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On 13-15 January 2022, the Hunga Tonga-Hunga Ha'apai underwater volcano erupted. This powerful eruption generated infrasonic waves with amplitudes of thousands of Pascals in the near field. The ground infrasonic stations in China, located approximately 10 000 km from the Hunga volcano, also received waves with frequencies from 0.01 to 0.05 Hz. However, the amplitude reached 17 Pa, which is higher than the predicted amplitude using the absorption model without considering the dispersion effect in the thin thermosphere. At high altitudes, dispersion exists and the sound speed depends on the ratio of the molecular mean collision ratio to sound frequency, which is proportional to the ratio (frequency/pressure). And attenuation coefficients are complex to model. We simulate dispersive sound speeds and attenuation coefficients at different frequencies according to theory and our experimental data. In the thermosphere, the dispersion effect causes noticeable changes of sound speed and then affects wave propagation paths in the far field. The abnormal attenuation coefficient has a smaller impact on thermospheric returns than that of the dispersive sound speed, but it is also not negligible. It explains the large amplitude of thermospheric signals received in our infrasound stations. This article is part of the theme issue 'Celebrating the 15th anniversary of the Royal Society Newton International Fellowship'.
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BACKGROUND: Scopolamine has been demonstrated to relieve motion sickness. However, repeated significance testing may increase false-positive results. OBJECTIVES: Review the efficacy and safety of scopolamine in the prevention of motion sickness by performing a meta-analysis with Trial Sequential Analysis (TSA). MATERIAL AND METHODS: Randomized controlled trials (RCTs) compared scopolamine with other medications or placebo were included. Primary outcomes were nausea reported and head movement time. RESULTS: Twenty studies with 753 participants were included. Scopolamine had a greater reported reduction in nausea than placebo (relative risk [RR] 0.35; 95% confidence interval [CI] 0.24 to 0.52; p<0.00001; I2 = 45%), while TSA showed the included sample size exceeded the required information size (RIS). There is no difference in head movement time between scopolamine and placebo (mean difference [MD] 2.02; 95% CI -1.2 to 5.25; p = 0.6; I2 = 0%), while the included sample size did not reach RIS. CONCLUSION: Scopolamine is effective for motion sickness nausea compared to placebo. The TSA recommends conducting more head movement trials to validate the objective efficacy of scopolamine. SIGNIFICANCE: Clarifying the efficacy of scopolamine for motion sickness, the TSA highlights the need for more prospective studies using head movement as an outcome.
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OBJECTIVE: To explore the molecular basis for a Chinese pedigree affected with Achromatopsia (ACHM). METHODS: A pedigree with ACHM which was admitted to the Women and Children's Hospital of Ningbo University on April 14, 2023 was selected as the study subject. Whole exome sequencing (WES) was carried out for the proband. Candidate variants were verified by Sanger sequencing and bioinformatic analysis. Related literature was reviewed, and clinical and genetic features of Chinese patients with ACHM due to variants of CNGA3 gene were summarized. RESULTS: WES revealed that the proband and his younger brother had both harbored compound heterozygous variants of the CNGA3 gene, namely c.1190G>T (p.Gly397Val) and c.2013del (p.Gly672ValfsTer69), which were respectively inherited from their mother and father. The c.1190G>T was a known pathogenic variant, whilst the c.2013del was unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.2013del variant was predicted to be likely pathogenic (PM2_Supporting+PVS1_Moderate+PM3+PP4). Literature review has identified 41 CNGA3 gene variants among 43 patients from 38 pedigrees, most of which were missense variants and had located in exon 8. Most patients were males, with nystagmus, photophobia, amblyopia and other symptoms during infancy/childhood as the main clinical manifestations, and there was a lack of genotype-phenotype correlation. CONCLUSION: The c.1190G>T (p.Gly397Val) and c.2013del (p.Gly672ValfsTer69) variants of the GNGA3 gene probably underlay the ACHM in the proband. Discovery of the c.2013del variant has enriched the mutational spectrum of the GNGA3 gene and provided a basis for genetic counseling and reproduction guidance for this pedigree.
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Defectos de la Visión Cromática , Canales Catiónicos Regulados por Nucleótidos Cíclicos , Adulto , Niño , Femenino , Humanos , Masculino , China , Defectos de la Visión Cromática/genética , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Pueblos del Este de Asia/genética , Secuenciación del Exoma , Mutación , LinajeRESUMEN
BACKGROUND: Hand function assessment heavily relies on specific task scenarios, making it challenging to ensure validity and reliability. In addition, the wide range of assessment tools, limited and expensive data recording, and analysis systems further aggravate the issue. However, smartphones provide a promising opportunity to address these challenges. Thus, the built-in, high-efficiency sensors in smartphones can be used as effective tools for hand function assessment. OBJECTIVE: This review aims to evaluate existing studies on hand function evaluation using smartphones. METHODS: An information specialist searched 8 databases on June 8, 2023. The search criteria included two major concepts: (1) smartphone or mobile phone or mHealth and (2) hand function or function assessment. Searches were limited to human studies in the English language and excluded conference proceedings and trial register records. Two reviewers independently screened all studies, with a third reviewer involved in resolving discrepancies. The included studies were rated according to the Mixed Methods Appraisal Tool. One reviewer extracted data on publication, demographics, hand function types, sensors used for hand function assessment, and statistical or machine learning (ML) methods. Accuracy was checked by another reviewer. The data were synthesized and tabulated based on each of the research questions. RESULTS: In total, 46 studies were included. Overall, 11 types of hand dysfunction-related problems were identified, such as Parkinson disease, wrist injury, stroke, and hand injury, and 6 types of hand dysfunctions were found, namely an abnormal range of motion, tremors, bradykinesia, the decline of fine motor skills, hypokinesia, and nonspecific dysfunction related to hand arthritis. Among all built-in smartphone sensors, the accelerometer was the most used, followed by the smartphone camera. Most studies used statistical methods for data processing, whereas ML algorithms were applied for disease detection, disease severity evaluation, disease prediction, and feature aggregation. CONCLUSIONS: This systematic review highlights the potential of smartphone-based hand function assessment. The review suggests that a smartphone is a promising tool for hand function evaluation. ML is a conducive method to classify levels of hand dysfunction. Future research could (1) explore a gold standard for smartphone-based hand function assessment and (2) take advantage of smartphones' multiple built-in sensors to assess hand function comprehensively, focus on developing ML methods for processing collected smartphone data, and focus on real-time assessment during rehabilitation training. The limitations of the research are 2-fold. First, the nascent nature of smartphone-based hand function assessment led to limited relevant literature, affecting the evidence's completeness and comprehensiveness. This can hinder supporting viewpoints and drawing conclusions. Second, literature quality varies due to the exploratory nature of the topic, with potential inconsistencies and a lack of high-quality reference studies and meta-analyses.
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Mano , Teléfono Inteligente , Humanos , Mano/fisiopatología , Mano/fisiología , Masculino , Femenino , Enfermedad de Parkinson/fisiopatología , Telemedicina/instrumentación , AncianoRESUMEN
Chronic itch is a maladaptive and debilitating symptom in patients with allergic contact dermatitis (ACD), adversely affecting their quality of life. There is a lack of effective treatments for ACD-associated uncontrollable itch. In this study, we explored the antipruritic effects of baicalein (BE), a bioactive flavonoid extracted from the root of Scutellaria baicalensis Georgi, and the underlying mechanisms in alleviating chronic itch triggered by diphenylcyclopropenone (DCP) in a mouse model of ACD. The ACD mice were intraperitoneally injected with BE (5, 30, and 60 mg·kg-1·d-1) for 7 days during the DCP challenge phase. The results showed that DCP-treated mice exhibited severe spontaneous scratching behaviors that was reduced after BE injections in a dose-dependent manner accompanied by inhibition of spinal astrocyte activation. We observed that the spinal astrocytic STAT3-LCN2 cascade plays a crucial role in controlling the activation of astrocytes in chronic itch. Intrathecal injection of the STAT3 inhibitor AG490 or Lcn2 siRNA significantly reduced scratching behavior and astrocyte activation in ACD mice. Moreover, BE markedly attenuated the increased phosphorylation of STAT3 (p-STAT3) and LCN2 expression in the spinal cords of ACD mice and in lipopolysaccharide-stimulated primary spinal astrocytes. Altogether, BE relieved chronic itch by suppressing the spinal astrocytic STAT3-LCN2 cascade. These findings provide a potential avenue for the management of chronic itch. Schematic summary of the main findings illustrating that BE alleviates chronic itch through suppressing the spinal astrocytic STAT3-LCN2 cascade. Specifically, BE suppresses the expression of p-STAT3 to inhibit the reactive state of astrocytes in spinal dorsal horn, and then decreases the expression of astrocytic LCN2 to alleviate chronic itch in ACD mice.
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OBJECTIVE: We aimed to determine the incidence of growth failure in infants with necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP) and whether initial laparotomy versus peritoneal drainage (PD) impacted the likelihood of growth failure. SUMMARY BACKGROUND DATA: Infants with surgical NEC and SIP have high mortality, and most have neurodevelopmental impairment and poor growth. Existing literature on growth outcomes for these infants is limited. METHODS: This is a preplanned secondary study of the Necrotizing Enterocolitis Surgery Trial dataset. The primary outcome was growth failure (Z-score for weight <-2.0) at 18 to 22 months. We used logistic regression, including diagnosis and treatment, as covariates. Secondary outcomes were analyzed using the Fisher exact or Pearson χ2 test for categorical variables and the Wilcoxon rank sum test or one-way ANOVA for continuous variables. RESULTS: Among 217 survivors, 207 infants (95%) had primary outcome data. Growth failure at 18 to 22 months occurred in 24/50 (48%) of NEC infants versus 65/157 (42%) SIP (P=0.4). The mean weight-for-age Z-score at 18 to 22 months in NEC infants was -2.05±0.99 versus -1.84±1.09 SIP (P=0.2), and the predicted mean weight-for-age Z-score SIP (Beta -0.27; 95% CI: -0.53, -0.01; P=0.041). Median declines in weight-for-age Z-score between birth and 18 to 22 months were significant in all infants but most severe (>2) in NEC infants (P=0.2). CONCLUSIONS: This first ever prospective study of growth outcomes in infants with surgical NEC or SIP demonstrates that growth failure is very common, especially in infants with NEC, and persists at 18-22 months.
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Enterocolitis Necrotizante , Perforación Intestinal , Humanos , Enterocolitis Necrotizante/cirugía , Enterocolitis Necrotizante/complicaciones , Perforación Intestinal/cirugía , Perforación Intestinal/etiología , Masculino , Femenino , Lactante , Recién Nacido , Drenaje/métodos , Laparotomía/métodos , Perforación Espontánea/cirugía , Perforación Espontánea/etiología , Trastornos del Crecimiento/etiología , Recien Nacido PrematuroRESUMEN
BACKGROUND: Ovarian clear cell carcinoma rarely responds to second-line chemotherapy, the recommended treatment for relapsed epithelial ovarian cancer. Here, we report the activity and safety of sintilimab in combination with bevacizumab in patients with relapsed or persistent ovarian clear cell carcinoma. METHODS: In the prospective, multicentre, single-arm, phase 2 INOVA trial, patients aged 18-75 years with histologically confirmed relapsed or persistent ovarian clear cell carcinoma were enrolled from eight tertiary hospitals in China. Eligible patients had an Eastern Cooperative Oncology Group performance status score of 0-2 and previous exposure to at least one cycle of platinum-containing chemotherapy. Enrolled patients received sintilimab (200 mg) and bevacizumab (15 mg/kg) intravenously every 3 weeks until disease progression. The primary endpoint was objective response rate assessed by independent central review based on Response Evaluation Criteria in Solid Tumours version 1.1. Eligible enrolled patients who received at least one cycle of treatment and had at least one tumour response assessment following the baseline assessment per protocol were included in the activity analysis. Patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04735861) and is ongoing. FINDINGS: Between April 8, 2021, and July 3, 2023, 51 patients were screened and 41 patients received at least one dose of sintilimab in combination with bevacizumab. Response evaluation was completed in 37 patients. Objective responses were observed in 15 patients (objective response rate 40·5%; 95% CI 24·8-57·9), of which five (14%) were complete responses and ten (27%) were partial responses. At data cutoff (Jan 29, 2024), the median follow-up was 16·9 months (IQR 7·5-23·4). Three (7%) patients developed grade 3 treatment-related adverse events including one patient with proteinuria, one patient with myocarditis, and one patient with rash. No treatment-related adverse events of worse than grade 3 severity were recorded. Treatment-related serious adverse events occurred in two (5%) patients including one patient with immune-related myocarditis and another with hypertension and renal dysfunction. No treatment-related deaths occurred. INTERPRETATION: Sintilimab in combination with bevacizumab showed promising anti-tumour activity and manageable safety in patients with relapsed or persistent ovarian clear cell carcinoma. Larger, randomised trials are warranted to compare this low-toxicity, chemotherapy-free combinatorial regimen with standard chemotherapy. FUNDING: National Key Technology Research and Development Program of China, National Natural Science Foundation of China, Beijing Xisike Clinical Oncology Research Foundation, and Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Soil Pb contamination is inevitable, as a result of phosphate mining. It is essential to explore more effective Pb remediation approaches in phosphate mining wasteland soil to ensure their viability for a gradual return of soil quality for cultivation. In this study, a Pb-resistant urease-producing bacterium, Serratia marcescens W1Z1, was screened for remediation using microbially induced carbonate precipitation (MICP). Magnesium polypeptide (MP) was prepared from soybean meal residue, and the combined remediation of Pb contamination with MP and MICP in phosphate mining wasteland soil was studied. Remediation of Pb using a combination of MP with MICP strain W1Z1 (WM treatment) was the most effective, with the least exchangeable Pb at 30.37% and the most carbonate-bound Pb at 40.82%, compared to the other treatments, with a pH increase of 8.38. According to the community analysis, MP moderated the damage to microbial abundance and diversity caused by MICP. Total nitrogen (TN) was positively correlated with Firmicutes, pH, and carbonate-bound Pb. Serratia inoculated with strain W1Z1 were positively correlated with bacteria belonging to the Firmicutes phylum and negatively correlated with bacteria belonging to Proteobacteria. The available phosphate (AP) in the phosphate mining wasteland soil could encapsulate the precipitated Pb by ion exchange with carbonate, making it more stable. Combined MP-MICP remediation of Pb contamination in phosphate mining wasteland soil was effective and improved the soil microenvironment.
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BACKGROUND: The patent foramen ovale (PFO) and interatrial block (IAB) are associated with cryptogenic stroke (CS). However, the role of the interaction between PFO and IAB in CS remains unclear. METHODS: This case-control study enrolled 256 patients with CS and 156 individuals without a history of stroke or transient ischemic attack. IAB was defined as P wave duration > 120 ms. PFO was evaluated by contrast transesophageal echocardiography, and classified as no-PFO, low-risk PFO and high-risk PFO. Multiplicative and additive interaction analysis were used to assess the interaction between PFO and IAB in CS. RESULTS: Multiplicative interaction analysis unveiled a significant interaction between IAB and low-risk PFO in CS (OR for interaction = 3.653, 95% CI, 1.115-12.506; P = 0.037). Additive interaction analysis indicated that 68.4% (95% CI, 0.333-1.050; P < 0.001) of the increased risk of CS related to low-risk PFO was attributed to the interaction with IAB. The results were robust in multivariate analysis. However, but no significant multiplicative or additive interaction was observed between IAB and high-risk PFO. When stratified by IAB, high-risk PFO was associated with CS in both patients with IAB (OR, 4.186; 95% CI, 1.617-10.839; P = 0.003) and without IAB (OR, 3.476; 95% CI, 1.790-6.750; P < 0.001). However, low-risk PFO was only associated with CS in patients with IAB (OR, 2.684; 95% CI, 1.007-7.149; P = 0.048) but not in those without IAB (OR, 0.753; 95% CI, 0.343-1.651; P = 0.479). CONCLUSION: The interaction between IAB and PFO might play an important role in CS, particularly in cases with low-risk PFO.
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Foramen Oval Permeable , Bloqueo Interauricular , Humanos , Foramen Oval Permeable/complicaciones , Foramen Oval Permeable/epidemiología , Foramen Oval Permeable/diagnóstico por imagen , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Estudios de Casos y Controles , Bloqueo Interauricular/complicaciones , Bloqueo Interauricular/epidemiología , Bloqueo Interauricular/fisiopatología , Adulto , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/complicaciones , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Accidente Cerebrovascular Isquémico/etiología , Factores de Riesgo , Anciano , Ecocardiografía Transesofágica/métodosRESUMEN
Cow milk possesses high nutritional value due to its rich array of beneficial fatty acids. It is important to understand the mechanisms involved in lipid metabolism in dairy cows. These mechanisms are driven by a complex molecular regulatory network. In addition, there are many regulatory factors involved in the process of fatty acid metabolism, including transcription factors and non-coding RNAs, amongst others. MicroRNAs (miRNAs) can regulate the expression of target genes and modulate various biological processes, including lipid metabolism. Specifically, miR-206 has been reported to impair lipid accumulation in nonruminant hepatocytes. However, the effects and regulatory mechanisms of miR-206 on lipid metabolism in bovine mammary cells remain unclear. In the present study, we investigated the effects of miR-206 on lipid-related genes and TAG accumulation. The direct downstream gene of miR-206 was subsequently determined via a dual-luciferase assay. Finally, the fatty acid content of bovine mammary epithelial cells (BMECs) upon ELOVL6 inhibition was examined. The results revealed that miR-206 overexpression significantly decreased triacylglycerol (TAG) concentration and abundances of the following: acetyl-coenzyme A carboxylase alpha (ACACA); fatty acid synthase (FASN); sterol regulatory element binding transcription factor 1 (SREBF1); diacylglycerol acyltransferase 1 (DGAT1); 1-acylglycerol-3-phosphate O-acyltransferase 6 (AGPAT6); lipin 1 (LPIN1); and fatty acid elongase 6 (ELOVL6). Overexpression of miR-206 was also associated with an increase in patatin-like phospholipase domain-containing 2 (PNPLA2), while inhibition of miR-206 promoted milk fat metabolism in vitro. In addition, we found that ELOVL6 is a direct target gene of miR-206 through mutation of the binding site. Furthermore, ELOVL6 intervention significantly decreased the TAG levels and elongation indexes of C16:0 and C16:1n-7 in BMECs. Finally, ELOVL6 siRNA partially alleviated the increased TAG accumulation caused by miR-206 inhibition. In summary, we found that miR-206 inhibits milk fatty acid synthesis and lipid accumulation by targeting ELOVL6 in BMECs. The results presented in this paper may contribute to the development of strategies for enhancing the quality of cow milk and its beneficial fatty acids, from the perspective of miRNA-mRNA networks.
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The continued evolution of H3 subtype avian influenza virus (AIV)-which crosses the interspecific barrier to infect humans-and the potential risk of genetic recombination with other subtypes pose serious threats to the poultry industry and human health. Therefore, rapid and accurate detection of H3 virus is highly important for preventing its spread. In this study, a method based on real-time reverse transcription recombinase-aided isothermal amplification (RT-RAA) was successfully developed for the rapid detection of H3 AIV. Specific primers and probes were designed to target the hemagglutinin (HA) gene of H3 AIV, ensuring highly specific detection of H3 AIV without cross-reactivity with other important avian respiratory viruses. The results showed that the detection limit of the RT-RAA fluorescence reading method was 224 copies/response within the 95% confidence interval, while the detection limit of the RT-RAA visualization method was 1527 copies/response within the same confidence interval. In addition, 68 clinical samples were examined and the results were compared with those of real-time quantitative PCR (RT-qPCR). The results showed that the real-time fluorescence RT-RAA and RT-qPCR results were completely consistent, and the kappa value reached 1, indicating excellent correlation. For visual detection, the sensitivity was 91.43%, the specificity was 100%, and the kappa value was 0.91, which also indicated good correlation. In addition, the amplified products of RT-RAA can be visualized with a portable blue light instrument, which enables rapid detection of H3 AIV even in resource-constrained environments. The H3 AIV RT-RAA rapid detection method established in this study can meet the requirements of basic laboratories and provide a valuable reference for the early diagnosis of H3 AIV.
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In recent years, the ready-to-eat foods market has grown significantly due to its high nutritional value and convenience. However, these foods are also at risk of microbial contamination, which poses food safety hazards. Additionally, traditional high-temperature sterilization methods can cause food safety and nutritional health problems such as protein denaturation and lipid oxidation. Therefore, exploring and developing effective sterilization technologies is imperative to ensure food safety and nutritional properties, and protect consumers from potential foodborne diseases. This paper focuses on electromagnetic wave-based pasteurization technologies, including thermal processing technologies such as microwave, radio frequency, and infrared, as well as non-thermal processing technologies like ultraviolet, irradiation, pulsed light, and photodynamic inactivation. Furthermore, it also reviews the antibacterial mechanisms, advantages, disadvantages, and recent applications of these technologies in ready-to-eat foods, and summarizes their limitations and prospects. By comparing the limitations of traditional high-temperature sterilization methods, this paper highlights the significant advantages of these pasteurization techniques in effectively inhibiting microbial growth, slowing lipid oxidation, and preserving food nutrition and flavor. This review may contribute to the industrial application and process optimization of these pasteurization technologies, providing an optimal choice for preserving various types of ready-to-eat foods.
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ETHNOPHARMACOLOGICAL RELEVANCE: Processed Buthus martensii Karsch (BmK) scorpion, also known as Quan-Xie, is a traditional Chinese medicine that is clinically used for the treatment of NAFLD due to its Tong-Luo-San-Jie effects. Our previous study showed that aqueous extract of processed BmK scorpion venom gland (pVg AE) inhibited macrophage inflammation by targeting Kv1.3 and identified the thermostable peptide BmKK2 as a potent Kv1.3 blocker. AIM OF THE STUDY: This study examined the therapeutic effects of processed BmK scorpions on NASH, specifically focusing on the involvement of their anti-inflammatory effects mediated by macrophage-expressed Kv1.3 in NASH. MATERIALS AND METHODS: In the present study, the anti-NASH effects of pVg AE were evaluated in high-fat diet (HFD)-induced NASH mouse models. Additionally, the in vitro anti-inflammatory mechanisms of pVg AE and BmKK2 were assessed using a palmitic acid (PA)-induced mouse bone marrow-derived macrophages (BMDMs) inflammation model. Protein and cytokine expression related to the Kv1.3-NF-κB pathway was analyzed by real-time PCR, immunoblotting and ELISA. The effect of pVg AE and BmKK2 on potassium channels was detected by whole-cell voltage-clamp recordings on transfected HEK293T cells or mouse BMDMs. Calcium ion imaging was used to evaluate intracellular calcium signaling. Furthermore, the study utilized Kv1.3 siRNA and a BMDMs and hepatocytes co-culture model to investigate the specific role of Kv1.3 in mediating the anti-NASH effects of pVg AE and BmKK2. RESULTS: Lipid accumulation upregulated Kv1.3 expression in macrophages in vivo and in vitro. However, pVg AE significantly reduced Kv1.3 expression and Kv1.3-positive macrophage infiltration. Treatment with pVg AE improved obesity, insulin resistance (IR), hepatic steatosis (HS), inflammation, and fibrosis in HFD-fed mice. Mechanistically, pVg AE and BmKK2 inhibited macrophage inflammation by targeting Kv1.3, which reduced PA-induced intracellular Ca2+ levels, resulting in the inhibition of the NF-κB pathway and TNFα release. CONCLUSIONS: This study demonstrates that Kv1.3-mediated macrophage inflammation is involved in the pathogenesis and treatment of NASH. pVg AE effectively alleviates metabolic stress-induced NASH by inhibiting this inflammation.
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BACKGROUND: Globally, breast cancer is the most common type of malignant tumor. It has been demonstrated that TMEM41A is abnormally expressed in a number of cancers and is linked to a dismal prognosis. TMEM41A's involvement in breast cancer remains unknown, though. METHODS: Data from databases such as TCGA were used in this study. Expression differences were compared using non-parametric tests. Cox regression analysis was employed, and analyses such as Nomogram were used to assess the significance of TMEM41A in predicting the prognosis of breast cancer. Lastly, it was looked into how immune cell infiltration in breast cancer is related to TMEM41A expression levels. RESULTS: The results suggest that TMEM41A is overexpressed in breast cancer and correlates with poor prognosis (P = 0.01), particularly in early-stage and ductal A breast cancer (P < 0.01). Breast cancer patients' expression of TMEM41A was found to be an independent risk factor (HR = 1.132, 95% CI 1.036-1.237) by multifactorial Cox regression analysis. The Nomogram prediction model's c-index was 0.736 (95% CI 0.684-0.787). The results of GSEA biofunctional enrichment analysis included the B cell receptor signaling pathway (P < 0.05). Ultimately, there was a significant correlation (P < 0.05) between TMEM41A expression in breast cancer and an infiltration of twenty immune cells. CONCLUSIONS: Breast cancer tissues overexpress TMEM41A, which is linked to immune cell infiltration and prognosis (particularly in early stage and luminal A breast cancer). Overexpression of TMEM41A is anticipated to serve as a novel prognostic indicator and therapeutic target for breast cancer.
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Based on the principle of cascade reaction, a fusion enzyme of dextransucrase and dextranase was designed without linker to catalyze the production of oligo-dextran with homogeneous molecular weight from sucrose in one catalytic step. Due to the different effects of temperature on the two components of the fusion enzyme, temperature served as the "toggle switch" for the catalytic efficiency of the two-level fusion enzyme, regulating the catalytic products of the fusion enzyme. Under optimal conditions, the fusion enzyme efficiently utilized 100 % of the sucrose, and the yield of oligo-dextran with a homogeneous molecular weight reached 70 %. The product has been purified and characterized. The probiotic potential of the product was evaluated by analyzing the growth of 10 probiotic species. Its cytotoxic and anti-inflammatory activities were also determined. The results showed that the long-chain oligo-dextran in this study had significantly better probiotic potential and anti-inflammatory activity compared to other oligosaccharides. This study provides a strategy for the application of oligo-dextran in the food and pharmaceutical industries.
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Dextranasa , Dextranos , Glucosiltransferasas , Temperatura , Dextranos/química , Dextranasa/metabolismo , Dextranasa/química , Dextranasa/genética , Glucosiltransferasas/metabolismo , Glucosiltransferasas/química , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Probióticos , Antiinflamatorios/farmacología , Antiinflamatorios/química , Animales , Sacarosa/química , Sacarosa/metabolismo , Peso MolecularRESUMEN
OBJECTIVE: To explore the clinical characteristics and genetic etiology of four children with Phelan-McDermid syndrome (PMS). METHODS: Four children who had visited the Ningbo Women and Children's Hospital between June 2, 2022 and May 8, 2023 were selected as the study subjects. Clinical data of the children were collected. Genomic DNA was extracted from peripheral blood samples of the children and their parents and subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing and quantitative PCR (q-PCR) analysis. RESULTS: All children had presented with speech and language delays and intellectual disability. Children 3 and 4 also presented with autistic behaviors. WES showed that the children 1 and 2 had respectively carried a heterozygous c.731T>C (p.Leu244Pro) and a c.2782_2851del (p.Gly928ArgfsTer4) variant of the SHANK3 gene. Sanger sequencing confirmed that their parents did not carry the same variant, suggesting that they were de novo in origin. Children 3 and 4 had respectively harbored a 121 Kb and 52.02 Kb heterozygous deletion at chromosome 22q13.33, which had both encompassed the SHANK3 and ACR genes mapped to 22q13.33. q-PCR results showed that the deletion of SHANK3 and ACR genes were de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.731T>C and c.2782_2851del variants were predicted to be likely pathogenic (PS2+PM2_Supporting+PP3) and pathogenic (PVS1+PM2_Supporting+PS2_Supporting), respectively. Furthermore, the 52.02 Kb and 121 Kb heterozygous deletions in 22q13.33 were both predicted to be pathogenic (2D+4C, 1.05 in score; 2D+4C, 1 in score). CONCLUSION: The four children were all diagnosed with PMS by genetic testing. Above finding has enriched the phenotypic and mutational spectrum of PMS, and provided a basis for clinical diagnosis and genetic counseling for their families.
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Deleción Cromosómica , Trastornos de los Cromosomas , Cromosomas Humanos Par 22 , Humanos , Cromosomas Humanos Par 22/genética , Femenino , Masculino , Preescolar , Niño , Trastornos de los Cromosomas/genética , Proteínas del Tejido Nervioso/genética , Secuenciación del Exoma , Pruebas Genéticas , Discapacidad Intelectual/genéticaRESUMEN
Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells. Herein, we constructed a PEGylated dendritic epirubicin (Epi) prodrug (Epi-P4D) to regulate the metabolism of cancer-associated fibroblasts (CAFs), thus enhancing Epi penetration into both multicellular tumor spheroids (MTSs) and tumor tissues in mouse colon cancer (CT26), mouse breast cancer (4T1) and human breast cancer (MDA-MB-231) models. Enhanced cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin, α-SMA, and collagen secretion. Besides, thinning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell (DC) maturation and subsequent immune activation, including elevating the CD4+ T cell population, reducing CD4+ and CD8+ T cell hyperactivation and exhaustion, and amplifying the natural killer (NK) cell proportion and effectively activating them. As a result, this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy.
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As a layered material with single/multi-atom thickness, two-dimensional transition metal sulfide WS2 has attracted extensive attention in the field of science for its excellent physical, chemical, optical, and electrical properties. The photoelectric properties of WS2 are even more promising than graphene. However, there are many existing preparation methods for WS2, but few reports on its direct growth on tungsten films. Therefore, this paper studies its preparation method and proposes an innovative two-dimensional material preparation method to grow large-sized WS2 with higher quality on metal film. In this experiment, it was found that the reaction temperature could regulate the growth direction of WS2. When the temperature was below 950 °C, the film showed horizontal growth, while when the temperature was above 1000 °C, the film showed vertical growth. At the same time, through Raman and band gap measurements, it is found that the different thicknesses of precursor film will lead to a difference in the number of layers of WS2. The number of layers of WS2 can be controlled by adjusting the thickness of the precursor.
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While Resolvin D1 (RvD1) shows promise in resolving inflammation in experimental autoimmune encephalomyelitis (EAE), its pro-resolving roles on dendritic cells (DCs) remain unknown, and the chemical instability of RvD1 poses significant challenges to its drug development. This study aims to investigate whether 4-(2'-methoxyphenyl)-1-[2'-[N-(2â³-pyridinyl)-p-fluorobenzamido]ethyl]piperazine (p-MPPF), a novel chemically stable analogue of RvD1, can play a pro-resolving role in EAE, particularly on DCs, and if p-MPPF could serve as a potential substitute for RvD1. We showed that both RvD1 and p-MPPF mediated the resolution of inflammation in EAE, as evidenced by ameliorated EAE progression, attenuated pathological changes in the spinal cord, altered cytokine expression profile in serum, and reduced proportion of pro-inflammatory immune cells in the spleen. Utilizing DCs derived from both the spleen and bone marrow of EAE, our investigation showed that RvD1 and p-MPPF prevented DC maturation, decreased pro-inflammatory cytokine secretion, shifted DCs away from a pro-inflammatory phenotype, increased the phagocytosis capacity of DCs, and suppressed their ability to induce differentiation of CD4+ T cells into Th1 and Th17 subsets. For underlying intracellular mechanisms, we found that RvD1 and p-MPPF down-regulated the lactate dehydrogenase A signaling pathways. Comparisons between RvD1 and p-MPPF showed that they exerted overlapped pro-resolving effects to a large extent. This study demonstrates that both RvD1 and p-MPPF exert therapeutic effects on EAE by mediating inflammation resolution, which is closely associated with modulating DC immune function towards a tolerogenic phenotype. SPM mimetics may serve as a more promising therapeutic drug.
Asunto(s)
Citocinas , Células Dendríticas , Ácidos Docosahexaenoicos , Encefalomielitis Autoinmune Experimental , Ratones Endogámicos C57BL , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Animales , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Ácidos Docosahexaenoicos/uso terapéutico , Ácidos Docosahexaenoicos/farmacología , Ácidos Docosahexaenoicos/química , Femenino , Ratones , Citocinas/metabolismo , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Médula Espinal/patología , Médula Espinal/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Piperazinas/farmacología , Piperazinas/uso terapéutico , Piperazinas/química , Células Cultivadas , Bazo/efectos de los fármacos , Bazo/inmunología , Células Th17/inmunología , Células Th17/efectos de los fármacosRESUMEN
Hinokiflavone (HF), classified as a flavonoid, is a main bioactive compound in Platycladus orientalis and Selaginella. HF exhibits activities including anti-HIV, anti-inflammatory, antiviral, antioxidant and anti-tumor effects. The study aimed to explore the function and the mechanisms of HF on acetaminophen (APAP)-induced acute liver injury. Results indicated that HF treatment mitigated the impact of APAP on viability and restored levels of MDA, GSH and SOD on HepG2 cells. The accumulation of reactive oxygen species (ROS) mitochondrial membrane potential (MMP) in HepG2 cells stimulated by APAP were also blocked by HF. HF reduced the levels of pro-apoptotic and pro-pyroptotic proteins. Flow cytometry analysis and fluorescence staining results were consistent with western blot analysis. Following HF treatment in the APAP-induced cell model, there was observed an augmentation in the phosphorylation of Stat3 and an increase in the expression of SIX4. However, not only silenced the SIX4 protein in HepG2 cells by siRNA, but also adding the Stat3 inhibitor (Stattic), attenuated the anti-apoptotic and anti-pyroptotic effects of HF significantly. Furthermore, HF alleviated liver damage in C57BL/6 mice model. Overall, our study demonstrated that HF mitigates apoptosis and pyroptosis induced by APAP in drug-induced liver injury (DILI) through the SIX4/Akt/Stat3 pathway in vivo and in vitro. HF may have promising potential for for the treatment of DILI.