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In the mammalian heart, cardiomyocytes are forced to withdraw from the cell cycle shortly after birth, limiting the ability of the heart to regenerate and repair. The development of multimodal regulation of cardiac proliferation has verified that pre-existing cardiomyocyte proliferation is an essential driver of cardiac renewal. With the continuous development of genetic lineage tracking technology, it has been revealed that cell cycle activity produces polyploid cardiomyocytes during the embryonic, juvenile, and adult stages of cardiogenesis, but newly formed mononucleated diploid cardiomyocytes also elevated sporadically during myocardial infarction. It implied that adult cardiomyocytes have a weak regenerative capacity under the condition of ischemia injury, which offers hope for the clinical treatment of myocardial infarction. However, the regeneration frequency and source of cardiomyocytes are still low, and the mechanism of regulating cardiomyocyte proliferation remains further explained. It is noteworthy to explore what force triggers endogenous cardiomyocyte proliferation and heart regeneration. Here, we focused on summarizing the recent research progress of emerging endogenous key modulators and crosstalk with other signaling pathways and furnished valuable insights into the internal mechanism of heart regeneration. In addition, myocardial transcription factors, non-coding RNAs, cyclins, and cell cycle-dependent kinases are involved in the multimodal regulation of pre-existing cardiomyocyte proliferation. Ultimately, awakening the myocardial proliferation endogenous modulator and regeneration pathways may be the final battlefield for the regenerative therapy of cardiovascular diseases.
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As a natural sweetener produced by honey bees, honey was recognized as being healthier for consumption than table sugar. Our previous study also indicated thatmetaboliteprofiles in mice fed honey and mixedsugardiets aredifferent. However, it is still noteworthy about the batch-to-batch consistency of the metabolic differences between two diet types. Here, the machine learning (ML) algorithms were applied to complement and calibrate HPLC-QTOF/MS-based untargeted metabolomics data. Data were generated from three batches of mice that had the same treatment, which can further mine the metabolite biomarkers. Random Forest and Extra-Trees models could better discriminate between honey and mixed sugar dietary patterns under five-fold cross-validation. Finally, SHapley Additive exPlanations tool identified phosphatidylethanolamine and phosphatidylcholine as reliable metabolic biomarkers to discriminate the honey diet from the mixed sugar diet. This study provides us new ideas for metabolomic analysis of larger data sets.
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Mel , Abelhas , Camundongos , Animais , Dieta , Sacarose na Dieta , Metabolômica , Aprendizado de Máquina , BiomarcadoresRESUMO
Brazilian propolis from Apis mellifera is widely studied worldwide due to its unique chemical composition and biological properties, such as antioxidant, antimicrobial, and anti-inflammatory. However, although many countries produce honey, another bee product, the consumption of propolis as a functional ingredient is linked to hydroethanolic extract. Hence, other food uses of propolis still have to be incorporated into food systems. Assuming that propolis is a rich source of flavonoids and is regarded as a food-grade ingredient for food and pharmaceutical applications, this review provides a theoretical and practical basis for optimising the bioactive properties of Brazilian propolis, encompassing the extraction processes and incorporating its bioactive compounds in the delivery systems for food applications. Overall, pharmacotechnical resources can optimise the extraction and enhance the chemical stability of phenolic compounds to ensure the bioactivity of food formulations.
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Ascomicetos , Ingredientes de Alimentos , Mel , Própole , Abelhas , Animais , Brasil , Antioxidantes/farmacologiaRESUMO
Knee osteoarthritis (KOA) is mainly characterized by degenerative changes in the knee joint's cartilage and surrounding soft tissues. The efficacy of Tuina in treating KOA has been confirmed, but the underlying mechanism needs to be investigated. This study aims to establish a scientifically feasible KOA rabbit model treated with Tuina to reveal the underlying mechanisms. For this, 18, 6-month-old normal-grade male New Zealand rabbits were randomly divided into sham, model, and Tuina groups, with 6 rabbits in each group. The KOA model was established by injecting 4% papain solution into the knee joint cavity. The Tuina group was intervened with Tuina combined with the knee joint rotary correction method for 4 weeks. Only the standard grasping and fixation were performed in sham and model groups. At the end of the 1-week intervention, the knee joint range of motion (ROM) was observed, and cartilage hematoxylin-eosin (HE) staining was done. The study shows that Tuina could inhibit chondrocyte apoptosis, repair cartilage tissue, and restore knee joint ROM. In conclusion, this study demonstrates the scientific feasibility of Tuina treatment for KOA model rabbits, highlighting its potential application in the study of KOA and similar knee joint-related conditions.
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Osteoartrite do Joelho , Masculino , Coelhos , Animais , Articulação do Joelho , Apoptose , Condrócitos , Amarelo de Eosina-(YS)RESUMO
Background: Lung cancer combined by chronic obstructive pulmonary disease (LC-COPD) is a common comorbidity and their interaction with each other poses significant clinical challenges. However, there is a lack of well-established consensus on the diagnosis and treatment of LC-COPD. Methods: A panel of experts, comprising specialists in oncology, respiratory medicine, radiology, interventional medicine, and thoracic surgery, was convened. The panel was presented with a comprehensive review of the current evidence pertaining to LC-COPD. After thorough discussions, the panel reached a consensus on 17 recommendations with over 70% agreement in voting to enhance the management of LC-COPD and optimize the care of these patients. Results: The 17 statements focused on pathogenic mechanisms (n=2), general strategies (n=4), and clinical application in COPD (n=2) and lung cancer (n=9) were developed and modified. These statements provide guidance on early screening and treatment selection of LC-COPD, the interplay of lung cancer and COPD on treatment, and considerations during treatment. This consensus also emphasizes patient-centered and personalized treatment in the management of LC-COPD. Conclusions: The consensus highlights the need for concurrent treatment for both lung cancer and COPD in LC-COPD patients, while being mindful of the mutual influence of the two conditions on treatment and monitoring for adverse reactions.
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This study explored the role of leucine-rich repeat neuronal 4 (LRRN4) in ovarian carcinogenesis using the p53- and Rb-defective human fallopian tube epithelial cell line FE25. We evaluated the expression of LRRN4 in FE25 cells with and without LRRN4 knockdown by short hairpin RNA (shRNA) and studied its effects on cell proliferation, cell cycle, migration, invasion, chemotherapeutic sensitivity, apoptosis, and xenograft formation. The results showed that FE25 shRNA-LRRN4 cells exhibited more aggressive malignant behaviors than FE25 cells, including faster proliferation and increased cell distribution in the G2/M phase, Akt pathway activation, cell migration, and cell invasion, as well as decreased sensitivity to chemotherapeutic drugs. FE25 shRNA-LRRN4 cells exhibited reduced levels of apoptosis and decreased expression of cleaved caspase 3, 7, 8, and 9, indicating reduced apoptotic activity. Additionally, FE25 shRNA-LRRN4 cells showed decreased LRRN4 and CK7 expression and increased WT1 expression, suggesting a potential role for LRRN4 in ovarian carcinogenesis. FE25 shRNA-LRRN4 generated a xenograft in mice with increased levels of WT1 and TP53 expression compared to their levels in cells. Overall, this study suggests that LRRN4 may play a role in ovarian carcinogenesis by promoting aggressive malignant behavior in FE25 cells through the activation of the Akt pathway. These findings provide insights into the potential molecular mechanisms underlying ovarian cancer and may have implications for the development of new therapeutic targets for this disease.
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One effective strategy for treating atherosclerosis is to inhibit the injury of vascular endothelial cells (VECs) induced by oxidized low-density lipoprotein (oxLDL) and high glucose (HG). This study synthesized and evaluated a series of novel Nrf2 activators derived from the marine natural product phidianidine for their ability to protect human umbilical VECs against oxLDL- and HG-induced injury. The results of in vitro bioassays demonstrated that compound D-36 was the most promising Nrf2 activator, effectively inhibiting the apoptosis of HUVECs induced by oxLDL and HG. Furthermore, Nrf2 knockdown experiments confirmed that compound D-36 protected against oxLDL- and HG-induced apoptosis in HUVECs by activating the Nrf2 pathway. These findings provide important insights into a new chemotype of marine-derived Nrf2 activators that could potentially be optimized to develop effective anti-atherosclerosis agents.
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BACKGROUND: We compared the perioperative efficacy and safety of da Vinci robot-assisted Ivor Lewis esophagectomy and McKeown esophagectomy for middle and lower thoracic esophageal cancer. METHODS: A retrospective case-control study method was used. A total of 181 patients with esophageal cancer admitted to three medical centers in China from February 2018 to October 2022 were collected and divided into two groups according to surgical method: da Vinci robot-assisted thoracic surgery (RATS) Ivor Lewis esophagectomy (Ivor Lewis group) and RATS McKeown esophagectomy (McKeown group), respectively. Propensity score matching (PSM) analysis was used to reduce selection bias caused by confounding factors. The perioperative indicators of the two groups were compared and analyzed. RESULTS: There was a statistically significant difference in age and tumor location between the Ivor Lewis group and the McKeown group. After PSM, the above factors were no longer statistically significant. There were 80 patients in each group after PSM. In terms of operative time (P = 0.005), anastomotic leakage (P = 0.029), and pulmonary infection (P = 0.035), the Ivor Lewis group has significant advantages; in terms of the number of lymph nodes dissected around the recurrent laryngeal nerve (P = 0.010), the McKeown group has significant advantages. CONCLUSION: Both RATS Ivor Lewis esophagectomy and McKeown esophagectomy are safe and effective for treatment of middle and lower thoracic esophageal cancer. Ivor Lewis has advantages in operative time, anastomotic leakage, and pulmonary infection, while McKeown has advantage in lymph node dissection around the recurrent laryngeal nerve.
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Hyperspectral imaging (HSI) has been applied to assess the texture profile analysis (TPA) of processed meat. However, whether the texture profiles of live fish muscle could be assessed using HSI has not been determined. In this study, we evaluated the texture profile of four muscle regions of live common carp by scanning the corresponding skin regions using HSI. We collected skin hyperspectral information from four regions of 387 scaled and live common carp. Eight texture indicators of the muscle corresponding to each skin region were measured. With the skin HSI of live common carp, six machine learning (ML) models were used to predict the muscle texture indicators. Backpropagation artificial neural network (BP-ANN), partial least-square regression (PLSR), and least-square support vector machine (LS-SVM) were identified as the optimal models for predicting the texture parameters of the dorsal (coefficients of determination for prediction (rp) ranged from 0.9191 to 0.9847, and the root-mean-square error for prediction ranged from 0.1070 to 0.3165), pectoral (rp ranged from 0.9033 to 0.9574, and RMSEP ranged from 0.2285 to 0.3930), abdominal (rp ranged from 0.9070 to 0.9776, and RMSEP ranged from 0.1649 to 0.3601), and gluteal (rp ranged from 0.8726 to 0.9768, and RMSEP ranged from 0.1804 to 0.3938) regions. The optimal ML models and skin HSI data were employed to generate visual prediction maps of TPA values in common carp muscles. These results demonstrated that skin HSI and the optimal models can be used to rapidly and accurately determine the texture qualities of different muscle regions in common carp.
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Psoriasis is a chronic autoimmune skin disease with a significant impact on quality of life and potential for severe comorbidities. Inflammation in the skin is induced by immune cells that overexpress pro-inflammatory cytokines, with the Th17 cell playing a crucial role. NLRP3 inflammasome activation is associated with inflammatory diseases and abnormal T cell differentiation. 3H-1,2-dithiole-3-thione (D3T), isolated from cruciferous vegetables, has anti-inflammatory effects and inhibits Th17 differentiation. This study aimed to investigate how D3T reduces skin inflammation and modulates Th17 cell differentiation by inhibiting NLRP3 inflammasome activation. In an imiquimod-induced psoriasis mouse model, D3T treatment demonstrated significant reductions in ear thickness, skin redness, and scaling compared to a control group. Our study also observed decreased expression of ki-67, NLRP3 inflammasome, and cleaved caspase-1 in skin samples, reduced levels of IL-6 and IL-17A in serum samples, and inhibition of Th17 differentiation after D3T application. D3T could also inhibit the expression of NLRP3, caspase-1, and IL-1ß in TNF-α stimulated HaCaT cells. The mechanical study also revealed that D3T could inhibit NLRP3 inflammasome activation by inhibiting the JNK pathway in HaCaT cells. These results indicate that targeting NLRP3 inflammasome activation is a promising strategy in the treatment of psoriasis.
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Inflamassomos , Psoríase , Animais , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Qualidade de Vida , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Caspase 1RESUMO
Neutrophil extracellular trap (NET) has been confirmed to be related to gut barrier injury during intestinal ischaemia-reperfusion (II/R). However, the specific molecular regulatory mechanism of NETs in II/R-induced intestinal barrier damage has yet to be fully elucidated. Here, we reported increased NETs infiltration accompanied by elevated inflammatory cytokines, cellular necroptosis and tight junction disruption in the intestine of human II/R patients. Meanwhile, NETs aggravated Caco-2 intestinal epithelial cell necroptosis, impairing the monolayer barrier in vitro. Moreover, Pad4-deficient mice were used further to validate the role of NETs in II/R-induced intestinal injury. In contrast, NET inhibition via Pad4 deficiency alleviated intestinal inflammation, attenuated cellular necroptosis, improved intestinal permeability, and enhanced tight junction protein expression. Notably, NETs prevented FUN14 domain-containing 1 (FUNDC1)-required mitophagy activation in intestinal epithelial cells, and stimulating mitophagy attenuated NET-associated mitochondrial dysfunction, cellular necroptosis, and intestinal damage. Mechanistically, silencing Toll-like receptor 4 (TLR4) or receptor-interacting protein kinase 3 (RIPK3) via shRNA relieved mitophagy limitation, restored mitochondrial function and reduced NET-induced necroptosis in Caco-2 cells, whereas this protective effect was reversed by TLR4 or RIPK3 overexpression. The regulation of TLR4/RIPK3/FUNDC1-required mitophagy by NETs can potentially induce intestinal epithelium necroptosis.
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Recent developments in the field of regenerative surgeries and medical applications have led to a renewed interest in adipose tissue-enriched mesenchymal stem cell scaffolds. Various advantages declared for the decellularized adipose matrix (DAM) have caused its extensive use in the transfer of stem cells or growth factors for soft tissue regeneration induction. Meanwhile, the long-term application of detergents toward DAM regeneration has been assumed as a risky obstacle in this era. Herein, a rapid, mechanical protocol was developed to prepare DAM (M-DAM) without chemicals/enzymes and was comprehensively compared with the ordinary DAM (traditional chemical method). Accordingly, this method could effectively hinder oils and cells, sustain the structural and biological elements, and contain a superior level of collagen content. In addition, more protein numbers, as well as higher basement membrane elements, glycoproteins, and extracellular matrix-related proteins were detected in the regenerated M-DAM. Also, superior adipogenesis and angiogenesis proteins were distinguished. The noncytotoxicity of the M-DAM was also approved, and a natural ecological niche was observed for the proliferation and differentiation of stem cells, confirming its great potential for vascularization and adipogenesis in vivo. The suggested technique could effectively prepare the modified DAM in variant constructions of tablets, powders, emulsions, hydrogels, and different three-dimensional-printed structures. Hence, this rapid, mechanical process can produce bioactive DAM, which has the potential to be widely used in various research fields of regenerative medicine.
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PURPOSE: Gastric metastasis of lung cancer is rare, and the cases of disappearance of gastric metastasis and liver metastasis caused by oxitinib treatment have not been reported. METHODS: A 47-year-old male patient with no history of diabetes, hypertension or smoking presented with chest discomfort after eating. At the time of consultation, the diagnosis of adenocarcinoma of the right lower lobe of the lung with liver and gastric metastasis was considered by pathological examination of biopsy of the fundus of the stomach near the cardia, pathological examination of CT-guided lung aspiration and pathological examination of liver occupancy aspiration, combined with immunohistochemical results. He was found to have exon 19 deletion in next generation sequencing. We performed osimertinib on him (EGFR-TKI) systemic therapy, followed by local radiation therapy to the right lower lung primary lesion. RESULTS: After systemic treatment with osimertinib and local radiotherapy of the primary site, the metastases disappeared and the primary site showed post-radiotherapy changes, and the evaluated efficacy was complete remission. CONCLUSIONS: This is the first report to our knowledge of a patient who presented with gastric and hepatic metastases from lung cancer and achieved complete remission with osimertinib and local radiotherapy, with good quality of life, which also provides a basis for future clinical work and is of great significance.
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Sensitisation to the lipid transfer protein Pru p 3 is associated with severe allergic reactions to peach, the proteins stability being thought to play a role in its allergenicity. Lipid binding increases susceptibility of Pru p 3 to digestion and so the impact of bile salts on the in vitro gastrointestinal digestibility of Pru p 3 was investigated and digestion products mapped by SDS-PAGE and mass spectrometry. Bile salts enhanced the digestibility of Pru p 3 resulting in an ensemble of around 100 peptides spanning the protein's sequence which were linked by disulphide bonds into structures of ~ 5-6 kDa. IgE binding studies with a serum panel from peach allergic subjects showed digestion reduced, but did not abolish, the IgE reactivity of Pru p 3. These data show the importance of including bile salts in vitro digestion systems and emphasise the need to profile of digestion in a manner that allows identification of immunologically relevant disulphide-linked peptide aggregates.
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Alérgenos , Prunus persica , Humanos , Proteólise , Ácidos e Sais Biliares , Dissulfetos , Imunoglobulina ERESUMO
The rearranged during transfection (RET) gene is one of the receptor tyrosine kinases and cell-surface molecules responsible for transmitting signals that regulate cell growth and differentiation. In non-small cell lung cancer (NSCLC), RET fusion is a rare driver gene alteration associated with a poor prognosis. Fortunately, two selective RET inhibitors (sRETi), namely pralsetinib and selpercatinib, have been approved for treating RET fusion NSCLC due to their remarkable efficacy and safety profiles. These inhibitors have shown the ability to overcome resistance to multikinase inhibitors (MKIs). Furthermore, ongoing clinical trials are investigating several second-generation sRETis that are specifically designed to target solvent front mutations, which pose a challenge for first-generation sRETis. The effective screening of patients is the first crucial step in the clinical application of RET-targeted therapy. Currently, four methods are widely used for detecting gene rearrangements: next-generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). Each of these methods has its advantages and limitations. To streamline the clinical workflow and improve diagnostic and treatment strategies for RET fusion NSCLC, our expert group has reached a consensus. Our objective is to maximize the clinical benefit for patients and promote standardized approaches to RET fusion screening and therapy.
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Background: H2.0-like homeobox (HLX) is highly expressed in several hematopoietic malignancies. However, the role of HLX in the carcinogenesis and progression of colorectal cancer (CRC) patients has rarely been reported. Methods: In this study, the data were collected from The Cancer Genome Atlas and Gene Expression Omnibus databases. The diagnostic value of HLX was analyzed by the R package "pROC." The overall survival was estimated using the "survival" and "survminer" packages. A nomogram was established to predict 1-, 3-, and 5-year overall survival of CRC patients. The CIBERSORT software was employed to calculate the relative proportions of 22 immune cells. Results: HLX expression was downregulated in CRC patients. Remarkably, HLX expression was increased with stage (stage I-stage III) of CRC, and the CRC patients with high HLX expression exhibited a poor prognosis. The promoter methylation level of HLX was prominently increased in CRC samples compared to paracancerous samples. We also found that the six miRNAs target HLX genes, leading to its downregulation, and HLX expression had a negative correlation with its downstream target gene BRI3BP in both CRC and normal samples. Finally, we found that the 12 immune infiltrating cells were observably different between high and low HLX expression groups. The HLX had a significant positive correlation with 8 immune checkpoints (PD-1 (PDCD1), CTLA4, PDL-1 (CD274), PDL-2 (PDCD1LG2), CD80, CD86, LAG3, and TIGIT) expressions. Conclusion: HLX probably played a carcinostasis role in the early stages of CRC but exhibited a cancer-promoting effect in the advanced stages. Meanwhile, HLX could serve as a reliable prognostic indicator for CRC.
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Neoplasias Colorretais , MicroRNAs , Humanos , Genes Homeobox , Prognóstico , MicroRNAs/genética , Carcinogênese , Neoplasias Colorretais/genéticaRESUMO
OBJECTIVE: To analyze the failure patterns in patients with different histological subtypes of sinonasal malignancies (SNMs). STUDY DESIGN: Retrospectively gathered data. SETTING: Academic university hospital. METHODS: Patients with SNMs treated at a tertiary referral center between January 1999 and January 2019 were included. We assessed the failure patterns within different histological subtypes. RESULTS: The study included 897 patients. The median follow-up time was 100 months. Adenoid cystic carcinoma (ACC) had a moderate risk of developing local recurrence (LR) and distant metastasis (DM). Compared with ACC, squamous cell carcinoma (SCC), adenocarcinoma (AC), soft tissue sarcoma (STS), and mucosal melanoma (MM) were classified as a high LR risk group. For DM, neuroendocrine carcinoma (NEC), STS, and MM were in the high-risk group. CONCLUSIONS: ACC had intermediate local and distant failure risks, while SCC, AC, STS, and MM were at high LR risks. NEC, STS, and MM were at high DM risk.
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Although dispersing Pt atomic clusters (ACs) on a conducting support is a promising way to minimize the Pt amount required in hydrogen evolution reaction (HER), the catalytic mass activity and durability of Pt ACs are often unsatisfactory for alkaline HER due to their unfavorable water dissociation and challenges in stabilizing them against agglomeration and detachment. Herein, we report a class of single-atom Cr-N4 sites with high oxophilicity interfaced with Pt ACs on mesoporous carbon for achieving a highly active and stable alkaline HER in an anion-exchange-membrane water electrolyzer (AEMWE). The as-made catalyst achieves the highest reported Pt mass activity (37.6 times higher than commercial Pt/C) and outstanding operational stability. Experimental and theoretical studies elucidate that the formation of a unique Pt-Cr quasi-covalent bonding interaction at the interface of Cr-N4 sites and Pt ACs effectively suppresses the migration and thermal vibration of Pt atoms to stabilize Pt ACs and contributes to the greatly enhanced catalytic stability. Moreover, oxophilic Cr-N4 sites adjacent to Pt ACs with favorable adsorption of hydroxyl species facilitate nearly barrierless water dissociation and thus enhance the HER activity. An AEMWE using this catalyst (with only 50 µgPt cm-2) can operate stably at an industrial-level current density of 500 mA cm-2 at 1.8 V for >100 h with a small degradation rate of 90 µV h-1.
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Flexible multifunctional composite films in which opposing surfaces have two or more distinct physical properties are highly applicable for wearable electronic devices, electrical power systems and biomedical engineering. However, fabrication of such "Janus" films can be time consuming, complex or economically not feasible. In this work, Janus polyimide (PI) films were prepared by femtosecond laser direct writing technology, which generated a honeycomb porous structure (HPS) on one side and a lawn-like structure (LLS) on the other. Deposition of silver nanowires (AGNWs) by drop coating on the LLS side (AGNWs@LLS) resulted in a film in which each face possessed highly distinct triple properties. The HPS side was superhydrophobic with a water contact angle (WCA) of â¼153.3° and electrically non-conductive, while the AGNWs@LLS side was superhydrophilic (WCA â¼7.8°) and highly conductive (â¼3.8 Ω). Moreover, the AGNWs@LLS face showed ultra-low thermal radiation performance, almost reaching saturation. On a heating table at â¼100 °C, the temperature of the AGNWs@LLS side remained at â¼44.5 °C, while the HPS side exhibited a temperature of â¼93.9 °C. This "triple Janus film" and lasing techniques developed might be useful for designing new materials for the integration and miniaturization of multifunctional electronic equipment.
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Frailty and depression were linked in observational studies, but the causality remains ambiguous. We intended to explore it using Mendelian randomization (MR). We obtained frailty genome-wide association study (GWAS) data from UK Biobank and TwinGen meta-analysis, and depression GWAS data from Psychiatric Genomics Consortium (PGC) and FinnGen (respectively recorded as PD and FD). We performed univariable and multivariable-adjusted MR with adjustments for body mass index (BMI) and physical activity (PA). Frailty was significantly associated with elevated risks of PD (OR, 1.860; 95% CI, 1.439 to 2.405; P < 0.001) and FD (OR, 1.745; 95% CI, 1.193 to 2.552; P = 0.004), and depression was meanwhile a susceptible factor for frailty (PD: ß, 0.146; 95% CI, 0.086 to 0.201; P < 0.001; and FD: ß, 0.112; 95% CI, 0.051 to 0.174; P < 0.001). This association was robust after adjustments for BMI or PA. Our study provides evidence of the bidirectional causal association between frailty and depression from genetic perspectives.