Primary Title: Assessing the Efficacy of the Stop OsteoARthritis (SOAR) program: A randomized delayed-controlled trial in persons at increased risk of early onset post-traumatic knee osteoarthritis.

OBJECTIVE: Assess the efficacy of an 8-week virtual, physiotherapist (PT)-guided knee health program (SOAR) to improve knee extensor strength in individuals at risk of post-traumatic knee osteoarthritis (PTOA). METHOD: In this superiority, randomized delayed-control trial, persons aged 16-35 years, 1-4 years after a self-reported knee joint injury were randomly assigned (1:1) to receive the SOAR program immediately (experimental group) or after a 9-week delay (control group). SOAR includes 1) one-time Knee Camp (virtual PT-guided group education, knee assessment, 1:1 exercise and physical activity goal-setting); 2) Weekly personalized home-based exercise and physical activity program with tracking; 3) Weekly 1:1 PT counseling (virtual). The primary outcome was change in isokinetic knee extensor strength (baseline to 9-weeks). Additional outcomes included change in self-reported knee-related quality-of-life (QOL), self-efficacy, self-management and kinesiophobia, and physical activity (accelerometer) at 9 and 18-weeks. Linear regression models estimated the effect of the 8-week intervention at the primary endpoint (9-week). RESULTS: 49 of 54 randomized participants completed the study (91%). Participants were a mean±SD age of 27±5.0 years, and 2.4±0.9 years post-injury. No mean between group differences for the primary (0.05; 95%CI: -0.10,0.19) or other outcomes were seen at 9 weeks except for greater improvements in perceived self-management (Partner in Health Scale; 11.3/96, 95%CI: 5.5,17.1) and kinesiophobia (Tampa Scale of Kinesiophobia; -4.4/33, 95%CI: -7.0,-1.8). CONCLUSION: For active persons with elevated risk of PTOA, an 8-week SOAR program did not change knee-related strength, QOL, self-efficacy, or physical activity, on average, but may benefit the ability to self-manage knee health and kinesiophobia.

One-Dimensional Non-coplanar Nitrogen Chains in Manganese Tetranitride under High Pressure.

Transition metal nitrides have great potential applications as incompressible and high energy density materials. Various polymeric nitrogen structures significantly affect their properties, contributing to their complex bonding modes and coordination conditions. Herein, we first report a new manganese polynitride MnN4 with bifacial trans-cis [N4]n chains by treating with high-pressure and high-temperature conditions in a diamond anvil cell. Our experiments reveal that MnN4 has a P-1 symmetry and could stabilize in the pressure range of 56-127 GPa. Detailed pressure-volume data and calculations of this phase indicate that MnN4 is a potential hard (255 GPa) and high energy density (2.97 kJ/g) material. The asymmetric interactions impel N1 and N4 atoms to hybridize to sp2-3, which causes distortions of [N4]n chains. This work discovers a new polynitride material, fills the gap for the study of manganese polynitride under high pressure, and offers some new insights into the formation of polymeric nitrogen structures.

Overcoming neutrophil-induced immunosuppression in postoperative cancer therapy: Combined sialic acid-modified liposomes with scaffold-based vaccines.

Immunotherapy is a promising approach for preventing postoperative tumor recurrence and metastasis. However, inflammatory neutrophils, recruited to the postoperative tumor site, have been shown to exacerbate tumor regeneration and limit the efficacy of cancer vaccines. Consequently, addressing postoperative immunosuppression caused by neutrophils is crucial for improving treatment outcomes. This study presents a combined chemoimmunotherapeutic strategy that employs a biocompatible macroporous scaffold-based cancer vaccine (S-CV) and a sialic acid (SA)-modified, doxorubicin (DOX)-loaded liposomal platform (DOX@SAL). The S-CV contains whole tumor lysates as antigens and imiquimod (R837, Toll-like receptor 7 activator)-loaded PLGA nanoparticles as immune adjuvants for cancer, which enhance dendritic cell activation and cytotoxic T cell proliferation upon localized implantation. When administered intravenously, DOX@SAL specifically targets and delivers drugs to activated neutrophils in vivo, mitigating neutrophil infiltration and suppressing postoperative inflammatory responses. In vivo and vitro experiments have demonstrated that S-CV plus DOX@SAL, a combined chemo-immunotherapeutic strategy, has a remarkable potential to inhibit postoperative local tumor recurrence and distant tumor progression, with minimal systemic toxicity, providing a new concept for postoperative treatment of tumors.

Self-Supervised Learning for Time Series Analysis: Taxonomy, Progress, and Prospects.

Self-supervised learning (SSL) has recently achieved impressive performance on various time series tasks. The most prominent advantage of SSL is that it reduces the dependence on labeled data. Based on the pre-training and fine-tuning strategy, even a small amount of labeled data can achieve high performance. Compared with many published self-supervised surveys on computer vision and natural language processing, a comprehensive survey for time series SSL is still missing. To fill this gap, we review current state-of-the-art SSL methods for time series data in this article. To this end, we first comprehensively review existing surveys related to SSL and time series, and then provide a new taxonomy of existing time series SSL methods by summarizing them from three perspectives: generative-based, contrastive-based, and adversarial-based. These methods are further divided into ten subcategories with detailed reviews and discussions about their key intuitions, main frameworks, advantages and disadvantages. To facilitate the experiments and validation of time series SSL methods, we also summarize datasets commonly used in time series forecasting, classification, anomaly detection, and clustering tasks. Finally, we present the future directions of SSL for time series analysis.

Characterization of a Clove Essential Oil Slow-Release Microencapsulated Composite Film and Its Preservation Effects on Blueberry.

In order to extend the shelf life of fruits and vegetables, a sodium alginate-sodium carboxymethyl cellulose composite film loaded with poly(vinyl alcohol) microcapsules was prepared in this paper. The optimal film substrate ratios were obtained after the response surface optimization. Poly(vinyl alcohol) microcapsules were prepared, clove essential oil was loaded into them to investigate the effects of microcapsules on the composite film properties, and the microcapsule composite film with the best overall performance was selected to be applied to blueberry preservation. The results showed that the composite film of 0.84% sodium alginate, 0.25% sodium carboxymethyl cellulose, and 0.56% glycerol presented excellent mechanical properties after adding 1.75% microcapsules. It had a good inhibitory effect on Escherichia coli, Staphylococcus aureus, and Penicillium and had a DPPH clearance rate of 83.78%. The low-temperature bonded composite film could slow down the respiration rate of blueberry, inhibit browning and water loss, effectively maintain the quality of blueberry, and have a significant preservation effect on the anthocyanin and soluble solid content of blueberry. The clove essential oil slow-release microencapsulated composite film can be used for blueberry preservation.

Molecular Characterization Analysis and Adaptive Responses of Spodoptera frugiperda (Lepidoptera: Noctuidae) to Nutritional and Enzymatic Variabilities in Various Maize Cultivars.

The fall armyworm, Spodoptera frugiperda Smith (Lepidoptera: Noctuidae), a common agricultural pest known for its extensive migration and wide host ranges, causes considerable harm to maize (Zea mays L.). In this study, we utilized two molecular marker genes, COI and Tpi, to compare the genetic characteristics of the collected original samples. Additionally, through an interactive study between S. frugiperda larvae and six maize varieties aiming to understand the insect's adaptability and resistance mechanisms, our analysis revealed that both the COI and Tpi genes identified S. frugiperda as the corn strain. Further examination of the larvae showed significant differences in nutritional indices, digestive, and detoxification enzyme activities. Special maize varieties were found to offer higher efficiency in nutrient conversion and assimilation compared with common varieties. This study revealed adaptations in S. frugiperda's digestive and detoxification processes in response to the different maize varieties. For instance, larvae reared on common maize exhibited elevated amylase and lipase activities. Interestingly, detoxification enzyme activities exhibited different patterns of variation in different maize varieties. The Pearson correlation analysis between nutritional indices, enzyme activities, and the nutritional content and secondary metabolites of maize leaves provided deeper insights into the pest's adaptability. The results highlighted significant relationships between specific nutritional components in maize and the physiological responses of S. frugiperda. Overall, our findings contribute substantially to the understanding of S. frugiperda's host plant adaptability, offering critical insights for the development of sustainable pest management strategies.

CircMCTP2 enhances the progression of bladder cancer by regulating the miR-99a-5p/FZD8 axis.

BACKGROUND: CircRNAs and miRNAs are involved in the progression of tumor. CircMCTP2 is considered as a novel tumor promoter. However, the exact functions of circMCTP2 in bladder cancer are still unclear. This study was designed to explore the underlying mechanisms of circMCTP2-modulated tumor development in bladder cancer. METHODS: The present study is an original research. The levels of circMCTP2 in a total of 39 bladder cancer specimens and cell lines were determined by RT-qPCR. The expression of FZD8 in T24 and RT-4 cells treated with miR-99a-5p mimics were examined using western blotting. In addition, the proliferative, migrative and invasive abilities of transfected cells were determined by CCK8 and Transwell assays. Furthermore, the apoptosis of transfected cells was evaluated using flow cytometry. Dual luciferase reporter assay was performed to elucidate the relationship between miR-99a-5p and circMCTP2/FZD8. RESULTS: The levels of circMCTP2 were elevated in bladder cancer samples and cells, and this was related to worse survival rate. Downregulation of circMCTP2 suppressed growth and metastasis of cells, whereas the apoptotic rate of cells was enhanced. The levels of miR-99a-5rp was elevated after the downregulation of circMCTP2. Moreover, reverse correlation between the expression of miR-99a-5p and circMCTP2 was revealed in bladder cancer specimens. Additionally, FZD8 was the putative target of miR-99a-5p and the mimics of miR-99a-5p inhibited the proliferation, migration and invasion of bladder cancer cells via the FZD8/Wnt-b-catenin axis. Moreover, circMCTP2 regulated the growth and metastasis of bladder cancer cells potentially through regulating the miR-99a-5p/FZD8/Wnt-b-catenin axis. In summary, circMCTP2 was considered as an oncogenic factor through regulating the miR-99a-5p/FZD8/Wnt-b-catenin axis. CONCLUSIONS: This novel signaling could regulate the biological behaviours of bladder cancer cells, and these findings highlighted circMCTP2 as a critical target for treating bladder cancer.

A Marine Natural Product, Harzianopyridone, as an Anti-ZIKV Agent by Targeting RNA-Dependent RNA Polymerase.

The Zika virus (ZIKV) is a mosquito-borne virus that already poses a danger to worldwide human health. Patients infected with ZIKV generally have mild symptoms like a low-grade fever and joint pain. However, severe symptoms can also occur, such as Guillain-Barré syndrome, neuropathy, and myelitis. Pregnant women infected with ZIKV may also cause microcephaly in newborns. To date, we still lack conventional antiviral drugs to treat ZIKV infections. Marine natural products have novel structures and diverse biological activities. They have been discovered to have antibacterial, antiviral, anticancer, and other therapeutic effects. Therefore, marine products are important resources for compounds for innovative medicines. In this study, we identified a marine natural product, harzianopyridone (HAR), that could inhibit ZIKV replication with EC50 values from 0.46 to 2.63 µM while not showing obvious cytotoxicity in multiple cellular models (CC50 > 45 µM). Further, it also reduced the expression of viral proteins and protected cells from viral infection. More importantly, we found that HAR directly bound to the ZIKV RNA-dependent RNA polymerase (RdRp) and suppressed its polymerase activity. Collectively, our findings provide HAR as an option for the development of anti-ZIKV drugs.

Effect of exogenous melatonin on antioxidant properties and fruit softening of 'Fengtang' plum fruit (Prunus salicina Lindl.) during storage at room temperature.

'Fengtang' plums soften quickly and lose flavor after harvest. This study comprehensively evaluated the effect of exogenous melatonin on the fruit quality of 'Fengtang' plums. According to our findings, exogenous melatonin prevented plum fruit from losing water, delayed the decline in firmness, and preserved a high TSS/TA level. Additionally, exogenous melatonin also enhanced the activity of antioxidant enzymes and increased the non-enzymatic antioxidants, thereby further increasing the antioxidant capacity of plum fruit. Notably, exogenous melatonin delayed the degradation of covalent soluble pectin (CSP), cellulose, and hemicellulose, as well as the rise in water-soluble pectin (WSP) concentration and the activity of cell wall degrading enzymes. Further investigation using atomic force microscopy (AFM) revealed that the chain-like structure of ionic-soluble pectin (ISP) and the self-assembly network structures of CSP were depolymerized, and melatonin treatment retarded the depolymerization of pectin structures. Our results showed that exogenous melatonin preserved the postharvest quality of plum fruits by controlling fruit softness and antioxidant capacity during storage.

LysSYL: a broad-spectrum phage endolysin targeting Staphylococcus species and eradicating S. aureus biofilms.

BACKGROUND: Staphylococcus aureus and its single or mixed biofilm infections seriously threaten global public health. Phage therapy, which uses active phage particles or phage-derived endolysins, has emerged as a promising alternative strategy to antibiotic treatment. However, high-efficient phage therapeutic regimens have yet to be established. RESULTS: In this study, we used an enrichment procedure to isolate phages against methicillin-resistant S. aureus (MRSA) XN108. We characterized phage SYL, a new member of the Kayvirus genus, Herelleviridae family. The phage endolysin LysSYL was expressed. LysSYL demonstrated stability under various conditions and exhibited a broader range of efficacy against staphylococcal strains than its parent phage (100% vs. 41.7%). Moreover, dynamic live/dead bacterial observation demonstrated that LysSYL could completely lyse MRSA USA300 within 10 min. Scan and transmission electron microscopy revealed evident bacterial cell perforation and deformation. In addition, LysSYL displayed strong eradication activity against single- and mixed-species biofilms associated with S. aureus. It also had the ability to kill bacterial persisters, and proved highly effective in eliminating persistent S. aureus when combined with vancomycin. Furthermore, LysSYL protected BALB/c mice from lethal S. aureus infections. A single-dose treatment with 50 mg/kg of LysSYL resulted in a dramatic reduction in bacterial loads in the blood, liver, spleen, lungs, and kidneys of a peritonitis mouse model, which resulted in rescuing 100% of mice challenged with 108 colony forming units of S. aureus USA300. CONCLUSIONS: Overall, the data provided in this study highlight the strong therapeutic potential of endolysin LysSYL in combating staphylococcal infections, including mono- and mixed-species biofilms related to S. aureus.

Balancing act: The dilemma of rapid hyperglycemia correction in diabetes management.

The global diabetes surge poses a critical public health challenge, emphasizing the need for effective glycemic control. However, rapid correction of chronic hyperglycemia can unexpectedly trigger microvascular complications, necessitating a reevaluation of the speed and intensity of glycemic correction. Theories suggest swift blood sugar reductions may cause inflammation, oxidative stress, and neurovascular changes, resulting in complications. Healthcare providers should cautiously approach aggressive glycemic control, especially in long-standing, poorly controlled diabetes. Preventing and managing these complications requires a personalized, comprehensive approach with education, monitoring, and interdisciplinary care. Diabetes management must balance short and long-term goals, prioritizing overall well-being. This editorial underscores the need for a personalized, nuanced approach, focusing on equilibrium between glycemic control and avoiding overcorrection.

Elucidating the cardioprotective mechanisms of sodium-glucose cotransporter-2 inhibitors beyond glycemic control.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as a pivotal intervention in diabetes management, offering significant cardiovascular benefits. Empagliflozin, in particular, has demonstrated cardioprotective effects beyond its glucose-lowering action, reducing heart failure hospitalizations and improving cardiac function. Of note, the cardioprotective mechanisms appear to be inde-pendent of glucose lowering, possibly mediated through several mechanisms involving shifts in cardiac metabolism and anti-fibrotic, anti-inflammatory, and anti-oxidative pathways. This editorial summarizes the multifaceted cardiovascular advantages of SGLT2 inhibitors, highlighting the need for further research to elucidate their full therapeutic potential in cardiac care.

High Homocysteine-Thiolactone Leads to Reduced MENIN Protein Expression and an Impaired DNA Damage Response: Implications for Neural Tube Defects.

DNA damage is associated with hyperhomocysteinemia (HHcy) and neural tube defects (NTDs). Additionally, HHcy is a risk factor for NTDs. Therefore, this study examined whether DNA damage is involved in HHcy-induced NTDs and investigated the underlying pathological mechanisms involved. Embryonic day 9 (E9) mouse neuroectoderm cells (NE4C) and homocysteine-thiolactone (HTL, active metabolite of Hcy)-induced NTD chicken embryos were studied by Western blotting, immunofluorescence. RNA interference or gene overexpression techniques were employed to investigate the impact of Menin expression changes on the DNA damage. Chromatin immunoprecipitation-quantitative polymerase chain reaction was used to investigate the epigenetic regulation of histone modifications. An increase in γH2AX (a DNA damage indicator) was detected in HTL-induced NTD chicken embryos and HTL-treated NE4C, accompanied by dysregulation of phospho-Atr-Chk1-nucleotide excision repair (NER) pathway. Further investigation, based on previous research, revealed that disruption of NER was subject to the epigenetic regulation of low-expressed Menin-H3K4me3. Overexpression of Menin or supplementation with folic acid in HTL-treated NE4C reversed the adverse effects caused by high HTL. Additionally, by overexpressing the Mars gene, we tentatively propose a mechanism whereby HTL regulates Menin expression through H3K79hcy, which subsequently influences H3K4me3 modifications, reflecting an interaction between histone modifications. Finally, in 10 human fetal NTDs with HHcy, we detected a decrease in the expression of Menin-H3K4me3 and disorder in the NER pathway, which to some extent validated our proposed mechanism. The present study demonstrated that the decreased expression of Menin in high HTL downregulated H3K4me3 modifications, further weakening the Atr-Chk1-NER pathway, resulting in the occurrence of NTDs.

Microbial metabolite trimethylamine-N-oxide induces intestinal carcinogenesis through inhibiting farnesoid X receptor signaling.

PURPOSE: Microbial dysbiosis is considered as a hallmark of colorectal cancer (CRC). Trimethylamine-N-oxide (TMAO) as a gut microbiota-dependent metabolite has recently been implicated in CRC development. Nevertheless, evidence relating TMAO to intestinal carcinogenesis remains largely unexplored. Herein, we aimed to examine the crucial role of TMAO in CRC progression. METHODS: Apcmin/+ mice were treated with TMAO or sterile PBS for 14 weeks. Intestinal tissues were isolated to evaluate the effects of TMAO on the malignant transformation of intestinal adenoma. The gut microbiota of mouse feces was detected by 16S rRNA sequencing analysis. HCT-116 cells were used to provide further evidence of TMAO on the progression of CRC. RESULTS: TMAO administration increased tumor cell and stem cell proliferation, and decreased apoptosis, accompanied by DNA damage and gut barrier impairment. Gut microbiota analysis revealed that TMAO induced changes in the intestinal microbial community structure, manifested as reduced beneficial bacteria. Mechanistically, TMAO bound to farnesoid X receptor (FXR), thereby inhibiting the FXR-fibroblast growth factor 15 (FGF15) axis and activating the Wnt/ß-catenin signaling pathway, whereas the FXR agonist GW4064 could blunt TMAO-induced Wnt/ß-catenin pathway activation. CONCLUSION: The microbial metabolite TMAO can enhance intestinal carcinogenesis by inhibiting the FXR-FGF15 pathway.

Inverted U-Shaped Association of Plasma Resolvin D2 With Atherosclerotic Cardiovascular Disease and the Mediation Effects of Serum Cholesterol: A Chinese Community-Based Study.

BACKGROUND: Resolvin D2 (RvD2) has been reported to protect against the development of atherosclerosis in animal models. The objective of this study was to examine the prospective association between plasma RvD2 and the risk of atherosclerotic cardiovascular disease (ASCVD) at the population level. METHODS AND RESULTS: A cohort of 2633 community-dwelling individuals aged 35-60 years was followed for 8 years in this study. Adjusted hazard ratios and 95% CIs for ASCVD outcomes according to baseline RvD2 levels were calculated using Cox proportional hazards models. Mediation analysis was used to test the indirect effect of serum cholesterol indicators on the association between RvD2 and ASCVD probability. In total, 284 new cases of ASCVD were identified during follow-up. An inverted U-shaped association between natural log (ln)-transformed RvD2 and incident ASCVD was determined, and the threshold value for lnRvD2 was 3.87. Below the threshold, each unit increase in lnRvD2 was associated with a 2.05-fold increased risk of ASCVD (95% CI, 1.13-3.74; P=0.019). Above the threshold, each unit increase in lnRvD2 was associated with a 36% reduced risk of ASCVD (95% CI, 0.51-0.80; P<0.001). In addition, the association between RvD2 and ASCVD probability was partially mediated by high-density lipoprotein cholesterol (15.81%) when lnRvD2 <3.87, but by total cholesterol (30.23%) and low-density lipoprotein cholesterol (30.13%) when lnRvD2 ≥3.87. CONCLUSIONS: Both lower and higher RvD2 levels are associated with a reduced risk of ASCVD, forming an inverted U-shaped relationship. Furthermore, this association is partially mediated by total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol.

A dual-functional microfluidic chip for guiding personalized lung cancer medicine: combining EGFR mutation detection and organoid-based drug response test.

Many efforts have been paid to advance the effectiveness of personalized medicine for lung cancer patients. Sequencing-based molecular diagnosis of EGFR mutations has been widely used to guide the selection of anti-lung-cancer drugs. Organoid-based assays have also been developed to ex vivo test individual responses to anti-lung-cancer drugs. After addressing several technical difficulties, a new combined strategy, in which anti-cancer medicines are first selected based on molecular diagnosis and then ex vivo tested on organoids, has been realized in a single dual-functional microfluidic chip. A DNA-based nanoruler has been developed to detect the existence of EGFR mutations and shrink the detection period from weeks to hours, compared with sequencing. The employment of the DNA-based nanoruler creates a possibility to purposively test anti-cancer drugs, either EGFR-TKIs or chemotherapy drugs, not both, on limited amounts of organoids. Moreover, a DNA-based nanosensor has been developed to recognize intracellular ATP variation without harming cell viability, realizing in situ monitoring of the whole course growth status of organoids for on-chip drug response test. The dual-functional microfluidic chip was validated by both cell lines and clinical samples from lung cancer patients. Furthermore, based on the dual-functional microfluidic chip, a fully automated system has been developed to span the divide between experimental procedures and therapeutic approaches. This study constitutes a novel way of combining EGFR mutation detection and organoid-based drug response test on an individual patient for guiding personalized lung cancer medicine.

The Role of the TLR4-MyD88 Signaling Pathway in the Immune Response of the Selected Scallop Strain "Hongmo No. 1" to Heat Stress.

The innate immunity of marine bivalves is challenged upon exposure to heat stress, especially with increases in the frequency and intensity of heat waves. TLR4 serves a classical pattern recognition receptor in recognizing pathogenic microorganisms and activating immune responses. In this study, three genes, HMTLR4, HMMyD88 and HMTRAF6, were characterized as homologs of genes in the TLR4-MyD88 signaling pathway in the selected scallop strain "Hongmo No. 1". According to RT-PCR, acute heat stress (32 °C) inhibited genes in the TLR4-MyD88 signaling pathway, and LPS stimulation-induced activation of TLR4-MyD88 signal transduction was also negatively affected at 32 °C. ELISA showed LPS-induced tumor necrosis factor alpha (TNF-α) or lysozyme (LZM) activity, but this was independent of temperature. RNA interference (RNAi) confirmed that HMTLR4 silencing suppressed the expression of its downstream gene, whether at 24 °C or at 32 °C. The level of TNF-α and the activity of LZM also decreased after injection with dsRNA, indicating a negative effect on the innate immunity of scallops. Additionally, acute heat stress affected the suppression of downstream gene expression when compared with that at 24 °C, which led us to the hypothesis that heat stress directly influences the downstream targets of HMTLR4. These results enrich the knowledge of scallop immunity under heat stress and can be beneficial for the genetic improvement of new scallop strains with higher thermotolerance.