The AT-hook protein AHL29 promotes Bacillus subtilis colonization by suppressing SWEET2-mediated sugar retrieval in Arabidopsis roots.

Beneficial Bacillus subtilis (BS) symbiosis could combat root pathogenesis, but it relies on root-secreted sugars. Understanding the molecular control of sugar flux during colonization would benefit biocontrol applications. The SWEET (Sugar Will Eventually Be Exported Transporter) uniporter regulates microbe-induced sugar secretion from roots; thus, its homologs may modulate sugar distribution upon BS colonization. Quantitative polymerase chain reaction revealed that gene transcripts of SWEET2, but not SWEET16 and 17, were significantly induced in seedling roots after 12 h of BS inoculation. Particularly, SWEET2-ß-glucuronidase fusion proteins accumulated in the apical mature zone where BS abundantly colonized. Yet, enhanced BS colonization in sweet2 mutant roots suggested a specific role for SWEET2 to constrain BS propagation, probably by limiting hexose secretion. By employing yeast one-hybrid screening and ectopic expression in Arabidopsis protoplasts, the transcription factor AHL29 was identified to function as a repressor of SWEET2 expression through the AT-hook motif. Repression occurred despite immunity signals. Additionally, enhanced SWEET2 expression and reduced colonies were specifically detected in roots of BS-colonized ahl29 mutant. Taken together, we propose that BS colonization may activate repression of AHL29 on SWEET2 transcription that would be enhanced by immunity signals, thereby maintaining adequate sugar secretion for a beneficial Bacillus association.

Water-Ice Microstructures and Hydration States of Acridinium Iodide Studied by Phosphorescence Spectroscopy.

Ice has been suggested to have played a significant role in the origin of life partly owing to its ability to concentrate organic molecules and promote reaction efficiency. However, the techniques for studying organic molecules in ice are absorption-based, which limits the sensitivity of measurements. Here we introduce an emission-based method to study organic molecules in water ice: the phosphorescence displays high sensitivity depending on the hydration state of an organic salt probe, acridinium iodide (ADI). The designed ADI aqueous system exhibits phosphorescence that can be severely perturbed when the temperature is higher than 110 K at a concentration of the order of 10-5 M, indicating changes in hydration for ADI. Using the ADI phosphorescent probe, it is found that the microstructures of water ice, i.e., crystalline vs. glassy, can be strongly dictated by a trace amount (as low as 10-5 M) of water-soluble organic molecules. Consistent with cryoSEM images and temperature-dependent Raman spectral data, the ADI is dehydrated in more crystalline ice and hydrated in more glassy ice. The current investigation serves as a starting point for using more sensitive spectroscopic techniques for studying water-organics interactions at a much lower concentration and wider temperature range.

IL-38 alleviates airway remodeling in chronic asthma via blocking the profibrotic effect of IL-36γ.

Airway remodeling is a major feature of asthma. Interleukin (IL)-36γ is significantly upregulated and promotes airway hyper-responsiveness (AHR) in asthma, but its role in airway remodeling is unknown. Here, we aimed to investigate the role of IL-36γ in airway remodeling, and whether IL-38 can alleviate airway remodeling in chronic asthma by blocking the effects of IL-36γ. IL-36γ was quantified in mice inhaled with house dust mite (HDM). Extracellular matrix (ECM) deposition in lung tissues and AHR were assessed following IL-36γ administration to mice. Airway inflammation, AHR, and remodeling were evaluated after IL-38 or blocking IL-36 receptor (IL-36R) treatment in asthmatic mice. The effects of lung fibroblasts stimulated with IL-36γ and IL-38 were quantified in vitro. Increased expression of IL-36γ was detected in lung tissues of HDM-induced asthmatic mice. The intratracheal instillation of IL-36γ to mice significantly enhanced the ECM deposition, AHR, and the number of activated lung fibroblasts around the airways. IL-38 or blocking IL-36R treated asthmatic mice showed a significant alleviation in the airway inflammation, AHR, airway remodeling, and number of activated fibroblasts around airways as compared with the HDM group. In vitro, IL-36γ promoted the activation and migration of human lung fibroblasts (HFL-1). The administration of IL-38 can counteract these biological processes induced by IL-36γ in HFL-1cells. The results indicated that IL-38 can mitigate airway remodeling by blocking the profibrotic effects of IL-36γ in chronic asthma. IL-36γ may be a new therapeutic target, and IL-38 is a potential candidate agent for inhibiting airway remodeling in asthma.

Toxin-Enabled "On-Demand" Liposomes for Enhanced Phototherapy to Treat and Protect against Methicillin-Resistant Staphylococcus aureus Infection.

An effective therapeutic strategy against methicillin-resistant Staphylococcus aureus (MRSA) that does not promote further drug resistance is highly desirable. While phototherapies have demonstrated considerable promise, their application toward bacterial infections can be limited by negative off-target effects to healthy cells. Here, a smart targeted nanoformulation consisting of a liquid perfluorocarbon core stabilized by a lipid membrane coating is developed. Using vancomycin as a targeting agent, the platform is capable of specifically delivering an encapsulated photosensitizer along with oxygen to sites of MRSA infection, where high concentrations of pore-forming toxins trigger on-demand payload release. Upon subsequent near-infrared irradiation, local increases in temperature and reactive oxygen species effectively kill the bacteria. Additionally, the secreted toxins that are captured by the nanoformulation can be processed by resident immune cells to promote multiantigenic immunity that protects against secondary MRSA infections. Overall, the reported approach for the on-demand release of phototherapeutic agents into sites of infection could be applied against a wide range of high-priority pathogens.

Assessing the efficacy of myopia control in monocular orthokeratology treated unilateral myopic children.

PURPOSE: To investigate the efficacy of myopia control by comparing the orthokeratology (Ortho-K) treated eyes and the emmetropic contralateral eyes in unilateral myopic children, and to identify the inter-individual influence factors. METHOD: In this retrospective study, 1566 medical records of children wearing Ortho-K lens were reviewed, and 62 children who received monocular Ortho-K lens for more than 1 year were analyzed. The change in axial length (AL) of the Ortho-K eyes and the emmetropic contralateral eyes was recorded. To evaluate the absolute and relative efficacy of myopia control, the intra-bilateral absolute reduction in AL growth (ibARAL) and the intra-bilateral relative reduction in AL growth (ibRRAL) were calculated as main outcomes. Association of the AL elongation, ibARAL and ibRRAL with age, sex and ocular parameters was analyzed by correlation analysis and generalized estimating equation (GEE) analysis. RESULT: The average initial wearing age was 10.76 ± 1.45 (ranged 8.5 to 15.8). The average baseline SER was - 2.15 ± 1.03 (ranged - 5.25 to -1.00) D in the Ortho-K eyes and - 0.01 ± 0.40 (ranged - 0.75 to 0.75) D in the contralateral eyes. At the 1-year follow-up, the average increased AL was significantly less in the Ortho-K eyes (0.07 ± 0.18 mm) than in the fellow eyes (0.48 ± 0.24 mm) (p < 0.001). The mean ibARAL was 0.41 ± 0.30 mm, and the mean ibRRAL was 83.4%±56.3%. In the GEE model, the AL change in Ortho-K eyes (ß = 0.051, p = 0.009, 95%CI: 0.012 to 0.090), the ibARAL (ß= -0.153, p = 0.000, 95%CI: -0.228 to -0.078) and the ibRRAL (ß= -0.196, p = 0.020, 95%CI: -0.361 to -0.030) were independently associated with the spherical equivalent refraction (SER) of the Ortho-K eyes, after adjusting for age, sex, and keratometry. CONCLUSION: In our study, the Ortho-K treatment was efficacious in controlling axial length growth in the monocular orthokeratology treated unilateral myopic eyes. The efficacy increased when the myopia was more severe. In the children from 8 to 16 years old, the effectiveness was independent of age and sex.

Comparison of peak expiratory Flow(PEF) and COPD assessment test (CAT) to assess COPD exacerbation requiring hospitalization: A prospective observational study.

BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (COPD) resulting in hospitalization is significantly associated with the increased morbidity and mortality, but there is a lack of an effective method to assess it. This study aimed to compare the ability of peak expiratory flow (PEF) and COPD assessment test (CAT) to assess COPD exacerbations requiring hospitalization. METHODS: A cohort of 110 patients with moderate to severe COPD was studied over a period of 12 months, and their daily morning PEFs and CAT scores were recorded throughout the study. RESULTS: After 12 months of follow-up, 72 patients experienced 156 COPD exacerbations, 74 (47%) that resulted in hospitalization and 82 (53%) that did not result in hospitalization. Change in CAT score from baseline to exacerbation was significantly related to change in PEF and Spearman's rho =0.375 (95% CI, 0.227 to 0.506; p < .001). Change in PEF and CAT score from baseline to hospitalized exacerbation was significantly larger than that from baseline to non-hospitalized exacerbation (p < .05). Multivariable analysis indicated that ΔPEF (OR 1.11, 95% CI 1.06-1.16, p < .001) and ΔCAT (OR 1.64 95% CI 1.18-2.27, p = .003) were independently associated with risk of hospitalized exacerbation. ROC analysis indicated that the optimal cutoff value of ΔPEF for identifying hospitalized exacerbation was 49 L/min (27% from baseline), with a sensitivity and specificity of 82.7% and 76.7% (area under the curve [AUC] = 0.872 (95% CI 0.80-0.944, p < .05). The optimal cutoff value of ΔCAT score for identifying hospitalized exacerbation was 10.5 (63% from baseline), with a sensitivity and specificity of 67.3% and 77.4% [AUC]=0.763 (95% CI 0.67-0.857, p < .05). The AUC of ΔPEF and ΔCAT combined for the identification of hospitalized exacerbation was 0.900 (95% CI 0.841-0.959, p < .05), which was larger than that of ΔCAT or ΔPEF. CONCLUSIONS: ΔPEF and ΔCAT were independently associated with risk of hospitalized exacerbation. Compared with CAT, PEF was superior to identify hospitalized exacerbation. Identification via PEF and CAT combined is more effective than using PEF or CAT alone. These results help to assess the severity of COPD exacerbation and provide valuable information for clinical decision-making.

Fluorinated Copolypeptide-Stabilized Microbubbles with Maleimide-Decorated Surfaces as Long-Term Ultrasound Contrast Agents.

Gas-filled microbubbles (MBs) have been clinically used as ultrasound (US) contrast agents for disease diagnosis and treatment. However, it remains a great challenge to resolve the dilemma of stability and contrast enhancement of MBs. Herein, amphiphilic copolypeptides bearing fluorinated blocks are synthesized to stabilize perfluorocarbon (PFC)-filled MBs, exhibiting unique stability under both long-term storage and US imaging conditions. The fluorinated inner layer reduces the internal Laplace pressure and greatly improves the stability of MBs, which can be further reinforced by crosslinking of the dipropargyl-containing middle blocks. To overcome the suppressed nonlinear oscillation of polymer shells, maleimide groups are introduced onto the surface of MBs, enabling in situ reaction with plasma proteins to enhance second harmonic signals without compromising the stability of MBs, conferring better US imaging performance than that of SonoVueTM MBs.

Dynamin-2 mediates clathrin-dependent endocytosis for amyloid-ß internalization in brain microvascular endothelial cells.

Dynamin is recognized as a crucial regulator for membrane fission and has three isoforms in mammals. But the expression patterns of dynamin isoforms and their roles in non-neuronal cells are incompletely understood. In this study, the expression profiles of dynamin isoforms and their roles in endocytosis was investigated in brain endothelial cells. We found that Dyn2 was expressed at highest levels, whereas the expression of Dyn1 and Dyn3 were far less than Dyn2. Live-cell imaging was used to investigate the effects of siRNA-mediated knockdown of individual dynamin isoforms on transferrin uptake, and we found that Dyn2, but not Dyn1 or Dyn3, is required for the endocytosis in brain endothelial cells. Results of dextran uptake assay showed that dynamin isoforms are not involved in the clathrin-independent fluid-phase internalization of brain endothelial cells, suggesting the specificity of the role of Dyn2 in clathrin-dependent endocytosis. Immunofluorescence and electron microscopy analysis showed that Dyn2 co-localizes with clathrin and acts at the late stage of vesicle fission in the process of endocytosis. Further results showed that Dyn2 is necessary for the basolateral-to-apical internalization of amyloid-ß into brain endothelial cells. We concluded that Dyn2, but not Dyn1 or Dyn3, mediates the clathrin-dependent endocytosis for amyloid-ß internalization particularly from basolateral to apical side into brain endothelial cells.

Substrate-Tuned Domino Annulation for Selective Synthesis of Poly-substituted Benzo[f]imidazo[2,1-a][2,7]naphthyridines and 3-Azaheterocyclic Substituted 2-Arylquinolines.

A domino annulation/oxidation of heterocyclic ketene aminals (HKAs) and 2-aminochalcones has been developed for the selective synthesis of poly-substituted benzo[f]imidazo[2,1-a][2,7]naphthyridines and 3-azaheterocyclic substituted 2-arylquinolines. These reactions proceed well under mild conditions without any additives. Plausible mechanisms for such a polycyclic ring system assembly were also proposed. Moreover, benzo[f]imidazo[2,1-a][2,7]naphthyridine 3g displayed a fluorescence effect, demonstrating the potential applications in organic optical materials.

[The Surgical Effects of Medial Rectus Recession on Divergence Insufficiency Esotropia].

OBJECTIVE: To study the surgical effects of medial rectus recession (MRR) on divergence insufficiency esotropia (DIE). METHODS: Nine DIE patients who were admitted to and had MRR at Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University between December 2017 and June 2020 were included in this retrospective study. All patients were followed up for 1 year at least. The postoperative esodeviation, near-distant disparity (NDD) and visual function were observed and compared. RESULTS: The mean age of the 9 patients was 28.8 years old (10-49 yr.), including 3 adolescent patients (≤18 yr.). The mean preoperative esodeviation was (19.8±13.2) PD for near and (32.6±15.3) PD at distance, while, the mean postoperative esodeviation 1 year after MMR was (-0.2±3.5) PD for near and (6.0±2.2) PD at distance, showing significant improvement over the mean preoperative esodeviation ( P=0.012, P=0.007). NDD dropped from (12.8±2.4) PD before the surgery to (6.0±2.2) PD 1 year after the surgery, showing significant improvement ( P=0.008), and remained stable 1 year after the surgery ( F=0.075, P=0.900). There was no significant improvement of near stereopsis ( P=0.306). Binocular function at distance was significantly improved after surgery (Worth 4 dots test : P=0.017; Bagolini striated glasses: P=0.035). The patients were divided into two groups, the adolescent group (age≤18 yr., n=3) and the adult group (age>18 yr., n=6). Prior to the operation, the mean spherical diopter of the adolescent group (OD -1.75 D, OS -1.92 D) was lower than that of the adult group (OD -6.17 D, OS -6.04 D) ( P=0.012). The average value of preoperative AC/A of the adolescent group was 4.33. It was 2.33 in the adult group, which was lower than the normal value, and significantly lower than that of the adolescent group ( P=0.12). There was no significant difference in esodeviation or NDD between the adolescent group and the adult group before and after operation. CONCLUSIONS: Medial rectus muscle recession can effectively improve the NDD and the binocular function at distance of patients with divergence insufficiency esotropia. Postoperative esodeviations both for near and at distance tend to regress after the surgery. Therefore, it is recommended that the amount of MRR be increased in the treatment of DIE.

Retraction Note: The fatty liver index (FLI) and incident hypertension: a longitudinal study among Chinese population.

An amendment to this paper has been published and can be accessed via the original article.

High-Fidelity End-Functionalization of Poly(ethylene glycol) Using Stable and Potent Carbamate Linkages.

Commercial PEG-amine is of unreliable quality, and conventional PEG functionalization relies on esterification and etherification steps, suffering from incomplete conversion, harsh reaction conditions, and functional-group incompatibility. To solve these challenges, we propose an efficient strategy for PEG functionalization with carbamate linkages. By fine-tuning terminal amine basicity, stable and high-fidelity PEG-amine with carbamate linkage was obtained, as seen from the clean MALDI-TOF MS pattern. The carbamate strategy was further applied to the synthesis of high-fidelity multi-functionalized PEG with varying reactive groups. Compared to with an ester linkage, amphiphilic PEG-PS block copolymers bearing carbamate junction linkage exhibits preferential self-assembly tendency into vesicles. Moreover, nanoparticles of the latter demonstrate higher drug loading efficiency, encapsulation stability against enzymatic hydrolysis, and improved in vivo retention at the tumor region.

LncRNA NEAT1 Promotes Deterioration of Hepatocellular Carcinoma Based on In Vitro Experiments, Data Mining, and RT-qPCR Analysis.

BACKGROUND/AIMS: Accumulated evidence indicates that lncRNA NEAT1 has important roles in various malignant tumors. In this study, we conducted a comprehensive analysis to explore the exact role of NEAT1 in hepatocellular carcinoma (HCC). METHODS: The effects of NEAT1 on cell proliferation, apoptosis, migration, and invasion were measured by in vitro experiments. The expression level and clinical value of NEAT1 in HCC was evaluated based on data from The Cancer Genome Atlas (TCGA), Oncomine, and in-house real-time quantitative (RT-qPCR). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) network analyses were conducted to investigate the potential molecular mechanisms of NEAT1. RESULTS: NEAT1 siRNA not only inhibited proliferation, migration, and invasion of HCC cells but also induced HCC cell apoptosis. A total of four records from TCGA, Oncomine, and RT-qPCR analysis were combined to assess the expression level of NEAT1 in HCC. The pooled standard mean deviation (SMD) indicated that NEAT1 was up-regulated in HCC (SMD = 0.54; 95% CI, 0.36-0.73; P < 0.0001). The area under the curve value of the summary receiver operating characteristic curve was 0.71. NEAT1 expression was also related to race (P = 0.025) and distant metastasis (P = 0.002). Additionally, the results of GO, KEGG pathway, and PPI network analyses suggest that NEAT1 may promote the progression of HCC by interacting with several tumor-related genes (SP1, MDM4, CREBBP, TRAF5, CASP8, TRAF1, KAT2A, and HIST4H4). CONCLUSIONS: NEAT1 contributes to the deterioration of HCC and provides a potential biomarker for the diagnosis and therapy of HCC.

Clinical Significance of miR-210 and its Prospective Signaling Pathways in Non-Small Cell Lung Cancer: Evidence from Gene Expression Omnibus and the Cancer Genome Atlas Data Mining with 2763 Samples and Validation via Real-Time Quantitative PCR.

BACKGROUND/AIMS: Since the function of microRNA (miR)-210 in non-small cell lung cancer (NSCLC) remains unclear, we aimed to explore the clinical significance of miR-210 in NSCLC. METHODS: NSCLC-related data from 1673 samples on Gene Expression Omnibus and 1090 samples on The Cancer Genome Atlas were obtained and analyzed. The expression level of miR-210 was validated via real-time quantitative PCR analysis with 125 paired clinical samples. A meta-analysis was performed to generate a comprehensive understanding of miR-210 expression and its clinical significance in NSCLC. In addition, bioinformatics analysis was also conducted to reveal the potential underlying mechanism of miR-210 action in NSCLC. RESULTS: miR-210 expression was consistently elevated in NSCLC solid tissue samples. However, its expression was controversial in easily obtained body fluids (i.e., blood, plasma, and serum). Moreover, an overall pooled meta-analysis implied a comparatively higher level of miR-210 expression in NSCLC cancerous tissue than in normal control tissue (P < 0.001). In addition, a meta-analysis of outcome revealed a significant diagnostic capacity of miR-210 in NSCLC by detecting its expression in serum and sputum (area under the summary receiver operating characteristic curve 0.82 and 0.81, respectively). miR-210 overexpression was associated with poor progression-free survival (PFS) in NSCLC and was negatively related to overall survival and disease-free survival. Bioinformatic gene enrichment and annotation analyses showed that the target genes of miR-210 were greatly enriched in cell adhesion and plasma membrane, and three pathways were considered to be the main functional circuits of miR-210: renin secretion, the cGMP-PKG signaling pathway, and cell adhesion molecules. CONCLUSION: In NSCLC, miR-210 expression was elevated and overexpression indicated poor PFS. Expression level of miR-210 in serum and sputum showed significant diagnostic value for NSCLC.

Expression of microRNA-99a-3p in Prostate Cancer Based on Bioinformatics Data and Meta-Analysis of a Literature Review of 965 Cases.

BACKGROUND microRNAs (miRNAs) have a role as biomarkers in human cancer. The aim of this study was to use bioinformatics data, and review of cases identified from the literature, to investigate the role of microRNA-99a-3p (miR-99a-3p) in prostate cancer, including the identification of its target genes and signaling pathways. MATERIAL AND METHODS Meta-analysis from a literature review included 965 cases of prostate cancer. Bioinformatics databases interrogated for miR-99a-3p in prostate cancer included The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and ArrayExpress. Twelve computational predictive algorithms were developed to integrate miR-99a-3p target gene prediction data. Bioinformatics analysis data from Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) network analysis were used investigate the possible pathways and target genes for miR-99a-3p in prostate cancer. RESULTS TCGA data showed that miR-99a was down-regulated in prostate cancer when compared with normal prostate tissue. Receiver-operating characteristic (ROC) curve area under the curve (AUC) for miR-99a-3p was 0.660 (95% CI, 0.587-0.732) or a moderate level of discriminations. Pathway analysis showed that miR-99a-3p was associated with the Wnt and vascular endothelial growth factor (VEGF) signaling pathways. The PPP3CA and HYOU1 genes, selected from the PPI network, were highly expressed in prostate cancer tissue compared with normal prostate tissue, and negatively correlated with the expression of miR-99a-3p. CONCLUSIONS In prostate cancer, miR-99a-3p expression was associated with the Wnt and VEGF signaling pathways, which might inhibit the expression of PPP3CA or HYOU1.

The fatty liver index (FLI) and incident hypertension: a longitudinal study among Chinese population.

BACKGROUND: Hypertension and nonalcoholic fatty liver both have been considered as the serious public health problems in recent years. However, the longitudinal association between hypertension and nonalcoholic fatty liver remains unclear in Chinese population. METHODS: This study was aimed to investigate the longitudinal association between nonalcoholic fatty liver assessed by fatty liver index and the incident hypertension among Chinese population and to evaluate the ability of FLI index, through comparing with the predictive value of other indexes. RESULTS: Four thousand six hundred eighty-six subjects (3177 males and 1509 females) were involved and followed up for 9 years. The subjects were divided into groups according to the fatty liver index. Univariate and multivariate Cox regression models were used to analyze the risk factors of hypertension. After 9 years of follow-up, 2047 subjects developed hypertension. The overall 9-year cumulative incidence of HTN was 43.7%, ranging from 36.0% (FLI <  30) to 75.3% (FLI ≥ 60) (P for trend < 0.001). Cox regression analyses indicated that nonalcoholic fatty liver assessed by fatty liver index was independently and positively associated with the risk of incident hypertension. In receiver operating characteristic (ROC) curve analysis, the ROC curve (AUC) of FLI was 0.701 (95% CI 0.686-0.716), which was larger than that of its components. CONCLUSION: The nonalcoholic fatty liver assessed by FLI independently predicted the incident hypertension among the Chinese population.

Engineering Semicarbazide-Bearing Polypeptide Conjugates for Efficient Tumor Chemotherapy and Imaging of Tumor Metastasis.

Polypeptide materials offer scalability, biocompatibility, and biodegradability, rendering them an ideal platform for biomedical applications. However, the preparation of polypeptides with specific functional groups, such as semicarbazide moieties, remains challenging. This work reports, for the first time, the straightforward synthesis of well-defined methoxy-terminated poly(ethylene glycol)-b-polypeptide hybrid block copolymers (HBCPs) containing semicarbazide moieties. This synthesis involves implementing the direct polymerization of environment-stable N-phenoxycarbonyl-functionalized α-amino acid (NPCA) precursors, thereby avoiding the handling of labile N-carboxyanhydride (NCA) monomers. The resulting HBCPs containing semicarbazide moieties enable facile functionalization with aldehyde/ketone derivatives, forming pH-cleavable semicarbazone linkages for tailored drug release. Particularly, the intracellular pH-triggered hydrolysis of semicarbazone moieties restores the initial semicarbazide residues, facilitating endo-lysosomal escape and thus improving therapeutic outcomes. Furthermore, the integration of the hypoxic probe (Ir(btpna)(bpy)2 ) into the pH-responsive nanomedicines allows sequential responses to acidic and hypoxic tumor microenvironments, enabling precise detection of metastatic tumors. The innovative approach for designing bespoke functional polypeptides holds promise for advanced drug delivery and precision therapeutics.

SIRT5-related lysine demalonylation of GSTP1 contributes to cardiomyocyte pyroptosis suppression in diabetic cardiomyopathy.

Sirtuin 5 (SIRT5), localized in the mitochondria, has been identified as a protein desuccinylase and demalonylase in the mitochondria since the depletion of SIRT5 boosted the global succinylation and malonylation of mitochondrial proteins. We investigated the role of SIRT5 in diabetic cardiomyopathy (DCM) and identified the mechanism regarding lysine demalonylation in this process. Wild-type and SIRT5 knockout mice were induced with DCM, and primary cardiomyocytes and cardiac fibroblasts extracted from wild-type and SIRT5 knockout mice were subjected to high glucose (HG). SIRT5 deficiency exacerbated myocardial injury in DCM mice, aggravated HG-induced oxidative stress and mitochondrial dysfunction in cardiomyocytes, and intensified cardiomyocyte senescence, pyroptosis, and DNA damage. DCM-induced SIRT5 loss diminished glutathione S-transferase P (GSTP1) protein stability, represented by significantly increased lysine malonylation (Mal-Lys) modification of GSTP1. SIRT5 overexpression alleviated DCM-related myocardial injury, which was reversed by GSTP1 knockdown. Reduced SIRT5 transcription in DCM resulted from the downregulation of SPI1. SPI1 promoted the transcription of SIRT5, thereby ameliorating DCM-associated myocardial injury. However, SIRT5 deletion resulted in a significant reversal of the protective effect of SPI1. These observations suggest that SPI1 activates SIRT5 transcriptionally to mediate GSTP1 Mal-Lys modification and protein stability, thus ameliorating DCM-associated myocardial injury.

A rapid aureochrome opto-switch enables diatom acclimation to dynamic light.

Diatoms often outnumber other eukaryotic algae in the oceans, especially in coastal environments characterized by frequent fluctuations in light intensity. The identities and operational mechanisms of regulatory factors governing diatom acclimation to high light stress remain largely elusive. Here, we identified the AUREO1c protein from the coastal diatom Phaeodactylum tricornutum as a crucial regulator of non-photochemical quenching (NPQ), a photoprotective mechanism that dissipates excess energy as heat. AUREO1c detects light stress using a light-oxygen-voltage (LOV) domain and directly activates the expression of target genes, including LI818 genes that encode NPQ effector proteins, via its bZIP DNA-binding domain. In comparison to a kinase-mediated pathway reported in the freshwater green alga Chlamydomonas reinhardtii, the AUREO1c pathway exhibits a faster response and enables accumulation of LI818 transcript and protein levels to comparable degrees between continuous high-light and fluctuating-light treatments. We propose that the AUREO1c-LI818 pathway contributes to the resilience of diatoms under dynamic light conditions.

Targeting Labile Iron-Mediated Ferroptosis Provides a Potential Therapeutic Strategy for Rhabdomyolysis-Induced Acute Kidney Injury.

Acute kidney injury (AKI) is a global health problem that occurs in a variety of clinical settings. Despite some advances in supportive clinical care, no medicinal intervention has been demonstrated to reliably prevent AKI thus far. Therefore, it is highly necessary to investigate the pathophysiology and mechanisms involved in AKI for the discovery of therapeutics. In the current study, a robust change in the level of renal malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) and elevated renal iron levels were observed in murine rhabdomyolysis-induced AKI (RM-AKI), which supports a pathogenic role of labile iron-mediated ferroptosis and provides a chance to utilize iron chelation for RM-AKI prevention. Given that the existing small molecule-based iron chelators did not show promising preventative effects against RM-AKI, we further designed and synthesized a new hydroxypyridinone-based iron chelator to potently inhibit labile iron-mediated ferroptosis. Lead compound AKI-02 was identified, which remarkably protected renal proximal tubular epithelial cells from ferroptosis as well as showed excellent iron chelation ability. Moreover, administration of AKI-02 led to renal function recovery, a result that was substantiated by the decreased contents of BUN and creatinine, as well as the reduced labile iron level and improved histopathology. Thus, our studies highlighted that targeting labile iron-mediated ferroptosis could provide therapeutic benefits against RM-AKI.