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Peng Liu,1,2,&ast; Tingting Lv,1,&ast; Yuanwei Liu,1,&ast; Xiaofei Zhang,1 Fei She,1 Rong He,1 Dan Li,1 Lianfeng Liu,1 Ping Zhang1 1Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of China; 2Department of Cardiology, Ordos Central Hospital, Ordos School of Clinical Medicine, Inner Mongolia Medical University, Inner Mongolia, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ping Zhang, Email zhpdoc@126.comObjective: Atrial fibrillation (AF) is known to increase the risk of thromboembolic events and major adverse cardiovascular events (MACE). The impact of paroxysmal atrial tachycardia (PAT) on these risks remains unclear.Methods: This retrospective cohort study was conducted involving 889 patients diagnosed with PAT and 1106 control patients without PAT, all of whom underwent their initial 24-hour ECG monitoring between 2015 to 2020. Kaplan–Meier survival analysis and Cox regression analysis were used to evaluate the association between PAT and the study endpoints, including thromboembolic events and MACE.Results: Over a mean follow-up period of 50.3 months, the incidence of thromboembolic events and MACE was significantly higher in the PAT group compared to the control group (6.5% vs 1.7% and 19.1% vs 9.9%, respectively). After adjusting for common risk factors and baseline imbalances, the PAT group exhibited a significantly elevated risk of thromboembolic events (hazard ratio [HR] 3.782, 95% confidence interval [CI] 2.212– 6.467; P < 0.001) and MACE (HR 1.795, 95% CI 1.398– 2.305; P < 0.001). However, the frequency of PAT episodes, heart rate, and maximum heart rate were not significantly associated with these outcomes. Within the PAT group, a history of stroke, transient ischemic attack, and chronic renal failure were identified as independent risk factors for thromboembolic events, while hypertension, coronary heart disease, heart failure, and chronic renal failure were independently associated with MACE.Conclusion: PAT, as detected by 24-hour dynamic ECG, is associated with an increased risk of thromboembolic events and MACE.Keywords: paroxysmal atrial tachycardia, thromboembolic events, ischemic stroke, transient ischemic attack, systemic thromboembolism, major adverse cardiovascular events

Ming-Yue Zhu,&ast; Rong Li,&ast; Jie Xu, Fei She, Xin Du, Wei Zhang Department of Emergency Medicine, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Zhang, Department of Emergency Medicine, the Fourth Medical Center, Chinese PLA General Hospital, No. 51 Fucheng Road, Haidian District, Beijing, 100048, People’s Republic of China, Tel +86 010-66867373, Email zhangw8642@126.comObjective: To clarify variations of diagnosis and treatment in the emergency care of critically ill patients not infected with novel coronavirus (COVID-19) prior to and amidst the COVID-19 pandemic.Methods: A retrospective cohort study was conducted to compare and analyze the diagnosis and treatment data of critically ill patients with non-COVID-19 infection who were admitted to the emergency department of the Fourth Medical Center of Chinese PLA General Hospital from January 2019 to November 2022. The variations in emergency care of the pandemic were summarized, and the influence of the pandemic on emergency care was assessed.Results: A total of 6634 critically ill patients with non-COVID-19 infection were included in this study. These patients were elderly, high incidence of chronic diseases, and extended emergency duration during the pandemic. Notably, the proportion of patients requiring intensive care was twofold higher compared to the period before the pandemic. Throughout the pandemic, patients experienced prolonged emergency durations, increased overall costs and daily expenses per patient. Further investigation revealed that elderly patients exhibited worse medical conditions, requiring lengthier emergency treatment and incurring escalated healthcare expenses. However, the presence of pre-existing chronic diseases did not appear to influence disease severity, nor extended emergency durations or heightened healthcare expenditures. Irrespective of the pandemic phase—be it short-term, medium-term, or long-term emergency care—greater healthcare spending was necessary.Conclusion: There was no difference in the disease spectrum of emergency critical ill patients with non-COVID-19 infection prior to and amidst the COVID-19 pandemic, nor the duration and expenditure in prior chronic illness patients. However, the disease severity and emergency duration have led to an increase in the total cost and economic intensity of emergency care for all patients during the epidemic. Especially, elderly patients required longer emergency duration, greater healthcare spending, and more inpatient medical resources than usual.Keywords: novel coronavirus epidemic, emergency, elderly

Shunhang Feng,1,2,&ast; Jiansheng Lin,1,2,&ast; Xiaoyan Zhang,1,2 Xin Hong,1,2 Wanyin Xu,1,2 Yancheng Wen,1,2 Feifei She1,2 1Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, People’s Republic of China; 2Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, School for Basic Medical Sciences, Fujian Medical University, Fuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feifei She, Fujian Medical University, Xueyuan Road 1, Minhou County, Fuzhou, Fujian Province, People’s Republic of China, Tel +86-135-1406-3583, Email Shefeifei@yeah.net Yancheng Wen, Fujian Medical University, Xueyuan Road 1, Minhou County, Fuzhou, Fujian Province, People’s Republic of China, Tel +86-157-0593-5209, Email hitwyc@qq.comPurpose: Helicobacter pylori is associated with the development of gastrointestinal diseases. However, its eradication is challenged by an increased rate of drug resistance. AlgC and GalU are important for the synthesis of UDP-glucose, which is a substrate for the synthesis of lipopolysaccharide (LPS) in H. pylori. In this study, we investigated the role of UDP-glucose in the intrinsic drug resistance in H. pylori.Methods: Gene knockout strains or complementation strains, including ΔalgC, ΔgalU, ΔgalE, Δhp0045, ΔalgC/algC&ast; and ΔgalU/galU&ast; were constructed in Hp26695; and ΔalgC and ΔgalU were also constructed in two clinical drug-resistant strains, Hp008 and Hp135. The minimum inhibitory concentrations (MIC) of H. pylori to amoxicillin (AMO), tetracycline (TET), clarithromycin (CLA), metronidazole (MNZ), levofloxacin (LEV), and rifampicin (RIF) were measured using MIC Test Strips. Silver staining was performed to examine the role of AlgC and GalU in LPS synthesis. Ethidium bromide (EB) accumulation assay was performed to assess the outer membrane permeability of H. pylori strains.Results: Knockout of algC and galU in H. pylori resulted in increased drug sensitivity to AMO, MNZ, CLA, LEV, and RIF; whereas knockout of hp0045 and galE, which are involved in GDP-fucose and UDP-galactose synthesis, respectively, did not significantly alter the drug sensitivity of H. pylori. Knockout of algC and galU in clinically drug-resistant strains resulted in significantly increased drug sensitivity to all the antibiotics, except MNZ. The lipid A-core structure was altered in ΔalgC and ΔgalU when their EB accumulation was higher than that in the wild type and complementation strains.Conclusion: UDP-glucose may play an important role in increasing drug resistance to AMO, MNZ, CLA, LEV, TET, and RIF by maintaining the lipid A-core structure and decreasing membrane permeability. AlgC and GalU may serve as potential drug targets for decreasing antibiotic resistance in clinical isolates.Keywords: H. pylori, UDP-glucose, algC, galU, intrinsic multidrug resistance

Wei Zhang, Yingfei Guo, Fei She, Shuangqing Liu, Xin Du, Hongsheng Liu Department of Emergency Medicine, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, 100048, People’s Republic of ChinaCorrespondence: Hongsheng Liu, Department of Emergency Medicine, the Fourth Medical Center, Chinese PLA General Hospital, 51 Fucheng Road, Haidian District, Beijing, 100048, People’s Republic of China, Tel +86 010-66867373, Email liuhomgss6@163.comObjective: To identify the factors influencing the completion rate of the course of rabies vaccinations without considering the economic factors or the drug supplies.Methods: Rabies vaccination data from the Fourth Medical Center of the PLA General Hospital from January 1 to December 31, 2020, were collected. This includes demographics, information on injury-causing animals, vaccination schemes, and injury assessments. Data on completed the course of rabies vaccinations were compared with data on uncompleted. Internal analysis of Zagreb regimen and Essen regimen was performed. The key factor affecting the completion of the course of rabies vaccinations was analyzed.Results: A total of 1633 patients completed the course of rabies vaccinations, while 462 patients did not. There were differences between the two groups in terms of the vaccination scheme, age, and previous history of rabies vaccinations. The results of a multivariate analysis of variance showed that only the vaccination scheme was significantly correlated with the completion rate of the course of rabies vaccinations. The internal analysis of the vaccination schemes showed that the duration of the vaccination scheme directly affected the completion rate of the course of rabies vaccinations, and the vaccination duration was negatively correlated with the completion rate of rabies vaccinations.Conclusion: The completion rate of the course of rabies vaccinations with Zagreb regimen was higher than Essen regimen. The completion rate was closely correlated with the vaccination scheme, but the duration of the vaccination scheme was the key factor. There was a linear relationship between the vaccination duration and the completion rate of the course of vaccinations, which can be represented by the following linear equation: the completion rate of the course of rabies vaccinations (%) = 98.342– 0.999 × vaccination duration (d). Duration is the critical factor affecting the completion rate. To improve the completion rate of vaccination, it is recommended to use a shorter vaccination duration regimen.Keywords: rabies, the completion rate, vaccination duration

Mengshi Zhong,1 Fei She,2 Weijie Wang,1 Lianshu Ding,1 Aifeng Wang1 1Department of Neurosurgery, Huai’an First Hospital Affiliated to Nanjing Medical University, Huai’an, 223300, People’s Republic of China; 2Department of Nursing Administration, Huai’an First Hospital Affiliated to Nanjing Medical University, Huai’an, 223300, People’s Republic of ChinaCorrespondence: Lianshu Ding; Aifeng Wang, Department of Neurosurgery, Huai’an First Hospital Affiliated to Nanjing Medical University, Huai’an, 223300, People’s Republic of China, Email dlshu@163.com; 13770483620@163.comObjective: To investigate the mediating effect of resilience on perceived social support and fear of cancer recurrence (FCR) in glioma patients.Methods: A total of 128 glioma patients were enrolled for the survey by Connor-Davidson resilience scale (CD-RISC), perceived social support scale (PSSS) and Chinese version of fear of progression questionnaire-short form (FoP-Q-SF). Structural equation model was used to analyze the effects of resilience.Results: The score of FCR in glioma patients was 29.52± 8.30. A total of 47 patients had FCR (total score ≥ 34), with an incidence of 36.7%. There was a correlation between FCR, resilience and social support (P< 0.01). The resilience between perceived social support and FCR in glioma patients had good fitting with the structural equation model. Resilience played a mediating role between perceived social support and FCR, with a mediating effect of 48.4%.Conclusion: The level of resilience can be improved by improving the perceived social support in patients with glioma to reduce the FCR of patients.Keywords: glioma, fear of cancer recurrence, resilience, perceived social support, mediating effect

Jiansheng Lin,1,2 Xiaoyan Zhang,1,2 Yancheng Wen,1,2 Hao Chen,1,2 Feifei She1,2 1Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, People’s Republic of China; 2Fujian Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, People’s Republic of ChinaCorrespondence: Feifei SheKey Laboratory of Ministry of Education For Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, People’s Republic of ChinaTel +86 591 22862863Email shefeifei@yeah.netBackground: The purpose of this study was to understand the function of rfaF gene in Helicobacter pylori antibiotic resistance.Methods: The gene homologous recombination method was used for knockout and complementation of H. pylori rfaF gene. Various constructed strains were analysed for drug sensitivity to amoxicillin (AMO), tetracycline (TET), clarithromycin (CLA), metronidazole (MET), levofloxacin (LEV), and chloramphenicol (CHL) by agar plate dilution method. Drug sensitivity was further confirmed using a growth inhibition curve. Ethidium bromide (EB) accumulation experiments were performed to assess cell membrane permeability. PCR and sequence analysis were used to detect the rfaF gene.Results: The minimum inhibitory concentrations (MIC) of TET, CHL, AMO, and CLA in 11,637 rfaF knockout strain (ΔrfaF strain) were 4, 4, 2, and 2 times higher than those in 11,637 wild type (WT) strain, respectively. A multidrug-resistant (MDR) ΔrfaF strain also displayed the same trend; however, the degrees of increase were relatively small. Growth inhibition experiments indicated that the growth of the 11,637 ΔrfaF strain was higher with antibiotics at the MIC of the 11,637 WT strain than that of 11,637 rfaF-complemented strain (ΔrfaF/rfaF strain), whereas the 11,637 WT strain did not exhibit any growth. The 11,637 ΔrfaF strain was significantly reduced compared with the cumulative EB fluorescence intensity of the 11,637 WT and of 11,637ΔrfaF/rfaF strain, and the same trend appeared in the MDR strain. Among the 10 clinical strains, 9 clinical strains were found to have mutations in the conserved sequence of rfaF amino acids.Conclusion: We found a new drug resistance gene, rfaF, in H. pylori, which changes the permeability of cell membrane to confer cross-resistance to AMO, TET, CLA, and CHL and is involved in clinical strain drug resistance. It can be used as a drug target.Keywords: rfaF, amoxicillin, clarithromycin, tetracycline, resistance

Abstract Background Uneven settlement will occur as a result of the collapsible deformation of the loess strata, and the hydraulic tunnel lining structure will also fail. In this work, laterally confined compression tests were carried out on loess and the double-line method was employed to evaluate the loess collapsibility. The deformation of the surrounding rock of a loess hydraulic tunnel under various ground stresses and its effect on the lining structure was modeled. Results Three stages were noted in the collapsible deformation of loess. The critical point between the former two stages corresponds to the pre-consolidation pressure of saturated loess and that between the latter two is taken as the structural yield pressure of unsaturated loess. Conclusion From the relationship between the collapsibility coefficient and vertical stress, the deformation of the tunnel under ground seepage primarily originates from two sources, i.e., the collapsible and compressive deformation. The latter source accounts for the deformation of loess adjacent to the lining when the seepage depth is low, while both sources are included when the bottom of the tunnel invert is infiltrated. The collapsible deformation is lower than that of the original stratum due to the stress relaxation during tunnel excavation. The tensile and compressive stresses of tunnel lining increase linearly with the seepage depth, with the maximum appearing at a position of 20 m away from the midline of the collapse and non-collapse domains. The results will provide a theoretical reference to the design and construction of hydraulic tunnels in collapsible loess stratum.

Nephrotic syndrome (NS) is a common urinary system disease that carries a poor progrnosis due to nonresponsivess to current treatments. The purpose of this study was to investigate the therapeutic effects of Forsythiaside (FA) in a rat model of adriamycin-induced nephropathy (AN). Compared with control group, FA treatment significantly reduced proteinuria, serum creatinine and urea nitrogen levels and reduced the number of apoptotic cells in the kidneys. FA alleviated Adr induced renal injury, and increased the sactivity of superoxide dismutase (SOD), while decreasing malondialdehyde (MDA) and lactate dehydrogenase (LDH) in the serum. In addition, FA, in a dose-dependent manner, decreased the levels of NF-kappaBp65/MIP-2 in the kidenys, reduced the serum level of pro-inflammatory cytokines (IL-6, IL-1 β and TNF-alpha), and increased the survival rate of Adr treated rats. Taken together, the results show that FA alleviates renal dysfunction in adriamycin-induced nephropathy rats.

An attempt has been made to compare the quality of pashmina shawls developed on traditional and woollen handlooms using both hand-spun and machine-spun yams for various physico-mechanical parameters. The experimental plan includes preparation of both hand-spun and machine-spun yams followed by the preparation of pashmina shawls from these yams on both traditional and woollen handlooms, and their quality evaluation. Number of fibres/cross-section, count, elongation percentage, tenacity and coefficient of friction show significant difference between hand-spun and machine-spun yams. The quality evaluation tests of fabrics reveal that weight/m², thickness, picks/inch, extension percentage, bending rigidity, frictional properties and total hand value show significant difference, whereas ends/inch, breaking load, tenacity, bending length, abrasion loss and shrinkage loss do not show significant difference. The study reveals that the overall quality of pashmina shawls developed on traditional loom using hand-spun yam is better than the other types of shawls developed and studied. [ABSTRACT FROM AUTHOR]

Helicobacter pylori is a well-known bacterial pathogen involved in the development of peptic ulcer, gastric adenocarcinoma and other forms of gastric cancer. Evidence has suggested that certain strain-specific genes in the plasticity region may play key roles in the pathogenesis of H. pylori-associated gastroduodenal diseases. Therefore there is considerable interest in the strain-specific genes located in the plasticity regions of H. pylori. JHP933 is encoded by the gene in the plasticity region of H. pylori strain J99. Recently, the crystal structure of JHP933 has confirmed it as a nucleotidyltransferase (NTase) superfamily protein and a putative active site has been proposed. However, no evidence from direct functional assay has been presented to confirm the active site and little is known about the functional mechanism of JHP933. Here, through superimposition with Cid1/NTP complex structures, we modelled the complex structures of JHP933 with different NTPs. Based on the models and using rational site-directed mutagenesis combined with enzymatic activity assays, we confirm the active site and identify several residues important for the nucleotidyl transferring function of JHP933. Furthermore, mutations of these active site residues result in the abolishment of the nucleotidyltransferase activity of JHP933. This work provides preliminary insight into the molecular mechanism underlying the pathophysiological role in H. pylori infection of JHP933 as a novel NTase superfamily protein.

Understanding the spin-dependent activity of nitrogen-coordinated single metal atom (M-N-C) electrocatalysts for oxygen reduction and evolution reactions (ORR and OER) remains challenging due to the lack of structure-defined catalysts and effective spin manipulation tools. Herein, both challenges using a magnetic field integrated heterogeneous molecular electrocatalyst prepared by anchoring cobalt phthalocyanine (CoPc) deposited carbon black on polymer-protected magnet nanoparticles, are addressed. The built-in magnetic field can shift the Co center from low- to high-spin (HS) state without atomic structure modification, affording one-order higher turnover frequency, a 50% increased H 2 O 2 selectivity for ORR, and a ≈4000% magnetocurrent enhancement for OER. This catalyst can significantly minimize magnet usage, enabling safe and continuous production of a pure H 2 O 2 solution for 100 h from a 100 cm 2 electrolyzer. The new strategy demonstrated here also applies to other metal phthalocyanine-based catalysts, offering a universal platform for studying spin-related electrochemical processes., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

The burgeoning emergence of drug-resistant Helicobacter pylori strains poses a significant challenge to the clinical success of eradication therapies and is primarily attributed to mutations within drug-targeting genes that lead to antibiotic resistance. This study investigated the effect of high salt conditions on the occurrence of drug-resistance mutations in H. pylori . We found that high salt condition significantly amplifies the frequency of drug resistance mutations in H. pylori . This can be chiefly attributed to our discovery indicating that high salt concentration results in elevated reactive oxygen species (ROS) levels, initiating DNA damage within H. pylori . Mechanistically, high salt condition suppresses lipopolysaccharide (LPS) synthesis gene expression, inducing alterations in the LPS structure and escalating outer membrane permeability. This disruption of LPS synthesis attenuates the expression and activity of SodB, facilitates increased ROS levels, and consequently increases the drug resistance mutation frequency. Impairing LPS synthesis engenders a reduction in intracellular iron levels, leading to diminished holo-Fur activity and increased apo-Fur activity, which represses the expression of SodB directly. Our findings suggest a correlation between high salt intake and the emergence of drug resistance in the human pathogen H. pylori , implying that dietary choices affect the risk of emergence of antimicrobial resistance.IMPORTANCEDrug resistance mutations mainly contribute to the emergence of clinical antibiotic-resistant Helicobacter pylori, a bacterium linked to stomach ulcers and cancer. In this study, we explored how elevated salt conditions influence the emergence of drug resistance in H. pylori . We demonstrate that H. pylori exhibits an increased antibiotic resistance mutation frequency when exposed to a high salt environment. We observed an increase in reactive oxygen species (ROS) under high salt conditions, which can cause DNA damage and potentially lead to mutations. Moreover, our results showed that high salt condition alters the bacterium's lipopolysaccharide (LPS) synthesis, leading to a reduced expression of SodB in a Fur-dependent manner. This reduction, in turn, elevates ROS levels, culminating in a higher frequency of drug-resistance mutations. Our research underscores the critical need to consider environmental influences, such as diet and lifestyle, in managing bacterial infections and combating the growing challenge of antibiotic resistance., Competing Interests: The authors declare no conflict of interest.

Background: Osimertinib is a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor that has become the first-line treatment for non-small cell lung cancer harboring EGFR mutations, with the potential risk of QT prolongation and heart failure. However, few cases have reported malignant ventricular arrhythmias. Here, we report a case of recurrent ventricular fibrillation (VF) and Torsade de Pointes (TdP) secondary to QT prolongation and heart failure induced by osimertinib., Case Summary: A 70-year-old woman presented with chest tightness and dyspnea for 1 week and ventricular fibrillation upon admission, with a medical history of lung adenocarcinoma harboring an EGFR exon 21 p.L858R mutation. She was under osimertinib for 3 months. Electrocardiography after defibrillation suggested QTc prolongation (655 ms) and T wave alternans. Ultrasound cardiography displayed left ventricular ejection fraction (LVEF) of 29% and severe mitral regurgitation. Laboratory tests indicated elevated N-terminal pro-B-type natriuretic peptide and hypokalemia. Genetic testing suggested no pathogenic mutations. We considered acquired long QT syndrome and heart failure with reduced ejection fraction induced by osimertinib as the chief causes of ventricular arrhythmia and hypokalemia as an important trigger. Despite intubation, sedation, and the administration intravenous magnesium and potassium and lidocaine, the patient presented with recurrent TdP, which was managed by a low dose of isoproterenol (ISO, 0.17 ug/min). An implantable cardioverter defibrillator was declined. The patient is surviving without any relapse, with QTc of 490 ms and LVEF of 42% after a 6-month follow up., Conclusion: Regular monitoring is required during osimertinib administration, considering the risk of life-threatening cardiac events, such as malignant arrhythmias and heart failure. ISO, with an individual dose and target heart rate, may be beneficial for terminating TdP during poor response to other therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Luo, Zhou, Yang, Qian, Zhao, She, Liu and Zhang.)

Glycolysis and gluconeogenesis are reciprocal metabolic pathways that utilize different carbon sources. Pyruvate kinase catalyzes the irreversible final step of glycolysis, yet the physiological function of its regulation is poorly understood. Through metabolomics and enzyme kinetics studies, we discovered that pyruvate kinase activity is inhibited during gluconeogenesis in the soil bacterium Bacillus subtilis . This regulation involves an extra C-terminal domain (ECTD) of pyruvate kinase, which is essential for autoinhibition and regulation by metabolic effectors. Introducing a pyruvate kinase mutant lacking the ECTD into B. subtilis resulted in defects specifically under gluconeogenic conditions, including inefficient carbon utilization, slower growth, and decreased resistance to the herbicide glyphosate. These defects are not caused by the phosphoenolpyruvate-pyruvate-oxaloacetate futile cycle. Instead, we identified two significant metabolic consequences of pyruvate kinase dysregulation during gluconeogenesis: increased carbon overflow into the medium and failure to expand glycolytic intermediates such as phosphoenolpyruvate (PEP). In silico analysis revealed that in wild-type cells, an expanded PEP pool enabled by pyruvate kinase regulation is critical for the thermodynamic feasibility of gluconeogenesis. Our findings underscore the importance of allosteric regulation during gluconeogenesis in coordinating metabolic flux, efficient energy utilization, and antimicrobial resistance.

Background: The predominant immune cells in solid tumors are M2-like tumor-associated macrophages (M2-like TAMs), which significantly impact the promotion of epithelial-mesenchymal transition (EMT) in tumors, enhancing stemness and facilitating tumor invasion and metastasis. However, the contribution of M2-like TAMs to tumor progression in gallbladder cancer (GBC) is partially known., Methods: Immunohistochemistry was used to evaluate the expression of M2-like TAMs and cancer stem cell (CSC) markers in 24 pairs of GBC and adjacent noncancerous tissues from patients with GBC. Subsequently, GBC cells and M2-like TAMs were co-cultured to examine the expression of CSC markers, EMT markers, and migratory behavior. Proteomics was performed on the culture supernatant of M2-like TAMs. The mechanisms underlying the induction of EMT, stemness, and metastasis in GBC by M2-like TAMs were elucidated using proteomics and transcriptomics. GBC cells were co-cultured with undifferentiated macrophages (M0) and analyzed. The therapeutic effect of gemcitabine combined with a chemokine (C-C motif) receptor 2 (CCR2) antagonist on GBC was observed in vivo., Results: The expression levels of CD68 and CD163 in M2-like TAMs and CD44 and CD133 in gallbladder cancer stem cells (GBCSCs) were increased and positively correlated in GBC tissues compared with those in neighboring noncancerous tissues. M2-like TAMs secreted a significant amount of chemotactic cytokine ligand 2 (CCL2), which activated the MEK/extracellular regulated protein kinase (ERK) pathway and enhanced SNAIL expression after binding to the receptor CCR2 on GBC cells. Activation of the ERK pathway caused nuclear translocation of ELK1, which subsequently led to increased SNAIL expression. GBCSCs mediated the recruitment and polarization of M0 into M2-like TAMs within the GBC microenvironment via CCL2 secretion. In the murine models, the combination of a CCR2 antagonist and gemcitabine efficiently inhibited the growth of subcutaneous tumors in GBC., Conclusions: The interaction between M2-like TAMs and GBC cells is mediated by the chemokine CCL2, which activates the MEK/ERK/ELK1/SNAIL pathway in GBC cells, promoting EMT, stemness, and metastasis. A combination of a CCR2 inhibitor and gemcitabine effectively suppressed the growth of subcutaneous tumors. Consequently, our study identified promising therapeutic targets and strategies for treating GBC., (© 2024. The Author(s).)

Platinum-Ruthenium (PtRu) bimetallic nanoparticles are promising catalysts for methanol oxidation reaction (MOR) required by direct methanol fuel cells. However, existing catalyst synthesis methods have difficulty controlling their composition and structures. Here, a direct Joule heating method to yield highly active and stable PtRu catalysts for MOR is shown. The optimized Joule heating condition at 1000 °C over 50 microseconds produces uniform PtRu nanoparticles (6.32 wt.% Pt and 2.97 wt% Ru) with an average size of 2.0 ± 0.5 nanometers supported on carbon black substrates. They have a large electrochemically active surface area (ECSA) of 239 m 2 g -1 and a high ECSA normalized specific activity of 0.295 mA cm -2 . They demonstrate a peak mass activity of 705.9 mA mg Pt -1 for MOR, 2.8 times that of commercial 20 wt.% platinum/carbon catalysts, and much superior to PtRu catalysts obtained by standard hydrothermal synthesis. Theoretical calculation results indicate that the superior catalytic activity can be attributed to modified Pt sites in PtRu nanoparticles, enabling strong methanol adsorption and weak carbon monoxide binding. Further, the PtRu catalyst demonstrates excellent stability in two-electrode methanol fuel cell tests with 85.3% current density retention and minimum Pt surface oxidation after 24 h., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Posttraumatic stress disorder (PTSD) is a complex mental disorder notable for traumatic experience memory. Although current first-line treatments are linked with clinically important symptom reduction, a large proportion of patients retained to experience considerable residual symptoms, indicating pathogenic mechanism should be illustrated further. Recent studies reported that newly formed myelin could shape neural circuit function and be implicated in fear memory preservation. However, its role in PTSD remains to be elucidated. In this study, we adopted a restraint stress-induced PTSD mouse model and found that PTSD-related neuropsychiatric symptoms were accompanied by increased myelination in the posterior parietal cortex and hippocampus. Fluoxetine, but not risperidone or sertraline, has a more profound rescue effect on neuropsychological behaviors and myelin abnormalities. Further mechanistic experiments revealed that fluoxetine could directly interfere with oligodendroglial differentiation by upregulating Wnt signaling. Our data demonstrated the correlation between PTSD and abnormal myelination, suggesting that the oligodendroglial lineage could be a target for PTSD treatment., (© 2024. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.)

Background: Few small-sample studies have quantified the T-wave alternans (TWA) value by 24-hour ambulatory recordings or exercise stress tests in patients with long QT syndrome (LQTS). The cutoff point of TWA ≥47 μV was based on patients with myocardial infarction. In our study, we aimed to (1) evaluate the association of TWA with life-threatening arrhythmic events (LAEs); (2) compare the predictive model of LAEs according to the TWA value measured by 24-hour ambulatory recordings and exercise stress tests; and (3) propose a cutoff point for the high risk of LAEs in patients with LQTS., Methods and Results: The study cohort included 110 patients with LQTS referred to our hospital, and the primary outcome was LAEs. Thirty-one patients with LQTS (31/110 [28.2%]) developed LAEs during the following 24 (12-47) months. Peak TWA value quantified from 12 leads by 24-hour ambulatory recordings in patients with LQTS with LAEs (LQTS-LAEs group) was significantly higher than LQTS without LAEs (LQTS-non-LAEs group) (64.0 [42.0-86.0] μV versus 43.0 [36.0-53.0] μV; P <0.01). There was no statistical difference in TWA value measured by exercise stress tests between the 2 groups (69.0 [54.5-127.5] μV versus 68.5 [53.3-99.8] μV; P =0.871). The new cutoff point of the peak TWA value measured by 24-hour ambulatory recordings was 55.5 μV, with a sensitivity of 75.0% and a specificity of 78.6%. A univariate Cox regression analysis revealed that TWA value ≥55.5 μV was a strong predictor of LAEs (hazard ratio [HR], 4.5 [2.1-9.6]; P <0.001]. A multivariate Cox regression analysis indicated that TWA value ≥55.5 μV remained significant (HR, 2.7 [1.1-6.8]; P =0.034)., Conclusions: Peak TWA measured by 24-hour ambulatory recordings was a more favorable risk stratification marker than exercise stress tests for patients with LQTS.

Active pharmaceutical ingredients (APIs) in the environment, primarily resulting from patient excretion, are of concern because of potential risks to wildlife. This has led to more restrictive regulatory policies. Here, we discuss the 'benign-by-design' approach, which encourages the development of environmentally friendly APIs that are also safe and efficacious for patients. We explore the challenges and opportunities associated with identifying chemical properties that influence the environmental impact of APIs. Although a straightforward application of greener properties could hinder the development of new drugs, more nuanced approaches could lead to drugs that benefit both patients and the environment. We advocate for an enhanced dialogue between research and development (R&D) and environmental scientists and development of a toolbox to incorporate environmental sustainability in drug development., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

TGF-β1 plays a pivotal role in the metastatic cascade of malignant neoplasms. N6-methyladenosine (m 6 A) stands as one of the most abundant modifications on the mRNA transcriptome. However, in the metastasis of gallbladder carcinoma (GBC), the effect of TGF-β1 with mRNA m 6 A modification, especially the effect of mRNA translation efficiency associated with m 6 A modification, remains poorly elucidated. Here we demonstrated a negative correlation between FOXA1 and TGF-β1 expression in GBC. Overexpression of FOXA1 inhibited TGF-β1-induced migration and epithelial-mesenchymal transition (EMT) in GBC cells. Mechanistically, we confirmed that TGF-β1 suppressed the translation efficiency of FOXA1 mRNA through polysome profiling analysis. Importantly, both in vivo and in vitro experiments showed that TGF-β1 promoted m 6 A modification on the coding sequence (CDS) region of FOXA1 mRNA, which was responsible for the inhibition of FOXA1 mRNA translation by TGF-β1. We demonstrated through MeRIP and RIP assays, dual-luciferase reporter assays and site-directed mutagenesis that ALKBH5 promoted FOXA1 protein expression by inhibiting m 6 A modification on the CDS region of FOXA1 mRNA. Moreover, TGF-β1 inhibited the binding capacity of ALKBH5 to the FOXA1 CDS region. Lastly, our study confirmed that overexpression of FOXA1 suppressed lung metastasis and EMT in a nude mice lung metastasis model. In summary, our research findings underscore the role of TGF-β1 in regulating TGF-β1/FOXA1-induced GBC EMT and metastasis by inhibiting FOXA1 translation efficiency through m 6 A modification., (© 2024. The Author(s).)

The aim of this investigation was to evaluate the differential expression of the sterol O-acyltransferase 1 (SOAT1) protein in gallbladder cancer tissues and cells, investigate the impact of Avastin on the proliferation, migration, invasion capabilities of gallbladder cancer cells, and its potential to induce cell apoptosis. Immunohistochemical analysis of samples from 145 gallbladder cancer patients was conducted, along with analysis of SOAT1 protein, mRNA expression levels, and cholesterol content in gallbladder cancer cell lines SGC-996, NOZ, and gallbladder cancer (GBC)-SD using Western blot and q-PCR techniques. Furthermore, the effects of Avastin on the proliferation, migration, and invasion capabilities of these gallbladder cancer cell lines were studied, and its ability to induce cell apoptosis was evaluated using flow cytometry, Western blot, and immunohistochemical methods. Additionally, gene expression and pathway analysis were performed, and the synergistic therapeutic effects of Avastin combined with gemcitabine were tested in a gallbladder cancer xenograft model. The study found that SOAT1 expression was significantly upregulated in GBC tissues and positively correlated with lymph node metastasis and TNM staging. In vitro experiments demonstrated that Avastin significantly inhibited the proliferation, migration, and invasion capabilities of SGC-996 and GBC-SD cell lines and induced apoptosis. RNA sequencing analysis revealed multiple differentially expressed genes in cells treated with Avastin, primarily enriched in biological pathways such as signaling transduction, malignant tumors, and the immune system. In vivo, experiments confirmed that Avastin could effectively suppress tumor growth in a gallbladder cancer xenograft model and enhanced the treatment efficacy when used in combination with gemcitabine. Overall, these findings provide new insights and strategies for targeted therapy in gallbladder cancer., (© 2024 Wiley Periodicals LLC.)

This study was designed to assess whether selenium-chitosan (Se-CTS) can protect porcine endometrial epithelial cells (PEECs) against damage and apoptosis induced by zearalenone (ZEA) via modulating the JNK/SAPK signaling pathway. The cell cycle, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and apoptosis rates of porcine endometrial epithelial cells were determined, as well as the expression levels of genes related to the SAPK/JNK signaling pathway. The results showed that 3.0 µmol/L Se-CTS decreased the percentage of ZEA-induced G1 phase in PEECs (P < 0.01), whereas 1.5 and 3.0 µmol/L Se-CTS increased the percentage of ZEA-induced percentage of G2 phase of PEECs (P < 0.01). Further, Se-CTS at 1.5 and 3.0 µmol/L improved the ZEA-induced decrease in MMP (P < 0.01), whereas Se-CTS at 0.5, 1.5, and 3.0 µmol/L reduced the increase in ROS levels and apoptosis rate induced by ZEA in PEECs (P < 0.01 or P < 0.05). Furthermore, 3.0 µmol/L Se-CTS ameliorated the increase in the expression of c-Jun N-terminal kinase (JNK), apoptosis signal-regulated kinase (ASK1), and c-Jun induced by ZEA (P < 0.01) and the reduction in mitogen-activated protein kinase kinase 4 (MKK4) and protein 53 (p53) expression (P < 0.01), while 1.5 µmol/L Se-CTS improved the expression of ASK1 and c-Jun induced by ZEA (P < 0.05). The results proved that Se-CTS alleviates ZEA-induced cell cycle stagnation, cell mitochondrial damage, and cell apoptosis via decreasing ZEA-produced ROS and modulating the JNK/SAPK signaling pathway., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Zinc-ion batteries (ZIBs) are promising energy storage devices with safe, nonflammable electrolytes and abundant, low-cost electrode materials. Their practical applications are hampered by various water-related undesirable reactions, such as the hydrogen evolution reaction (HER), corrosion of zinc metal, and water-induced decay of cathode materials. Polymer hydrogel electrolytes were used to control these reactions. However, salt, water, and polymeric backbones intervene in polymer hydrogels, and currently, there are no systematic studies on how salt and water concentrations synergistically affect polymer hydrogels' electrochemical performance. Here, we used an in situ polymerization method to synthesize polyacrylamide (PAM) hydrogels with varied Zn(ClO 4 ) 2 (0.5 to 2.0 mol kg -1 ) and water (40 to 90 wt %) concentrations. Their electrochemical performances in Zn||Ti half-cells, Zn||Zn symmetrical cells, and Zn||V 2 O 5 full cells have been comprehensively evaluated. Although the ionic conductivity of electrolytes increases with the salt concentration, a high salt concentration of 2.0 mol kg -1 with more Zn 2+ solvated H 2 O would induce more severe HER and Zn corrosion at the electrolyte/electrode interfaces. A narrow window of the water concentration at 70-80 wt % is optimal to balance needs for achieving a high ionic conductivity and restricting water-related undesirable reactions. The chemically more active water counts roughly 64.1-73.1 wt % of the total water in electrolytes. PAM hydrogel electrolyte with 1.0 mol kg -1 Zn(ClO 4 ) 2 and 80 wt % water enables 1200 h of stable cycling in a Zn||Zn symmetric cell and 99.24% of Coulombic efficiency in a Zn||Ti half-cell. Due to the water-induced decay of V 2 O 5 , the electrolyte with 70 wt % water delivers the best performance in a Zn||V 2 O 5 full cell, which can retain 73.7% of its initial capacity after 400 charge/discharge cycles. Our results show that achieving precise control of salt and water concentrations of hydrogel electrolytes in their optimal windows to reduce the fraction of chemically more active water while retaining high ionic conductivity is essential to enabling high-performance ZIBs.