ketones and borylated triazoles.

A divergent radical borylation of vinyl azides with N-heterocyclic carbene (NHC) boranes in the presence of tBuSH is described. The protocol enables the divergent synthesis of α-boryl ketones and borylated triazoles with excellent functional group tolerance and a broad substrate scope. Remarkably, this work shows that vinyl azides can serve as unprecedented five-atom synthons for the construction of 1,2,3-triazoles without N2 extrusion.

Panax notoginseng powder -assisted preparation of carbon-quantum-dots/BiOCl with enriched oxygen vacancies and boosted photocatalytic performance.

Low activity of photocatalysts is a serious bottleneck to the practical application of photocatalytic technology. In this paper, a series of BiOCl composite photocatalysts containing carbon quantum dots (CQDs) were successfully prepared by adding Panax notoginseng powder (PNP) to the solvothermal synthesis system of BiOCl as a template agent and a raw material for 0D CQDs. CQDs/BiOCl exhibit 2D flake structures and 3D flower-like microspheres self-assembled from thin flakes, holding rich oxygen vacancies (OVs). After detailed characterization, it was found that the amount of OVs on BiOCl could be regulated according to the amount of PNP added. The CQDs/OVs-BiOCl photocatalysts exhibit higher photogenerated charge separation efficiency and photocatalytic activity than the bare BiOCl. When the mass ratio of PNP/BiOCl is 1.0%, the photocatalyst demonstrates the maximum degradation activity for rhodamine B (RhB) and perfluorooctanoic acid (PFOA). In view of the solid observations, a photocatalytic enhancement mechanism of CQDs/BiOCl was elucidated.

The efficacy and safety of lenvatinib in the treatment of solid tumors: an up-to-date meta-analysis.

Aim: We performed an updated meta-analysis to evaluate the efficacy and safety of lenvatinib in cancer patients. Materials & methods: Databases were searched to identify relevant trials. Data were extracted to evaluate overall survival, progression-free survival, overall response rate and grade ≥3 adverse events. Results: The pooled analysis demonstrated that lenvatinib significantly improved progression-free survival (hazard ratio: 0.43; 95% CI: 0.23-0.80; p = 0.008), overall survival (hazard ratio: 0.85; 95% CI: 0.75-0.97; p = 0.013) and overall response rate (relative risk: 6.89; 95% CI: 2.22-21.36; p = 0.001) compared with control therapy. However, the use of lenvatinib can increase the risk of severe infection. Conclusion: Lenvatinib-containing regimens are associated with better progression-free survival, overall survival and overall response rate, but can induce severe infection.

Aetiology of superficial fungal infections of the foot in urban outpatients in mainland China: A multicentre, prospective case study.

BACKGROUND: In China, the prevalence of superficial fungal infections of the foot is high and recurrence is common. However, a prospective, large-scale and multicentre study on the aetiology of superficial fungal infections of the foot is still lacking. OBJECTIVES: To study the epidemiology of aetiological agents of superficial fungal infections of the foot in urban outpatients in mainland China, as well as to understand the aetiology features of the pathogenic agent. METHODS: The study was designed as a multicentre, prospective epidemiological survey. A total of 1704 subjects were enrolled from seven geographical areas in mainland China. For each subject, one mycological sample and one bacterial sample were collected. KOH wet mount examination and culture were performed at local laboratories. The bacterial results were only reported in those with positive mycology. Further morphological identification and, if necessary, molecular biological identification were conducted in a central laboratory. RESULTS: Of 1704 enrolled subjects, 1327 (77.9%) subjects had positive fungal culture results. The incidence of dermatophytes, yeasts and moulds was 90.1%, 8.1% and 1.1%, respectively. The most frequently isolated aetiological agent (fungus) was Trichophyton rubrum. Moccasin form was the most commonly reported clinical diagnosis of superficial fungal infections. The most frequently isolated bacterial genus in patients was Staphylococcus. CONCLUSION: This study prospectively investigated the clinical and mycological features of human dermatophytosis in mainland China. T rubrum was the most frequently isolated fungus, and moccasin form was the most commonly reported clinical diagnosis of superficial fungal infections.

[Analysis of survey data of popularization of traditional Chinese medicine health culture knowledge in 2017].

To continuously track and analyze the popularization and change trend of traditional Chinese medicine(TCM) health culture knowledge, so as to provide scientific basis for formulating relevant policies, strategies and measures for popularizing Chinese medicine health culture knowledge. In this study, PPS combined with random sampling method was used to survey residents aged between 15 and 69 in 328 survey sites in 30 provinces, autonomous regions and municipalities(excluding Tibet Autonomous Region, Hong Kong, Macao and Taiwan). In the study, a standardized questionnaire was used to survey the contact, cognition, trust and use of Chinese medicine health culture knowledge. A total of 89 107 people were respondent in this study, including 87 287 valid questionnaires, with an effective rate of 97.96%. Among them, the urban residents accounted for 51.35%, rural residents accounted for 48.65%; males took up 48.25%, and females took up 51.75%. In 2017, the national Chinese medicine health culture knowledge popularization rate was 91.72%, the reading rate was 89.61%, the trust rate was 89.60%, and the action rate was 55.53%. The study found that TCM health culture knowledge was more popular among young people, high-education residents and non-sickness groups. It is recommended to strengthen the popularization of traditional Chinese medicine in key areas and key populations, provide differentiated Chinese medicine health education to population in different areas, and cooperation with mass media to provide diversified contents and forms.

[Analysis of knowledge acquisition behavior of traditional Chinese medicine based on internet].

The study aims at understanding the situation of Chinese residents' access to Chinese medicine health culture knowledge through the Internet and analyze its influencing factors. A multi-stage PPS sampling method was used to collect 90 720 people for questionnaire survey. The survey found thatthe probability of Chinese residents accessing Chinese medicine health culture knowledge through the Internet was 54.7%. The females(with the males as reference, OR=1.076, 95% CI 1.018-1.137) and central population(with the east as reference, OR=1.235, 95% CI 1.048-1.456), people with Chinese medicine health culture literacy(with the people who do not have Chinese medicine health culture literacy as reference, OR=2.363, 95% CI 1.976-2.827) had a higher probability of acquiring Chinese medicine health culture knowledge through the Internet. Referring to people who were illiterate or less literate,the OR values of people who went to elementary school, junior school, high school/vocational/technical school and junior college/university was 2.396(95% CI 2.062-2.784),4.481(95% CI 3.751-5.352), 6.687(95% CI 5.541-8.07),and 9.109(95% CI 7.385-11.235). The higher the age, the lower the probability of acquiring Chinese medicine health culture knowledge through the Internet. Taking civil servants as a reference, teachers, students, farmers, and workers had a low probability of acquiring Chinese medicine health culture knowledge through the Internet. The OR values was 0.736(95% CI 0.548-0.988),0.609(95% CI 0.449-0.826), 0.424(95% CI 0.325-0.554),and 0.707(95% CI 0.539-0.927). Regions, gender, age, education level, occupation, and possession of Chinese medicine health culture literacy are factors influencing whether residents obtain Chinese medicine health culture knowledge through the Internet.

[Analysis of Chinese citizens' traditional Chinese medicine health culture literacy level and its influence factors in 2017].

To analyze the TCM health culture level and influence factors of Chinese citizens in 2017. PPS sampling combined with random sampling was used to select the residents aged between 15-69 years old in 30 provinces as the respondents,and a questionnaire study was conducted to investigate their TCM health culture level. In 2017,there were 87 287 valid questionnaires for Chinese citizens' TCM health culture level,including 48. 25% male and 51. 75% female,with a sex ratio of 1 ∶ 1. 073. In 2017,the overall TCM health culture level was 13. 39%,specifically 18. 77% for the urban areas and 10. 51% for the rural areas. Compared with people who were illiterate or less literate,people with an educational background of elementary school,junior high school,high school/vocational/technical school and junior college/university had a higher TCM health culture level,and the OR values were 1. 584( 95% CI[1. 166,2. 152]),2. 827( 95%CI[1. 839,4. 345]),5. 651( 95%CI[3. 637,8. 781]),9. 785( 95%CI[6. 187,15. 477]) in order. With civil servants as the reference,medical workers had a higher TCM health culture level( OR = 1. 829,95%CI[1. 279,2. 616]),while farmers had the lowest TCM health culture level( OR = 0. 493,95% CI[0. 349,0. 697]). Compared with people with the annual household income per capita of 20 000 yuan and below,people with the annual household income per capita between 20 000-50 000,50 000-80 000,80 000 yuan or above had a higher TCM health culture level,and the OR values were 1. 176( 95% CI[0. 963,1. 437]),1. 458( 95%CI[1. 168,1. 820]) and 1. 930( 95%CI[1. 509,2. 469]). Based on the differences between urban and rural areas,the influence factors of citizens' TCM health culture level include education,occupation and income.

Ammoxetine attenuates diabetic neuropathic pain through inhibiting microglial activation and neuroinflammation in the spinal cord.

BACKGROUND: Diabetic neuropathic pain (DNP) is a common and distressing complication in patients with diabetes, and the underlying mechanism remains unclear. Tricyclic antidepressants (TCAs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are recommended as first-line drugs for DNP. Ammoxetine is a novel and potent SNRI that exhibited a strong analgesic effect on models of neuropathic pain, fibromyalgia-related pain, and inflammatory pain in our primary study. The present study was undertaken to investigate the chronic treatment properties of ammoxetine on DNP and the underlying mechanisms for its effects. METHODS: The rat model of DNP was established by a single streptozocin (STZ) injection (60 mg/kg). Two weeks after STZ injection, the DNP rats were treated with ammoxetine (2.5, 5, and 10 mg/kg/day) for 4 weeks. The mechanical allodynia and locomotor activity were assayed to evaluate the therapeutic effect of ammoxetine. In mechanism study, the activation of microglia, astrocytes, the protein levels of pro-inflammatory cytokines, the mitogen-activated protein kinases (MAPK), and NF-κB were evaluated. Also, microglia culture was used to assess the direct effects of ammoxetine on microglial activation and the signal transduction mechanism. RESULTS: Treatment with ammoxetine for 4 weeks significantly relieved the mechanical allodynia and ameliorated depressive-like behavior in DNP rats. In addition, DNP rats displayed increased activation of microglia in the spinal cord, but not astrocytes. Ammoxetine reduced the microglial activation, accumulation of pro-inflammatory cytokines, and activation of p38 and c-Jun N-terminal kinase (JNK) in the spinal cord of DNP rats. Furthermore, ammoxetine displayed anti-inflammatory effects upon challenge with LPS in BV-2 microglia cells. CONCLUSION: Our results suggest that ammoxetine may be an effective treatment for relieving DNP symptoms. Moreover, a reduction in microglial activation and pro-inflammatory release by inhibiting the p-p38 and p-JNK pathways is involved in the mechanism.

YL-0919, a dual 5-HT1A partial agonist and SSRI, produces antidepressant- and anxiolytic-like effects in rats subjected to chronic unpredictable stress.

YL-0919 has been identified as a novel dual 5-HT1A partial agonist and serotonin reuptake inhibitor. In the current study, we demonstrated that YL-0919 produced prominent antidepressant-like and anxiolytic-like effects in a chronic unpredictable stress (CUS) rat model. Male SD rats were exposed to CUS for 5 weeks; YL-0919 (1.25 and 2.5 mg/kg) or a positive control fluoxetine (Flx, 10 mg/kg) was orally administered daily. YL-0919 or Flx treatment significantly increased the sucrose preference rate, the locomotor activity in an open field test (OFT), the latency to feed in a novelty-suppressed feeding test (NSFT), and both the percentage of time spent in the open arms and the number of entries into the open arms in an elevated plus-maze test. YL-0919 or Flx treatment significantly suppressed the serum levels of ACTH and corticosterone in CUS-exposed rats. Additionally, YL-0919 or Flx treatment significantly enhanced the levels of cAMP, the expression of phosphorylated cAMP response element-binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus of CUS-exposed rats. Similar to Flx, YL-0919 treatment significantly enhanced the dendritic complexity, and increased the number of dendritic nodes as well as the spine length and number of branch nodes in the hippocampal pyramidal neurons of CUS-exposed rats. Overall, our results reveal that YL-0919 suppresses the HPA axis and exerts antidepressant-like and anxiolytic-like effects in CUS-exposed rats, which are associated with the enhanced cAMP signaling and hippocampal dendritic complexity.