A Hydroxylamine-Mediated Amidination of Lysine Residues That Retains the Protein's Positive Charge.

Lysine-specific peptide and protein modification strategies are widely used to study charge-related functions and applications. However, these strategies often result in the loss of the positive charge on lysine, significantly impacting the charge-related properties of proteins. Herein, we report a strategy to preserve the positive charge and selectively convert amines in lysine side chains to amidines using nitriles and hydroxylamine under aqueous conditions. Various unprotected peptides and proteins were successfully modified with a high conversion rate. Moreover, the reactive amidine moiety and derived modification site enable subsequent secondary modifications. Notably, positive charges were retained during the modification. Therefore, positive charge-related protein properties, such as liquid‒liquid phase separation behaviour of α-synuclein, were not affected. This strategy was subsequently applied to a lysine rich protein to develop an amidine-containing coacervate DNA complex with outstanding mechanical properties. Overall, our innovative strategy provides a new avenue to explore the characteristics of positively charged proteins.

Nonlinear dose-response association of moderate-to-vigorous physical activity with hyperuricemia in US adults: NHANES 2007-2018.

BACKGROUND: The relationship between physical activity and hyperuricemia (HUA) remains inconsistent, and the dose-response association between moderate-to- vigorous physical activity (MVPA) level and HUA still unclear. In this study, we aimed to investigate the dose-response association of MVPA with HUA, and to explore an appropriate range of MVPA level for preventing HUA. METHODS: Data from the US National Health and Nutrition Examination Survey (NHANES) 2007-2018 were used, including 28740 non-gout adult Americans. MVPA level was self-reported using the Global Physical Activity Questionnaire and serum uric acid was measured using timed endpoint method. The dose-response relationship between MVPA level and HUA was modeled with restricted cubic spline analysis. Logistic regression analysis were applied to estimate odd ratios (ORs) and 95% confidence intervals (CIs) of the relationships between MVPA level and HUA. RESULTS: A total of 28740 adults were included in the study (weighted mean age, 47.3 years; 46.5% men), with a prevalence rate of HUA was 17.6%. The restricted cubic spline functions depicted a general U-shaped relationship between MVPA level and HUA. The MVPA level of 933 and 3423 metabolic equivalent (MET) -min/wk were the cut-off discriminating for the risk of HUA. Participants with MVPA levels in the range of 933-3423 MET-min/wk had lower risk of HUA and they had the lowest risk when MVPA levels at around 1556 MET-min/wk. Compared with the moderate-activity group (600-2999 Met-min/wk), the low-activity group (< 600 Met-min/wk) had a greater risk of HUA (OR, 1.13 [95%CI, 1.02-1.26]) after fully adjusting for potential confounders. CONCLUSIONS: Compared with the moderate MVPA level, the low MVPA level was associated with the higher risk of HUA. And there may be a U-shaped dose-response relationship between MVPA level and HUA. When MVPA level was approximately 933-3423 MET-min/wk, the risk of HUA may at a lower level and the risk reached the lowest when MVPA level at around 1556 MET-min/wk.

Fabrication of bovine serum albumin nanofibrils: Physicochemical characteristics, emulsifying and foaming activities.

Bovine serum albumin nanofibrils (BSNs) were fabricated under thermal treatment (85 °C) at acidic condition (pH 2.0) and the incubation time on the structural, and physicochemical characteristics were probed. The formation and development of BSNs have been detected and confirmed by Thioflavin T (ThT) fluorescence and circular dichroism (CD) measurements. The structural alterations of bovine serum albumin (BSA) have also been investigated using intrinsic fluorescence and Congo red (CGR) UV-vis spectroscopy. Atomic force microscopy (AFM) outcomes displayed the morphologies of BSNs at varied time, with a diameter of about 3 nm and a contour length of about 200 nm at 24 h. The apparent viscosities of BSNs at three different pH were in the following order: pH 3.0 > pH 5.0 > pH 7.0. Emulsifying and foaming properties of BSA were pronouncedly enhanced through fibrillation, which was highly correlated with the interfacial properties and structural characteristics. Highest EAI 54.2 m2/g was attained at 48 h and no pronounced alterations were observed for EAI at 24 h and 48 h. Maximum value of FC was obtained at 48 h for BSA. This study will provide some useful information in understanding the formation of BSNs and broaden their application in food systems as functional food ingredients.

Prevalence of Autism Spectrum Disorder Among Children and Adolescents in the United States from 2021 to 2022.

PURPOSE: The prevalence of autism spectrum disorder (ASD) among children and adolescents seem to be high in countries around the world, and it's worth understanding the latest prevalence and trends of ASD in children and adolescents. The purpose of this study was to examine the latest prevalence and decade trend of ASD among individuals aged 3-17 years in the United States. METHODS: A total of 13,198 individuals aged 3-17 years were included. Annual data were examined from the National Health Interview Survey (2021-2022). Weighted prevalence for each of the selected developmental disabilities were calculated. RESULTS: This cross-sectional study estimated the weighted prevalence of autism spectrum disorder were 3.05, 3.79, and 3.42% among individuals aged 3-17 years in the US in 2021, 2022, and the 2-year overall, respectively. We also observed a decade-long upward trend even after adjusting for demographic characteristics (P for trend < .05). CONCLUSION: The results of this study showed that the prevalence of ASD among children and adolescents aged 3-17 years in the United States remained high and has increased over the past decade. The further investigation is necessary to evaluate potential modifiable risk factors and causes of ASD.

Phage tailspike protein coated gold nanoparticles combined with smartphone for rapid bacterial detection and photothermal sterilization.

The integration of recognition and therapeutic functions in multifunctional biosensors is of great importance in guaranteeing food security and reducing the occurrence of foodborne illness caused by foodborne pathogens. In this study, a biosensor utilizing a "sense-and-treat" approach was developed by integrating phage tailspike protein (TSP) with gold nanoparticles (AuNPs@TSP). The synthesized AuNPs@TSP showed strong binding affinity towards Salmonella typhimurium causing color changes and exhibited effective bactericidal activity when exposed to near-infrared (NIR) irradiation. This biosensor facilitated rapid colorimetric detection of S. typhimurium in 50 min, with a LOD (limit of detection) of 2.53 × 103 CFU/mL output on a smartphone APP after analyzing the red-green-blue (RGB) values from color rendering results. Furthermore, the biosensor displayed high selectivity, rapid response time, and broad applicability when tested with real samples. Moreover, the biosensor exhibited a remarkably efficient antibacterial efficacy of 100 % against S. typhimurium under 808 nm light irradiation for 6 min. This study provides a comprehensive investigation into the potential utilization of biosensors for rapid detection and eradication of foodborne pathogens in food industry.

piSTING: A Pocket-Independent Agonist Based on Multivalency-Driven STING Oligomerization.

The stimulator of interferon genes (STING) pathway is a potent therapeutic target for innate immunity. Despite the efforts to develop pocket-dependent small-molecule STING agonists that mimic the endogenous STING ligand, cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), most of these agonists showed disappointing results in clinical trials owing to the limitations of the STING pocket. In this study, we developed novel pocket-independent STING-activating agonists (piSTINGs), which act through multivalency-driven oligomerization to activate STING. Additionally, a piSTING-adjuvanted vaccine elicited a significant antibody response and inhibited tumour growth in therapeutic models. Moreover, a piSTING-based vaccine combination with aPD-1 showed remarkable potential to enhance the effectiveness of immune checkpoint blockade (ICB) immunotherapy. In particular, piSTING can strengthen the impact of STING pathway in immunotherapy and accelerate the clinical translation of STING agonists.

Mechanism of the Pulvinus-Driven Leaf Movement: An Overview.

Leaf movement is a manifestation of plant response to the changing internal and external environment, aiming to optimize plant growth and development. Leaf movement is usually driven by a specialized motor organ, the pulvinus, and this movement is associated with different changes in volume and expansion on the two sides of the pulvinus. Blue light, auxin, GA, H+-ATPase, K+, Cl-, Ca2+, actin, and aquaporin collectively influence the changes in water flux in the tissue of the extensor and flexor of the pulvinus to establish a turgor pressure difference, thereby controlling leaf movement. However, how these factors regulate the multicellular motility of the pulvinus tissues in a species remains obscure. In addition, model plants such as Medicago truncatula, Mimosa pudica, and Samanea saman have been used to study pulvinus-driven leaf movement, showing a similarity in their pulvinus movement mechanisms. In this review, we summarize past research findings from the three model plants, and using Medicago truncatula as an example, suggest that genes regulating pulvinus movement are also involved in regulating plant growth and development. We also propose a model in which the variation of ion flux and water flux are critical steps to pulvinus movement and highlight questions for future research.

Design, Synthesis, and Anti-Leukemic Evaluation of a Series of Dianilinopyrimidines by Regulating the Ras/Raf/MEK/ERK and STAT3/c-Myc Pathways.

Although the long-term survival rate for leukemia has made significant progress over the years with the development of chemotherapeutics, patients still suffer from relapse, leading to an unsatisfactory outcome. To discover the new effective anti-leukemia compounds, we synthesized a series of dianilinopyrimidines and evaluated the anti-leukemia activities of those compounds by using leukemia cell lines (HEL, Jurkat, and K562). The results showed that the dianilinopyrimidine analog H-120 predominantly displayed the highest cytotoxic potential in HEL cells. It remarkably induced apoptosis of HEL cells by activating the apoptosis-related proteins (cleaved caspase-3, cleaved caspase-9 and cleaved poly ADP-ribose polymerase (PARP)), increasing apoptosis protein Bad expression, and decreasing the expression of anti-apoptotic proteins (Bcl-2 and Bcl-xL). Furthermore, it induced cell cycle arrest in G2/M; concomitantly, we observed the activation of p53 and a reduction in phosphorylated cell division cycle 25C (p-CDC25C) / Cyclin B1 levels in treated cells. Additionally, the mechanism study revealed that H-120 decreased these phosphorylated signal transducers and activators of transcription 3, rat sarcoma, phosphorylated cellular RAF proto-oncogene serine / threonine kinase, phosphorylated mitogen-activated protein kinase kinase, phosphorylated extracellular signal-regulated kinase, and cellular myelocytomatosis oncogene (p-STAT3, Ras, p-C-Raf, p-MEK, p-MRK, and c-Myc) protein levels in HEL cells. Using the cytoplasmic and nuclear proteins isolation assay, we found for the first time that H-120 can inhibit the activation of STAT3 and c-Myc and block STAT3 phosphorylation and dimerization. Moreover, H-120 treatment effectively inhibited the disease progression of erythroleukemia mice by promoting erythroid differentiation into the maturation of erythrocytes and activating the immune cells. Significantly, H-120 also improved liver function in erythroleukemia mice. Therefore, H-120 may be a potential chemotherapeutic drug for leukemia patients.

Detection of SARS-CoV-2 using machine learning-enabled paper-assisted ratiometric fluorescent sensors based on target-induced magnetic DNAzyme.

The development of an advanced analytical platform with regard to SARS-CoV-2 is crucial for public health. Herein, we present a machine learning platform based on paper-assisted ratiometric fluorescent sensors for highly sensitive detection of the SARS-CoV-2 RdRp gene. The assay involves target-induced rolling circle amplification to generate magnetic DNAzyme, which is then detectable using the paper-assisted ratiometric fluorescent sensor. This sensor detects the SARS-CoV-2 RdRp gene with a visible-fluorescence color response. Moreover, leveraging different fluorescence responses, the ResNet algorithm of machine learning assists in accurately identifying fluorescence images and differentiating the concentration of the SARS-CoV-2 RdRp gene with over 99% recognition accuracy. The machine learning platform exhibits exceptional sensitivity and color responsiveness, achieving a limit of detection of 30 fM for the SARS-CoV-2 RdRp gene. The integration of intelligent artificial vision with the paper-assisted ratiometric fluorescent sensor presents a novel approach for the on-site detection of COVID-19 and holds potential for broader use in disease diagnostics in the future.

A New Indole Derivative, LWX-473, Overcomes Glucocorticoid Resistance in Jurkat Cells by Activating Mediators of Apoptosis.

BACKGROUND: Glucocorticoids (GCs) are commonly used as the primary chemotherapy for lymphoid malignancies, including acute lymphoblastic leukemia (ALL). However, the development of GC resistance limits their prolonged use. METHODS: In this study, we investigated the potential of a newly synthesized indole derivative called LWX-473, in combination with the classic GC Dexamethasone (DEX), to enhance the responsiveness of Jurkat cells to GC treatment. RESULTS: Our findings demonstrate that LWX-473 alone or in combination with DEX significantly improves GC-induced cell apoptosis and arrests the cell cycle in the G1 phase. Notably, the combination of LWX-473 and DEX exhibits superior efficacy in killing Jurkat cells compared to LWX-473 alone. Importantly, this compound demonstrates reduced toxicity towards normal cells. CONCLUSIONS: Our study reveals that LWX-473 has the ability to restore the sensitivity of Jurkat cells to DEX by modulating the mitochondrial membrane potential, activating the expression of DEX-liganded glucocorticoid receptor (GR), and inhibiting key molecules in the JAK/STAT signaling pathway. These findings suggest that LWX-473 could be a potential therapeutic agent for overcoming GC resistance in lymphoid malignancies.

Nuclear-targeted chimeric peptide nanorods to amplify innate anti-tumor immunity through localized DNA damage and STING activation.

Stimulator of the interferon genes (STING) pathway is appealing but challenging to potentiate the innate anti-tumor immunity. In this work, nuclear-targeted chimeric peptide nanorods (designated as PFPD) are constructed to amplify innate immunity through localized DNA damage and STING activation. Among which, the chimeric peptide (PpIX-FFVLKPKKKRKV) is fabricated with photosensitizer and nucleus targeting peptide sequence, which can self-assemble into nanorods and load STING agonist of DMXAA. The uniform nanosize distribution and good stability of PFPD improve the sequential targeting delivery of drugs towards tumor cells and nuclei. Under light irradiation, PFPD produce a large amount of reactive oxygen species (ROS) to destroy nuclear DNA in situ, and the released cytosolic DNA fragment will efficiently activate innate anti-tumor immunity in combination with STING agonist. In vitro and in vivo results indicate the superior ability of PFPD to activate natural killer cells and T cells, thus efficiently eradicating lung metastatic tumor without inducing unwanted side effects. This work provides a sophisticated strategy for localized activation of innate immunity for systemic tumor treatment, which may inspire the rational design of nanomedicine for tumor precision therapy.

Association between plasma polyunsaturated fatty acids and depressive among US adults.

Background: Depression is associated with greater functional impairment and high societal costs than many other mental disorders. Research on the association between plasma polyunsaturated fatty acids (PUFAs) levels and depression have yielded inconsistent results. Objective: To evaluate whether plasma n-3 and n-6 PUFAs levels are associated with depression in American adults. Methods: A cross-sectional study included 2053 adults (aged ≥20 y) in the National Health and Nutrition Examination Survey (NHANES), 2011-2012. The level of plasma n-3 and n-6 PUFAs were obtained for analysis. Self-reported Patient Health Questionnaire-9 (PHQ-9) was used to identify the depression status. Binary logistic regression analysis was performed to evaluate the association between quartiles of plasma n-3 and n-6 PUFAs and depression after adjustments for confounders. Results: The study of 2053 respondents over 20 years of age with a weighted depression prevalence of 7.29% comprised 1,043 men (weighted proportion, 49.13%) and 1,010 women (weighted, 50.87%), with a weighted mean (SE) age of 47.58 (0.67) years. Significantly increased risks of depression over non-depression were observed in the third quartiles (OR = 1.65, 95% CI = 1.05-2.62) for arachidonic acid (AA; 20:4n-6); the third quartiles (OR = 2.20, 95% CI = 1.20-4.05) for docosatetraenoic acid (DTA; 22:4n-6); the third (OR = 2.33, 95% CI = 1.34-4.07), and highest quartiles (OR = 1.83, 95% CI = 1.03-3.26) for docosapentaenoic acid (DPAn-6; 22:5n-6); and the third (OR = 2.18, 95% CI = 1.18-4.03) and highest quartiles (OR = 2.47, 95% CI = 1.31-4.68) for docosapentaenoic acid (DPAn-3; 22:5n-3); the second (OR = 2.13, 95% CI = 1.24-3.66), third (OR = 2.40, 95% CI = 1.28-4.50), and highest quartiles (OR = 2.24, 95% CI = 1.08-4.69) for AA/docosahexaenoic acid (DHA; 22:6n-3) ratio compared with the lowest quartile after adjusting for confounding factors. Conclusion: Higher plasma levels of AA, DTA, DPAn-6, DPAn-3 PUFAs, and AA/DHA ratio may be potential risk factors for depression in US adults.

Glucans from Armillaria luteo-virens: Structural Characterization and In Vivo Immunomodulatory Investigation under Different Administration Routes.

Polysaccharides fromArmillaria luteo-virens (ALP) were investigated for structural characterization and immunomodulatory activities. Three fractions (ALP-1, ALP-2, and ALP-3) were obtained with the yield of 2.4, 3.7, and 3.0 wt %, respectively. ALP-1 was proposed as a ß-(1 → 3)(1 → 6)-glucan with a triple-helix conformation; ALP-2 and ALP-3 were both identified as α-(1 → 4)(1 → 6)-glucan differing in their Mw and branching degree with a spherical conformation. The in vitro digestibility experiment and in vivo experiments using cyclophosphamide (CY)-treated mice demonstrated that intraperitoneal injection of α-glucan (1 mg·kg-1·day-1) and intragastric gavage of ß-glucan (10 mg·kg-1·day-1) both effectively restored the decrease in body weight, immune organ indexes, immune cell activities, serum immune marker levels, colonic short-chain fatty acids (SCFA) levels, and Bacteroidetes/Firmicutes ratio in immunosuppression mice. This study provides novel insights into the immunomodulatory activity of α- and ß-glucans under different administration routes, thereby promoting their application in both food and pharmaceutical areas.

Phosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures.

α-Synuclein forms amyloid fibrils that are critical in the progression of Parkinson's disease and serves as the pathological hallmark of this condition. Different posttranslational modifications have been identified at multiple sites of α-synuclein, influencing its conformation, aggregation and function. Here, we investigate how disease-related phosphorylation and O-GlcNAcylation at the same α-synuclein site (S87) affect fibril structure and neuropathology. Using semi-synthesis, we obtained homogenous α-synuclein monomer with site-specific phosphorylation (pS87) and O-GlcNAcylation (gS87) at S87, respectively. Cryo-EM revealed that pS87 and gS87 α-synuclein form two distinct fibril structures. The GlcNAc situated at S87 establishes interactions with K80 and E61, inducing a unique iron-like fold with the GlcNAc molecule on the iron handle. Phosphorylation at the same site prevents a lengthy C-terminal region including residues 73 to 140 from incorporating into the fibril core due to electrostatic repulsion. Instead, the N-terminal half of the fibril (1-72) takes on an arch-like fibril structure. We further show that both pS87 and gS87 α-synuclein fibrils display reduced neurotoxicity and propagation activity compared with unmodified α-synuclein fibrils. Our findings demonstrate that different posttranslational modifications at the same site can produce distinct fibril structures, which emphasizes link between posttranslational modifications and amyloid fibril formation and pathology.

IL-12-Overexpressed Nanoparticles Suppress the Proliferation of Melanoma Through Inducing ICD and Activating DC, CD8+ T, and CD4+ T Cells.

Purpose: The drug resistance and low response rates of immunotherapy limit its application. This study aimed to construct a new nanoparticle (CaCO3-polydopamine-polyethylenimine, CPP) to effectively deliver interleukin-12 (IL-12) and suppress cancer progress through immunotherapy. Methods: The size distribution of CPP and its zeta potential were measured using a Malvern Zetasizer Nano-ZS90. The morphology and electrophoresis tentative delay of CPP were analyzed using a JEM-1400 transmission electron microscope and an ultraviolet spectrophotometer, respectively. Cell proliferation was analyzed by MTT assay. Proteins were analyzed by Western blot. IL-12 and HMGB1 levels were estimated by ELISA kits. Live/dead staining assay was performed using a Calcein-AM/PI kit. ATP production was detected using an ATP assay kit. The xenografts in vivo were estimated in C57BL/6 mice. The levels of CD80+/CD86+, CD3+/CD4+ and CD3+/CD8+ were analyzed by flow cytometry. Results: CPP could effectively express EGFP or IL-12 and increase ROS levels. Laser treatment promoted CPP-IL-12 induced the number of dead or apoptotic cell. CPP-IL-12 and laser could further enhance CALR levels and extracellular HMGB1 levels and decrease intracellular HMGB1 and ATP levels, indicating that it may induce immunogenic cell death (ICD). The tumors and weights of xenografts in CPP-IL-12 or laser-treated mice were significantly reduced than in controls. The IL-12 expression, the CD80+/CD86+ expression of DC from lymph glands, and the number of CD3+/CD8+T or CD3+/CD4+T cells from the spleen increased in CPP-IL-12-treated or laser-treated xenografts compared with controls. The levels of granzyme B, IFN-γ, and TNF-α in the serum of CPP-IL-12-treated mice increased. Interestingly, CPP-IL-12 treatment in local xenografts in the back of mice could effectively inhibit the growth of the distant untreated tumor. Conclusion: The novel CPP-IL-12 could overexpress IL-12 in melanoma cells and achieve immunotherapy to melanoma through inducing ICD, activating CD4+ T cell, and enhancing the function of tumor-reactive CD8+ T cells.

Evaluation of the control efficacy of antagonistic bacteria from V-Ti magnetite mine tailings on kiwifruit brown spots in pot and field experiments.

Seemingly barren heavy-metal-polluted vanadium (V) and titanium (Ti) magnetite mine tailings contain various functional microbes, yet it is unclear whether this includes microbial resources relevant to the biological control of plant diseases. Kiwifruit brown leaf spot disease, caused by Corynespora cassiicola, can seriously reduce kiwifruit yield. To discover effective control measures for kiwifruit leaf spot, 18 bacteria strains among 136 tailing-isolated bacteria from V-Ti magnetite mine tailings were identified as inhibiting C. cassiicola by the confrontation plate method, indicating that antagonistic bacteria surviving in the V-Ti magnetite mine tailings were present at a low level. The 18 antagonistic strains could be divided into two BOX-A1R clusters. The 13 representative strains that were selected for phylogenetic tree construction based on their 16S rRNA sequences belonged to the Bacillus genus. Five predominant strains exhibited different toxin-production times and intensities, with four of them initiating toxin production at 32 h. Among them, Bacillus sp. KT-10 displayed the highest bacteriostatic rate (100%), with a 37.5% growth inhibition rate and an antagonistic band of 3.2 cm against C. cassiicola. Bacillus sp. KT10 also showed a significant inhibitory effect against the expansion speed of kiwifruit brown spots in the pot. The relative control effect was 78.48 and 83.89% at 7 days after the first and last spraying of KT-10 dilution, respectively, confirming a good effect of KT-10 on kiwifruit brown leaf spots in the field. This study demonstrated for the first time that there are some antagonistic bacteria to pathogenic C. cassiicola in V-Ti magnetite mine tailings, and Bacillus sp. KT10 was found to have a good control effect on kiwifruit brown leaf spots in pots and fields, which provided an effective biological control measurement for kiwifruit brown leaf spots.

Elevated Kallistatin promotes the occurrence and progression of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and the development of non-alcoholic steatohepatitis (NASH) might cause irreversible hepatic damage. Hyperlipidemia (HLP) is the leading risk factor for NAFLD. This study aims to illuminate the causative contributor and potential mechanism of Kallistatin (KAL) mediating HLP to NAFLD. 221 healthy control and 253 HLP subjects, 62 healthy control and 44 NAFLD subjects were enrolled. The plasma KAL was significantly elevated in HLP subjects, especially in hypertriglyceridemia (HTG) subjects, and positively correlated with liver injury. Further, KAL levels of NAFLD patients were significantly up-regulated. KAL transgenic mice induced hepatic steatosis, inflammation, and fibrosis with time and accelerated inflammation development in high-fat diet (HFD) mice. In contrast, KAL knockout ameliorated steatosis and inflammation in high-fructose diet (HFruD) and methionine and choline-deficient (MCD) diet-induced NAFLD rats. Mechanistically, KAL induced hepatic steatosis and NASH by down-regulating adipose triglyceride lipase (ATGL) and comparative gene identification 58 (CGI-58) by LRP6/Gɑs/PKA/GSK3ß pathway through down-regulating peroxisome proliferator-activated receptor γ (PPARγ) and up-regulating kruppel-like factor four (KLF4), respectively. CGI-58 is bound to NF-κB p65 in the cytoplasm, and diminishing CGI-58 facilitated p65 nuclear translocation and TNFα induction. Meanwhile, hepatic CGI-58-overexpress reverses NASH in KAL transgenic mice. Further, free fatty acids up-regulated KAL against thyroid hormone in hepatocytes. Moreover, Fenofibrate, one triglyceride-lowering drug, could reverse hepatic steatosis by down-regulating KAL. These results demonstrate that elevated KAL plays a crucial role in the development of HLP to NAFLD and may be served as a potential preventive and therapeutic target.

Predictive value of volumetric parameters based on 18F-PSMA-1007 PET/CT for prostate cancer metastasis.

Purpose of the report: To explore the value of 18F-labeled prostate-specific membrane antigen (PSMA-1007) positron emission tomography (PET)/computed tomography (CT), the maximum standardized uptake value (SUVmax) of the primary tumor, prostate PSMA-tumor volume (PSMA-TVp), and prostate total lesion PSMA (TL-PSMAp) for predicting prostate cancer (PCa) metastasis and follow-up evaluation in primary PCa lesions. Materials and methods: 18F-PSMA-1007 PET/CT data of 110 consecutive newly diagnosed PCa patients were retrospectively analyzed. Patients were divided into non-metastatic, oligometastatic, and extensive metastatic groups. The predictive power was assessed using the receiver operating characteristic curve. Multi-group one-way analysis of variance and post-hoc tests were used to compare the groups. Patients were monitored post-therapy to evaluate treatment effectiveness. Results: Among the 110 patients, 66.4% (73) had metastasis (29 oligometastatic, 44 extensive metastasis). AUCs for Gleason score (GS), total prostate-specific antigen(TPSA), SUVmax, TL-PSMAp, and PSMA-TVp were 0.851, 0.916, 0.834, 0.938, and 0.923, respectively. GS, TPSA, SUVmax, TL-PSMAp, and PSMA-TVp were significantly different among the groups. In the post-hoc tests, differences in GS, TPSA, SUVmax, TL-PSMAp, and PSMA-TVp between the non-metastatic and oligometastatic groups and non-metastatic and extensive metastatic groups were significant (P<0.010). Differences in TL-PSMAp and PSMA-TVp between oligometastatic and extensive metastatic groups were significant (P=0.039 and 0.015, respectively), while those among GS, TPSA, and SUVmax were not. TL-PSMAp and PSMA-TVp distinguished between oligometastatic and extensive metastases, but GS, TPSA, and SUVmax did not. In individuals with oligometastasis, the implementation of active treatment for both primary and metastatic lesions may result in a more favorable prognosis. Conclusions: 18F-PSMA-1007 PET/CT volumetric parameters PSMA-TVp and TL-PSMAp can predict PCa oligometastasis.

m6A-methylated KCTD21-AS1 regulates macrophage phagocytosis through CD47 and cell autophagy through TIPR.

Blocking immune checkpoint CD47/SIRPα is a useful strategy to engineer macrophages for cancer immunotherapy. However, the roles of CD47-related noncoding RNA in regulating macrophage phagocytosis for lung cancer therapy remain unclear. This study aims to investigate the effects of long noncoding RNA (lncRNA) on the phagocytosis of macrophage via CD47 and the proliferation of non-small cell lung cancer (NSCLC) via TIPRL. Our results demonstrate that lncRNA KCTD21-AS1 increases in NSCLC tissues and is associated with poor survival of patients. KCTD21-AS1 and its m6A modification by Mettl14 promote NSCLC cell proliferation. miR-519d-5p gain suppresses the proliferation and metastasis of NSCLC cells by regulating CD47 and TIPRL. Through ceRNA with miR-519d-5p, KCTD21-AS1 regulates the expression of CD47 and TIPRL, which further regulates macrophage phagocytosis and cancer cell autophagy. Low miR-519d-5p in patients with NSCLC corresponds with poor survival. High TIPRL or CD47 levels in patients with NSCLC corresponds with poor survival. In conclusion, we demonstrate that KCTD21-AS1 and its m6A modification promote NSCLC cell proliferation, whereas miR-519d-5p inhibits this process by regulating CD47 and TIPRL expression, which further affects macrophage phagocytosis and cell autophagy. This study provides a strategy through miR-519-5p gain or KCTD21-AS1 depletion for NSCLC therapy by regulating CD47 and TIPRL.

Epithelium-derived kallistatin promotes CD4+ T-cell chemotaxis to TH2-type inflammation in chronic rhinosinusitis.

BACKGROUND: The function of kallistatin in airway inflammation, particularly chronic rhinosinusitis with nasal polyps (CRSwNP), has not been elucidated. OBJECTIVE: We sought to investigate the role of kallistatin in airway inflammation. METHODS: Kallistatin and proinflammatory cytokine expression levels were detected in nasal polyps. For the in vivo studies, we constructed the kallistatin-overexpressing transgenic mice to elucidate the role of kallistatin in airway inflammation. Furthermore, the levels of plasma IgE and proinflammatory cytokines in the airways were evaluated in the kallistatin-/- rat in vivo model under a type 2 inflammatory background. Finally, the Notch signaling pathway was explored to understand the role of kallistatin in CRSwNP. RESULTS: We showed that the expression of kallistatin was significantly higher in nasal polyps than in the normal nasal mucosa and correlated with IL-4 expression. We also discovered that the nasal mucosa of kallistatin-overexpressing transgenic mice expressed higher levels of IL-4 expression, associating to TH2-type inflammation. Interestingly, we observed lower IL-4 levels in the nasal mucosa and lower total plasma IgE of the kallistatin-/- group treated with house dust mite allergen compared with the wild-type house dust mite group. Finally, we observed a significant increase in the expression of Jagged2 in the nasal epithelium cells transduced with adenovirus-kallistatin. This heightened expression correlated with increased secretion of IL-4, attributed to the augmented population of CD4+CD45+Notch1+ T cells. These findings collectively may contribute to the induction of TH2-type inflammation. CONCLUSIONS: Kallistatin was demonstrated to be involved in the CRSwNP pathogenesis by enhancing the TH2 inflammation, which was found to be associated with more expression of IL-4, potentially facilitated through Jagged2-Notch1 signaling in CD4+ T cells.