Tuberculous meningitis (TBM) is a prevalent global intracranial infection and the most lethal and disabling form of tuberculosis. TBM with mixed intracranial infections is clinically rare but has a higher mortality rate. To investigate the clinical characteristics of TBM with mixed intracranial infections, demographic and clinical data of TBM and pulmonary tuberculosis (PTB) patients admitted to Shenzhen Third People's Hospital between January 2015 and October 2022 were collected anonymously. A total of 207 cases of TBM were diagnosed, of which 16 cases (7.73%) were TBM with mixed intracranial infections. The overall mortality rate of TBM cases was 16.4%, while the mortality rate of TBM cases with mixed intracranial infections was as high as 35.7%. Compared to simple TBM cases, TBM cases with mixed intracranial infections had severer clinical symptoms. The percentage of human immune deficiency virus (HIV)-positive TBM cases with mixed intracranial infections reached up to 68.8%. HIV co-infection, CD4+/CD8+ T-cell counts less than 1, cranial nerve impairment, paralysis, cerebral infarction, PRO less than 450 mg/L, WBC less than 10 × 106 /L, and CL more than 120 mmol/L were risk factors for TBM cases with mixed intracranial infections. Compared to PTB, HIV co-infection, CD4+ T cell less than 550 /uL, and age less than 45 years were risk factors for TBM, and TBM was associated with higher mortality rates. Our study provides additional data to better understand single TBM and TBM with mixed intracranial infections. More than two-thirds of TBM cases with mixed intracranial infections were HIV-positive. Clinicians should consider the possibility of multiple infections in people with TBM/HIV co-infection. IMPORTANCE: TBM can cause severe neurological damage and death, and TBM with mixed intracranial infections can exacerbate the damage and poor prognosis of the disease. TBM with mixed intracranial infections is a rare disease, which has led to an incomplete understanding of its clinical features. This study investigated the clinical features of TBM and its associated factors by comparing the characteristics of TBM with mixed intracranial infections, single TBM and pulmonary tuberculosis. This information will help to improve the understanding of TBM, diagnostic accuracy and treatment outcomes.
High-altitude myocardial injury (HAMI) represents a critical form of altitude illness for which effective drug therapies are generally lacking. Notoginsenoside R1, a prominent constituent derived from Panax notoginseng, has demonstrated various cardioprotective properties in models of myocardial ischemia/reperfusion injury, sepsis-induced cardiomyopathy, cardiac fibrosis, and myocardial injury. The potential utility of notoginsenoside R1 in the management of HAMI warrants prompt investigation. Following the successful construction of a HAMI model, a series of experimental analyses were conducted to assess the effects of notoginsenoside R1 at dosages of 50â¯mg/Kg and 100â¯mg/Kg. The results indicated that notoginsenoside R1 exhibited protective effects against hypoxic injury by reducing levels of CK, CK-MB, LDH, and BNP, leading to improved cardiac function and decreased incidence of arrhythmias. Furthermore, notoginsenoside R1 was found to enhance Nrf2 nuclear translocation, subsequently regulating the SLC7A11/GPX4/HO-1 pathway and iron metabolism to mitigate ferroptosis, thereby mitigating cardiac inflammation and oxidative stress induced by high-altitude conditions. In addition, the application of ML385 has confirmed the involvement of Nrf2 nuclear translocation in the therapeutic approach to HAMI. Collectively, the advantageous impacts of notoginsenoside R1 on HAMI have been linked to the suppression of ferroptosis via Nrf2 nuclear translocation signaling.
OBJECTIVE: This study was performed to explore the differences in the clinical characteristics and oxidative stress indicators, inflammatory factors, and pathological proteins in serum between Parkinson's disease (PD) with anxiety (PD-A) and with no anxiety (PD-NA) patients, and further correlations among clinical characteristics and above variables were analyzed in PD-A and PD-NA groups. METHODS: A total of 121 patients with PD were enrolled in this study and assessed by the Hamilton Anxiety Scale (14 items) (HAMA-14). These patients were divided into PD-A and PD-NA groups according to a cut-off point of 7 of HAMA-14. Demographic variables were collected, and clinical symptoms were assessed by multiple rating scales. The levels of free radicals, inflammatory factors, and pathological proteins in serum were measured by chemical colorimetric method and enzyme-linked immunosorbent assay (ELISA). The differences of above variables were compared between PD-A and PD-NA groups, and the correlations of clinical symptoms with the abovevariables were analyzed in PD-A and PD-NA groups. RESULTS: The frequency of PD-A was 62.81%. PD-A group exhibited significantly impaired motor dysfunction and multiple non-motor symptoms, including fatigue, sleep behavior disorder, restless leg syndrome and autonomic dysfunction, and dramatically compromised activities of daily living compard with PD-NA group. PD-A group displayed prominently increasedlevels of hydroxyl radical (·OH) and tumor necrosis factor (TNF)-α, and a decreased nitric oxide (NO) level in serum compared with PD-NA group (P<0.001, P = 0.001, P= 0.027, respectively). ·OH, NO, and TNF-α were identified as the risk factors of PD-A (OR = 1.005, P = 0.036; OR = 0.956, P = 0.017; OR = 1.039, P = 0.033, respectively). In PD patients, HAMA-14 score was significantly and positively correlated with the levels of ·OH and TNF-α in serum (P<0.001, P = 0.002, respectively). In PD-A group, ·OH level was significantly and negatively correlated with Aß1-42 level, while TNF-α level was significantly and positively correlated with P-tau (S396) level in serum. CONCLUSIONS: The frequency of PD-A is high. PD-A patients present more severe motor dysfunction and multiple non-motor symptoms, and poorer activities of daily living. The increased levels of ·OH and TNF-α levels and the decreased NO level in serum are all associated with more severe anxiety in PD patients.Findings from this study may provide in-depth insights into the clinical characteristics, underlying mechanisms of PD-A, and potential correlations among anxiety, oxidative stress, inflammation, and cognitive decline in PD patients.
Anxiety , Inflammation , Oxidative Stress , Parkinson Disease , Humans , Parkinson Disease/blood , Parkinson Disease/psychology , Parkinson Disease/diagnosis , Male , Female , Oxidative Stress/physiology , Aged , Middle Aged , Anxiety/blood , Anxiety/psychology , Inflammation/blood
BACKGROUND: With regard to head and neck squamous cell carcinoma (HNSCC), its occurrence and advancement are controlled by genetic and epigenetic anomalies. PIWI-interacting RNAs (piRNAs) are recognized with significance in tumor, but the precise molecular mechanisms of piRNAs in HNSCC largely remain undisclosed. METHODS: Differentially expressed piRNAs were identified by RNA sequencing. The expression of piR-hsa-23533 was evaluated using quantitative real-time PCR and RNA in situ hybridization. The impacts of piR-hsa-23533 on the proliferation and apoptosis of HNSCC cells were investigated by a series of in vitro and in vivo assays. RESULTS: piR-hsa-23533 exhibits upregulation within HNSCC cells and tissues. Besides, piR-hsa-23533 overexpression promotes proliferation while inhibiting apoptosis in vitro and in vivo, while piR-hsa-23533 silencing has an opposite function. From the mechanistic perspective, piR-hsa-23533 can bind to Ubiquitin-specific protease 7 (USP7), as shown through RNA pull-down and RNA immunoprecipitation assays, promoting USP7 mRNA and protein expression. CONCLUSIONS: These findings highlight the functional importance of piR-hsa-23533 in HNSCC and may assist in the development of anti-HNSCC therapeutic target.
With the strengthening of the cross-regional flows of the economy, information, innovation, and population, this paper constructs a network model of multi-flow integration and analyzes the spatial pattern and influencing factors of urban networks in Chengdu-Chongqing Urban Agglomeration using social network analysis and spatial analysis technology. The main conclusions are as follows. (1) The density and efficiency are in the transition stage from the primary level to the medium level in the comprehensive network. (2) The overall pattern keeps a polyhedral pyramid structure with Chengdu â Chongqing as the core axis, and the grade of each axis has been significantly raised. (3) Four groups are formed using the social network method and show a geographic proximity effect. In addition, the connections within each group are relatively close, but the connections between the groups are significantly different. (4) Location conditions, economic development level, enterprise development level, scientific research investment, scientific and technological development level, and government support have a greater impact on the formation of the comprehensive network of Chengdu-Chongqing urban agglomeration. Information application level and transportation accessibility show a small impact and human capital level has not yet produced a significant impact.
This study investigated the properties of chitosan/zein/tea polyphenols (C/Z/T) films and analyzed the release kinetics of tea polyphenols (TP) in various food simulants to enhance the sustainability and functionality of food packaging. The results revealed that TP addition enhanced the hydrophilicity, opacity and mechanical properties of film, and improved the compatibility between film matrix. 1.5â¯% TP film showed the lowest lightness (76.4) and the highest chroma (29.1), while 2â¯% TP film had the highest hue angle (1.5). However, the excessive TP (above 1â¯% concentration) led to a decrease in compatibility and mechanical properties of film. The TP concentration (2â¯%) resulted in the highest swelling degree in aqueous (750.6â¯%), alcoholic (451.1â¯%), and fatty (6.4â¯%) food simulants. The cumulative release of TP decreased to 16.32â¯%, 47.13â¯%, and 5.87â¯% with the increase of TP load in the aqueous, alcoholic, and fatty food simulants, respectively. The Peleg model best described TP release kinetics. The 2â¯% TP-loaded film showed the highest DPPH (97.13â¯%) and ABTS (97.86â¯%) free radical scavenging activity. The results showed TP release influenced by many factors and obeyed Fick's law of diffusion. This study offered valuable insights and theoretical support for the practical application of active films.
The pathogenesis of attention-deficit/hyperactivity disorder (ADHD) has not been fully elucidated. Gestational hypertension could double the probability of ADHD in the offspring, while the initial bacterial communication between the mother and offspring has been associated with psychiatric disorders. Thus, we hypothesize that antihypertensive treatment during pregnancy may abate the impairments in neurodevelopment of the offspring. To test this hypothesis, we chose Captopril and Labetalol, to apply to pregnant spontaneously hypertensive rat (SHR) dams and examined the outcomes in the male offspring. Our data demonstrated that maternal treatment with Captopril and Labetalol had long-lasting changes in gut microbiota and behavioral alterations, including decreased hyperactivity and increased curiosity, spatial learning and memory in the male offspring. Increased diversity and composition were identified, and some ADHD related bacteria were found to have the same change in the gut microbiota of both the dam and offspring after the treatments. LC-MS/MS and immunohistochemistry assays suggested elevated expression of brain derived neurotrophic factor (BDNF) and dopamine in the prefrontal cortex and striatum of offspring exposed to Captopril/ Labetalol, which may account for the improvement of the offspring's psychiatric functions. Therefore, our results support the beneficial long-term effects of the intervention of gestational hypertension in the prevention of ADHD.
Antihypertensive Agents , Attention Deficit Disorder with Hyperactivity , Behavior, Animal , Captopril , Gastrointestinal Microbiome , Prenatal Exposure Delayed Effects , Rats, Inbred SHR , Animals , Gastrointestinal Microbiome/drug effects , Pregnancy , Attention Deficit Disorder with Hyperactivity/drug therapy , Attention Deficit Disorder with Hyperactivity/chemically induced , Female , Antihypertensive Agents/pharmacology , Captopril/pharmacology , Male , Rats , Behavior, Animal/drug effects , Labetalol/pharmacology , Brain-Derived Neurotrophic Factor/metabolism , Hypertension, Pregnancy-Induced/chemically induced , Dopamine/metabolism
OBJECTIVES: Differentiating gastric atypical hyperplasia (AH) from dysplasia, including low-grade dysplasia (LGD) and high-grade dysplasia (HGD), poses significant challenges in small biopsies and specimens with technical artifacts. This study aims to establish objective diagnostic criteria for these conditions through combined morphologic and immunohistochemical (IHC) analyses. METHODS: Between January 2018 and September 2020, a total of 123 gastric mucosa biopsy specimens were collected at Anyang Tumor Hospital. According to the WHO Classification of Digestive System Tumors (5th edition), specimens were categorized into three groups: AH (n=48), LGD (n=30), and HGD (n=45). Morphologic characteristics were assessed, and IHC staining for MUC5AC, MUC6, MUC2, CD10, P53, and Ki67 was performed, followed by statistical analysis. RESULTS: Histologically, AH was predominantly marked by a pronounced inflammatory background (60.42%), intestinal metaplasia (64.58%), indistinct boundaries (83.33%), and a distinct maturation gradient (97.72%). AH nuclei were typically circular (97.92%), with a high nucleus-to-cytoplasm ratio (64.58%), prominent nucleoli (47.92%), and preserved polarity (89.58%). In contrast, LGD and HGD typically exhibited well-defined boundaries with an absent maturation gradient. LGD nuclei were rod-shaped (96.67%), with a low nucleus-to-cytoplasm ratio (96.67%) and preserved polarity (100%), whereas HGD demonstrated a loss of cellular polarity (77.78%). IHC findings revealed a consistent maturation gradient in AH, with polarized MUC5AC and MUC6 expression, significantly reduced in LGD (86.67%), and absent in HGD. P53 expression in HGD showed a predominant 'mutation-type pattern' (66.67%), contrasting with 'wild-type pattern' expression in AH and LGD (100%, 93.33%). Ki67 expression patterns varied from a 'pit neck pattern' in AH (95.83%) to a 'polarity pattern' in LGD (76.67%) and a 'diffuse pattern' in HGD (57.78%). The expression patterns of MUC5AC, MUC6, CD10, P53, and Ki67 varied significantly across the three groups (P<0.001). CONCLUSIONS: The integration of histomorphological features and expression profiles of MUC5AC, MUC6, P53, and Ki67 is instrumental in diagnosing gastric atypical hyperplasia and dysplasia.
BACKGROUND: Fibrosis has important pathoetiological and prognostic roles in chronic liver disease. This study evaluates the role of radiomics in staging liver fibrosis. METHOD: After literature search in electronic databases (Embase, Ovid, Science Direct, Springer, and Web of Science), studies were selected by following precise eligibility criteria. The quality of included studies was assessed, and meta-analyses were performed to achieve pooled estimates of area under receiver-operator curve (AUROC), accuracy, sensitivity, and specificity of radiomics in staging liver fibrosis compared to histopathology. RESULTS: Fifteen studies (3718 patients; age 47 years [95% confidence interval (CI): 42, 53]; 69% [95% CI: 65, 73] males) were included. AUROC values of radiomics for detecting significant fibrosis (F2-4), advanced fibrosis (F3-4), and cirrhosis (F4) were 0.91 [95%CI: 0.89, 0.94], 0.92 [95%CI: 0.90, 0.95], and 0.94 [95%CI: 0.93, 0.96] in training cohorts and 0.89 [95%CI: 0.83, 0.91], 0.89 [95%CI: 0.83, 0.94], and 0.93 [95%CI: 0.91, 0.95] in validation cohorts, respectively. For diagnosing significant fibrosis, advanced fibrosis, and cirrhosis the sensitivity of radiomics was 84.0% [95%CI: 76.1, 91.9], 86.9% [95%CI: 76.8, 97.0], and 92.7% [95%CI: 89.7, 95.7] in training cohorts, and 75.6% [95%CI: 67.7, 83.5], 80.0% [95%CI: 70.7, 89.3], and 92.0% [95%CI: 87.8, 96.1] in validation cohorts, respectively. Respective specificity was 88.6% [95% CI: 83.0, 94.2], 88.4% [95% CI: 81.9, 94.8], and 91.1% [95% CI: 86.8, 95.5] in training cohorts, and 86.8% [95% CI: 83.3, 90.3], 94.0% [95% CI: 89.5, 98.4], and 88.3% [95% CI: 84.4, 92.2] in validation cohorts. Limitations included use of several methods for feature selection and classification, less availability of studies evaluating a particular radiological modality, lack of a direct comparison between radiology and radiomics, and lack of external validation. CONCLUSION: Although radiomics offers good diagnostic accuracy in detecting liver fibrosis, its role in clinical practice is not as clear at present due to comparability and validation constraints.
Radiology , Radiomics , Male , Humans , Middle Aged , Liver Cirrhosis/diagnostic imaging , Area Under Curve , Databases, Factual
As a selective and potent inhibitor targeting the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib obtained approval from the US Food and Drug Administration (FDA) in 2017 for adult patients with acute myeloid leukemia (AML) with an IDH2 mutation. In vitro investigations demonstrated that enasidenib affects various drug metabolic enzymes and transporters. This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug), omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. Results showed that following the co-administration of enasidenib (100 mg, once daily) for 28 days, the PK parameters AUC(0-∞) and Cmax of dextromethorphan increased by 1.37 (90% confidence interval (CI): 0.96, 1.96) and 1.24 (90% CI: 0.94, 1.65)-fold, respectively, compared to dextromethorphan alone. For flurbiprofen, these parameters increased by 1.14 (90%CI: 1.01, 1.29) and 0.97 (90% CI 0.86, 1.08)-fold, respectively, when compared to flurbiprofen alone. Conversely, midazolam exhibited decreases to 0.57 (90% CI 0.34, 0.97) and 0.77 (90% CI 0.39, 1.53)-fold, respectively, in comparison to midazolam alone. The parameters for omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)-fold, respectively, compared to omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)-fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib.
The identification of novel 4-hydroxy-2-quinolone-3-carboxamide antibacterials with improved properties is of great value for the control of antibiotic resistance. In this study, a series of N-heteroaryl-substituted 4-hydroxy-2-quinolone-3-carboxamides were developed using the bioisosteric replacement strategy. As a result of our research, we discovered the two most potent GyrB inhibitors (WBX7 and WBX18), with IC50 values of 0.816 µM and 0.137 µM, respectively. Additional antibacterial activity screening indicated that WBX18 possesses the best antibacterial activity against MRSA, VISA, and VRE strains, with MIC values rangingbetween0.5and 2 µg/mL, which was 2 to over 32 times more potent than that of vancomycin. In vitro safety and metabolic stability, as well as in vivo pharmacokinetics assessments revealed that WBX18 is non-toxic to HUVEC and HepG2, metabolically stable in plasma and liver microsomes (mouse), and displays favorable in vivo pharmacokinetic properties. Finally, docking studies combined with molecular dynamic simulation showed that WBX18 could stably fit in the active site cavity of GyrB.
Anti-Bacterial Agents , DNA Gyrase , Microbial Sensitivity Tests , Topoisomerase II Inhibitors , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Humans , DNA Gyrase/metabolism , Topoisomerase II Inhibitors/pharmacology , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/chemical synthesis , Structure-Activity Relationship , Animals , Molecular Structure , Dose-Response Relationship, Drug , Mice , Hep G2 Cells , Molecular Docking Simulation , Microsomes, Liver/metabolism , Microsomes, Liver/chemistry
Objective:To explore the selection, efficacy and application of indications for parapharyngeal space tumor resection assisted by plasma and HD endoscopic system through oral approach. Methods:The clinical data of 23 patients with parapharyngeal space tumor resection assisted by plasma and HD endoscopic system were retrospectively analyzed in Department of Otolaryngology Head and Neck Surgery, the First Affiliated Hospital of Bengbu Medical University from January 2013 to June 2023. All cases were examined by high-resolution CT and MRI before operation, and some cases were examined by CTA or DSA. During the operation, the high definition nasal endoscopic recording system was assisted, and low temperature plasma knife was used in some cases. The follow-up time was from 3 to 115 months, and the median follow-up time was 45 months. Results:There were no deaths in this group. All patients had complete tumor resection. The maximum tumor diameter was as follows: ï¼5.20±1.00ï¼ cm, the operation time wasï¼128.70±46.67ï¼ min, and the average blood loss wasï¼80.87±32.74ï¼ mL. One case of vascular smooth muscle tumor had more bleeding during the operation and was assisted by tracheotomy after operation. One case of nourishing vascular bleeding after operation of giant Schwannoma was investigated and hemostasis + external carotid artery ligation. Bleeding in the remaining cases was below 120 mL. Postoperative pathologies were all benign tumors, including 11 pleomorphic adenoma, 4 schwannoma, 2 base cell adenoma, 1 epidermoid cyst, 1 lymphatic cyst with infection, 1 angiomyoma, 1 solitary fibroma, 1 salivary gland cyst, and 1 tendon giant cell tumor. All patients were followed up. One patient originating from vagal schwannoma had 2-month vocal cord paralysis and 1 recurrenceï¼recurrence of the skull base of schwannomaï¼. Conclusion:Oral approach assisted by plasma and high-definition endoscopic system is suitable for partial selective resection of benign tumors in parapharyngeal space, which has the advantages of less trauma and rapid recovery. When the tumor is blood-rich, suspected to be malignant, the top of the tumor is deep into the cranial base nerve canal,located outside the internal carotid artery, and larger than 6.0 cm considering pleomorphic adenoma, it is recommended to conduct an external open or auxiliary cervical small incision approach.
Adenoma, Pleomorphic , Neurilemmoma , Pharyngeal Neoplasms , Humans , Adenoma, Pleomorphic/surgery , Endoscopy , Neurilemmoma/surgery , Parapharyngeal Space/pathology , Pharyngeal Neoplasms/surgery , Pharyngeal Neoplasms/pathology , Retrospective Studies
BACKGROUND: This study aimed to explore the expression, molecular mechanism and its biological function of potassium two pore domain channel subfamily K member 1 (KCNK1) in bladder cancer (BC). METHODS: We integrated large numbers of external samples (n = 1486) to assess KCNK1 mRNA expression levels and collected in-house samples (n = 245) for immunohistochemistry (IHC) experiments to validate at the KCNK1 protein level. Single-cell RNA sequencing (scRNA-seq) analysis was performed to further assess KCNK1 expression and cellular communication. The transcriptional regulatory mechanisms of KCNK1 expression were explored by ChIP-seq, ATAC-seq and ChIA-PET data. Highly expressed co-expressed genes (HECEGs) of KCNK1 were used to explore potential signalling pathways. Furthermore, the immunoassay, clinical significance and molecular docking of KCNK1 were calculated. RESULTS: KCNK1 mRNA was significantly overexpressed in BC (SMD = 0.58, 95% CI [0.05; 1.11]), validated at the protein level (p < 0.0001). Upregulated KCNK1 mRNA exhibited highly distinguishing ability between BC and control samples (AUC = 0.82 [0.78-0.85]). Further, scRNA-seq analysis revealed that KCNK1 expression was predominantly clustered in BC epithelial cells and tended to increase with cellular differentiation. BC epithelial cells were involved in cellular communication mainly through the MK signalling pathway. Secondly, the KCNK1 transcription start site (TSS) showed promoter-enhancer interactions in three-dimensional space, while being transcriptionally regulated by GRHL2 and FOXA1. Most of the KCNK1 HECEGs were enriched in cell cycle-related signalling pathways. KCNK1 was mainly involved in cellular metabolism-related pathways and regulated cell membrane potassium channel activity. KCNK1 expression was associated with the level of infiltration of various immune cells. Immunotherapy and chemotherapy (docetaxel, paclitaxel and vinblastine) were more effective in BC patients in the high KCNK1 expression group. KCNK1 expression correlated with age, pathology grade and pathologic_M in BC patients. CONCLUSIONS: KCNK1 was significantly overexpressed in BC. A complex and sophisticated three-dimensional spatial transcriptional regulatory network existed in the KCNK1 TSS and promoted the upregulated of KCNK1 expression. The high expression of KCNK1 might be involved in the cell cycle, cellular metabolism, and tumour microenvironment through the regulation of potassium channels, and ultimately contributed to the deterioration of BC.
Gene Expression Regulation, Neoplastic , Potassium Channels, Tandem Pore Domain , Urinary Bladder Neoplasms , Humans , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Molecular Docking Simulation , Potassium Channels, Tandem Pore Domain/genetics , Potassium Channels, Tandem Pore Domain/metabolism , Signal Transduction , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/pathology
RNA-binding proteins (RBPs) are critical regulators for RNA transcription and translation. As a key member of RBPs, ELAV-like family protein 2 (CELF2) has been shown to regulate RNA splicing and embryonic hematopoietic development and was frequently seen dysregulated in acute myeloid leukemia (AML). However, the functional role(s) of CELF2 in hematopoiesis and leukemogenesis has not been fully elucidated. In the current study, we showed that Celf2 deficiency in hematopoietic system led to enhanced HSCs self-renewal and differentiation toward myeloid cells in mice. Loss of Celf2 accelerated myeloid cell transformation and AML development in MLL-AF9-induced AML murine models. Gene expression profiling integrated with RNA immunoprecipitation sequencing (RIP-Seq), together with biochemical experiments revealed that CELF2 deficiency stabilizes FAT10 mRNA, promotes FAT10 translation, thereby increases AKT phosphorylation and mTORC1 signaling pathway activation. Notably, combination therapy with a mTORC1 inhibitor (Rapamycin) and a MA9/DOTL1 inhibitor (EPZ-5676) reduced the leukemia burden in MLL-AF9 mice lacking Celf2 in vivo. Our study elucidated a novel mechanism by which the CELF2/FAT10-AKT/mTORC1 axis regulates the proliferation of normal blood cells and the development of AML, thus providing potential therapeutic targets for myeloid leukemia suppression.
CELF Proteins , Leukemia, Myeloid, Acute , Mechanistic Target of Rapamycin Complex 1 , Nerve Tissue Proteins , RNA-Binding Proteins , Animals , Humans , Mice , CELF Proteins/genetics , CELF Proteins/metabolism , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , Mechanistic Target of Rapamycin Complex 1/genetics , Mice, Knockout , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/genetics , Signal Transduction/genetics
The P2-layered metal oxide cathode materials are crucial for constructing high-rate sodium-ion batteries (SIBs); however, its practical application is hindered by the high Na+ diffusion barrier resulting from Na+/vacancy ordering. Herein, a Li/Zn cosubstitution P2-Na0.67Ni0.33Mn0.67O2 (NLNZM) cathode was synthesized via a sol-gel method assisted with citric acid, which can induce the rearrangement of Na+ sites to disrupt ordered structures. The XRD Rietveld refinement confirms a higher occupancy of Na+ at Nae sites with low diffusion barriers through the Li/Zn cosubstitution. In addition, the highly reversible phase evolution of the NLNZM is confirmed through in situ XRD results, thereby ensuring the stability of the structure with low volume change rate (0.78%). Furthermore, Li and Zn can reduce the surface energy and increase the interlayered distance to achieve rapid interfacial kinetics. As a result, the NLNZM has exhibited a high reversible capacity of 152.8 mAh g-1 and an outstanding rate performance of 103.4 mAh g-1 at 5C. After 200 cycles at 5C, the capacity retention rate is 81.1%. This work proposes a cosubstitution strategy to induce Na+/vacancy disorder for achieving rapid Na+ migration as a cathode material for SIBs.
Herein, a new heterogeneous CoSe2-x@NC material with abundant selenium vacancies is synthesized via an in-situ carbonization-selenization process from cobaltic metal organic framework (Co-MOF). The obtained CoSe2-x@NC has a unique electronic structure and rich active sites, which can activate peroxymonosulfate (PMS) to degrade carbamazepine (CBZ) with superior catalytic performance and stability. The quenchingexperiments and EPR test show that SO4â¢- is the dominant reactive oxidation species (ROSs) for CBZ degradation. Significantly, systemic electrochemical tests and theoretical calculations illustrated that the dominant role of SO4â¢- is attributed to the existence of abundant selenium vacancies in CoSe2-x@NC, which can adjust the density of electron cloud of the Co atoms in CoSe2-x@NC to improve the PMS adsorption and promoting the conversion of transition metallic redox pairs (Co3+/Co2+). This work provides a facile way to improve the activity and stability of CoSe2 by defect engineering in the PMS based advanced oxidation process (AOPs).
Glioblastoma (GBM), the deadliest central nervous system cancer, presents a poor prognosis and scant therapeutic options. Our research spotlights OH2, an oncolytic viral therapy derived from herpes simplex virus 2 (HSV-2), which demonstrates substantial antitumor activity and favorable tolerance in GBM. The extraordinary efficacy of OH2 emanates from its unique mechanisms: it selectively targets tumor cells replication, powerfully induces cytotoxic DNA damage stress, and kindles anti-tumor immune responses. Through single-cell RNA sequencing analysis, we discovered that OH2 not only curtails the proliferation of cancer cells and tumor-associated macrophages (TAM)-M2 but also bolsters the infiltration of macrophages, CD4+ and CD8+ T cells. Further investigation into molecular characteristics affecting OH2 sensitivity revealed potential influencers such as TTN, HMCN2 or IRS4 mutations, CDKN2A/B deletion and IDO1 amplification. This study marks the first demonstration of an HSV-2 derived OV's effectiveness against GBM. Significantly, these discoveries have driven the initiation of a phase I/II clinical trial (ClinicalTrials.gov: NCT05235074). This trial is designed to explore the potential of OH2 as a therapeutic option for patients with recurrent central nervous system tumors following surgical intervention.
Brain Neoplasms , Glioblastoma , Oncolytic Virotherapy , Oncolytic Viruses , Humans , Oncolytic Viruses/genetics , Glioblastoma/genetics , Glioblastoma/therapy , CD8-Positive T-Lymphocytes , Brain Neoplasms/genetics , Brain Neoplasms/therapy
BACKGROUND: Internet hospitals in China are an emerging medical service model similar to other telehealth models used worldwide. Internet hospitals are currently in a stage of rapid development, giving rise to a series of new opportunities and challenges for patient care. Little research has examined the views of chronic disease physicians regarding internet hospitals in China. OBJECTIVE: We aimed to explore the experience and views of chronic disease physicians at 3 tertiary hospitals in Changsha, China, regarding opportunities and challenges in internet hospital care. METHODS: We conducted semistructured qualitative interviews with physicians (n=26) who had experience working in internet hospitals affiliated with chronic disease departments in 3 tertiary hospitals in Changsha, Hunan province, south central China. Interviews were transcribed verbatim and analyzed by content analysis using NVivo software (version 11; Lumivero). RESULTS: Physicians emphasized that internet hospitals expand opportunities to conduct follow-up care and health education for patients with chronic illnesses. However, physicians described disparities in access for particular groups of patients, such as patients who are older, patients with lower education levels, patients with limited internet or technology access, and rural patients. Physicians also perceived a gap between patients' expectations and the reality of limitations regarding both physicians' availability and the scope of services offered by internet hospitals, which raised challenges for doctor-patient boundaries and trust. Physicians noted challenges in doctor-patient communication related to comprehension and informed consent in internet hospital care. CONCLUSIONS: This study explored the experience and views of physicians in 3 tertiary hospitals in Changsha, China, regarding access to care, patients' expectations versus the reality of services, and doctor-patient communication in internet hospital care. Findings from this study highlight the need for physician training in telehealth communication skills, legislation regulating informed consent in telehealth care, public education clarifying the scope of internet hospital services, and design of internet hospitals that is informed by the needs of patient groups with barriers to access, such as older adults.
Physicians , Telemedicine , Humans , Aged , Motivation , Hospitals , Communication , Qualitative Research , China , Chronic Disease
The mechanosensitive channel of large conductance (MscL) acts as an "emergency release valve" that protects bacterial cells from acute hypoosmotic stress, and it serves as a paradigm for studying the mechanism underlying the transduction of mechanical forces. MscL gating is proposed to initiate with an expansion without opening, followed by subsequent pore opening via a number of intermediate substates, and ends in a full opening. However, the details of gating process are still largely unknown. Using in vivo viability assay, single channel patch clamp recording, cysteine cross-linking, and tryptophan fluorescence quenching approach, we identified and characterized MscL mutants with different occupancies of constriction region in the pore domain. The results demonstrated the shifts of constriction point along the gating pathway towards cytoplasic side from residue G26, though G22, to L19 upon gating, indicating the closed-expanded transitions coupling of the expansion of tightly packed hydrophobic constriction region to conduct the initial ion permeation in response to the membrane tension. Furthermore, these transitions were regulated by the hydrophobic and lipidic interaction with the constricting "hot spots". Our data reveal a new resolution of the transitions from the closed to the opening substate of MscL, providing insights into the gating mechanisms of MscL.
Escherichia coli Proteins , Ion Channels , Ion Channels/genetics , Ion Channels/chemistry , Ion Channels/metabolism , Ion Channel Gating/physiology , Escherichia coli Proteins/chemistry , Constriction
Cantharidin, a terpenoid produced by blister beetles, has been used in traditional Chinese medicine to treat various ailments and cancers. However, its biological activity, impact, and anticancer mechanisms remain unclear. The Cantharidin chemical gene connections were identified using various databases. The GSE21815 dataset was used to collect the gene expression information. Differential gene analysis and gene ontology analyses were performed. Gene set enrichment analysis was used to assess the activation of disease pathways. Weighted gene co-expression network analysis and differential analysis were used to identify illness-associated genes, examine differential genes, and discover therapeutic targets via protein-protein interactions. MCODE analysis of major subgroup networks was used to identify critical genes influenced by Cantharidin, examine variations in the expression of key clustered genes in colorectal cancer vs. control samples, and describe the subject operators. Single-cell GSE188711 dataset was preprocessed to investigate Cantharidin's therapeutic targets and signaling pathways in colorectal cancer. Single-cell RNA sequencing was utilized to identify 22 cell clusters and marker genes for two different cell types in each cluster. The effects of different Cantharidin concentrations on colorectal cancer cells were studied in vitro. One hundred and ninety-seven Cantharidin-associated target genes and 480 critical genes implicated in the development of the illness were identified. Cantharidin significantly inhibited the proliferation and migration of HCT116 cells and promoted apoptosis at certain concentrations. Patients on current therapy develop inherent and acquired resistance. Our study suggests that Cantharidin may play an anti-CRC role by modulating immune function.
