Abstract Pharmacological inhibition of vacuolar-type H + -ATPase (V-ATPase) by its specific inhibitor can abrogate tumor metastasis, prevent autophagy, and reduce cellular signaling responses. Bafilomycin A1, a member of macrolide antibiotics and an autophagy inhibitor, serves as a specific and potent V-ATPases inhibitor. Although there are many V-ATPase structures reported, the molecular basis of specific inhibitors on V-ATPase remains unknown. Here, we report the cryo-EM structure of bafilomycin A1 bound intact bovine V-ATPase at an overall resolution of 3.6-Å. The structure reveals six bafilomycin A1 molecules bound to the c-ring. One bafilomycin A1 molecule engages with two c subunits and disrupts the interactions between the c-ring and subunit a , thereby preventing proton translocation. Structural and sequence analyses demonstrate that the bafilomycin A1-binding residues are conserved in yeast and mammalian species and the 7’-hydroxyl group of bafilomycin A1 acts as a unique feature recognized by subunit c .
A 48-year-old woman with a high-grade intraepithelial neoplasia of the gastric antrum was referred for ESD treatment.The difficulty of ESD is to expose the submucosa,especially in difficult sites and lesions with severe fibrosis.Adequate submucosal exposure is the most critical technology to reduce complications and improving efficiency.Here we report a novel entire traction method to facilitate safe and efficient ESD.
This was a multicenter, single-arm, open-label, phase Ib/II study (NCT04255576), aimed to evaluate the efficacy and safety of JMT103 in patients with unresectable or surgically-challenging giant cell tumor of bone (GCTB). JMT103 (2 mg/kg) was administered subcutaneously every four weeks, with loading doses on days 8 and 15. The primary endpoint was the objective tumor response rate (OTR) based on best response, defined as the proportion of patients who achieved elimination of at least 90% of the giant cells or radiologic complete or partial response per the modified Inverse Choi density/size (mICDS) or modified European Organization for Research and Treatment of Cancer (mEORTC) within 12 weeks. Secondary endpoints included objective response rate (ORR) per mICDS and mEORTC, and safety. A total of 139 patients were enrolled, and 135 were analyzed for efficacy. OTR, determined by the independent review committee (IRC) was 93.3% (95% CI 87.7-96.9). Treatment-related adverse events occurred in 90 (64.7%) patients, with hypophosphatemia and hypocalcemia being the most common. No serious treatment-related adverse events were observed. Thus, JMT103 demonstrates potential as a therapeutic option for GCTB. Giant cell tumor of bone (GCTB) is a rare primary osteolytic bone tumor with high local recurrence rate after surgical resection. Here the authors conduct a phase Ib/II trial, evaluating the efficacy and safety of JMT103 (RANK-RANKL inhibitor) in patients with unresectable or surgically-challenging GCTB.
The photochemistry of Diazo Meldrum's acid (DM) was investigated by fs time-resolved UV-vis and IR spectroscopic methods. UV (266 nm) excitation of DM pumps the molecule to the S 5 and S 7 excited states. After fast internal conversion (IC), the S 2 state is formed, which will undergo Wolff rearrangement to form vibrationally excited ketene, which relaxes in 9 ps. The S 2 state will also relax to the S 1 state, which isomerizes to diazirine, fragments to form carbene, and relaxes further to the ground state of DM. The singlet carbene absorbs at 305 nm, is formed within 300 fs of the laser pulse, and has a lifetime of 2.3 ps in acetonitrile. The lifetime of DM in the S 2 and S 1 states is less than 300 fs. The quantum efficiency of DM decomposition is approximately 50% in chloroform with 266 nm excitation.
ObjectiveTo observe effects of low level lead diet on cellular immune function in mice.MethodsMice were randomly divided into six groups.They received different level lead diets for eight weeks.Serum TNF-α level and lymphocyte subsets were measured.The pathological and ultra structural changes of spleen were determined.ResultsLow level lead diet resulted in a decreased number of CD\-4 T-cell.But significant difference was found in CD\-8 T-cell among all groups( P 0.05).Serum TNF-α in the lowest level was significantly increased;but other groups were lower than control group.The splenic coefficients of all trial groups significantly decreased compared with the control group.ConclusionThe low level of lead diet,even at relative low level of lead diet could impaire cell-mediated immunity and be harmful to the spleen and thymus.In spite of no other overt clinical disorder,immune function was impaired.
Significance: Fluorescent probes and mass spectrometry are the two most popular and complementary methods to quantify thiols in biological systems. In this review, we focus on the widely used and commercially available methods to detect and quantify thiols in living cells and the general approaches applied in mass spectrometry-based thiol quantification. We hope that this review can serve as a general guide for redox biologists who are interested in thiol species. Sulfur, one of the most important elements in living systems, contributes to every aspect of physiology and pathology. Thiols, including cysteine, homocysteine, glutathione, hydrogen sulfide, and hydropersulfides, are the main players in the redox biology system. Therefore, quantifying these thiol species in biological systems is one of the important steps to understand their roles in biology. Recent Advances: Fluorescent probes and mass spectrometry-based methods have been developed to detect and/or quantify thiols in biological systems. Mass spectrometry-based methods have been the gold standard for metabolite quantification in cells. Fluorescent probes can directly detect or quantify thiol species in living cells with spatial and temporal resolutions. Additionally, organelle-specific fluorescent probes have been widely developed. These two methods are complementary to each other. Critical Issues: Reliable quantification of thiol species using fluorescent probes remains challenging. Future Directions: When developing fluorescent probes, we suggest using both the fluorescent probes and mass spectrometry-based thiol quantification methods to cross-check the results. In addition, we call on chemical biologists to move beyond qualitative probes and focus on probes that can provide quantitative results in live cells. These quantitative measurements based on fluorescent probes should be validated with mass spectrometry-based methods. More importantly, chemical biologists should make their probes accessible to the biology end users. Regarding mass spectrometry-based methods, quantification of the derivatized thiol specifies should fit into the general metabolomics workflow. Antioxid. Redox Signal. 36, 354-365.
Objective To observe the changes of serum levels of interleukin- 17( IL-17) and interleukin- 23( IL-23) in children with mycoplasma pneumoniae pneumonia,to explore their clinical significances. Methods A total of 40 children with mycoplasma pneumoniae pneumonia were selected as observation group from 2013 to 2014 in Nanjing Tongren Hospital Affiliated to Medical College of Southeast University,and 40 healthy children were selected as control group at the same time. Children of observation group were given conventional treatment after treatment. Serum levels of IL-17 and IL-23,abnormal rate of C- reactive protein were compared between the two groups before and after treatment. Results Before treatment,serum levels of IL-17 and IL-23 of observation group were statistically significantly higher than those of control group( P 0. 05); after treatment,no statistically significant differences of serum level of IL-17 or IL-23 was found between the two groups( P 0. 05),while serum levels of IL-17 and IL-23 of observation group were statistically significantly lower than those before treatment( P 0. 05). Before treatment,the abnormal rate of C- reactive protein of observation group was statistically significantly higher than that of control group( P 0. 05); after treatment,no statistically significant differences of the abnormal rate of C- reactive protein was found between the two groups( P 0. 05). Conclusion Detection of serum levels of IL-17 and IL-23 is with certain clinical significance to judge the disease progression and efficacy in children with mycoplasma pneumoniae pneumonia,can be used as evaluation index for disease development and clinical outcome.
Objective:To study the effect of individual nursing intervention on the treatment compliance and quality of life(QOL) of patients with chronic heart failure(CHF).Method:Choosing Zaozhuang City High-tech Zone Singren Street Community Health Center 68 cases were randomly divided into intervention group(n=34) and the control group(n=34).The control group was given routine nursing,the intervention group was given individual nursing intervention,all tracking observation for 3 months,observed treatment nursing was intervention before and after two groups of patients treatment compliance and QOL score changes and comparison.Result:The treatment nursing after 3 months,QOL scores of the intervention group was than before treatment,there were significantly improve(t=2.868,P0.05),the quality of life to improve effect was obviously superior to the control group(t=2.147,P0.05).Treatment compliance of the intervention group was obviously higher than that of the control group( 字2=3.319,P0.05).Conclusion:Individual nursing intervention obviously increase the treatment compliance for patients with CHF,so as to improve the quality of life of the patients.
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