Association between the triglyceride glucose index and depression: a meta-analysis.

Background: Obesity and diabetes have been associated with depressive symptoms. The aim of this systematic review and meta-analysis was to evaluate the association between the triglyceride glucose index (TyG index) a novel indicator of insulin resistance (IR) and depression in the adult population. Methods: Relevant observational studies were acquired through comprehensive searches of the Medline, Web of Science, Embase, Wanfang, and China National Knowledge Internet databases. To account for heterogeneity, a random-effects model was employed to combine the findings. Additionally, multiple subgroup analyses were conducted to assess the impact of various study characteristics on the outcome. Results: The meta-analysis comprised eight datasets from six cross-sectional studies, encompassing a total of 28,973 adults. The pooled findings suggested that subjects with a high TyG index, compared to those with a low TyG index, were associated with a higher prevalence of depression (odds ratio [OR]: 1.41, 95% confidence interval (CI): 1.28-1.56, p<0.001; I2 = 19%). Sensitivity analyses, by omitting one dataset at a time, showed consistent results (OR: 1.39-1.45, p<0.05). Further subgroup analyses showed consistent results in participants aged <50 years old and in those aged ≥50 years old, in men and in women, in studies with different cutoff values for the TyG index, and in studies with different methods for the diagnosis of depression (for each subgroup difference, p>0.05). Conclusion: A high TyG index may be associated with a higher prevalence of depression in the adult population.

Constructing Hydrangea-Like Iron-Cobalt Phosphides via Boron-Assisted strategy as an Efficient Catalyst for Water Splitting at High Current Density.

Finding suitable bifunctional catalysts for industrial hydrogen production is the key to fully building a hydrogen energy society. Here we report a modulation of the surface morphology of electrodeposited CoP to form hydrangea-like Cobalt-Iron bimetallic phosphide (B-CoFeP@CoP) via ion-exchange and NaBH4-assisted methods. This catalyst exhibited excellent bifunctional catalytic capability at high current densities, achieving a current density of 500 mA cm-2 at a small overpotential (387 mV for OER and 252 mV for HER). When assembled into an OWS electrolyzer, this catalyst showed a fairly low cell voltage (≈1.88 V) at 500 mA cm-2 current density.，Furthermore, B-CoFeP@CoP shows ceaseless durability over 120 h in both freshwater and seawater with almost no change in the cell voltage. A combined experimental and theoretical study identified that the unique hydrangea-like structure provided a larger electrochemically active surface area and more effective active sites. Further analysis indicates that during the OER process, phosphides ensure that bimetallic active sites adsorb more OOH * intermediates and further DFT calculations showed that B-Fe2P and B-Co2P acted as active centers for dissociation of H2O and desorption of H2, respectively, to synergistically catalyze the HER process.

[Rapid Start-up of Continuous Autotrophic Nitrogen Removal Reactor by Hybrid-inoculating PN and PN/A Granular Sludges].

The rapid cultivation of partial nitritation/ANAMMOX （PN/A） granular sludge in a continuous-flow mode is one of the key technologies for efficient biological nitrogen removal in domestic wastewater treatment. Compared with that in PN/A granular sludge, PN granular sludge demonstrates a shorter incubation period and suitability for batch culture. It is also a good carrier for enriching ANAMMOX （AMX） bacteria. In this study, we established a continuous-flow autotrophic nitrogen removal process in three continuously stirred tank reactors （CSTR） （R1-R3） by hybrid-inoculating PN/A and PN granular sludge at the mass ratios of 3∶1, 1∶1, and 1∶3, respectively. By implementing high ammonium nitrogen loading and short hydraulic retention time, continuous autotrophic nitrogen removal processes were successfully started up in the three CSTRs. The results showed that compared with that of R1 and R2, R3 had a longer start-up time but a similar steady-state nitrogen removal performance. The total nitrogen removal load of R3 could be more than 2.6 kg·ï¼ˆm3·d）-1. Intriguingly, the inoculated PN granular sludge served as a precursor for PN/A granular sludge cultivation. This approach facilitated the enrichment of anaerobic ammonia-oxidizing bacteria （AMX） by introducing abundant ammonium-oxidizing bacteria （AOB） and nitrite nitrogen substrates into the CSTR. According to the results of high-throughput sequencing, the microbial abundance and diversity of the mature granules in R1-R3 were significantly higher than those of the inoculation sludge. AOB （genus Nitrosomonas）, AMX （genera Candidatus Kuenenia and Candidatus Brocadia）, and symbiotic heterotrophs, such as Chloroflexi, Bacteroidetes, and Chlorobi, drove the autotrophic nitrogen removal process and maintained the stability of the granular structure. In summary, a novel start-up strategy of hybrid-inoculating granular sludge was provided for a continuous-flow autotrophic nitrogen removal in engineering application.

VlMYB4 and VlCDF3 co-targeted the VlLOG11 promoter to regulate fruit setting in grape (Vitis vinifera L).

KEY MESSAGE: The VlLOG11 mediates the cytokinin signaling pathway to regulate grape fruit setting. Fruit set, as an accepted agronomic trait, is inextricably linked with fruit quality and yield. Previous studies have demonstrated that exogenous treatment with the synthetic cytokinin analog, forchlorfenuron (CPPU), significantly enhances fruit set. In this study, a significant reduction in endogenous cytokinins was found by measuring the content of cytokinins in young grape berries after CPPU treatment. LONELY GUYs (VlLOGs), a key cytokinin-activating enzyme working in the biosynthesis pathway of cytokinins, exhibited differential expression. Some differentially expressed VlLOGs genes were presented by RNA seq data and their functions and regulation patterns were further investigated. The results showed that VlLOG11 was differentially expressed in young grape berries after CPPU treatment. Overexpression of VlLOG11 in tomato increases the amount of fruit set, and upregulated the expression of genes associated with cytokinin signaling including SlHK4, SlHK5, SlHP3, SlHP4, SlPHP1, SlPHP2. VlMYB4 and VlCDF3 could regulate the expression of VlLOG11 by directly binding to its promoter in young grape berries during fruit set. These results strongly demonstrated that VlMYB4/VlCDF3-VlLOG11 regulatory module plays a key role in the process of fruit setting in grape. This provided a basis for the molecular mechanism of VlLOG11-mediated cytokinin biosynthesis in young grape fruit set.

Self-assembly of a ruthenium-based cGAS-STING photoactivator for carrier-free cancer immunotherapy.

The cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway promotes antitumor immune responses by sensing cytosolic DNA fragments leaked from nucleus and mitochondria. Herein, we designed a highly charged ruthenium photosensitizer (Ru1) with a ß-carboline alkaloid derivative as the ligand for photo-activating of the cGAS-STING pathway. Due to the formation of multiple non-covalent intermolecular interactions, Ru1 can self-assemble into carrier-free nanoparticles (NPs). By incorporating the triphenylphosphine substituents, Ru1 can target and photo-damage mitochondrial DNA (mtDNA) to cause the cytoplasmic DNA leakage to activate the cGAS-STING pathway. Finally, Ru1 NPs show potent antitumor effects and elicit intense immune responses in vivo. In conclusion, we report the first self-assembling mtDNA-targeted photosensitizer, which can effectively activate the cGAS-STING pathway, thus providing innovations for the design of new photo-immunotherapeutic agents.

PDK3 drives colorectal carcinogenesis and immune evasion and is a therapeutic target for boosting immunotherapy.

Pyruvate Dehydrogenase Kinase 3 (PDK3) has emerged as a significant player in various cancer types, yet its specific impact on cancers including colon cancer remains ambiguous. Through pan-cancer analysis using TCGA data, we found that the expression of PDK3 and the composition of the immune microenvironment for different tumors were highly heterogeneous across tumors. PDK3 is highly expressed in colorectal cancer and may promote tumor proliferation by activating PI3K-AKT signaling. In addition, we found that PDK3 was able to inhibit tumor antigen presentation signals to suppress immune killing. High PDK3 expression predicts less CD8+ T cell infiltration and effector function. Moreover, inhibition of PDK3 expression bolstered CD8+ T cell-mediated cytotoxicity CD8+ T cell infiltration and activation in vivo. Notably, PDK3 was found to facilitate STAT1 activation and elevate programmed death-ligand 1 (PD-L1) expression in colon cancer cells. Importantly, PDK3 inhibition combination with PD-1 blockade significantly activates the infiltrated CD8+ T cells to suppress tumor growth and improves the survival benefit in several murine tumor models. In summary, these findings underscore PDK3's role in fueling colon cancer growth by orchestrating PI3K-AKT signaling and PD-L1 expression and dampening CD8+ T cell function.

Combining blood pressure variability and heart rate variability to analyze the autonomic nervous function of rotenone induced Parkinson's rat model.

BACKGROUND: Parkinson's patients have significant autonomic dysfunction, early detect the disorder is a major challenge. To assess the autonomic function in the rat model of rotenone induced Parkinson's disease (PD), Blood pressure and ECG signal acquisition are very important. NEW METHOD: We used telemetry to record the electrocardiogram and blood pressure signals from awake rats, with linear and nonlinear analysis techniques calculate the heart rate variability (HRV) and blood pressure variability (BPV). we applied nonlinear analysis methods like sample entropy and detrended fluctuation analysis to analyze blood pressure signals. Particularly, this is the first attempt to apply nonlinear analysis to the blood pressure evaluate in rotenone induced PD model rat. RESULTS: HRV in the time and frequency domains indicated sympathetic-parasympathetic imbalance in PD model rats. Linear BPV analysis didn't reflect changes in vascular function and blood pressure regulation in PD model rats. Nonlinear analysis revealed differences in BPV, with lower sample entropy results and increased detrended fluctuation analysis results in the PD group rats. COMPARISON WITH EXISTING METHODS AND CONCLUSIONS: our experiments demonstrate the ability to evaluate autonomic dysfunction in models of Parkinson's disease by combining the analysis of BPV with HRV, consistent with autonomic impairment in PD patients. Nonlinear analysis by blood pressure signal may help in early detection of the PD. It indicates that the fluctuation of blood pressure in the rats in the rotenone model group tends to be regular and predictable, contributes to understand the PD pathophysiological mechanisms and to find strategies for early diagnosis.

Nomogram models predicting prognosis for patients with t(8;21) acute myeloid leukemia: a SEER-based study.

BACKGROUND: Acute myeloid leukemia (AML) with t(8;21) manifests as a diverse hematological malignancy. Although it was categorized into a favorable subtype, 30-40% of patients experience relapse. The objective of this research was to devise a nomogram for the accurate anticipation of both overall survival (OS) and cancer-specific survival (CSS) in t(8;21) AML. METHODS: From the Surveillance, Epidemiology, and End Results (SEER) database, individuals diagnosed with t(8;21) AML from 2000 to 2018 were selected. Prognostic factors for t(8;21) AML were identified using Cox regression analysis and Akaike Information Criterion (AIC), forming the basis for constructing prognostic nomograms. RESULTS: Key variables, including first primary tumor, age group, race, and chemotherapy, were identified and integrated into the nomogram. The C-index values for the nomograms predicting OS and CSS were 0.753 (validation: 0.765) and 0.764 (validation: 0.757), respectively. Ultimately, based on nomogram scores, patients were stratified into high-risk and low-risk groups, revealing significant disparities in both OS and CSS between these groups (P < 0.001). CONCLUSION: This study innovatively crafted nomograms, incorporating clinical and therapeutic variables, to forecast the 1-, 3-, and 5-year survival rates for individuals with t(8;21) AML.

Frequency of lymph node metastases at different neck levels in patients with oral squamous cell carcinoma: a systematic review and meta-analysis.

BACKGROUND: Currently, neck dissection is a standard treatment for the majority of oral squamous cell carcinoma (OSCC) patients. However, the procedure can lead to a series of complications, significantly reducing patient quality of life and even affecting the antitumor immune response in patients undergoing immunotherapy. Therefore, in the era of precision surgery, gaining a deeper understanding of the patterns of lymph node metastasis (LNM) in OSCC is crucial. MATERIALS AND METHODS: Literature searches were performed on PubMed, Embase, Web of Science, Cochrane Library, WANFANGDATA and China National Knowledge Infrastructure (CNKI) (inception to April 10, 2024). In addition, a manual searching was conducted in Scopus, Google Scholar, and Education Resources Information Center (ERIC). We included observational studies that evaluated the frequency of LNM in OSCC patients. Systematic review and a random effects model meta-analysis were performed. RESULTS: The search identified 4694 articles, of which 17 studies included in our study. We calculated the frequency of LNM according to the data reported in the articles. Frequency of LNM=number of patients with positive lymph node / number of patients with OSCC. The frequency of LNM was 12% in level I (95%CI: 0.11 to 0.15, I2=38.01%), 20% in level II (95%CI: 0.17 to 0.22, I2=47.71%), 10% in level III (95%CI: 0.08 to 0.12, I2=49.10%), 2% in level VI (95%CI: 0.01 to 0.03, I2=27.58%), 1% in level V (95%CI: 0.00 to 0.01, I2=11.37%). CONCLUSION: The frequency of LNM is consistent with the "cascade theory" and appears to be no significant difference from different primary sites. The frequency of LNM were low in levels I-III and were very low in level IV-V which implicated that more conservative treatments may be considered for OSCC in the future. This study will help clinicians better determine the extent of surgery and preserve lymph nodes during neck dissection.

Oxidized ATP Suppresses B Lymphocyte Activity to Attenuate Antibody-mediated Rejection of Kidney Allografts in Mice.

BACKGROUND: Antibody-mediated rejection (AMR) is a major cause of renal allograft dysfunction and loss. Targeting B cells and/or donor-specific antibody removal using plasma exchange and anti-CD20 antibodies are increasingly used in clinical practice, but the efficacy remains limited. Recent studies suggest that targeting purinergic P2X7 receptor/ATP axis can have profound immune regulatory effects in transplant models, but the mechanisms involved remain incompletely defined. METHODS: Purified B cells were isolated from the spleen of Balb/C mice and cultured with oxidized ATP at different concentrations. Proliferation and differentiation of B cells were examined. Effects of oxidized ATP were examined in a presensitized animal model where kidney allograft rejection mimics aspects of clinical AMR. Histopathology was assessed at the time of rejection or on day 5 after kidney transplantation. Infiltrating immune cells in renal allografts were detected by flow cytometry. RESULTS: Oxidized ATP inhibited B-cell activation and proliferation in vitro, significantly attenuated histological signs of graft injury and prolonged kidney allograft survival. Mechanistically, oxidized ATP inhibited antibody secretion by activated B cells in response to lipopolysaccharide stimulation and markedly suppressed the production of donor-specific antibody in kidney allograft recipients. Oxidized ATP also reduced graft infiltration by other inflammatory cells. CONCLUSIONS: These findings provide evidence for the involvement of the purinergic P2X7 receptor pathway in AMR and suggest that targeting this pathways may have important clinical implications.

Intelligent diagnostic model for pterygium by combining attention mechanism and MobileNetV2.

AIM: To evaluate the application of an intelligent diagnostic model for pterygium. METHODS: For intelligent diagnosis of pterygium, the attention mechanisms-SENet, ECANet, CBAM, and Self-Attention-were fused with the lightweight MobileNetV2 model structure to construct a tri-classification model. The study used 1220 images of three types of anterior ocular segments of the pterygium provided by the Eye Hospital of Nanjing Medical University. Conventional classification models-VGG16, ResNet50, MobileNetV2, and EfficientNetB7-were trained on the same dataset for comparison. To evaluate model performance in terms of accuracy, Kappa value, test time, sensitivity, specificity, the area under curve (AUC), and visual heat map, 470 test images of the anterior segment of the pterygium were used. RESULTS: The accuracy of the MobileNetV2+Self-Attention model with 281 MB in model size was 92.77%, and the Kappa value of the model was 88.92%. The testing time using the model was 9ms/image in the server and 138ms/image in the local computer. The sensitivity, specificity, and AUC for the diagnosis of pterygium using normal anterior segment images were 99.47%, 100%, and 100%, respectively; using anterior segment images in the observation period were 88.30%, 95.32%, and 96.70%, respectively; and using the anterior segment images in the surgery period were 88.18%, 94.44%, and 97.30%, respectively. CONCLUSION: The developed model is lightweight and can be used not only for detection but also for assessing the severity of pterygium.

Silk Fibroin Microneedles Loaded with Lipopolysaccharide-Pretreated Bone Marrow Mesenchymal Stem Cell-Derived Exosomes for Oral Ulcer Treatment.

Oral ulcers, superficial lesions on the surface of the oral mucosa, have a high incidence rate, and their main symptoms include local pain and erosion. Lipopolysaccharide (LPS)-preconditioned bone marrow mesenchymal stem cells and their secreted exosomes (LPS-pre-Exos) have been shown to promote recovery in various inflammatory conditions and wounds. However, studies documenting LPS-pre-Exos as a therapeutic intervention for oral mucosal-like diseases are lacking. In this study, we prepared a silk fibroin microneedle (MN) patch consisting of LPS-pre-Exos and zeolitic imidazolate framework-8 (ZIF-8) that localized at the tip and base, respectively, and used this MN patch for oral ulcer treatment. Upon insertion into the oral mucosa, continuous LPS-pre-Exos release was observed, which promoted macrophage polarization and tissue healing. Additionally, the ZIF-8 framework in the MN patch facilitated the controlled release of Zn2+, which demonstrated potent antimicrobial properties via synergistic effects. The in vitro experimental results showed that the silk fibroin MN patch can continuously release LPS-pre-Exos and Zn2+ for more than 7 days. Thus, the LPS-pre-Exos and ZIF-8-loaded silk fibroin MN patch exhibited good anti-inflammatory and antibacterial properties, promoting oral ulcer healing, and showed good histocompatibility. Hence, it may represent a potentially valuable strategy for facilitating oral ulcer healing.

A Summed Score From Cardiopulmonary Exercise Test Parameters Predicts 1-Year Mortality in Newly Diagnosed Interstitial Lung Disease.

BACKGROUND: Cardiopulmonary exercise testing (CPET) is a unique diagnostic tool that assesses the functional capacity of the heart, lungs, and peripheral oxidative system in an integrated manner. However, the clinical utility of CPET for evaluating interstitial lung disease (ILD) remains uncertain. The objective of this study was to determine the predictive value of CPET for mortality in subjects with ILD. METHODS: We prospectively enrolled subjects with ILD who underwent CPET at a tertiary medical center in Taiwan and followed up their survival status for 12 months. Mortality prediction was based on comparing CPET parameters between subjects who survived and those who died. We further analyzed CPET parameters that showed significant differences using receiver operating characteristic curves to identify their optimal cutoff values. RESULTS: A total of 106 newly diagnosed subjects with ILD underwent CPET, and the 1-y mortality rate was 7.5%. Six CPET variables were found to be significant predictors of mortality: peak oxygen consumption, oxygen pulse, end-tidal partial pressure of carbon dioxide, heart rate recovery 1 min after CPET, minute ventilation to carbon dioxide output slope, and functional aerobic impairment. We calculated a summed score by adding the number of CPET variables that exceeded their cutoff values. Subjects with a summed score of 6 had a 1-y survival rate of only 25%, whereas subjects with scores of 0-5 had a survival rate of 98%. CONCLUSIONS: In conclusion, the summed score represents a useful tool for screening patients with ILD who can undergo a CPET to determine their prognosis.

Helicobacter Pylori-Enhanced hnRNPA2B1 Coordinates with PABPC1 to Promote Non-m6A Translation and Gastric Cancer Progression.

Helicobacter pylori (H. pylori) infection is the primary risk factor for the pathogenesis of gastric cancer (GC). N6-methyladenosine (m6A) plays pivotal roles in mRNA metabolism and hnRNPA2B1 as an m6A reader is shown to exert m6A-dependent mRNA stabilization in cancer. This study aims to explore the role of hnRNPA2B1 in H. pylori-associated GC and its novel molecular mechanism. Multiple datasets and tissue microarray are utilized for assessing hnRNPA2B1 expression in response to H. pylori infection and its clinical prognosis in patients with GC. The roles of hnRNPA2B1 are investigated through a variety of techniques including glucose metabolism analysis, m6A-epitranscriptomic microarray, Ribo-seq, polysome profiling, RIP-seq. In addition, hnRNPA2B1 interaction with poly(A) binding protein cytoplasmic 1 (PABPC1) is validated using mass spectrometry and co-IP. These results show that hnRNPA2B1 is upregulated in GC and correlated with poor prognosis. H. pylori infection induces hnRNPA2B1 upregulation through recruiting NF-κB to its promoter. Intriguingly, cytoplasm-anchored hnRNPA2B1 coordinated PABPC1 to stabilize its relationship with cap-binding eIF4F complex, which facilitated the translation of CIP2A, DLAT and GPX1 independent of m6A modification. In summary, hnRNPA2B1 facilitates the non-m6A translation of epigenetic mRNAs in GC progression by interacting with PABPC1-eIF4F complex and predicts poor prognosis for patients with GC.

Risk factors and long-term outcomes for human herpesvirus 6 encephalitis in the early period after allogeneic stem cell transplantation.

Human herpesvirus 6 (HHV6) encephalitis is a rare but life-threatening complication for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, reports on susceptibility factors and clinical outcomes are limited. We enrolled HHV6 encephalitis patients following allo-HSCT between 2018 and 2022, then conducted a 1:4 nested case-control cohort study to evaluate risk factors and long-term outcomes. Among 1350 patients, 20 (1.48%) developed HHV6 encephalitis, with a median onset time of 25.5 days after HSCT. Patient age<30 (odds ratio [OR], 3.24, P = 0.016) and NK cell count<115/ul at 21 days (OR, 6.07, P = 0.018) were identified as independent risk factors in multivariate analysis. Moreover, the HHV6 encephalitis group was significantly associated with higher incidence of grade II-IV graft-versus-host disease (aGVHD) (hazard ratio [HR], 5.52, P < 0.001) and transplant-associated microangiopathy (HR,9.86, P < 0.001), and demonstrated a significantly higher non-relapse mortality (NRM) (HR, 5.28, P = 0.004) and a lower overall survival (HR, 4.34, P = 0.001) or progression-free survival (HR, 3.94, P = 0.001) compared to control group. In conclusion, patients <30 years old or with delayed NK cell recovery are more susceptible to HHV6 encephalitis after allo-HSCT, and patients with HHV6 encephalitis after transplantation have poorer clinical outcomes.

Protective effects of curcumin on corneal endothelial cell PANoptosis and monocyte adhesion induced by tumor necrosis factor-alpha and interferon-gamma in rats.

Decrease of human corneal endothelial cell (CEC) density leads to corneal edema, progressive corneal opacity, and reduced visual acuity. A reduction in CEC density may be related to elevated levels of inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interferon (INF)-γ. PANoptosis, characterized by the activation of apoptosis, necroptosis, and pyroptosis, could be a factor in the loss of CECs driven by TNF-α and INF-γ. Cytokines also stimulate monocytes adhesion to endothelium. It has been shown in previous research that curcumin plays protective roles against numerous corneal inflammatory diseases. However, it is not determined whether curcumin acts as an anti-PANoptotic agent or if it mitigates monocyte adhesion to CECs. Therefore, this research aimed to explor the potential therapeutic effects of curcumin and its underlying mechanisms in the loss of CECs. CEC injury models were established, and curcumin was injected subconjunctivally. Clinical evaluation of the corneas was conducted using a scoring system and anterior segment photography. Corneal observation was performed with hematoxylin and eosin staining and immunostaining of zona occludens-1(ZO-1). Apoptotic cells within the corneal endothelium were observed using TUNEL staining. The detection of primary proteins expression was accomplished through Western blot analysis. Interleukin (IL)-1ß and macrophage chemotactic protein 1 (MCP-1) levels were determined via ELISA, while the expression of cleaved caspase-3, gasdermin-D (GSDMD), phosphor-mixed lineage kinase domain-like protein (p-MLKL) and intercellular cell adhesion molecule-1 were confirmed by immunofluorescence. Myeloperoxidase (MPO) activity was measured in aqueous humors. Curcumin treatment attenuated the loss of CECs and corneal edema caused by TNF-α and IFN-γ. Besides, it decreased the count of TUNEL-positive cells, and inhibited the upregulation of cleaved caspase-3, cleaved caspase-6, cleaved caspase-7, and cleaved poly (ADP-ribose) polymerase. Moreover, both the expression and phosphorylation of MLKL and receptor-interacting protein 3 were decreased in curcumin-treated rats. Furthermore, curcumin also lowered the expression of cleaved caspase-1, diminished the levels of IL1ß and MCP-1, and inhibited the activity of MPO. Besides, the expression of intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, as well as the number of CD11b-positive cells adhered to the CECs decreased for the administration of curcumin.

Therapeutic Nonsense Suppression Modalities: From Small Molecules to Nucleic Acid-Based Approaches.

Nonsense mutations are genetic mutations that create premature termination codons (PTCs), leading to truncated, defective proteins in diseases such as cystic fibrosis, neurofibromatosis type 1, Dravet syndrome, Hurler syndrome, Beta thalassemia, inherited bone marrow failure syndromes, Duchenne muscular dystrophy, and even cancer. These mutations can also trigger a cellular surveillance mechanism known as nonsense-mediated mRNA decay (NMD) that degrades the PTC-containing mRNA. The activation of NMD can attenuate the consequences of truncated, defective, and potentially toxic proteins in the cell. Since approximately 20% of all single-point mutations are disease-causing nonsense mutations, it is not surprising that this field has received significant attention, resulting in a remarkable advancement in recent years. In fact, since our last review on this topic, new examples of nonsense suppression approaches have been reported, namely new ways of promoting the translational readthrough of PTCs or inhibiting the NMD pathway. With this review, we update the state-of-the-art technologies in nonsense suppression, focusing on novel modalities with therapeutic potential, such as small molecules (readthrough agents, NMD inhibitors, and molecular glue degraders); antisense oligonucleotides; tRNA suppressors; ADAR-mediated RNA editing; targeted pseudouridylation; and gene/base editing. While these various modalities have significantly advanced in their development stage since our last review, each has advantages (e.g., ease of delivery and specificity) and disadvantages (manufacturing complexity and off-target effect potential), which we discuss here.

The effectiveness of gliding arc discharge plasma in sterilizing artificial seawater contaminated with Vibrio parahaemolyticus.

The rapid proliferation of the halophilic pathogen Vibrio parahaemolyticus poses a severe health hazard to halobios and significantly impedes intensive mariculture. This study aimed to evaluate the potential application of gliding arc discharge plasma (GADP) to control the infection of Vibrio parahaemolyticus in mariculture. This study investigated the inactivation ability of GADP against Vibrio parahaemolyticus in artificial seawater (ASW), changes in the water quality of GADP-treated ASW, and possible inactivation mechanisms of GADP against Vibrio parahaemolyticus in ASW. The results indicate that GADP effectively inactivated Vibrio parahaemolyticus in ASW. As the volume of ASW increased, the time required for GADP sterilization also increased. However, the complete sterilization of 5000 mL of ASW containing Vibrio parahaemolyticus of approximately 1.0 × 104 CFU/mL was achieved within 20 min. Water quality tests of the GADP-treated ASW demonstrated that there were no significant changes in salinity or temperature when Vibrio parahaemolyticus (1.0 ×104 CFU/mL) was completely inactivated. In contrast to the acidification observed in plasma-activated water (PAW) in most studies, the pH of ASW did not decrease after treatment with GADP. The H2O2 concentration in the GADP-treated ASW decreased after post-treatment. The NO2-concentration in the GADP-treated ASW remained unchanged after post-treatment. Further analysis revealed that GADP induced oxidative stress in Vibrio parahaemolyticus, which increased cell membrane permeability and intracellular ROS levels of Vibrio parahaemolyticus. This study provides a viable solution for infection with the halophilic pathogen Vibrio parahaemolyticus and demonstrates the potential of GADP in mariculture.

Functional characterization of polyphenol oxidase OfPPO2 supports its involvement in parallel biosynthetic pathways of acteoside.

Acteoside is a bioactive phenylethanoid glycoside widely distributed throughout the plant kingdom. Because of its two catechol moieties, acteoside displays a variety of beneficial activities. The biosynthetic pathway of acteoside has been largely elucidated, but the assembly logic of two catechol moieties in acteoside remains unclear. Here, we identified a novel polyphenol oxidase OfPPO2 from Osmanthus fragrans, which could hydroxylate various monophenolic substrates, including tyrosine, tyrosol, tyramine, 4-hydroxyphenylacetaldehyde, salidroside, and osmanthuside A, leading to the formation of corresponding catechol-containing intermediates for acteoside biosynthesis. OfPPO2 could also convert osmanthuside B into acteoside, creating catechol moieties directly via post-modification of the acteoside skeleton. The reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis and subcellular localization assay further support the involvement of OfPPO2 in acteoside biosynthesis in planta. These findings suggest that the biosynthesis of acteoside in O. fragrans may follow "parallel routes" rather than the conventionally considered linear route. In support of this hypothesis, the glycosyltransferase OfUGT and the acyltransferase OfAT could direct the flux of diphenolic intermediates generated by OfPPO2 into acteoside. Significantly, OfPPO2 and its orthologs constitute a functionally conserved enzyme family that evolved independently from other known biosynthetic enzymes of acteoside, implying that the substrate promiscuity of this PPO family may offer acteoside-producing plants alternative ways to synthesize acteoside. Overall, this work expands our understanding of parallel pathways plants may employ to efficiently synthesize acteoside, a strategy that may contribute to plants' adaptation to environmental challenges.