Droplet Energy Harvesting System Based on Total-Current Nanogenerator.

The droplet-based nanogenerator (DNG) is a highly promising technology for harvesting high-entropy water energy in the era of the Internet of Things. Yet, despite the exciting progress made in recent years, challenges have emerged unexpectedly for the AC-type DNG-based energy system as it transitions from laboratory demonstrations to real-world applications. In this work, we propose a high-performance DNG system based on the total-current nanogenerator concept to address these challenges. This system utilizes the water-charge-shuttle architecture for easy scale-up, employs the field effect to boost charge density of the triboelectric layer, adopts an on-solar-panel design to improve compatibility with solar energy, and is equipped with a novel DC-DC buck converter as power management circuit. These features allow the proposed system to overcome the existing bottlenecks of DNG and empower the system with superior performances compared with previous ones. Notably, with the core architecture measuring only 15 cm × 12.5 cm × 0.3 cm in physical dimensions, this system reaches a record-high open-circuit voltage of 4200 V, capable of illuminating 1440 LEDs, and can charge a 4.7 mF capacitor to 4.5 V in less than 24 min. In addition, the practical potential of the proposed DNG system is further demonstrated through a self-powered, smart greenhouse application scenario. These demonstrations include the continuous operation of a thermohygrometer, the operation of a Bluetooth plant monitor, and the all-weather energy harvesting capability. This work will provide valuable inspiration and guidance for the systematic design of next-generation DNG to unlock the sustainable potential of distributed water energy for real-world applications.

Seroprevalence of the novel swine acute diarrhea syndrome coronavirus in China assessed by enzyme-linked immunosorbent assay.

The endemic outbreak of SADS-CoV has resulted in economic losses and potentially threatened the safety of China's pig industry. The molecular epidemiology of SADS-CoV in pig herds has been investigated in many provinces in China. However, there are no data over a long-time span, and there is a lack of extensive serological surveys to assess the prevalence of SADS-CoV in Chinese swine herds since the discovery of SADS-CoV. In this study, an indirect anti-SADS-CoV IgG enzyme-linked immunosorbent assay (ELISA) based on the SADS-CoV S1 protein was established to investigate the seroprevalence of SADS-CoV in Chinese swine herds. Cross-reactivity assays, indirect immunofluorescence, and western blotting assays showed that the developed ELISA had excellent SADS-CoV specificity. In total, 12,978 pig serum samples from 29 provinces/municipalities/autonomous regions in China were tested from 2022 to 2023. The results showed that the general seroprevalence of SADS-CoV in China was 59.97%, with seroprevalence ranging from 16.7% to 77.12% in different provinces and from 42.61% to 68.45% in different months. SADS-CoV is widely prevalent in China, and its seroprevalence was higher in Northeast China, North China, and Central China than in other regions. Among the four seasons, the prevalence of SADS-CoV was the highest in spring and the lowest in autumn. The results of this study provide the general seroprevalence profile of SADS-CoV in China, facilitating the understanding of the prevalence of SADS-CoV in pigs. More importantly, this study is beneficial in formulating preventive and control measures for SADS-CoV and may provide directions for vaccine development.

Genome-wide association study and genomic prediction for resistance to brown planthopper in rice.

The brown planthopper (BPH) is the most destructive insect pest that threatens rice production globally. Developing rice varieties incorporating BPH-resistant genes has proven to be an effective control measure against BPH. In this study, we assessed the resistance of a core collection consisting of 502 rice germplasms by evaluating resistance scores, weight gain rates and honeydew excretions. A total of 117 rice varieties (23.31%) exhibited resistance to BPH. Genome-wide association studies (GWAS) were performed on both the entire panel of 502 rice varieties and its subspecies, and 6 loci were significantly associated with resistance scores (P value < 1.0e-8). Within these loci, we identified eight candidate genes encoding receptor-like protein kinase (RLK), nucleotide-binding and leucine-rich repeat (NB-LRR), or LRR proteins. Two loci had not been detected in previous study and were entirely novel. Furthermore, we evaluated the predictive ability of genomic selection for resistance to BPH. The results revealed that the highest prediction accuracy for BPH resistance reached 0.633. As expected, the prediction accuracy increased progressively with an increasing number of SNPs, and a total of 6.7K SNPs displayed comparable accuracy to 268K SNPs. Among various statistical models tested, the random forest model exhibited superior predictive accuracy. Moreover, increasing the size of training population improved prediction accuracy; however, there was no significant difference in prediction accuracy between a training population size of 737 and 1179. Additionally, when there existed close genetic relatedness between the training and validation populations, higher prediction accuracies were observed compared to scenarios when they were genetically distant. These findings provide valuable resistance candidate genes and germplasm resources and are crucial for the application of genomic selection for breeding durable BPH-resistant rice varieties.

Effects of electroacupuncture on chronic urinary retention after pelvic or lumbosacral tumor resection surgeries: a retrospective cohort study.

Background: Chronic urinary retention (CUR) resulting from lower motor neuron lesions (LMNL) is a medical condition secondary to pelvic or lumbosacral tumor resection surgeries. Electroacupuncture (EA) is proved to be effective and safe in treating certain lower urinary tract disorders. However, the clinical benefit and optimal duration of EA treatment for CUR following LMNL remain unknown. Methods: Using a retrospective cohort design, 20 eligible patients diagnosed with CUR resulting from LMNL secondary to pelvic or lumbosacral tumor resection surgeries were included from March 1, 2017, to June 30, 2020. The patients were treated by EA three times a week for 2 to 12 weeks and followed up for 24 weeks after treatment. The electric stimulators with a 5-Hz continuous wave (5-10 mA intensity) were separately connected to bilateral Ciliao (BL32), bilateral Zhongliao (BL33), and bilateral Huiyang (BL35), and stimulators with a 10-Hz continuous wave (1-2 mA intensity) were connected to bilateral Sanyinjiao (SP6). Current intensity was adjusted according to the patients' individual tolerance. The median follow-up was 32 weeks (range, 26-36 weeks). Responders were defined as patients whose post-void residuals (PVR) reduced by 50% or more from baseline. Adverse event was recorded. Results: Totally 20 patients [mean (standard deviation) age, 48.1 (15.5) years; 9 men (45.0%); 11 women (55.0%)] were included. Of the 20 patients, 14 (70.0%) had responded to EA treatment and stopped catheterization for achieving satisfactory spontaneous urination (PVR <100 mL without complications), 7 (35.0%) had complete resolution (90-100% reduction in PVR from baseline), and 13 (65.0%) scored 1 (much better) or 2 (moderately better) in the Patient Global Impression of Improvement (PGI-I) assessment. Moreover, 6 (30.0%) patients had responded within 4 weeks of EA treatment. According to Kaplan-Meier survival curve, we found that more than 50% patients could respond to EA treatment within 8 weeks or longer. None of the responders had ever experienced relapse in 24 weeks after EA treatment ended. None of the patients manifested urinary tract infection (UTI), newly diagnosed hydroureter or hydronephrosis. One patient diagnosed with hydronephrosis at baseline recovered after 12-week EA treatment. Two patients with UTI at baseline were prescribed antibiotics and did not present UTI again during the follow-up. Conclusions: EA could be a promising treatment option for CUR caused by LMNL following pelvic or lumbosacral tumor resection surgeries, with long-term effects and a good safety profile. The optimal duration of EA should be of 8 weeks at least. But this was a retrospective cohort study of a small sample size, so future studies are needed to investigate EA in larger populations in randomized controlled trials.

Discovery of a novel SHP2 allosteric inhibitor using virtual screening, FMO calculation, and molecular dynamic simulation.

CONTEXT: SHP2 is a non-receptor protein tyrosine phosphatase to remove tyrosine phosphorylation. Functionally, SHP2 is an essential bridge to connect numerous oncogenic cell-signaling cascades including RAS-ERK, PI3K-AKT, JAK-STAT, and PD-1/PD-L1 pathways. This study aims to discover novel and potent SHP2 inhibitors using a hierarchical structure-based virtual screening strategy that combines molecular docking and the fragment molecular orbital method (FMO) for calculating binding affinity (referred to as the Dock-FMO protocol). For the SHP2 target, the FMO method prediction has a high correlation between the binding affinity of the protein-ligand interaction and experimental values (R2 = 0.55), demonstrating a significant advantage over the MM/PBSA (R2 = 0.02) and MM/GBSA (R2 = 0.15) methods. Therefore, we employed Dock-FMO virtual screening of ChemDiv database of ∼2,990,000 compounds to identify a novel SHP2 allosteric inhibitor bearing hydroxyimino acetamide scaffold. Experimental validation demonstrated that the new compound (E)-2-(hydroxyimino)-2-phenyl-N-(piperidin-4-ylmethyl)acetamide (7188-0011) effectively inhibited SHP2 in a dose-dependent manner. Molecular dynamics (MD) simulation analysis revealed the binding stability of compound 7188-0011 and the SHP2 protein, along with the key interacting residues in the allosteric binding site. Overall, our work has identified a novel and promising allosteric inhibitor that targets SHP2, providing a new starting point for further optimization to develop more potent inhibitors. METHODS: All the molecular docking studies were employed to identify potential leads with Maestro v10.1. The protein-ligand binding affinities of potential leads were further predicted by FMO calculations at MP2/6-31G* level using GAMESS v2020 system. MD simulations were carried out with AmberTools18 by applying the FF14SB force field. MD trajectories were analyzed using VMD v1.9.3. MM/GB(PB)SA binding free energy analysis was carried out with the mmpbsa.py tool of AmberTools18. The docking and MD simulation results were visualized through PyMOL v2.5.0.

Injectable platelet-rich fibrin promotes proliferation and trichogenic inductivity of dermal papilla cells through activating TGF-ß/Smad signaling pathway.

Dermal papilla cell (DPC) belongs to a specialized mesenchymal stem cell for hair follicle regeneration. Maintaining the ability of DPCs to stimulate hair in vitro culture is important for hair follicle morphogenesis and regeneration. As the third generation of platelet concentrate, injectable platelet-rich fibrin (i-PRF) is a novel biomaterial containing many growth factors and showing promising effects on tissue reconstruction. We aimed to explore the influences of i-PRF on the proliferative, migratory, as well as trichogenic ability of DPCs and compared the effects of i-PRF and platelet-rich plasma (PRP), the first generation of platelet concentrate. Both PRP and i-PRF facilitated DPCs proliferation, and migration, along with trichogenic inductivity as well as stimulated the TGF-ß/Smad pathway, while the impacts of i-PRF were more significant than PRP. A small molecule inhibitor of TGF-beta receptor I, Galunisertib, was also applied to treat DPCs, and it rescued the impacts of i-PRF on the proliferative, migratory, trichogenic inductivity, and proteins-associated with TGF-ß/Smad pathway in DPCs. These findings revealed that i-PRF had better effects than PRP in enhancing the proliferative, migratory, and hair-inducing abilities of DPCs by the TGF-ß/Smad pathway, which indicated the beneficial role of i-PRF in hair follicle regeneration.

Intellectual landscapes and emerging trends of non-steroidal mineralocorticoid receptor antagonists: a bibliometric and visual analysis.

PURPOSE: With increasing studies, non-steroidal mineralocorticoid receptor (MR) antagonists have been increasingly recognized as a major novel dimension in cardiorenal disease therapy. This bibliometric analysis aimed to uncover current research status and identify future research directions in the study of non-steroidal MR antagonists to inform subsequent investigations. METHODS: Relevant English-language literature was retrieved from the Science Citation Index Expanded of the Web of Science Core Collection on January 10, 2024. Analyses of countries, institutions, authors, journals, documents, cited references and keywords were performed by the CiteSpace and VOSviewer software. RESULTS: Overall, 498 documents, including 297 articles and 201 reviews, were included and analyzed. The United States (n = 188), Bayer AG (n = 78), and Professor Peter Kolkhof (n = 59) were the most prolific country, institution, and author in this field, respectively. Cluster analysis of cited references identified major clusters like cardiovascular disease, chronic kidney disease, and omecamtiv mecarbil. Keyword analysis indicated that sodium-glucose transport protein (SGLT)-2 inhibitors, pharmacotherapy, clinical trial, and guideline have emerged recently. CONCLUSION: The field of non-steroidal MR antagonists is gradually gaining momentum as a novel pharmacotherapy in cardiorenal diseases, especially diabetic kidney disease, hypertension, and heart failure. Future studies will focus on add-on pharmacotherapy by combining non-steroidal MR antagonists with SGLT-2 inhibitors and the development and publication of clinical guidelines to facilitate patient management.

Factors related to acupuncture response in patients with chronic prostatitis/chronic pelvic pain syndrome: secondary analysis of a randomized controlled trial.

PURPOSE: Acupuncture has been recommended as an effective therapy to improve symptoms of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). We conducted this secondary analysis to explore the factors that may influence the response of patients with CP/CPPS to acupuncture. METHODS: This secondary analysis was based on a randomized controlled trial demonstrating the efficacy of acupuncture among patients with CP/CPPS. Responder is defined as a patient with a decrease of ≥ 6 points in National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) total score from baseline at the 32 week. 206 patients who received acupuncture treatment and completed 32-week follow-up were included in this secondary analysis. Descriptive statistics were used to describe the demographic and clinical characteristics of both responders and non-responders in acupuncture group. Logistic regression analysis with bootstrapping was made to identify potential factors that contributed to the effectiveness of acupuncture for treating CP/CPPS. Responders and non-responders were listed as dependent variables. RESULTS: In this study, 130 (63.11%) patients were assessed as responders. The results showed that men with non-sedentariness (OR 4.170 [95%CI 1.837 to 9.463; P = 0.001]), non-smoking habit (OR 2.824 [95%CI 1.453 to 5.487; P = 0.002]), without comorbidity (OR 8.788 [95%CI 1.912 to 40.295; P = 0.005]), and severe NIH-CPSI total score (OR 0.227 [95%CI 0.114 to 0.450; P < 0.0001]) benefited more from acupuncture intervention. CONCLUSION: CP/CPPS patients who are active, non-smokers, without comorbidity, and had severe symptoms may be more likely to respond to acupuncture.

Nonlinear error analysis of fast optical delay lines.

Optical delay lines have wide applications in terahertz time-domain spectroscopy and optical coherence tomography. In this study, a fast-rotating optical delay line (FRODL) with 24 turntable reflection surfaces was designed. By analyzing the working principle of the FRODL, a mathematical model was established for the nonlinear parameter error of the FRODL delay time. By constructing the polarization Michelson interference system and testing the FRODL structure, the error of actual assembly parameters of the FRODL was approximately 0.015 mm, the actual delay time of the FRODL was greater than 43.5 ps, and the linearity was 99.785%.

Traditional Chinese Medicine formula Dai-Zong-Fang alleviating hepatic steatosis in db/db mice via gut microbiota modulation.

Introduction: Hepatic steatosis is a hepatic pathological change closely associated with metabolic disorders, commonly observed in various metabolic diseases such as metabolic syndrome (MetS), with a high global prevalence. Dai-Zong-Fang (DZF), a traditional Chinese herbal formula, is widely used in clinical treatment for MetS, exhibiting multifaceted effects in reducing obesity and regulating blood glucose and lipids. This study aims to explore the mechanism by which DZF modulates the gut microbiota and reduces hepatic steatosis based on the gut-liver axis. Methods: This study utilized db/db mice as a disease model for drug intervention. Body weight and fasting blood glucose were monitored. Serum lipid and transaminase levels were measured. Insulin tolerance test was conducted to assess insulin sensitivity. Hematoxylin and eosin (HE) staining was employed to observe morphological changes in the liver and intestine. The degree of hepatic steatosis was evaluated through Oil Red O staining and hepatic lipid determination. Changes in gut microbiota were assessed using 16S rRNA gene sequencing. Serum lipopolysaccharide (LPS) levels were measured by ELISA. The expression levels of intestinal tight junction proteins, intestinal lipid absorption-related proteins, and key proteins in hepatic lipid metabolism were examined through Western blot and RT-qPCR. Results: After DZF intervention, there was a decrease in body weight, alleviation of glucose and lipid metabolism disorders, reduction in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and mitigation of insulin resistance in mice. DZF significantly modulated the diversity of the gut microbiota, with a notable increase in the abundance of the Bacteroidetes phylum. PICRUSt indicated that DZF influenced various functions in gut microbiota, including carbohydrate and amino acid metabolism. Following DZF intervention, serum LPS levels decreased, intestinal pathological damage was reduced, and the expression of intestinal tight junction protein occludin was increased, while the expression of intestinal lipid absorption-related proteins cluster of differentiation 36 (CD36) and apolipoprotein B48 (ApoB48) were decreased. In the liver, DZF intervention resulted in a reduction in hepatic steatosis and lipid droplets, accompanied by a decrease fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1) and fatty acid transport protein 2 (FATP2). Conversely, there was an increase in the expression of the fatty acid oxidation-related enzyme carnitine palmitoyltransferase-1𝛂 (CPT-1𝛂). Conclusion: DZF can regulate the structure and function of the intestinal microbiota in db/db mice. This ameliorates intestinal barrier damage and the detrimental effects of endotoxemia on hepatic metabolism. DZF not only inhibits intestinal lipid absorption but also improves hepatic lipid metabolism from various aspects, including de novo lipogenesis, fatty acid uptake, and fatty acid oxidation. This suggests that DZF may act on the liver and intestine as target organs, exerting its effects by improving the intestinal microbiota and related barrier and lipid absorption functions, ultimately ameliorating hepatic steatosis and enhancing overall glucose and lipid metabolism.

A three-dimensional (3D) liver-kidney on a chip with a biomimicking circulating system for drug safety evaluation.

The liver and kidney are the major detoxifying organs in the human body and play an important role in pharmacokinetics. Drug-induced hepatotoxicity and nephrotoxicity can cause irreversible damage to the liver and kidney and are a major cause of drug failure in later stages. Both animal models and conventional cell culture have a number of limitations, such as animal ethics and gene mismatching and there is an urgent need to develop a new drug toxicity evaluation approach. In this paper, a 3D liver-kidney on a chip with a biomimicking circulating system (LKOCBCS) was constructed to obtain kidney and liver models in vitro for drug safety evaluation. LKOCBCS, which has a parallel circulating system mimicking biological circulation, consists of 3D biomimetic tissue of liver lobules similar to that of the human liver constructed by 3D bioprinting and renal proximal tubule barriers fabricated by ultrafast laser assisted etching. The proposed LKOCBCS facilitates the communication between the liver and the kidney, including the exchange of nutrients, compounds, and metabolites. The results revealed that the glucose concentration and cell metabolism stabilized after 7 days. A dynamically repeated low-dose administration of cyclosporine A (CsA) was fed to the system, and hepatotoxicity and nephrotoxicity were observed on day 3 according to the changes in toxicity markers. The high levels of drug induced biomarkers expressed in LKOCBCS indicate that this system is more sensitive than the monoculture liver chip and it is highly potential in replacing animal models for effective drug toxicity screening.

Endosymbiotic Fungal Diversity and Dynamics of the Brown Planthopper across Developmental Stages, Tissues, and Sexes Revealed Using Circular Consensus Sequencing.

Endosymbiotic fungi play an important role in the growth and development of insects. Understanding the endosymbiont communities hosted by the brown planthopper (BPH; Nilaparvata lugens Stål), the most destructive pest in rice, is a prerequisite for controlling BPH rice infestations. However, the endosymbiont diversity and dynamics of the BPH remain poorly studied. Here, we used circular consensus sequencing (CCS) to obtain 87,131 OTUs (operational taxonomic units), which annotated 730 species of endosymbiotic fungi in the various developmental stages and tissues. We found that three yeast-like symbionts (YLSs), Polycephalomyces prolificus, Ophiocordyceps heteropoda, and Hirsutella proturicola, were dominant in almost all samples, which was especially pronounced in instar nymphs 4-5, female adults, and the fat bodies of female and male adult BPH. Interestingly, honeydew as the only in vitro sample had a unique community structure. Various diversity indices might indicate the different activity of endosymbionts in these stages and tissues. The biomarkers analyzed using LEfSe suggested some special functions of samples at different developmental stages of growth and the active functions of specific tissues in different sexes. Finally, we found that the incidence of occurrence of three species of Malassezia and Fusarium sp. was higher in males than in females in all comparison groups. In summary, our study provides a comprehensive survey of symbiotic fungi in the BPH, which complements the previous research on YLSs. These results offer new theoretical insights and practical implications for novel pest management strategies to understand the BPH-microbe symbiosis and devise effective pest control strategies.

Family resilience, patient-reported symptoms in young stroke dyads: The effect of caregiver readiness and social support.

AIMS AND OBJECTIVES: To investigate empirically the direct effect and potential mechanism of family resilience on patient-reported outcomes among young stroke dyads in China. BACKGROUND: Young patients with stroke have been becoming an important public health issue. According to relevant theories and previous studies, we found that family resilience might play an important role in patient's symptoms. However, it is less clear about the specific relationship and potential mechanisms of these two variables. DESIGN: We used a prospective cross-sectional design. METHODS: A multi-item questionnaire was used to assess the constructs of interest. Researchers progressively constructed and validated conditional process models. The PROCESS macro was used to verify the research hypotheses. RESULTS: A total of 560 questionnaires were collected in this study. We found that family resilience of stroke patients and their spouses had a direct effect on the physical, psychological and social aspects of patient-reported symptoms. We further revealed that caregiver preparedness partially mediated the relationship between family resilience and patient's symptoms in stroke patient-spouse dyads, while perceived social support moderated the relationship between caregiver preparedness and patient's symptoms. Finally, we observed that the impact of caregiver readiness and social support on patients' symptoms predominantly manifested in physical and physiological outcomes. CONCLUSIONS: Our research provides evidence about the positive impact of family resilience on patient-reported symptoms in young stroke dyads. Meanwhile, it further revealed how caregiver preparedness and perceived social support may play out in the relationship. PRACTICE IMPLICATIONS: Our research introduces a novel perspective and pathway to enhance short-term recovery outcomes for patients. It also furnishes clinicians and nurses with evidence to guide the implementation of interventions aimed at improving patient health outcomes and facilitating smoother transitions from the hospital to home. IMPACT: What problem did the study address? Families play a crucial role in a patient's recovery process from illness, with family resilience serving as an important force for families to overcome adversity. However, the impact on patient symptoms and the underlying mechanisms of this relationship are uncertain. Empirical research is required to validate these aspects. What were the main findings? Family resilience has a positive impact on the physical, psychological and social aspects of patient-reported symptoms in young stroke dyads. Both the actor effect and partner effect are supported. The impact of caregiver readiness and social support on patient-reported symptoms is primarily observed in physical and physiological outcomes. Where and on whom will the research have an impact? This study offers a novel approach to enhance the short-term recovery of stroke patients. The researchers believe that the findings of this study will play an even more significant role during patients' transition from the hospital to home. REPORTING METHOD: This study followed the STROBE statement of cross-sectional studies. PATIENT OR PUBLIC CONTRIBUTION: The study was conducted by patients, their spouses, healthcare professionals and the research team.

Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study.

BACKGROUND: Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma. METHODS: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881. FINDINGS: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). Most treatment-related adverse events were grade 1-2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups. INTERPRETATION: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting. FUNDING: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

An ethanolic extract of Arctium lappa L. leaves ameliorates experimental atherosclerosis by modulating lipid metabolism and inflammatory responses through PI3K/Akt and NF-κB singnaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Atherosclerosis (AS), a lipid-induced inflammatory condition of the arteries, is a primary contributor to atherosclerotic cardiovascular diseases including stroke. Arctium lappa L. leaf (ALL), an edible and medicinal herb in China, has been documented and commonly used for treating stroke since the ancient times. However, the elucidations on its anti-AS effects and molecular mechanism remain insufficient. AIM OF THE STUDY: To investigate the AS-ameliorating effects and the underlying mechanism of action of an ethanolic extract of leaves of Arctium lappa L. (ALLE). MATERIALS AND METHODS: ALLE was reflux extracted using with 70% ethanol. An HPLC method was established to monitor the quality of ALLE. High fat diet (HFD) and vitamin D3-induced experimental AS in rats were used to determine the in vivo effects; and oxidized low-density lipoprotein-induced RAW264.7 macrophage foam cells were used for in vitro assays. Simvatatin was used as positive control. Biochemical assays were implemented to ascertain the secretions of lipids and pro-inflammatory mediators. Haematoxylin-eosin (H&E) and Oil red O stains were employed to assess histopathological alterations and lipid accumulation conditions, respectively. CCK-8 assays were used to measure cytotoxicity. Immunoblotting assay was conducted to measure protein levels. RESULTS: ALLE treatment significantly ameliorated lipid deposition and histological abnormalities of aortas and livers in AS rats; improved the imbalances of serum lipids including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C); notably attenuated serum concentrations of inflammation-associated cytokines/molecules including TNF-α, IL-6, IL-1ß, VCAM-1, ICAM-1and MMP-9. Mechanistic studies demonstrated that ALLE suppressed the phosphorylation/activation of PI3K, Akt and NF-κB in AS rat aortas and in cultured foam cells. Additionally, the PI3K agonist 740Y-P notably reversed the in vitro inhibitory effects of ALLE on lipid deposition, productions of TC, TNF-α and IL-6, and protein levels of molecules of PI3K/Akt and NF-κB singnaling pathways. CONCLUSIONS: ALLE ameliorates HFD- and vitamin D3-induced experimental AS by modulating lipid metabolism and inflammatory responses, and underlying mechanisms involves inhibition of the PI3K/Akt and NF-κB singnaling pathways. The findings of this study provide scientific justifications for the traditional application of ALL in managing atherosclerotic diseases.

Binding Free Energy Calculation Based on the Fragment Molecular Orbital Method and Its Application in Designing Novel SHP-2 Allosteric Inhibitors.

The accurate prediction of binding free energy is a major challenge in structure-based drug design. Quantum mechanics (QM)-based approaches show promising potential in predicting ligand-protein binding affinity by accurately describing the behavior and structure of electrons. However, traditional QM calculations face computational limitations, hindering their practical application in drug design. Nevertheless, the fragment molecular orbital (FMO) method has gained widespread application in drug design due to its ability to reduce computational costs and achieve efficient ab initio QM calculations. Although the FMO method has demonstrated its reliability in calculating the gas phase potential energy, the binding of proteins and ligands also involves other contributing energy terms, such as solvent effects, the 'deformation energy' of a ligand's bioactive conformations, and entropy. Particularly in cases involving ionized fragments, the calculation of solvation free energy becomes particularly crucial. We conducted an evaluation of some previously reported implicit solvent methods on the same data set to assess their potential for improving the performance of the FMO method. Herein, we develop a new QM-based binding free energy calculation method called FMOScore, which enhances the performance of the FMO method. The FMOScore method incorporates linear fitting of various terms, including gas-phase potential energy, deformation energy, and solvation free energy. Compared to other widely used traditional prediction methods such as FEP+, MM/PBSA, MM/GBSA, and Autodock vina, FMOScore showed good performance in prediction accuracies. By constructing a retrospective case study, it was observed that incorporating calculations for solvation free energy and deformation energy can further enhance the precision of FMO predictions for binding affinity. Furthermore, using FMOScore-guided lead optimization against Src homology-2-containing protein tyrosine phosphatase 2 (SHP-2), we discovered a novel and potent allosteric SHP-2 inhibitor (compound 8).

Lactate score classification of hepatocellular carcinoma helps identify patients with tumors that respond to immune checkpoint blockade therapy.

PURPOSE: Hepatocellular carcinoma (HCC) responds poorly to immunotherapy, and the durable response rate is 10-20%. Here, we aim to characterize HCC classifications based on lactate genes to identify patients who may benefit from immunotherapy. METHODS: Lactate-related genes were applied for HCC classification in the current study, and lactate Cluster 1 (LC1) and lactate Cluster 2 (LC2) were defined. Differential genes from LC1 and LC2 helped define the following lactate phenotype clusters: lactate phenotype Cluster 1 (LPC1), lactate phenotype Cluster 2 (LPC2) and lactate phenotype Cluster 3 (LPC3). Based on the cluster annotation, the lactate score was defined and analyzed to evaluate the immunotherapy response. RESULTS: All the classified clusters were analyzed, and they showed different immune signatures. The survival rate of LPC3 was higher than that of LPC2 (LPC3 vs. LPC2, P = 0.027) and LPC1 (LPC3 vs. LPC1, P = 0.027). Then, the lactate score was annotated and confirmed to be effective in predicting responses to immune checkpoint blockade therapy. CONCLUSION: In the current study, we developed a classification system for HCC and defined the lactate score, which was validated to be partially effective in estimating responses among tumor patients.

Upregulation of PTPN1 aggravates endotoxemia-induced cardiac dysfunction through inhibiting mitophagy.

OBJECTIVES: To investigate the role of protein tyrosine phosphatase non-receptor type 1 (PTPN1) in mitophagy during sepsis and its underlying mechanisms and determine the therapeutic potential of PTPN1 inhibitors in endotoxemia-induced cardiac dysfunction. METHODS: A mouse model of endotoxemia was established by administering an intraperitoneal injection of lipopolysaccharide (LPS). The therapeutic effect of targeting PTPN1 was evaluated using its inhibitor Claramine (CLA). Mitochondrial structure and function as well as the expression of mitophagy-related proteins were evaluated. Rat H9c2 cardiomyocytes were exposed to mouse RAW264.7 macrophage-derived conditioned medium. Cryptotanshinone, a specific p-STAT3 (Y705) inhibitor, was used to confirm the role of STAT3 in PTPN1-mediated mitophagy following LPS exposure. Electrophoretic mobility shift and dual luciferase reporter assays were performed to discern the mechanisms by which STAT3 regulated the expression of PINK1 and PRKN. RESULTS: CLA alleviated LPS-induced myocardial damage, cardiac dysfunction, and mitochondrial injury and dysfunction in the mouse heart. PTPN1 upregulation exacerbated LPS-induced mitochondrial injury and dysfunction in H9c2 cardiomyocytes, but inhibited LPS-induced mitophagy. LPS promoted the interaction between PTPN1 and STAT3 and reduced STAT3 phosphorylation at Tyr705 (Y705), which was required to inhibit mitophagy by PTPN1. Upon LPS stimulation, PTPN1 negatively regulated the transcription of PINK1 and PRKN through dephosphorylation of STAT3 at Y705. STAT3 regulated the transcription of PINK1 and PRKN by binding to STAT3-responsive elements in their promoters. CONCLUSION: PTPN1 upregulation aggravates endotoxemia-induced cardiac dysfunction by impeding mitophagy through dephosphorylation of STAT3 at Y705 and negative regulation of PINK1 and PRKN transcription.

Risk factors and prediction models for bronchiolitis obliterans after severe adenoviral pneumonia.

Severe adenoviral pneumonia (SAP) can cause post-infectious bronchiolitis obliterans (PIBO) in children. We aimed to investigate the relevant risk factors for PIBO and develop a predictive nomogram for PIBO in children with SAP. This prospective study analysed the clinical data of hospitalised children with SAP and categorised them into the PIBO and non-PIBO groups. Least absolute shrinkage and selection operator (LASSO) regressions were applied to variables that exhibited significant intergroup differences. Logistic regression was adopted to analyse the risk factors for PIBO. Additionally, a nomogram was constructed, and its effectiveness was assessed using calibration curves, C-index, and decision curve analysis. A total of 148 hospitalised children with SAP were collected in this study. Among them, 112 achieved favourable recovery, whereas 36 developed PIBO. Multivariable regression after variable selection via LASSO revealed that aged < 1 year (OR, 2.38, 95% CI, 0.82-6.77), admission to PICU (OR, 24.40, 95% CI, 7.16-105.00), long duration of fever (OR, 1.16, 95% CI, 1.04-1.31), and bilateral lung infection (OR, 8.78, 95% CI, 1.32-195.00) were major risk factors for PIBO. The nomogram model included the four risk factors: The C-index of the model was 0.85 (95% CI, 0.71-0.99), and the area under the curve was 0.85 (95% CI, 0.78-0.92). The model showed good calibration with the Hosmer-Lemeshow test (χ2 = 8.52, P = 0.38) and was useful in clinical settings with decision curve analysis. CONCLUSION: Age < 1 year, PICU admission, long fever duration, and bilateral lung infection are independent risk factors for PIBO in children with SAP. The nomogram model may aid clinicians in the early diagnosis and intervention of PIBO. WHAT IS KNOWN: • Adenoviruses are the most common pathogens associated with PIBO. • Wheezing, tachypnoea, hypoxemia, and mechanical ventilation are the risk factors for PIBO. WHAT IS NEW: • Age < 1 year, admission to PICU, long duration of fever days, and bilateral lung infection are independent risk factors for PIBO in children with SAP. • A prediction model presented as a nomogram may help clinicians in the early diagnosis and intervention of PIBO.