A novel gain-of-function phosphorylation site modulates PTPN22 inhibition of TCR signaling.

Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is encoded by a major autoimmunity gene and is a known inhibitor of T cell receptor (TCR) signaling and drug target for cancer immunotherapy. However, little is known about PTPN22 posttranslational regulation. Here, we characterize a phosphorylation site at Ser325 situated C terminal to the catalytic domain of PTPN22 and its roles in altering protein function. In human T cells, Ser325 is phosphorylated by glycogen synthase kinase-3 (GSK3) following TCR stimulation, which promotes its TCR-inhibitory activity. Signaling through the major TCR-dependent pathway under PTPN22 control was enhanced by CRISPR/Cas9-mediated suppression of Ser325 phosphorylation and inhibited by mimicking it via glutamic acid substitution. Global phospho-mass spectrometry showed Ser325 phosphorylation state alters downstream transcriptional activity through enrichment of Swi3p, Rsc8p, and Moira domain binding proteins, and next-generation sequencing revealed it differentially regulates the expression of chemokines and T cell activation pathways. Moreover, in vitro kinetic data suggest the modulation of activity depends on a cellular context. Finally, we begin to address the structural and mechanistic basis for the influence of Ser325 phosphorylation on the protein's properties by deuterium exchange mass spectrometry and NMR spectroscopy. In conclusion, this study explores the function of a novel phosphorylation site of PTPN22 that is involved in complex regulation of TCR signaling and provides details that might inform the future development of allosteric modulators of PTPN22.

Characterization of metallothionein genes from Broussonetia papyrifera: metal binding and heavy metal tolerance mechanisms.

BACKGROUND: Broussonetia papyrifera is an economically significant tree with high utilization value, yet its cultivation is often constrained by soil contamination with heavy metals (HMs). Effective scientific cultivation management, which enhances the yield and quality of B. papyrifera, necessitates an understanding of its regulatory mechanisms in response to HM stress. RESULTS: Twelve Metallothionein (MT) genes were identified in B. papyrifera. Their open reading frames ranged from 186 to 372 bp, encoding proteins of 61 to 123 amino acids with molecular weights between 15,473.77 and 29,546.96 Da, and theoretical isoelectric points from 5.24 to 5.32. Phylogenetic analysis classified these BpMTs into three subclasses: MT1, MT2, and MT3, with MT2 containing seven members and MT3 only one. The expression of most BpMT genes was inducible by Cd, Mn, Cu, Zn, and abscisic acid (ABA) treatments, particularly BpMT2e, BpMT2d, BpMT2c, and BpMT1c, which showed significant responses and warrant further study. Yeast cells expressing these BpMT genes exhibited enhanced tolerance to Cd, Mn, Cu, and Zn stresses compared to control cells. Yeasts harboring BpMT1c, BpMT2e, and BpMT2d demonstrated higher accumulation of Cd, Cu, Mn, and Zn, suggesting a chelation and binding capacity of BpMTs towards HMs. Site-directed mutagenesis of cysteine (Cys) residues indicated that mutations in the C domain of type 1 BpMT led to increased sensitivity to HMs and reduced HM accumulation in yeast cells; While in type 2 BpMTs, the contribution of N and C domain to HMs' chelation possibly corelated to the quantity of Cys residues. CONCLUSION: The BpMT genes are crucial in responding to diverse HM stresses and are involved in ABA signaling. The Cys-rich domains of BpMTs are pivotal for HM tolerance and chelation. This study offers new insights into the structure-function relationships and metal-binding capabilities of type-1 and - 2 plant MTs, enhancing our understanding of their roles in plant adaptation to HM stresses.

A Primary Report 166 Cases of Abdominal or Pelvic Neuroblastoma Surgery Utilizing the International Neuroblastoma Surgical Report Form (INSRF).

BACKGROUND AND AIMS: Surgery is pivotal in the management of neuroblastoma (NB), particularly in patients with Image-Defined Risk Factors (IDRFs). The International Neuroblastoma Surgical Report Form (INSRF) was introduced to enhance surgical reporting quality and analyze the defining role of extensive surgery in NB. This study reports our experience with INSRF and explores new criteria for evaluating the extent of surgical resection. METHODS: INSRF was deployed to critically analyze 166 patients with abdominal or pelvic NB who underwent surgery at our department between October 2021 and June 2023. Patient demographics, clinical characteristics, surgical datasets, and postoperative complications were described in detail. Receiver operating characteristic (ROC) curves were used to explore a new method to evaluate the extent of resection. A questionnaire was formulated to obtain attitudes/feedback and commentary from surgical oncologists with INSRF. RESULTS: 166 neuroblastoma patients with a median disease age 36.50 months. This study collated 320 INSRF reports. Among the 166 index cases, 137 were documented by two surgeons, with a concordance rate of 16.78%. Items with high inconsistency were (i) the extent of tumor resection (29.20%), (ii) renal vein involvement (25.55%), (iii) abdominal aorta encasement (16.79%), and (iv) mesenteric infiltration (17.52%). According to INSRF, the extent of resection was complete excision in 86 (51.81%) patients, minimal residual tumor < 5 cm3 in 67 (40.36%) patients, and incomplete excision > 5 cm3 in 13 (7.83%) patients. In ROC curve analysis, the number of vessels encased by tumors > 3 had a high predictive value in determining that a tumor could not be completely resected (AUC 0.916, sensitivity 0.838, specificity 0.826) using INSRF as the gold standard reference. The questionnaires showed that surgeons agreed that the extent of resection and tumor involvement of organ/vascular structures were important, while the definition and intervention(s) of intraoperative complications were less operational and understandable. CONCLUSIONS: INSRF has significant clinical application in neuroblastoma surgery. The extent of resection can be predicted based on the number of tumor-encased blood vessels. Supplementary information should be considered with the INSRF to aid practitioner reporting. Multicenter studies are needed to explore the defining role of INSRF in NB surgical management.

The evolutionary adaptation of shrimp hemocyanin subtypes and the consequences on their structure and functions.

Hemocyanin is the main respiratory protein of arthropods and is formed by hexameric and/or oligomeric subunits. Due to changes in the living environment and gene rearrangement, various hemocyanin subtypes and subunits evolved in crustaceans. This paper reviews the various hemocyanin subtypes and isoforms in shrimp and analyses published genomic data of sixteen hemocyanin family genes from Litopenaeus vannamei to explore the evolution of hemocyanin genes, subunits, and protein structure. Analysis of hemocyanin subtypes distribution and structure in various tissues was also performed and related to multiple and tissue-specific functions, i.e., immunological activity, immune signaling, phenoloxidase activity, modulation of microbiota homeostasis, and energy metabolism. The functional diversity of shrimp hemocyanin due to molecular polymorphism, transcriptional regulation, alternative splicing, degradation into functional peptides, interaction with other proteins or genes, and structural differences will also be highlighted for future research. Inferences would be drawn from other crustaceans to explain how evolution has changed the structure-function of hemocyanin and its implication for evolutionary research into the multifunctionality of hemocyanin and other related proteins in shrimp.

Physiology or Psychology: What Drives Human Emissions of Carbon Dioxide and Ammonia?

Humans are the primary sources of CO2 and NH3 indoors. Their emission rates may be influenced by human physiological and psychological status. This study investigated the impact of physiological and psychological engagements on the human emissions of CO2 and NH3. In a climate chamber, we measured CO2 and NH3 emissions from participants performing physical activities (walking and running at metabolic rates of 2.5 and 5 met, respectively) and psychological stimuli (meditation and cognitive tasks). Participants' physiological responses were recorded, including the skin temperature, electrodermal activity (EDA), and heart rate, and then analyzed for their relationship with CO2 and NH3 emissions. The results showed that physiological engagement considerably elevated per-person CO2 emission rates from 19.6 (seated) to 46.9 (2.5 met) and 115.4 L/h (5 met) and NH3 emission rates from 2.7 to 5.1 and 8.3 mg/h, respectively. CO2 emissions reduced when participants stopped running, whereas NH3 emissions continued to increase owing to their distinct emission mechanisms. Psychological engagement did not significantly alter participants' emissions of CO2 and NH3. Regression analysis revealed that CO2 emissions were predominantly correlated with heart rate, whereas NH3 emissions were mainly associated with skin temperature and EDA. These findings contribute to a deeper understanding of human metabolic emissions of CO2 and NH3.

Influence of Ventilation on Formation and Growth of 1-20 nm Particles via Ozone-Human Chemistry.

Ozone reaction with human surfaces is an important source of ultrafine particles indoors. However, 1-20 nm particles generated from ozone-human chemistry, which mark the first step of particle formation and growth, remain understudied. Ventilation and indoor air movement could have important implications for these processes. Therefore, in a controlled-climate chamber, we measured ultrafine particles initiated from ozone-human chemistry and their dependence on the air change rate (ACR, 0.5, 1.5, and 3 h-1) and operation of mixing fans (on and off). Concurrently, we measured volatile organic compounds (VOCs) and explored the correlation between particles and gas-phase products. At 25-30 ppb ozone levels, humans generated 0.2-7.7 × 1012 of 1-3 nm, 0-7.2 × 1012 of 3-10 nm, and 0-1.3 × 1012 of 10-20 nm particles per person per hour depending on the ACR and mixing fan operation. Size-dependent particle growth and formation rates increased with higher ACR. The operation of mixing fans suppressed the particle formation and growth, owing to enhanced surface deposition of the newly formed particles and their precursors. Correlation analyses revealed complex interactions between the particles and VOCs initiated by ozone-human chemistry. The results imply that ventilation and indoor air movement may have a more significant influence on particle dynamics and fate relative to indoor chemistry.

Squalene Depletion in Skin Following Human Exposure to Ozone under Controlled Chamber Conditions.

A major component of human skin oil is squalene, a highly unsaturated hydrocarbon that protects the skin from atmospheric oxidants. Skin oil, and thus squalene, is continuously replenished on the skin surface. Squalene is also quickly consumed through reactions with ozone and other oxidants. This study examined the extent of squalene depletion in the skin oils of the forearm of human volunteers after exposure to ozone in a climate chamber. Temperature, relative humidity (RH), skin coverage by clothing, and participants' age were varied in a controlled manner. Concentrations of squalene were determined in skin wipe samples collected before and after ozone exposure. Exposures to ozone resulted in statistically significant decreases in post-exposure squalene concentrations compared to pre-exposure squalene concentrations in the skin wipes when squalene concentrations were normalized by concentrations of co-occurring cholesterol but not by co-occurring pyroglutamic acid (PGA). The rate of squalene loss due to ozonolysis was lower than its replenishment on the skin surface. Within the ranges examined, temperature and RH did not significantly affect the difference between normalized squalene levels in post-samples versus pre-samples. Although not statistically significant, skin coverage and age of the volunteers (three young adults, three seniors, and three teenagers) did appear to impact squalene depletion on the skin surfaces.

Diagnostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging in pediatric opsoclonus myoclonus ataxia syndrome presenting with neuroblastoma.

BACKGROUND: Early precision diagnosis and effective treatment of opsoclonus myoclonus ataxia syndrome (OMAS) patients presenting with neuroblastoma can prevent serious neurological outcomes. OBJECTIVE: To assess the diagnostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging in pediatric OMAS with neuroblastoma. MATERIALS AND METHODS: A retrospective evaluation of 45 patients diagnosed with OMAS who underwent 18F-FDG PET/CT was performed. A univariate analysis was performed to compare clinical characteristics between OMAS with and without neuroblastoma. Univariate and multivariate logistic regression analyses were applied to identify independent risk factors for OMAS with neuroblastoma and to develop the clinical model. Finally, independent risk factors and PET/CT were fitted to build the combined model for the diagnosis of OMAS with neuroblastoma and presented as a nomogram. Receiver operating characteristic curve, decision curve, and calibration curve analyses were conducted to evaluate the performance of the models. RESULTS: Among 45 patients, 27 were PET/CT-positive, 23/27 lesions were neuroblastoma, and four were false positives. One of the false positive patients was confirmed to be adrenal reactive hyperplasia by postoperative pathology, and the symptoms of OMAS disappeared in the remaining three cases during clinical follow-up. The average maximal standardized uptake value of PET/CT-positive lesions was 2.6. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET/CT were 100%, 81.8%, 85.2%, 100%, and 91.1%, respectively. Age at diagnosis, lactate dehydrogenase, and neuron-specific enolase showed statistically significant differences between OMAS with and without neuroblastoma. Lactate dehydrogenase was identified as the independent risk factor to develop the clinical model, and the clinical model demonstrated an area under the curve (AUC) of 0.82 for the diagnosis of OMAS with neuroblastoma, with an AUC as high as 0.91 when combined with PET/CT. The decision curve analysis and calibration curve demonstrated that the nomogram had good consistency and clinical usefulness. CONCLUSION: In patients with OMAS, 18F-FDG PET/CT has a high diagnostic accuracy in detecting tumors of the neuroblastoma, especially when combined with the independent risk factor serum lactate dehydrogenase.

Risk factors, impact and treatment of postoperative lymphatic leakage in children with abdominal neuroblastoma operated on by laparotomy.

BACKGROUND: Lymphatic leakage is one of the postoperative complications of neuroblastoma. The purpose of this study is to summarize the clinical characteristics and risk factors of lymphatic leakage and try to find effective prevention and treatment measures. METHODS: A retrospective study included 186 children with abdominal neuroblastoma, including 32 children of lymphatic leakage and 154 children of non-lymphatic leakage. The clinical information, surgical data, postoperative abdominal drainage, treatment of lymphatic leakage and prognosis of the two groups were collected and analyzed. RESULTS: The incidence of lymphatic leakage in this cohort was 14% (32 children). Through univariate analysis of lymphatic leakage group and non-lymphatic leakage group, we found that lymphatic leakage increased the complications, prolonged the time of abdominal drainage and hospitalization, and delayed postoperative chemotherapy (p < 0.05). In this cohort, the median follow-up time was 46 (95% CI: 44-48) months. The follow-up data of 7 children were partially missing. 147 children survived, of which 23 had tumor recurrence (5 children recurred in the surgical area). 37 children died, of which 32 had tumor recurrence (9 children recurred in the operation area). In univariate analysis, there was no statistical difference in overall survival (p = 0.21) and event-free survival (p = 0.057) between lymphatic leakage group and non-lymphatic leakage group, while 3-year cumulative incidence of local progression was higher in lymphatic leakage group (p = 0.015). However, through multivariate analysis, we found that lymphatic leakage did not affect event-free survival, overall survival and cumulative incidence of local progression in children with neuroblastoma. Resection of 5 or more lymphatic regions was an independent risk factor for lymphatic leakage after neuroblastoma surgery. All 32 children with lymphatic leakage were cured by conservative treatment without surgery. Of these, 75% (24/32) children were cured by fat-free diet or observation, 25% (8/32) children were cured by total parenteral nutrition. The median drain output at diagnosis in total parenteral nutrition group was higher than that in non-total parenteral nutrition group (p < 0.001). The cut-off value was 17.2 ml/kg/day. CONCLUSIONS: Lymphatic leakage does not affect the prognosis of children with neuroblastoma, but long-term drain output caused by lymphatic leakage will still adversely affect postoperative complications and follow-up treatment, which requires attention and active treatment measures. More attention should be paid to the children with 5 or more lymphatic regions resection, and the injured lymphatic vessels should be actively found and ligated after tumor resection to reduce the postoperative lymphatic leakage. Early application of total parenteral nutrition is recommended for those who have drain output at diagnosis of greater than 17.2 ml/kg/day. LEVEL OF EVIDENCE: Level III, Treatment study (Retrospective comparative study).

Structure and characterization of Tremella fuciformis polysaccharides/whey protein isolate nanoparticles for sustained release of curcumin.

BACKGROUND: Whey protein isolate (WPI) nanoparticles can be used in a strategy to improve the bioavailability of curcumin (CUR) although they are generally not stable. Previous studies have indicated that Tremella fuciformis polysaccharides (TFPs) can increase the stability of WPI. This work investigated systematically the characterization and structure of TFP/WPI nanoparticles with differing CUR content. RESULTS: The highest encapsulation efficiency of CUR was 98.8% and the highest loading content was 47.88%. The TFP-WPI-CUR with 20 mg mL-1 of CUR had the largest particle size (653.67 ± 21.50 nm) and lowest zeta potential (-38.97 ± 2.51 mV), and the capacity to retain stability across a variety of salt ion and pH conditions for 21 days. According to the findings of the structural analysis, the addition of TFPs and CUR rendered the structure of WPI amorphous, and the ß-sheet was reduced. Finally, in vitro release indicated that the TFP-WPI-CUR combination could regulate the sustained release behavior of CUR. CONCLUSION: In summary, TFP-WPI nanoparticles can be used as carriers for the delivery of CUR, and can expand applications of CUR in the functional food, dietary supplement, pharmaceutical, and beverage industries. © 2023 Society of Chemical Industry.

Synthetic microbial communities: Novel strategies to enhance the quality of traditional fermented foods.

Consumers are attracted to traditional fermented foods due to their unique flavor and nutritional value. However, the traditional fermentation technique can no longer accommodate the requirements of the food industry. Traditional fermented foods produce hazardous compounds, off-odor, and anti-nutritional factors, reducing product stability. The microbial system complexity of traditional fermented foods resulting from the open fermentation process has made it challenging to regulate these problems by modifying microbial behaviors. Synthetic microbial communities (SynComs) have been shown to simplify complex microbial communities and allow for the targeted design of microbial communities, which has been applied in processing traditional fermented foods. Herein, we describe the theoretical information of SynComs, particularly microbial physiological processes and their interactions. This paper discusses current approaches to creating SynComs, including designing, building, testing, and learning, with typical applications and fundamental techniques. Based on various traditional fermented food innovation demands, the potential and application of SynComs in enhancing the quality of traditional fermented foods are highlighted. SynComs showed superior performance in regulating the quality of traditional fermented foods using the interaction of core microorganisms to reduce the hazardous compounds of traditional fermented foods and improve flavor. Additionally, we presented the current status and future perspectives of SynComs for improving the quality of traditional fermented foods.

The Social Inequality of Music: University Students from a Higher Social Class Are More Likely to Build Relationships and Feel Happiness Through Music.

The relationship between young people's music use and well-being has gained extensive interest in recent years. The relationship-building function of music is one of its most important functions. While many studies have documented the positive effects of this function, there is a lack of research discussing this topic from the perspective of social stratification. This study sampled 691(63.8% male, M age = 19.43, SD = 1.42) Chinese university students to examine the social class differences among university students in acquiring well-being through the relationship-building function of music. The results revealed that university students from a higher social class are more likely to acquire well-being through the relationship-building function of music. In addition, interdependent self-construal plays a moderating role in the mediating model. The mediating effect was only significant when university students have a higher level of interdependent self-construal. These results indicated social class differences among university students in the building of relationships with music, underscoring the need for future research and interventions to address social inequality in the context of music's functions.

Macromolecular crowding amplifies allosteric regulation of T-cell protein tyrosine phosphatase.

T-cell protein tyrosine phosphatase (TC-PTP) is a negative regulator of T-cell receptor and oncogenic receptor tyrosine kinase signaling and implicated in cancer and autoimmune disease. TC-PTP activity is modulated by an intrinsically disordered C-terminal region (IDR) and suppressed in cells under basal conditions. In vitro structural studies have shown that the dynamic reorganization of IDR around the catalytic domain, driven by electrostatic interactions, can lead to TC-PTP activity inhibition; however, the process has not been studied in cells. Here, by assessing a mutant (378KRKRPR383 mutated into 378EAAAPE383, called TC45E/A) with impaired tail-PTP domain interaction, we obtained evidence that the downmodulation of TC-PTP enzymatic activity by the IDR occurs in cells. However, we found that the regulation of TC-PTP by the IDR is only recapitulated in vitro when crowding polymers that mimic the intracellular environment are present in kinetic assays using a physiological phosphopeptide. Our FRET-based assays in vitro and in cells confirmed that the effect of the mutant correlates with an impairment of the intramolecular inhibitory remodeling of TC-PTP by the IDR. This work presents an early example of the allosteric regulation of a protein tyrosine phosphatase being controlled by the cellular environment and provides a framework for future studies and targeting of TC-PTP function.

Elevated exosome-transferrable lncRNA EPB41L4A-AS1 in CD56bright NK cells is responsible for the impaired NK function in neuroblastoma patients by suppressing cell glycolysis.

NK cells are one of key immune components in neuroblastoma (NB) surveillance and eradication. Glucose metabolism as a major source of fuel for NK activation is exquisitely regulated. Our data revealed a diminished NK activation and a disproportionally augmented CD56bright subset in NB. Further study showed that NK cells in NB presented with an arrested glycolysis accompanied by an elevated expression of the long noncoding RNA (lncRNA) EPB41L4A-AS1, a known crucial participant in glycolysis regulation, in the CD56bright NK subset. The inhibitory function of lncRNA EPB41L4A-AS1 was recapitulated. Interestingly, our study demonstrated that exosomal lncRNA EPB41L4A-AS1 was transferrable from CD56bright NK to CD56dim NK and was able to quench the glycolysis of target NK. Our data demonstrated that an arrested glycolysis in patient NK cells was associated with an elevated lncRNA in CD56bright NK subset and a cross-talk between heterogeneous NK subsets was achieved by transferring metabolic inhibitory lncRNA through exosomes.

Lacticaseibacillus paracasei fermentation broth identified peptide, Y2Fr, and its antibacterial activity on Vibrio parahaemolyticus.

Although Vibrio parahaemolyticus infections cause severe diseases of large yellow croaker (Larimichthys crocea), using antibiotics and other chemical agents to treat these infections could result in antimicrobial resistance, environmental pollution, and other associated problems. This study identified seven peptides from Lacticaseibacillus paracasei fermentation broth using ultra-high-performance liquid chromatography-mass spectrometry and screened antimicrobial peptide Y2Fr (VEIKNGLLKLNGKPLLIR) through its net charge, hydrophobicity and predicted secondary structure. Antibacterial activity analysis revealed that Y2Fr had a minimum inhibitory concentration (MIC) of 125 µg/mL, minimum bactericidal concentration (MBC) of 250 µg/mL against V. parahaemolyticus and a time-kill of 3 h. In a bacterial membrane environment, the secondary structure of peptide Y2Fr changed from a random coil to a ß-sheet to enhance its membrane permeability and binding to bacteria DNA to exert its antibacterial effect. Further molecular docking analysis revealed that peptide Y2Fr could bind to the membrane protein KKI11460.1 and DNA polymerase A0A0L8TVA4 of V. parahaemolyticus through hydrogen bonds. Meanwhile, treatment of Y2Fr with mammalian red blood cells and plasma revealed that it was noncytotoxic, nonhemolytic, and stable under physiological conditions. Thus, peptide Y2Fr has great potential use in treating and preventing infections caused by V. parahaemolyticus or similar bacteria in aquatic animals.

Ferroptosis inhibitor liproxstatin-1 alleviates metabolic dysfunction-associated fatty liver disease in mice: potential involvement of PANoptosis.

Ferroptosis is a new form of regulated cell death characterized by excessive iron accumulation and uncontrollable lipid peroxidation. The role of ferroptosis in metabolic dysfunction-associated fatty liver disease (MAFLD) is not fully elucidated. In this study we compared the therapeutic effects of ferroptosis inhibitor liproxstatin-1 (LPT1) and iron chelator deferiprone (DFP) in MAFLD mouse models. This model was established in mice by feeding a high-fat diet with 30% fructose in water (HFHF) for 16 weeks. The mice then received LPT1 (10 mg·kg-1·d-1, ip) or DFP (100 mg·kg-1·d-1, ig) for another 2 weeks. We showed that both LPT1 and DFP treatment blocked the ferroptosis markers ACSL4 and ALOX15 in MAFLD mice. Furthermore, LPT1 treatment significantly reduced the liver levels of triglycerides and cholesterol, lipid peroxidation markers 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), and ameliorated the expression of lipid synthesis/oxidation genes (Pparα, Scd1, Fasn, Hmgcr and Cpt1a), insulin resistance, mitochondrial ROS content and liver fibrosis. Importantly, LPT1 treatment potently inhibited hepatic apoptosis (Bax/Bcl-xL ratio and TUNEL+ cell number), pyroptosis (cleavages of Caspase-1 and GSDMD) and necroptosis (phosphorylation of MLKL). Moreover, LPT1 treatment markedly inhibited cleavages of PANoptosis-related caspase-8 and caspase-6 in MAFLD mouse liver. In an in vitro MAFLD model, treatment with LPT1 (100 nM) prevented cultured hepatocyte against cell death induced by pro-PANoptosis molecules (TNF-α, LPS and nigericin) upon lipid stress. On the contrary, DFP treatment only mildly attenuated hepatic inflammation but failed to alleviate lipid deposition, insulin resistance, apoptosis, pyroptosis and necroptosis in MAFLD mice. We conclude that ferroptosis inhibitor LPT1 protects against steatosis and steatohepatitis in MAFLD mice, which may involve regulation of PANoptosis, a coordinated cell death pathway that involves apoptosis, pyroptosis and necroptosis. These results suggest a potential link between ferroptosis and PANoptosis.

Complexities in the role of acetylation dynamics in modifying inducible gene activation parameters.

High levels of histone acetylation are associated with the regulatory elements of active genes, suggesting a link between acetylation and gene activation. We revisited this model, in the context of EGF-inducible gene expression and found that rather than a simple unifying model, there are two broad classes of genes; one in which high lysine acetylation activity is required for efficient gene activation, and a second group where the opposite occurs and high acetylation activity is inhibitory. We examined the latter class in more detail using EGR2 as a model gene and found that lysine acetylation levels are critical for several activation parameters, including the timing of expression onset, and overall amplitudes of the transcriptional response. In contrast, DUSP1 responds in the canonical manner and its transcriptional activity is promoted by acetylation. Single cell approaches demonstrate heterogenous activation kinetics of a given gene in response to EGF stimulation. Acetylation levels modify these heterogenous patterns and influence both allele activation frequencies and overall expression profile parameters. Our data therefore point to a complex interplay between acetylation equilibria and target gene induction where acetylation level thresholds are an important determinant of transcriptional induction dynamics that are sensed in a gene-specific manner.

Mangiferin exerts neuroprotective effects against focal cerebral ischemia in mice by regulating NF-κB signaling pathway.

PURPOSE: Mangiferin is a natural free radical scavenging antioxidant that induces excitation of the central nervous system. However, the mechanism of neuroprotective effect of mangiferin on focal cerebral ischemia has not been fully investigated. The aim of this study was to investigate the protective effect of mangiferin on focal cerebral ischemia in mice. METHODS: Middle cerebral artery occlusion (MCAO) was performed to investigate the effect of mangiferin on focal cerebral ischemia. Mice were randomly divided into 5 groups: sham, MCAO, MCAO + 5 mg/kg mangiferin, MCAO + 20 mg/kg mangiferin and MCAO + 5 mg/kg nimodipine. Neurobehavioral scores, brain edema, brain injury scores, relative infarct size and expression of some inflammatory factors in the brain were evaluated. NF-κB pathway was detected by Western blotting and immunofluorescence. RESULTS: The results showed that mangiferin effectively attenuated MCAO-induced brain injury, including improvement of neurological impairment, reduction of brain edema, and reduction of infarct size. Compared with the MCAO group, mangiferin significantly inhibited MCAO-induced neuroinflammation, which can be proved by reduced expression levels of TNF-α, IL-1ß, iNOS and COX-2. In addition, we found that phosphorylation of IκBα was inhibited and the expression of NF-κB p65 in the nucleus was reduced after the addition of mangiferin. CONCLUSION: Our study suggested that mangiferin exerts neuroprotective effects on focal cerebral ischemia in mice by regulating the NF-κB signaling pathway. Mangiferin may be an effective treatment for cerebral ischemia and other neurological disorders.

Modulation of SREBP Expression and Fatty Acid Levels by Bacteria-Induced ER Stress Is Mediated by Hemocyanin in Penaeid Shrimp.

Many environmental and pathogenic insults induce endoplasmic reticulum (ER) stress in animals, especially in aquatic ecosystems, where these factors are crucial for life. In penaeid shrimp, pathogens and environmental stressors induce hemocyanin expression, but the involvement of hemocyanin in ER stress response is unknown. We demonstrate that in response to pathogenic bacteria (Vibrio parahaemolyticus and Streptococcus iniae), hemocyanin, ER stress proteins (Bip, Xbp1s, and Chop), and sterol regulatory element binding protein (SREBP) are induced to alter fatty acid levels in Penaeus vannamei. Interestingly, hemocyanin interacts with ER stress proteins to modulate SREBP expression, while ER stress inhibition with 4-Phenylbutyric acid or hemocyanin knockdown attenuates the expression of ER stress proteins, SREBP, and fatty acid levels. Contrarily, hemocyanin knockdown followed by tunicamycin treatment (ER stress activator) increased their expression. Thus, hemocyanin mediates ER stress during pathogen challenge, which consequently modulates SREBP to regulate the expression of downstream lipogenic genes and fatty acid levels. Our findings reveal a novel mechanism employed by penaeid shrimp to counteract pathogen-induced ER stress.

Safety and feasibility of laparoscopic resection of abdominal neuroblastoma without image-defined risk factors: a single-center experience.

OBJECTIVE: To explore the criteria, safety and efficacy of laparoscopic surgery in pediatric neuroblastoma (NB). METHODS: A retrospective study of 87 patients with NB without image-defined risk factors (IDRFs) between December 2016 and January 2021 at Beijing Children's Hospital was conducted. Patients were divided into two groups according to the surgical procedure. RESULTS: Between the 87 patients, there were 54 (62.07%) cases in the open surgery group and 33 (37.93%) cases in the laparoscopic surgery group. There were no significant differences between the two groups regarding demographic characteristics, genomic and biological features, operating time or postoperative complications. However, in terms of intraoperative bleeding (p = 0.013) and the time to start postoperative feeding after surgery (p = 0.002), the laparoscopic group was obviously better than the open group. Furthermore, there was no significant difference in the prognosis between the two groups, and no recurrence or death was observed. CONCLUSION: For children with localized NB who have no IDRFs, laparoscopic surgery could be performed safely and effectively. Surgeons who are skilled in this can help children reduce surgical injuries, speed up postoperative recovery, and obtain the same prognosis as open surgery.