LECs regulate neutrophil clearance through IL-17RC/CMTM4/NF-κB axis at sites of inflammation or infection.

The lymphatic system plays a vital role in the regulation of tissue fluid balance and the immune response to inflammation or infection. The effects of lymphatic endothelial cells (LECs) on the regulation of neutrophil migration have not been well studied. In three murine models: imiquimod-induced skin inflammation, S. aureus-induced skin infection, and ligature-induced periodontitis, we show that numerous neutrophils migrate from inflamed or infected tissues to the draining lymph nodes via lymphatic vessels. Moreover, inflamed or infected tissues express a high level of IL-17A and TNF-α, simultaneously with a significant increase in the release of neutrophil attractors, including CXCL1, CXCL2, CXCL3, and CXCL5. Importantly, in vitro stimulation of LECs with IL-17A plus TNF-α synergistically promoted these chemokine secretion. Mechanistically, tetra-transmembrane protein CMTM4 directly binds to IL-17RC in LECs. IL-17A plus TNF-α stimulates CXC chemokine secretion by promoting NF-κB signaling. In contrast, knockdown of CMTM4 abrogates IL-17A plus TNF-α activated NF-κB signaling pathways. Lastly, the local administration of adeno-associated virus for CMTM4 in Prox1-CreERT2 mice, mediating LEC-specific overexpression of CMTM4, promotes the drainage of neutrophils by LECs and alleviates immune pathological responses. Thus, our findings reveal the vital role of LECs-mediated neutrophil attraction and clearance at sites of inflammation or infection.

Evaluation of Organic Hydride/Acid Pairs as a Type of Thermodynamic-Potential-Regulated Multisite Proton-Coupled Electron Transfer Reagents.

Organic hydride/acid pairs have been reported as multisite proton-coupled electron transfer (MS-PCET) reagents in reductive MS-PCET reactions recently. Since the key step for an organic hydride/acid pair acting as an MS-PCET reagent is a chemical process of the organic hydride/acid pair releasing a formal hydrogen atom, the bond dissociation free energy of the organic hydride/acid pair releasing a formal hydrogen atom is a valuable thermodynamic parameter for objectively evaluating the thermodynamic potential for an organic hydride/acid pair to act as an MS-PCET reagent. Now, organic hydride/acid pairs of 216 organic hydrides have been demonstrated to be a potential type of thermodynamically potential-regulated MS-PCET reagent. Without a doubt, organic hydride/acid pairs reflect the change of N-substituted organic hydrides from simple hydride reductants to thermodynamically-regulated MS-PCET reagents, which could significantly expand the availability of novel MS-PCET reagents.

Identification of high-risk imaging features in hypertrophic cardiomyopathy using electrocardiography: A deep-learning approach.

BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) are at risk of sudden death, and individuals with ≥1 major risk markers are considered for primary prevention implantable cardioverter-defibrillators. Guidelines recommend cardiac magnetic resonance (CMR) imaging to identify high-risk imaging features. However, CMR imaging is resource intensive and is not widely accessible worldwide. OBJECTIVE: The purpose of this study was to develop electrocardiogram (ECG) deep-learning (DL) models for the identification of patients with HCM and high-risk imaging features. METHODS: Patients with HCM evaluated at Tufts Medical Center (N = 1930; Boston, MA) were used to develop ECG-DL models for the prediction of high-risk imaging features: systolic dysfunction, massive hypertrophy (≥30 mm), apical aneurysm, and extensive late gadolinium enhancement. ECG-DL models were externally validated in a cohort of patients with HCM from the Amrita Hospital HCM Center (N = 233; Kochi, India). RESULTS: ECG-DL models reliably identified high-risk features (systolic dysfunction, massive hypertrophy, apical aneurysm, and extensive late gadolinium enhancement) during holdout testing (c-statistic 0.72, 0.83, 0.93, and 0.76) and external validation (c-statistic 0.71, 0.76, 0.91, and 0.68). A hypothetical screening strategy using echocardiography combined with ECG-DL-guided selective CMR use demonstrated a sensitivity of 97% for identifying patients with high-risk features while reducing the number of recommended CMRs by 61%. The negative predictive value with this screening strategy for the absence of high-risk features in patients without ECG-DL recommendation for CMR was 99.5%. CONCLUSION: In HCM, novel ECG-DL models reliably identified patients with high-risk imaging features while offering the potential to reduce CMR testing requirements in underresourced areas.

Thermodynamic evaluations of the acceptorless dehydrogenation and hydrogenation of pre-aromatic and aromatic N-heterocycles in acetonitrile.

N-heterocycles are important chemical hydrogen-storage materials, and the acceptorless dehydrogenation and hydrogenation of N-heterocycles as organic hydrogen carriers have been widely studied, with the main focus on the catalyst synthesis and design, investigation of the redox mechanisms, and extension of substrate scope. In this work, the Gibbs free energies of the dehydrogenation of pre-aromatic N-heterocycles (YH2) and the hydrogenation of aromatic N-heterocycles (Y), i.e., ΔGH2R(YH2) and ΔGH2A(Y), were derived by constructing thermodynamic cycles using Hess' law. The thermodynamic abilities for the acceptorless dehydrogenation and hydrogenation of 78 pre-aromatic N-heterocycles (YH2) and related 78 aromatic N-heterocycles (Y) were well evaluated and discussed in acetonitrile. Moreover, the applications of the two thermodynamic parameters in identifying pre-aromatic N-heterocycles possessing reversible dehydrogenation and hydrogenation properties and the selection of the pre-aromatic N-heterocyclic hydrogen reductants in catalytic hydrogenation were considered and are discussed in detail. Undoubtedly, this work focuses on two new thermodynamic parameters of pre-aromatic and aromatic N-heterocycles, namely ΔGH2R(YH2) and ΔGH2A(Y), which are important supplements to our previous work to offer precise insights into the chemical hydrogen storage and hydrogenation reactions of pre-aromatic and aromatic N-heterocycles.

Efficacy of Electronic Cigarettes vs Varenicline and Nicotine Chewing Gum as an Aid to Stop Smoking: A Randomized Clinical Trial.

Importance: Electronic cigarettes (ECs) are often used by smokers as an aid to stopping smoking, but evidence is limited regarding their efficacy compared with nicotine replacement therapy (NRT), and no evidence is available on how their efficacy compares with that of varenicline. Objective: To evaluate whether ECs are superior to NRT and noninferior to varenicline in helping smokers quit. Design, Setting, and Participants: This was a randomized clinical trial conducted at 7 sites in China and including participants who were smoking at least 10 cigarettes per day and motivated to quit, not using stop-smoking medications or EC, and willing to use any of the study products. Participants were first recruited in May 2021, and data analysis was conducted in December 2022. Interventions: A cartridge-based EC (30 mg/mL nicotine salt for 2 weeks and 50 mg/mL after that), varenicline (0.5 mg, once a day for 3 days; 0.5 mg, twice a day for 4 days; and 1 mg, twice a day, after that), and 2 mg (for smokers of ≤20 cigarettes per day) or 4 mg (>20 cigarettes per day) nicotine chewing gum, all provided for 12 weeks and accompanied by minimal behavioral support (an invitation to join a self-help internet forum). Main Outcomes and Measures: The primary outcome was sustained abstinence from smoking at 6 months as validated by an expired-air carbon monoxide reading (<8 parts per million). Participants lost to follow-up were included as nonabstainers. Results: Of 1068 participants, 357 (33.5%) were female, and the mean (SD) age was 33.9 (3.1) years. A total of 409 (38.3%), 409 (38.3%), and 250 (23.4%) participants were randomized to the EC, varenicline, and NRT arms, respectively. The 6-month biochemically validated abstinence rates were 15.7% (n = 64), 14.2% (n = 58), and 8.8% (n = 22) in the EC, varenicline, and NRT study arms, respectively. The quit rate in the EC arm was noninferior to the varenicline arm (absolute risk reduction, 1.47%; 95% CI, -1.41% to 4.34%) and higher than in the NRT arm (odds ratio, 1.92; 95% CI, 1.15-3.21). Treatment adherence was similar in all study arms during the initial 3 months, but 257 participants (62.8%) in the EC arm were still using ECs at 6 months, with no further use in the 2 other study arms. The most common adverse reactions were throat irritation (32 [7.8%]) and mouth irritation (28 [6.9%]) in the EC arm, nausea (36 [8.8%]) in the varenicline arm, and throat irritation (20 [8.0%]) and mouth irritation (22 [8.8%]) in the NRT arm. No serious adverse events were recorded. Conclusions and Relevance: The results of this randomized clinical trial found that when all treatments were provided with minimal behavior support, the efficacy of EC was noninferior to varenicline and superior to nicotine chewing gum. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2100048156.

Atherosclerotic Cardiovascular Disease Risk and Longitudinal Risk Factor Management Among Patients With Breast Cancer.

BACKGROUND: Cardiovascular disease is the leading cause of noncancer mortality for breast cancer survivors. Data are limited regarding patient-level atherosclerotic cardiovascular disease (ASCVD) risk estimation and preventive medication use. This study aimed to characterize ASCVD risk and longitudinal preventive medication use for a cohort of patients with nonmetastatic breast cancer. PATIENTS AND METHODS: This retrospective cohort study included 326 patients at an academic medical center in Boston, Massachusetts diagnosed with nonmetastatic breast cancer or ductal carcinoma in situ from January 2009 through December 2015. Patient demographics, clinical characteristics, laboratory studies, medication exposure, and incident cardiovascular outcomes were collected. Estimated 10-year ASCVD risk was calculated for all patients from nonlaboratory clinical parameters. RESULTS: Median follow up time was 6.5 years (IQR 5.0, 8.1). At cancer diagnosis, 23 patients (7.1%) had established ASCVD. Among those without ASCVD, 10-year estimated ASCVD risk was ≥20% for 77 patients (25.4%) and 7.5% to <20% for 114 patients (37.6%). Two-hundred and sixteen patients (66.3%) had an indication for lipid-lowering therapy at cancer diagnosis, 123 of whom (57.0%) received a statin during the study. Among 100 patients with ASCVD or estimated 10-year ASCVD risk ≥20%, 92 (92.0%) received an antihypertensive medication during the study. Clinic blood pressure >140/90 mmHg was observed in 33.0% to 55.6% of these patients at each follow up assessment. CONCLUSION: A majority of patients in this breast cancer cohort had an elevated risk of ASCVD at the time of cancer diagnosis. Modifiable ASCVD risk factors were frequently untreated or uncontrolled in the years following cancer treatment.

Clonal Hematopoiesis of Indeterminate Potential in Chronic Thromboembolic Pulmonary Hypertension: A Multicenter Study.

BACKGROUND: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is multifactorial and growing evidence has indicated that hematological disorders are involved. Clonal hematopoiesis of indeterminate potential (CHIP) has recently been associated with an increased risk of both hematological malignancies and cardiovascular diseases. However, the prevalence and clinical relevance of CHIP in patients with CTEPH remains unclear. METHODS: Using stepwise calling on next-generation sequencing data from 499 patients with CTEPH referred to 3 centers between October 2006 and December 2021, CHIP mutations were identified. We associated CHIP with all-cause mortality in patients with CTEPH. To provide insights into potential mechanisms, the associations between CHIP and inflammatory markers were also determined. RESULTS: In total, 47 (9.4%) patients with CTEPH carried at least 1 CHIP mutation at a variant allele frequency of ≥2%. The most common mutations were in DNMT3A, TET2, RUNX1, and ASXL1. During follow-up (mean, 55 months), deaths occurred in 22 (46.8%) and 104 (23.0%) patients in the CHIP and non-CHIP groups, respectively (P<0.001, log-rank test). The association of CHIP with mortality remained robust in the fully adjusted model (hazard ratio, 2.190 [95% CI, 1.257-3.816]; P=0.006). Moreover, patients with CHIP mutations showed higher circulating interleukin-1ß and interleukin-6 and lower interleukin-4 and IgG galactosylation levels. CONCLUSIONS: This is the first study to show that CHIP mutations occurred in 9.4% of patients with CTEPH are associated with a severe inflammatory state and confer a poorer prognosis in long-term follow-up.

Sensorineural hearing loss induced by gefitinib: A CARE-compliant case report and literature reviews.

RATIONALE: Gefitinib is a potent and selective orally active growth factor receptor (EGFR)-tyrosine kinase inhibitor that is commonly used to treat advanced non-small cell lung cancer patients with activating EGFR mutations. Hearing impairment with gefitinib was sparsely reported. In this report, we describe a case of sensorineural deafness associated with the administration of gefitinib, with a Naranjo score of 7. PATIENT CONCERNS: An 81-year-old female was diagnosed with lung adenocarcinoma with bone metastasis and an EGFR-activating mutation. The patient was prescribed gefitinib tablets at a daily dose of 250 mg for lung adenocarcinoma treatment. However, the patient experienced moderate to severe bilateral sensorineural deafness, primarily in her right ear, after taking gefitinib. Following the cessation of gefitinib administration, the patient exhibited partial restoration of auditory function. Upon resuming the medication, she experienced a worsening of deafness. DIAGNOSES: The otoscopic audiogram and hearing test indicated moderate to severe bilateral sensorineural deafness. INTERVENTIONS: The otolaryngologist recommended bilateral hearing aids to enhance hearing function. OUTCOMES: Throughout our follow-up period, the patient did not receive a hearing aid implant. LESSONS: This article first reported the ototoxicity caused by gefitinib. While rare, our report highlights that gefitinib-induced sensorineural deafness is possible and its mechanisms are still unclear. This adverse reaction should be monitored closely during clinical application of gefitinib to improve patient outcomes.

Thermodynamic Evaluations of Amines as Hydrides or Two Hydrogen Ions Reductants and Imines as Protons or Two Hydrogen Ions Acceptors, as Well as Their Application in Hydrogenation Reactions.

Since the hydrogenation of imines (X) and the dehydrogenation of amines (XH2) generally involve the two hydrogen ions (H- + H+) transfer, the thermodynamic abilities of various amines releasing hydrides or two hydrogen ions as well as various imines accepting protons or two hydrogen ions are important and characteristic physical parameters. In this work, the pKa values of 84 protonated imines (XH+) in acetonitrile were predicted. Combining Gibbs free energy changes of amines releasing hydrides in acetonitrile from our previous work with the pKa(XH+) values, the Gibbs free energy changes of amines releasing two hydrogen ions and imines accepting two hydrogen ions were derived using Hess's law by constructing thermochemical cycles, and the thermodynamic evaluations of amines as hydrides or two hydrogen ions reductants and imines as protons or two hydrogen ions acceptors are well compared and discussed. Eventually, the practical application of thermodynamic data for amines and imines on hydrogenation feasibility, mechanism, and possible elementary steps was shown and discussed in this paper from the point of thermodynamics.

Roles of trained immunity in the pathogenesis of periodontitis.

Periodontitis is a chronic, inflammatory, and destructive disease caused by the imbalance of host immune response and dental biofilm, and has strong epidemiological and pathogenesis correlations with systemic diseases. The immune response in periodontitis involves both innate and adaptive immunity, with numerous immune cells and inflammatory pathways participating in a complex network of interactions. In the past decade, the concept of "trained immunity" has emerged, which highlights the memory characteristics of innate immunity, thus opening up a new avenue of research. There is growing interest in exploring the role of trained immunity in chronic inflammatory and metabolic diseases such as atherosclerosis and diabetes mellitus. Evidence suggests that trained immunity may also regulate the onset and progression of periodontitis, serving as a bridge between periodontitis-related comorbidities. In this review, we summarize concepts related to trained immunity and its development. Furthermore, we present current evidence that endorses the notion of trained immunity in periodontitis and analyze possible roles it may assume regarding periodontitis-associated inflammatory reactions from a cellular perspective. Finally, we discuss various clinical therapeutic strategies for periodontitis and its associated comorbidities that target trained immunity. We hope that more researchers will pay attention to this emerging concept, thereby providing deeper insights into this novel field.

Peroxinredoxin 6 reduction accelerates cigarette smoke extract­induced senescence by regulating autophagy in BEAS­2B cells.

Cigarette smoke (CS)-induced accelerated senescence and insufficient autophagy has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Peroxiredoxin (PRDX) 6 is a protein with prevalent antioxidant capacity. Previous studies indicate that PRDX6 could activate autophagy and alleviate senescence in other diseases. The present study investigated whether PRDX6-regulated autophagy was involved in the regulation of CS extract (CSE)-induced BEAS-2B cell senescence via the knockdown of PRDX6 expression. Furthermore, the present study evaluated the mRNA levels of PRDX6, autophagy and senescence-associated genes in the small airway epithelium from patients with COPD by analyzing the GSE20257 dataset from the Gene Expression Omnibus database. The results demonstrated that CSE reduced PRDX6 expression levels and transiently induced the activation of autophagy, followed by the accelerated senescence of BEAS-2B cells. Knockdown of PRDX6 induced autophagy degradation and accelerated senescence in CSE-treated BEAS-2B cells. Furthermore, autophagy inhibition by 3-Methyladenine increased P16 and P21 expression levels, while autophagy activation by rapamycin reduced P16 and P21 expression levels in CSE-treated BEAS-2B cells. The GSE20257 dataset revealed that patients with COPD had lower PRDX6, sirtuin (SIRT) 1 and SIRT6 mRNA levels, and higher P62 and P16 mRNA levels compared with non-smokers. P62 mRNA was significantly correlated with P16, P21 and SIRT1, which indicated that insufficient autophagic clearance of damaged proteins could be involved in accelerated cell senescence in COPD. In conclusion, the present study demonstrated a novel protective role for PRDX6 in COPD. Furthermore, a reduction in PRDX6 could accelerate senescence by inducing autophagy impairment in CSE-treated BEAS-2B cells.

Risk factors of multidrug-resistant bacteria infection in patients with ventilator-associated pneumonia: A systematic review and meta-analysis.

BACKGROUND: Multidrug-resistant (MDR) bacteria-induced VAP often has high lethality. We present this systematic review and meta-analysis to assess the risk factors for MDR bacterial infection in patients with VAP. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library were searched for studies regarding MDR bacterial infection in VAP patients, from Jan 1996 to Aug 2022. Study selection, data extraction, and quality assessment of included studies were conducted by two reviewers independently, and potential risk factors for MDR bacterial infection were identified. RESULTS: Meta-analysis showed that the score of the Acute Physiology and Chronic Health Evaluation II (APACHE-II) [OR = 1.009, 95% (CI 0.732, 1.287)], Simplified Acute Physiology Score II (SAPS-II) [OR = 2.805, 95%CI (0.854, 4.755)], length of hospital-stay before VAP onset (days) [OR = 2.639, 95%CI (0.387, 4.892)], in-ICU duration [OR = 3.958, 95%CI (0.894, 7.021)], Charlson index [OR = 1.000, 95%CI (0.889, 1.111)], overall hospital-stay [OR = 20.742, 95%CI (18.894, 22.591)], Medication of Quinolones [OR = 2.017, 95%CI (1.339, 3.038)], medication of carbapenems [OR = 3.527, 95%CI (2.476, 5.024)], combination of more than 2 prior antibiotics [OR = 3.181, 95%CI (2.102, 4.812)], and prior use of antibiotics [OR 2.971, 95%CI (2.001, 4.412)] were independent risk factors of MDR bacterial infection in VAP patients. Diabetes and mechanical ventilation duration before VAP onset showed no association with risk for MDR bacterial infection. CONCLUSIONS: This study has identified 10 risk factors associated with MDR bacterial infection in VAP patients. Identification of these factors would be able to facilitate the treatment and prevention of MDR bacterial infection in clinical practice.

Comparing FRET Pairs that Report on Intersubunit Rotation in Bacterial Ribosomes.

Mediated by elongation factor G (EF-G), ribosome translocation along mRNA is accompanied by rotational movement between ribosomal subunits. Here, we reassess whether the intersubunit rotation requires GTP hydrolysis by EF-G or can occur spontaneously. To that end, we employ two independent FRET assays, which are based on labeling either ribosomal proteins (bS6 and bL9) or rRNAs (h44 of 16S and H101 of 23S rRNA). Both FRET pairs reveal three FRET states, corresponding to the non-rotated, rotated and semi-rotated conformations of the ribosome. Both FRET assays show that in the absence of EF-G, pre-translocation ribosomes containing deacylated P-site tRNA undergo spontaneous intersubunit rotations between non-rotated and rotated conformations. While the two FRET pairs exhibit largely similar behavior, they substantially differ in the fraction of ribosomes showing spontaneous fluctuations. Nevertheless, instead of being an invariable intrinsic property of each FRET pair, the fraction of spontaneously fluctuating molecules changes in both FRET assays depending on experimental conditions. Our results underscore importance of using multiple FRET pairs in studies of ribosome dynamics and highlight the role of thermally-driven large-scale ribosome rearrangements in translation.

Tuberculosis combined with Burkitt lymphoma in a kidney transplant recipient: A case report and literature review.

RATIONALE: Tuberculosis (TB) and post-transplant lymphoproliferative disorder are serious complications affecting the long-term survival of kidney transplant recipients (KTRs). Both of complications have overlapping clinical symptoms, signs, and high similar imaging presentation, which make early clinical diagnosis challenging. In this paper, we reported a rare case of post-transplant pulmonary TB combined with Burkitt lymphoma (BL) in KTR. PATIENT CONCERNS: A 20-year-old female KTR presented to our hospital with abdominal pain and multiple nodules throughout the body. DIAGNOSES: TB is diagnosed based on the lung histopathology showed fibrous connective tissue hyperplasia with number of chronic inflammatory changes, localized necrosis, granuloma formation and multinucleated giant cells were seen in the lung tissue. Moreover, lung histopathology specimen tested positive for TB gene. TB The culture for tuberculosis was positive. BL was diagnosed as metastatic after completion of liver and bone marrow biopsy. INTERVENTIONS: After an early diagnosis of TB, the patient received intensification of anti-tubercular therapy. Because the patient was diagnosed with BL, rituximab, cardioprotection, hepatoprotection and alkalinization of urine were added. OUTCOMES: After an early diagnosis of TB, the patient received anti-tubercular therapy and her clinical symptoms and imaging manifestations improved. After the diagnosis of BL was made, the patient's condition progressed rapidly, followed by multi-organ damage and died 3 months later. LESSONS: Therefore, in organ transplant patients, who present with multiple nodules and normal tumor markers, they should be alerted to the possibility of concurrent TB and post-transplant lymphoproliferative disorder, and perfect tests such as Epstein-Barr virus, ß2-microglobulin, lactate dehydrogenase, γ-interferon release test and Xpert Mycobacterium TB/rifampicin test and perform early lesion site biopsy to clarify the diagnosis with a view to improving the prognosis.

Halobacterium wangiae sp. nov. and Halobacterium zhouii sp. nov., two extremely halophilic archaea isolated from sediment of a salt lake and saline soil of an inland saltern.

Two novel halophilic archaeal strains, Gai3-17T and XZYJT26T, were isolated from the sediment of Gaize salt lake and the saline soil of Mangkang ancient solar saltern in Tibet, PR China, respectively. Strains Gai3-17T and XZYJT26T were related to each other (96.5 and 89.7% similarity, respectively) and showed 97.5-95.4 and 91.5-87.7% similarities to the current members of Halobacterium based on 16S rRNA and rpoB' genes. The phylogenomic analysis indicated that strains Gai3-17T and XZYJT26T formed two distinct clades and clustered with the Halobacterium species. The two strains can be differentiated from the type strains of the six species with validly published names based on several phenotypic characteristics. The phospholipids of the two strains were phosphatidic acid, phosphatidylglycerol and phosphatidylglycerol phosphate methyl ester. One major glycolipid, sulphated galactosyl mannosyl glucosyl diether, was detected in strain Gai3-17T, while four glycolipids, mannosyl glucosyl diether, sulphated mannosyl glucosyl diether, disulphated mannosyl glucosyl diether and sulphated galactosyl mannosyl glucosyl diether were observed in strain XZYJT26T. The average nucleotide identity, digital DNA-DNA hybridization and amino acid identity values among the two strains and the members of Halobacterium were no more than 81, 25 and 77 %, respectively. These overall genome-related indices were below the threshold values for species boundary, indicating that strains Gai3-17T and XZYJT26T represent two novel species of Halobacterium. Thus, two novel species, Halobacterium wangiae sp. nov. and Halobacterium zhouii sp. nov., are proposed to accommodate strains Gai3-17T (=CGMCC 1.16101T=JCM 33551T) and XZYJT26T (=CGMCC 1.16682T=JCM 33556T), respectively.

Comparing FRET pairs that report on intersubunit rotation in bacterial ribosomes.

Mediated by elongation factor G (EF-G), ribosome translocation along mRNA is accompanied by rotational movement between ribosomal subunits. Here, we reassess whether the intersubunit rotation requires GTP hydrolysis by EF-G or can occur spontaneously. To that end, we employ two independent FRET assays, which are based on labeling either ribosomal proteins (bS6 and bL9) or rRNAs (h44 of 16S and H101 of 23S rRNA). Both FRET pairs reveal three FRET states, corresponding to the non-rotated, rotated and semi-rotated conformations of the ribosome. Both FRET assays show that in the absence of EF-G, pre-translocation ribosomes containing deacylated P-site tRNA undergo spontaneous intersubunit rotations between non-rotated and rotated conformations. While the two FRET pairs exhibit largely similar behavior, they substantially differ in the fraction of ribosomes showing spontaneous fluctuations. Nevertheless, instead of being an invariable intrinsic property of each FRET pair, the fraction of spontaneously fluctuating molecules changes in both FRET assays depending on experimental conditions. Our results underscore importance of using multiple FRET pairs in studies of ribosome dynamics and highlight the role of thermally-driven large-scale ribosome rearrangements in translation.

[Percutaneous minimally invasive osteotomy with 8-shaped bandage and hallux valgus splint fixation for the treatment of moderate hallux valgus].

OBJECTIVE: To observe clinical effect of percutaneous minimally invasive osteotomy with 8-shaped bandage and hallux valgus splint fixation in treating moderate hallux valgus. METHODS: Totally 23 patients with moderate hallux valgus were treated with percutaneous minimally invasive osteotomy with 8-shaped bandage and hallux valgus splint fixation from August 2019 to January 2021, and 1 patient was loss to follow-up, and finally 22 patients(30 feet) were included, 4 males (6 feet) and 18 females(24 feet), aged from 27 to 66 years old with an average of(50.59±11.95) years old. Hallux valgus angle (HVA), intermetatarsal angle (IMA), metatarsal span (the distance between the first and the fifth metatarsal bones), changed of soft tissue width, American Orthopaedic Foot and Ankle Society(AOFAS) score, and Visual Analogue Scale (VAS) were collected and compared before operation and 6 months after operation. RESULTS: Twenty-two patients were followed up from 5.7 to 6.4 months with an average of (6.13±0.85) months. The first metatarsal osteotomy of patients were obtained bone union, and deformity of the toes was corrected. Complications such as avascular necrosis of metatarsal head and transfer metatarsalgia were not occurred. Postoperative HVA, IMA, metatarsal span, soft tissue width, VAS, AOFAS score at 6 months were significantly improved compared with pre-operation (P<0.01). According to AOFAS score at 6 months after operation, 10 feet were excellent, 18 good and 2 poor. Two feet with poor were excellent after prolonged 8-shaped bandage and hallux valgus splint fixation time. CONCLUSION: Percutaneous minimally invasive osteotomy with 8-shaped bandage and hallux valgus splint fixation for the treatment of moderate hallux valgus could better correct deformity of hallux valgus, relieve foot symptoms, good recovery of postoperative function, and has a significant clinical efficacy.

Eriodictyol regulated ferroptosis, mitochondrial dysfunction, and cell viability via Nrf2/HO-1/NQO1 signaling pathway in ovarian cancer cells.

This study aimed to investigate the antitumor effect and the underlying molecular mechanism of eriodictyol on ovarian cancer cells. CaoV3 and A2780 were exposed to eriodictyol at different concentrations of 0-800 µM. Cell apoptosis and viability were determined by TdT-mediated dUTP Nick-End Labeling (TUNEL) assay and Cell Counting Kit-8 (CCK-8) assay, respectively. Mitochondrial membrane potential was evaluated by flow cytometers with a JC-1 detection kit. Fe2+ content was evaluated using an iron assay kit. The section of tumor tissues was observed using hematoxylin-eosin (H&E) staining and nuclear factor erythroid 2-related factor 2 (Nrf2) expression was detected by immunohistochemistry (IHC) staining. Eriodictyol suppressed cell viability and induced cell apoptosis of CaoV3 and A2780 cells. Half maximal inhibitory concentration (IC50 ) value of CaoV3 at 24 and 48 h was (229.74 ± 5.13) µM and (38.44 ± 4.68) µM, and IC50 value of A2780 at 24 and 48 h was (248.32 ± 2.54) µM and (64.28 ± 3.19) µM. Fe2+ content and reactive oxygen species production were increased and protein levels of SLC7A11 and GPX4 were decreased by eriodictyol. Besides, eriodictyol reduced the ratio of JC-1 fluorescence ratio, glutathione and malondialdehyde contents but elevated Cytochrome C level. Nrf2 phosphorylation were obviously downregulated by eriodictyol. Finally, eriodictyol suppressed tumor growth, aggravated mitochondrial dysfunction and downregulated Nrf2 expression in tumor tissue in mice. Eriodictyol regulated ferroptosis, mitochondrial dysfunction and cell viability via Nrf2/HO-1/NQO1 signaling pathway in ovarian cancer.