Neutrophil accumulation raises defence against Streptococcus equi ssp. zooepidemicus in the absence of Gasdermin D.

Streptococcus equi ssp. zooepidemicus (SEZ) predominantly acts as a zoonotic pathogen, capable of infecting a diverse range of animal species including human. Gasdermin D (GSDMD) exhibited comprehensive functions in host against different pathogenic microorganism. This study aimed to investigate the role of GSDMD in host against SEZ. Mice were administrated with SEZ via intranasal intubation for 24 h (3 × 106CFU), GSDMD protein expression significantly increased in the lung tissue of mice infected with SEZ. For further research on the role of GSDMD during SEZ infection, GSDMD-/- mice and WT mice were treated with SEZ via intranasal intubation for 24 h (3 × 106CFU). GSDMD-/- mice showed less severe lung tissue due to fewer bacteria colonization. Numerous neutrophils were recruited into lung tissues in GSDMD-/- mice, related to the release of CXCL1 and CXCL2 regulated by p65 phosphorylation. In further study, neutrophils of WT and GSDMD-/- mice were isolated and treated with SEZ (multiplicity of infection, MOI = 10, 4 h). The absence of GSDMD alleviated the death of neutrophils, in addition, GSDMD deficiency could promote translocation of p65 from the cytoplasm into the nucleus in neutrophil, which may contribute to the release of IL-1ß and TNF-α. This study demonstrated a novel function of GSDMD in host immune response to SEZ invading, indicating that GSDMD deficiency ameliorated SEZ infection through enhancing neutrophil accumulation into infected site, and activating NF-κB pathway in neutrophil to release cytokines against SEZ. Our study suggested that inhibition of host GSDMD may be an effective method against SEZ.

Promoting threshold voltage of P2-Na0.67Ni0.33Mn0.67O2 with Cu2+ cation doping toward high-stability cathode for sodium-ion battery.

P2-type Na0.67Ni0.33Mn0.67O2 has attracted considerable attraction as a cathode material for sodium-ion batteries owing to its high operating voltage and theoretical specific capacity. However, when the charging voltage is higher than 4.2 V, the Na0.67Ni0.33Mn0.67O2 cathode undergoes a detrimental irreversible phase transition of P2-O2, leading to a drastic decrease in specific capacity. To address this challenge, we implemented a Cu-doping strategy (Na0.67Ni0.23Cu0.1Mn0.67O2) in this work to stabilize the structure of the transition metal layer. The stabilization strategy involved reinforcing the transition metal-oxygen (TMO) bonds, particularly the MnO bond and inhibiting interlayer slip during deep desodiation. As a result, the irreversible phase transition voltage is delayed, with the threshold voltage increasing from 4.2 to 4.4 V. Ex-situ X-ray diffraction measurements revealed that the Na0.67Ni0.23Cu0.1Mn0.67O2 cathode maintains the P2 phase within the voltage window of 2.5-4.3 V, whereas the P2-Na0.67Ni0.33Mn0.67O2 cathode transforms entirely into O2-type Na0.67Ni0.33Mn0.67O2 when the voltage exceeds 4.3 V. Furthermore, absolute P2-O2 phase transition of the Na0.67Ni0.23Cu0.1Mn0.67O2 cathode occurred at 4.6 V, indicating that Cu2+ doping enhances the stability of the layer structure and increases the threshold voltage. The resulting Na0.67Ni0.23Cu0.1Mn0.67O2 cathode exhibited superior electrochemical properties, demonstrating an initial reversible specific capacity of 89.1 mAh/g at a rate of 2C (360 mA g-1) and retaining more than 78 % of its capacity after 500 cycles.

Drug Repurposing by Siderophore Conjugation: Synthesis and Biological Evaluation of Siderophore-Methotrexate Conjugates as Antibiotics.

Drug repurposing is considered a promising strategy to fight antimicrobial resistance (AMR). Methotrexate (Mtx), a classical anticancer drug, could strongly inhibit bacterial dihydrofolate reductase (DHFR). However, its poor permeability into bacteria and potent human cytotoxicity make it unsuitable as an antibacterial. Herein, we reported the conjugation of Mtx with a siderophore to construct "Trojan horse" antibacterials. The most potent conjugate 8 with nanomolar minimum inhibitory concentration (MIC) values exhibited over 1.00×103 -fold improved activity against Gram-positive Streptococcus pneumoniae (S. pneumoniae) and Gram-negative Yersinia enterocolitica (Y. enterocolitica) compared with Mtx, while possessing 2.31×103 -fold reduced human cytotoxicity, resulting in 2.08×106 -fold improvements in the therapeutic index. This proof-of-principle study verifies that siderophore conjugation is an effective strategy for developing new antibacterials from anticancer drugs.

Caspase-1 deficiency impairs neutrophils recruitment and bacterial clearance in Streptococcus equi ssp. zooepidemicus infected mice.

Streptococcus equi ssp. zooepidemicus (S. zooepidemicus, SEZ) is a zoonotic bacterial pathogen that can cause various inflammation, including pneumonia. As the most abundant leukocytes in the circulation, neutrophils are the first wave of leukocytes to arrive in the lung upon infection. This study aims to evaluate the effect of caspase-1 on the host response to SEZ infection in a mouse model. Intranasal exposure to SEZ induced the expression of caspase-1 in wild-type mice lung, and increased the number of neutrophils in the alveolar cavity and alveolar wall. In addition, caspase-1 deficiency reduced the transcription levels of IL-1α, IL-1ß, IL-6, and TNF-α in the lungs of infected mice, which was accompanied by decreased recruitment of pulmonary neutrophils. Moreover, knocking out caspase-1 decreased the bactericidal activity of neutrophils and promoted the pulmonary bacterial load. In line with this, the mortality of caspase-1-/- mice infected with SEZ was significantly increased compared with those of caspase-1+/+ mice. Collectively, recruiting neutrophils and enhancing the bactericidal ability of neutrophils are important means for caspase-1 to promote bacterial clearance.

Time-dependent enantiodivergent synthesis via sequential kinetic resolution.

The preparation of both enantiomers of chiral molecules is among the most fundamental tasks in organic synthesis, medicinal chemistry and materials science. Achieving this goal typically requires reversing the absolute configuration of the chiral component employed in the reaction system that is being used. The task becomes challenging when the natural source of the chiral component is not available in both configurations. Herein, we report a time-dependent enantiodivergent synthesis, in which an Ir-catalysed allylic substitution reaction uses one catalyst sequentially to promote two kinetic resolution reactions, enabling the synthesis of both enantiomers of the product using the same enantiomer of a chiral catalyst. The appropriate permutation of individual reaction rates is essential for the isolation of the chiral products in opposite configurations with high enantiopurity when quenched at different reaction times. This work provides an alternative solution for the preparation of both enantiomers of chiral molecules.

Total synthesis and antimicrobial evaluation of natural albomycins against clinical pathogens.

Development of effective antimicrobial agents continues to be a great challenge, particularly due to the increasing resistance of superbugs and frequent hospital breakouts. There is an urgent need for more potent and safer antibiotics with novel scaffolds. As historically many commercial drugs were derived from natural products, discovery of antimicrobial agents from complex natural product structures still holds a great promise. Herein, we report the total synthesis of natural albomycins δ1 (1a), δ2 (1b), and ε (1c), which validates the structures of these peptidylnucleoside compounds and allows for synthetic access to bioactive albomycin analogs. The efficient synthesis of albomycins enables extensive evaluations of these natural products against model bacteria and clinical pathogens. Albomycin δ2 has the potential to be developed into an antibacterial drug to treat Streptococcus pneumoniae and Staphylococcus aureus infections.

Stevens rearrangement of thioethers with arynes: a facile access to multi-substituted ß-keto thioethers.

An effective method for the synthesis of multi-substituted ß-keto thioethers via Stevens rearrangement of simple ß-keto thioethers with arynes has been developed. In these reactions, successive C-S/C-H/C-C bonds were formed in one pot under mild and transition-metal free conditions to afford multi-substituted ß-keto thioethers in moderate to good yields.

A new ternary copper(II) complex derived from 2-(2'-pyridyl)benzimidazole and glycylglycine: synthesis, characterization, DNA binding and cleavage, antioxidation and HSA interaction.

A new ternary copper(II)-dipeptide complex [Cu(glygly)(HPB)(Cl)]⋅2H2O (glygly=glycylglycine anion, HPB=2-(2'-pyridyl)benzimidazole) has been synthesized and characterized. The DNA interaction of the complex was studied by spectroscopic methods, viscosity, and electrophoresis measurements. The antioxidant activity was also investigated using the pyrogallol autoxidation assay. Besides, the interaction of the complex with human serum albumin (HSA) in vitro was examined by multispectroscopic techniques. The complex partially intercalated to CT-DNA with a high binding constant (Kb=7.28×10(5) M(-1)), and cleaved pBR322 DNA efficiently via an oxidative mechanism in the presence of Vc, with the HO· and O2(-) as the active species, and the SOD as a promoter. Furthermore, the complex shows a considerable SOD-like activity with the IC50 value of 3.8386 µM. The complex exhibits desired binding affinity to HSA, in which hydrogen bond or vander Waals force played a major role. The alterations of HSA secondary structure induced by the complex were confirmed by UV-visible, CD, synchronous fluorescence and 3D fluorescence spectroscopy.

[Urumqi 11 689 secondary school teachers of throat disease investigation].

OBJECTIVE: To investigate the prevalence of throat disease in secondary school teachers of Urumqi. METHOD: Use Stage-Two random sampling at 11689 teachers from 109 secondary schools in Urumqi; Draw 3 217 from 11689 teachers in 109 secondary schools to accept voice self-assessment questionnaire survey and routine examination of throat, and the one who were confirmed abnormal in routine inspection would be underway stroboscopic laryngoscopy. RESULT: The total illness prevalence rate of throat disease in secondary school teachers of Urumqi is 28.23%; there is no statistic difference of illness prevalence rate between male and female teachers (P > 0.05). However, results showed statistical significance of illness prevalence rate in teachers of different racial-groups with different years of teaching experience (P < 0.05). Teachers who have 5 to 15 years of teaching experience suffer a high incidence of throat diseases. Among eight racial groups involved in investigation, Kazak teachers are in the highest illness prevalence rate. The results of assessment for voice disorder index between teachers with and without throat diseases showed statistical difference in total score TVH (P < 0.05), which is shown significant in the physical and emotional areas (P < 0.05), while there is no statistical difference in function. Diseases of pharyngeal portion are mainly chronic pharyngitis and hyperplastic tonsil in tongue root; Diseases of laryngeal portion are mainly chronic laryngitis and vocal nodule for female, while mainly chronic laryngitis and vocal polypus for male. CONCLUSION: There is no significant difference in illness prevalence rate of throat disease for secondary school teachers in Urumqi between genders; the highest prevalence rate is in teachers who have 5 to 15 years teaching experience; among different racial groups, Kazak teachers are of the highest illness prevalence rate; the illness prevalence of throat diseases is related with voice disorder index.

[Voice fatigue test analysis in secondary school teachers].

OBJECTIVE: To investigate the status of voice fatigue and throat disease in the secondary school teachers in Urumqi. METHODS: This study included 11 689 teachers from 109 secondary schools offered by Teaching and Researching Center of Urumqi as the second-stage random sampling. Among them, 3217 teachers were selected to carry out voice fatigue test and routine examination of throat. For those with abnormal routine inspection results, the stroboscopic laryngoscopy were added. RESULTS: The failure rate difference of 3217 secondary school teachers voice fatigue tests during different periods had statistical significance (F = 202.653, P < 0.05). The failure rate difference of voice fatigue test among different throat diseases groups had statistical significance (F = 9.516, P < 0.05). There was statistical significance in failure rates of the voice fatigue tests between 908 cases of disease group and 2309 cases of normal group among different genders and periods (P < 0.05). Female teachers had higher failure rates than male teachers in voice fatigue tests. High failure rates appeared when high volume required for male and female teachers in voice fatigue tests. There was statistical significance in mean value sound pressure level (MVSPL) and mean value fundamental frequency (MVF0) of the voice fatigue tests between different gender and periods (P < 0.05). Male teachers had higher MVSPL than female teachers, female teachers had higher MVF0 than male teachers. There was statistical significance in failure rates of the voice fatigue tests among teachers from different tribes in different periods (P < 0.05). The Uighur had the highest failure rate, while Han had the lowest. Make further pairwise comparisons, failure rates difference of the Han and the Uighur in the voice fatigue tests during different periods had statistical significance. Comparison among other tribes had no statistical significance (P > 0.05). CONCLUSIONS: Voice fatigue is common in secondary school teachers. Female teachers tend to get voice fatigue more easily, when required high volume, the voice fatigue is more serious. Uighurs teachers have highest degree of voice fatigue.