The correlation between TRIM28 expression and immune checkpoints in CRPC.

This study delves into the unexplored realm of castration-resistant prostate cancer (CRPC) by investigating the role of TRIM28 and its intricate molecular mechanisms using high-throughput single-cell transcriptome sequencing and advanced bioinformatics analysis. Our comprehensive examination unveiled dynamic TRIM28 expression changes, particularly in immune cells such as macrophages and CD8+ T cells within CRPC. Correlation analyses with TCGA data highlighted the connection between TRIM28 and immune checkpoint expression and emphasized its pivotal influence on the quantity and functionality of immune cells. Using TRIM28 knockout mouse models, we identified differentially expressed genes and enriched pathways, unraveling the potential regulatory involvement of TRIM28 in the cGAS-STING pathway. In vitro, experiments further illuminated that TRIM28 knockout in prostate cancer cells induced a notable anti-tumor immune effect by inhibiting M2 macrophage polarization and enhancing CD8+ T cell activity. This impactful discovery was validated in an in situ transplant tumor model, where TRIM28 knockout exhibited a deceleration in tumor growth, reduced proportions of M2 macrophages, and enhanced infiltration of CD8+ T cells. In summary, this study elucidates the hitherto unknown anti-tumor immune role of TRIM28 in CRPC and unravels its potential regulatory mechanism via the cGAS-STING signaling pathway. These findings provide novel insights into the immune landscape of CRPC, offering promising directions for developing innovative therapeutic strategies.

Determinants of parental demand of human papillomavirus vaccination for adolescent daughters in China: Contingent valuation survey.

BACKGROUND: Several types of human papillomavirus (HPV) vaccines have been approved for use in adolescent girls in China. These vaccines are regulated as non-National Immunisation Program vaccines and are optional and generally fully self-paid by vaccinees. OBJECTIVE: To assess parents' demand for HPV vaccination by eliciting their willingness-to-pay for their adolescent daughters to be vaccinated against HPV and to examine the determinants of demand for HPV vaccination in China. METHODS: A contingent valuation survey was conducted across three cities in Shandong Province in eastern China. We selected 11 junior middle schools with different socioeconomic features and randomly selected 6 classes in each school, and questionnaires were distributed to all girls aged 12-16 in the 66 classes for their parents to complete. A payment card approach was used to elicit parental willingness-to-pay for HPV vaccination for their daughters. We also collected a wide array of socioeconomic and psychological variables and interval regressions were applied to examine the determinants of parental willingness-to-pay. RESULTS: A total of 1074 eligible parents who completed valid questions were included in analyses. Over 85% of parents believed HPV vaccines were, in general, necessary and beneficiary. However, only around 10% believed that their daughters would be infected by HPV. About 8% of parents would not accept HPV vaccine even if the vaccine were free mainly due to concerns about the potential side effects and vaccine safety and quality issues, and 27.37% would only accept the vaccine if it were free. The median willingness-to-pay was 300 CNY (42 USD). Several factors were positively correlated with higher willingness-to-pay: income, urban residence (relative to rural residence), mothers (relative to fathers), parents' beliefs about vaccine benefits, whether they should make decisions for their daughters, and whether their daughters would be susceptible to HPV. Though education-level was not significantly correlated with willingness-to-pay in the main regressions, a subgroup analysis revealed interesting dynamics in the relation between education and willingness-to-pay across different income-levels. CONCLUSIONS: There is a large gap between parents' willingness-to-pay and the market price of HPV vaccine for girls in China. Parents generally believed the HPV vaccines were beneficial and necessary but when asked for their daughters, most parents did not believe their daughters would be infected by HPV despite the high prevalence in China. Future focus should be on ensuring the provision of accurate health information about HPV prevalence, vaccine quality, and safety to promote vaccine uptake, and promotional efforts tailored to different income groups might yield better effects. Government involvement in negotiating more widely acceptable and affordable prices or subsidising may be necessary for protecting high-risk population groups.

Advancements in bioscavenger mediated detoxification of organophosphorus poisoning.

Background: Organophosphorus compounds, widely used in agriculture and industry, pose a serious threat to human health due to their acute neurotoxicity. Although traditional interventions for organophosphate poisoning are effective, they often come with significant side effects. Objective: This paper aims to evaluate the potential of enzymes within biological organisms as organophosphorus bioclearing agents. It analyses the technical challenges in current enzyme research, such as substrate specificity, stereoselectivity, and immunogenicity, while exploring recent advancements in the field. Methods: A comprehensive review of literature related to detoxifying enzymes or proteins was conducted. Existing studies on organophosphorus bioclearing agents were summarised, elucidating the biological detoxification mechanisms, with a particular focus on advancements in protein engineering and novel delivery methods. Results: Current bioclearing agents can be categorised into stoichiometric and catalytic bioclearing agents, both of which have shown some success in preventing organophosphate poisoning. Technological advancements have significantly improved various properties of bioclearing agents, yet challenges remain, particularly in substrate specificity, stereoselectivity, and immunogenicity. Future research will focus on expanding the substrate spectrum, enhancing catalytic efficiency, prolonging in vivo half-life, and developing convenient administration methods. Conclusion: With the progression of clinical trials, bioclearing agents are expected to become widely used as a new generation of therapeutic organophosphate detoxifiers.

Diagnostic values of different musculoskeletal ultrasound signs, serum uric acid, and their combined detection for gouty arthritis.

Objectives: The study aimed to investigate the diagnostic values of different musculoskeletal ultrasound (MSUS) signs, serum uric acid (SUA), and their combined detection for gouty arthritis (GA). Patients and methods: In this retrospective study, 70 patients (62 males, 8 females; mean age: 46.1±14.1 years; range, 25 to 86 years) diagnosed with GA (the GA group) between August 2022 and March 2023 and 70 patients (54 females, 16 males; mean age: 49.0±14.1 years; range, 21 to 75 years) diagnosed with rheumatoid arthritis and osteoarthritis during the same period (the non-GA group) were included. The positive rate of MSUS signs and SUA in both groups was recorded to compare the differences. The correlations of MSUS signs and SUA with GA were analyzed using Spearman's rank correlation analysis. The diagnostic values of different MSUS signs, SUA, and their combined detection for GA were analyzed using a receiver operating characteristic, the area under the curve (AUC), sensitivity, specificity, and the Youden index. Results: The positive rate of the double contour (DC) sign (chi-squared [χ2 ]=102.935, p<0.001), hyperechoic spots (χ2=56.395, p<0.001), bone erosions (χ2 =10.080, p<0.001), and SUA (χ2 =41.117, p <0.001) were higher in the GA group than in the non-GA group. The positive rate of the DC sign (rs=0.829, p=0.001), hyperechoic spots (rs=0.631, p<0.001), bone erosion (rs=0.268, p=0.001), and SUA (rs=0.542, p<0.001) were positively correlated with GA. Among the single-indicator measures, the DC sign exhibited the highest diagnostic value (AUC=0.907, sensitivity=81.4%, specificity=100%, p<0.001). Among the combined-indicator measures, the DC sign combined with SUA exhibited the highest diagnostic value (AUC=0.929, sensitivity=91.4%, specificity=94.3%, p<0.001), higher than DC sign detection alone. Conclusion: The DC sign combined with SUA yielded a high diagnostic value and can thus provide a reliable basis for effectively and efficiently diagnosing GA.

A sandwich-type photoelectrochemical biosensor based on Ru(bpy)32+ sensitized In2S3 for aflatoxin B1 detection.

Aflatoxin B1 (AFB1), classified as a class I carcinogen, is a widespread mycotoxin that poses a serious threat to public health and economic development, and the food safety problems caused by AFB1 have aroused worldwide concern. The development of accurate and sensitive methods for the detection of AFB1 is significant for food safety monitoring. In this work, a sandwich-type photoelectrochemical (PEC) biosensor for AFB1 detection was constructed on the basis of an aptamer-antibody structure. A good photocurrent response was obtained due to the sensitization of In2S3 by Ru(bpy)32+. In addition, this sandwich-type sensor constructed by modification with the antibody, target detector, and aptamer layer by layer attenuated the migration hindering effect of photogenerated carriers caused by the double antibody structure. The aptamer and antibody synergistically recognized and captured the target analyte, resulting in more reliable PEC response signals. CdSe@CdS QDs-Apt were modified as a signal-off probe onto the sensor platform to quantitatively detect AFB1 with a "signal-off" response, which enhanced the sensitivity of the sensor. The PEC biosensor showed a linear response range from 10-12 to 10-6 g mL-1 with a detection limit of 0.023 pg mL-1, providing a feasible approach for the quantitative detection of AFB1 in food samples.

Exploring microstructures of metal-doped oxides via simulated Raman spectrum.

Solid solution of metal-doped oxide has been widely used in material industry and catalysis process. Its performance is highly correlated with the distribution of doped ions. Due to the complex distribution of doped ions in solid solution and its variation with temperatures, to obtain the microstructures of metal-doped ions in solid solution remains a substantial challenge. Taken Ce1-xZrxO2 as a model, the global structure searching, structures proportion with temperature determined by Boltzmann distribution, and the weighted simulation Raman spectra were integrated to explore the microstructures of metal-doped solid solution oxides. It was further verified by application into rutile and anatase TiO2 mixture, indicating that the present method is feasible to deduce the microstructure of metal composite oxides. We anticipate that it provides a powerful solution to explore microstructures of solid solution and complex metal oxides.

Suppressing Organic Bromine but Promoting Bromate: Is the Ultraviolet/Ozone Process a Double-Edged Sword for the Toxicity of Wastewater to Mammalian Cells?

Brominated byproducts and toxicity generation are critical issues for ozone application to wastewater containing bromide. This study demonstrated that ultraviolet/ozone (UV/O3, 100 mJ/cm2, 1 mg-O3/mg-DOC) reduced the cytotoxicity of wastewater from 14.2 mg of pentol/L produced by ozonation to 4.3 mg of pentol/L (1 mg/L bromide, pH 7.0). The genotoxicity was also reduced from 1.65 to 0.17 µg-4-NQO/L by UV/O3. Compared with that of O3 alone, adsorbable organic bromine was reduced from 25.8 to 5.3 µg/L by UV/O3, but bromate increased from 32.9 to 71.4 µg/L. The UV/O3 process enhanced the removal of pre-existing precursors (highly unsaturated and phenolic compounds and poly aromatic hydrocarbons), while new precursors were generated, yet the combined effect of UV/O3 on precursors did not result in a significant change in toxicity. Instead, UV radiation inhibited HOBr concentration through both rapid O3 decomposition to reduce HOBr production and decomposition of the formed HOBr, thus suppressing the AOBr formation. However, the hydroxyl radical-dominated pathway in UV/O3 led to a significant increase of bromate. Considering both organic bromine and bromate, the UV/O3 process effectively controlled both cytotoxicity and genotoxicity of wastewater to mammalian cells, even though an emphasis should be also placed on managing elevated bromate. Futhermore, other end points are needed to evaluate the toxicity outcomes of the UV/O3 process.

Niraparib enhances antitumor immunity and contributes to the efficacy of PD-L1 blockade in cervical cancer.

PURPOSE: With the development of immunotherapy research, the role of immune checkpoint blockade (ICB) in the treatment of cervical cancer has been emphasized, but many patients still can't receive long-term benefits from ICB. Poly ADP ribose polymerase inhibitor (PARPi) has been proved to exert significant antitumor effects in multiple solid tumors. Whether cervical cancer patients obtain better benefits from the treatment regimen of PARPi combined with ICB remains unclear. METHODS: The alteration of PD-L1 expression induced by niraparib in cervical cancer cells and its underlying mechanism were assessed by western blot and immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR).The regulation of PTEN by KDM5A was confirmed using Chromatin immunoprecipitation (ChIP) assay and RNA interference. Analyzing the relationship between PD-L1 and immune effector molecules through searching online databases. Therapeutic efficacy of niraparib, PD-L1 blockade or combination was assessed in syngeneic tumor model. The changes of immune cells and cytokines in vivo was detected by immunohistochemistry (IHC) and qRT-PCR. RESULTS: We found that niraparib upregulated PD-L1 expression and potentiated the antitumor effects of PD-L1 blockade in a murine cervical cancer model. Niraparib inhibited the Pten expression by increasing the abundance of KDM5A, which expanded PD-L1 abundance through activating the PI3K-AKT-S6K1 pathway. PD-L1 was positively correlated with immune effector molecules including TNF-α, IFN-γ, granzyme A and granzyme B based on biological information analysis. Niraparib increased the infiltration of CD8+ T cells and the level of IFN-γ, granzyme B in vivo. CONCLUSION: Our findings demonstrates the regulation of niraparib on local immune microenvironment of cervical cancer, and provides theoretical basis for supporting the combination of PARPi and PD-L1 blockade as a potential treatment for cervical cancer.

Genome-Wide CRISPR Screen Identifies an NF2-Adherens Junction Mechanistic Dependency for Cardiac Lineage.

BACKGROUND: Cardiomyocyte differentiation involves a stepwise clearance of repressors and fate-restricting regulators through the modulation of BMP (bone morphogenic protein)/Wnt-signaling pathways. However, the mechanisms and how regulatory roadblocks are removed with specific developmental signaling pathways remain unclear. METHODS: We conducted a genome-wide CRISPR screen to uncover essential regulators of cardiomyocyte specification in human embryonic stem cells using a myosin heavy chain 6 (MYH6)-GFP (green fluorescence protein) reporter system. After an independent secondary single guide ribonucleic acid validation of 25 candidates, we identified NF2 (neurofibromin 2), a moesin-ezrin-radixin like (MERLIN) tumor suppressor, as an upstream driver of early cardiomyocyte lineage specification. Independent monoclonal NF2 knockouts were generated using CRISPR-Cas9, and cell states were inferred through bulk RNA sequencing and protein expression analysis across differentiation time points. Terminal lineage differentiation was assessed by using an in vitro 2-dimensional-micropatterned gastruloid model, trilineage differentiation, and cardiomyocyte differentiation. Protein interaction and post-translation modification of NF2 with its interacting partners were assessed using site-directed mutagenesis, coimmunoprecipitation, and proximity ligation assays. RESULTS: Transcriptional regulation and trajectory inference from NF2-null cells reveal the loss of cardiomyocyte identity and the acquisition of nonmesodermal identity. Sustained elevation of early mesoderm lineage repressor SOX2 and upregulation of late anticardiac regulators CDX2 and MSX1 in NF2 knockout cells reflect a necessary role for NF2 in removing regulatory roadblocks. Furthermore, we found that NF2 and AMOT (angiomotin) cooperatively bind to YAP (yes-associated protein) during mesendoderm formation, thereby preventing YAP activation, independent of canonical MST (mammalian sterile 20-like serine-threonine protein kinase)-LATS (large tumor suppressor serine-threonine protein kinase) signaling. Mechanistically, cardiomyocyte lineage identity was rescued by wild-type and NF2 serine-518 phosphomutants, but not NF2 FERM (ezrin-radixin-meosin homology protein) domain blue-box mutants, demonstrating that the critical FERM domain-dependent formation of the AMOT-NF2-YAP scaffold complex at the adherens junction is required for early cardiomyocyte lineage differentiation. CONCLUSIONS: These results provide mechanistic insight into the essential role of NF2 during early epithelial-mesenchymal transition by sequestering the repressive effect of YAP and relieving regulatory roadblocks en route to cardiomyocytes.

Hyperoside mitigates photoreceptor degeneration in part by targeting cGAS and suppressing DNA-induced microglial activation.

Activated microglia play an important role in driving photoreceptor degeneration-associated neuroinflammation in the retina. Controlling pro-inflammatory activation of microglia holds promise for mitigating the progression of photoreceptor degeneration. Our previous study has demonstrated that pre-light damage treatment of hyperoside, a naturally occurring flavonol glycoside with antioxidant and anti-inflammatory activities, prevents photooxidative stress-induced photoreceptor degeneration and neuroinflammatory responses in the retina. However, the direct impact of hyperoside on microglia-mediated neuroinflammation during photoreceptor degeneration remains unknown. Upon verifying the anti-inflammatory effects of hyperoside in LPS-stimulated BV-2 cells, our results here further demonstrated that post-light damage hyperoside treatment mitigated the loss of photoreceptors and attenuated the functional decline of the retina. Meanwhile, post-light damage hyperoside treatment lowered neuroinflammatory responses and dampened microglial activation in the illuminated retinas. With respect to microglial activation, hyperoside mitigated the pro-inflammatory responses in DNA-stimulated BV-2 cells and lowered DNA-stimulated production of 2'3'-cGAMP in BV-2 cells. Moreover, hyperoside was shown to directly interact with cGAS and suppress the enzymatic activity of cGAS in a cell-free system. In conclusion, the current study suggests for the first time that the DNA sensor cGAS is a direct target of hyperoside. Hyperoside is effective at mitigating DNA-stimulated cGAS-mediated pro-inflammatory activation of microglia, which likely contributes to the therapeutic effects of hyperoside at curtailing neuroinflammation and alleviating neuroinflammation-instigated photoreceptor degeneration.

Neuroticism personality, social contact, and dementia risk: A prospective cohort study.

BACKGROUND: Personality traits, especially neuroticism, can influence susceptibility to dementia. Social contact mitigates stress and risk of dementia, the extent to which social contact can mitigate excess risk associated with neuroticism remains unclear. We aim to investigate whether active social contact is associated with lower neuroticism-associated excess risk of dementia. METHODS: This prospective cohort study examined 393,939 UK Biobank participants (mean [SD] age: 56.4 [8.1] years; 53.7 % female) assessed from 2006 to 2010 and followed up until December 2022. Neuroticism was measured using the Revised Eysenck Personality Questionnaire. Social contact levels were assessed based on household size, contact with family or friends, and group participation. Dementia was determined using linked electronic health records. RESULTS: High neuroticism was associated with increased all-cause dementia risk and cause-specific dementia. Among high neuroticism participants, excess risk of all-cause dementia showed a stepwise decrease with increasing social contact (low: hazard ratios (HR) = 1.27, 95 % confidence interval (CI) = 1.15-1.40; intermediate: HR = 1.20, 95 % CI = 1.12-1.28; high: HR = 1.07, 95 % CI = 1.00-1.15). High social contact similarly decreased excess risk of cause-specific dementia, comparable to those with low neuroticism. LIMITATIONS: Neuroticism and social contact information relied on self-report questionnaires at baseline, with a potential temporal relationship between these factors. CONCLUSION: Active social contact is associated with a stepwise reduction in excess dementia risk and potentially eliminate excess risk of dementia with high neuroticism individuals, supporting social contact as a preventive strategy to attenuate excess risks of dementia from neuroticism personality trait.

Expanding the clinical spectrum of anti-DPPX encephalitis: a multicenter retrospective study.

Objective: Anti-dipeptidyl-peptidase-like protein-6 (DPPX) encephalitis is a rare autoimmune encephalitis, and clinical and experimental information regarding this disease is limited. We conducted this study to comprehensively describe the clinical characteristics, ancillary test results, neuroimaging results, and treatment response in a group of Chinese patients with anti-DPPX encephalitis for better understanding this disease. Methods: We recruited 14 patients who tested positive for anti-DPPX antibodies in the serum and/or cerebrospinal fluid from 11 medical centers between March 2021 and June 2023. This retrospective study evaluated data on symptoms, autoantibody test, auxiliary examinations, treatments, and outcomes. Results: The average age at diagnosis was 45.93 ± 4.62 years (range: 11-72 years), and 9 of the 14 patients were males. The main symptoms included cognitive impairment (50.0%, 7/14), central nervous system hyperexcitability (42.9%, 6/14), gastrointestinal dysfunction (35.7%, 5/14), and psychiatric disorders (35.7%, 5/14). Notably, we discovered specific findings on 18F-fluorodeoxyglucose positron-emission tomography (PET)/magnetic resonance imaging in two patients. Co-existing autoantibodies were identified in two patients. Parainfection was identified in four patients. One patient had other autoimmune diseases, and one had tumor. Eleven patients received immunotherapy and most patients improved at discharge. Surprisingly, three male patients but no female patients relapsed during the 6 months of follow-up. Conclusion: The development and outcome of anti-DPPX encephalitis are variable. Male patients were predominant in our cohort. The most common symptoms were the classical triad of prodromal gastrointestinal dysfunction, cognitive and mental disorders, and central nervous system hyperexcitability. Infections, immune dysregulation, and tumors may be important etiologies. Long-term monitoring of disease development should be done in male patients. Overall, our results highlight novel clinical characteristics of anti-DPPX encephalitis.

Asparagine Synthetase Marks a Distinct Dependency Threshold for Cardiomyocyte Dedifferentiation.

BACKGROUND: Adult mammalian cardiomyocytes have limited proliferative capacity, but in specifically induced contexts they traverse through cell-cycle reentry, offering the potential for heart regeneration. Endogenous cardiomyocyte proliferation is preceded by cardiomyocyte dedifferentiation (CMDD), wherein adult cardiomyocytes revert to a less matured state that is distinct from the classical myocardial fetal stress gene response associated with heart failure. However, very little is known about CMDD as a defined cardiomyocyte cell state in transition. METHODS: Here, we leveraged 2 models of in vitro cultured adult mouse cardiomyocytes and in vivo adeno-associated virus serotype 9 cardiomyocyte-targeted delivery of reprogramming factors (Oct4, Sox2, Klf4, and Myc) in adult mice to study CMDD. We profiled their transcriptomes using RNA sequencing, in combination with multiple published data sets, with the aim of identifying a common denominator for tracking CMDD. RESULTS: RNA sequencing and integrated analysis identified Asparagine Synthetase (Asns) as a unique molecular marker gene well correlated with CMDD, required for increased asparagine and also for distinct fluxes in other amino acids. Although Asns overexpression in Oct4, Sox2, Klf4, and Myc cardiomyocytes augmented hallmarks of CMDD, Asns deficiency led to defective regeneration in the neonatal mouse myocardial infarction model, increased cell death of cultured adult cardiomyocytes, and reduced cell cycle in Oct4, Sox2, Klf4, and Myc cardiomyocytes, at least in part through disrupting the mammalian target of rapamycin complex 1 pathway. CONCLUSIONS: We discovered a novel gene Asns as both a molecular marker and an essential mediator, marking a distinct threshold that appears in common for at least 4 models of CMDD, and revealing an Asns/mammalian target of rapamycin complex 1 axis dependency for dedifferentiating cardiomyocytes. Further study will be needed to extrapolate and assess its relevance to other cell state transitions as well as in heart regeneration.

Relation of poverty with treatment-seeking behavior and antibiotic misuse among UTI patients in Pakistan.

Objective: The current study aimed to assess the relation between multi-dimension poverty, treatment-seeking behavior, and antibiotic misuse among urinary tract infection (UTI) patients. Method: A cross-sectional approach was utilized to recruit patients who had a history of UTI in the previous month from two provinces of Pakistan. The treatment-seeking behavior and antibiotic misuse data were collected on a self-developed questionnaire, whereas the poverty data were collected on a modified multi-dimension poverty index (MPI). Descriptive statistics were applied to summarize the data. The logistic regression analysis was carried out to assess the association of multi-dimension poverty with patient treatment-seeking behavior and antibiotic misuse. Results: A total of 461 participants who had UTI symptoms in the previous month were recruited. Most of the participants in the severely deprived stage treated the UTI (p < 0.001); however, there was a high proportion of the participants who consulted with friends and family for UTI treatment (p < 0.001). The patients with deprivation status (deprived and severely deprived) were less associated with formal consultation. The poorer subgroups were less likely to practice antibiotic course completion. Conclusion: The current study highlighted that poverty plays an important role in antibiotic misuse. Poorer subgroups were associated with informal consultations and the incompletion of the antibiotic course. Further studies are needed to explore the potential role of poverty in treatment-seeking behavior and antibiotic misuse.

Necroptosis pathway emerged as potential diagnosis markers in spinal cord injury.

The present research focused on identifying necroptosis-related differentially expressed genes (NRDEGs) in spinal cord injury (SCI) to highlight potential therapeutic and prognostic target genes in clinical SCI. Three SCI-related datasets were downloaded, including GSE151371, GSE5296 and GSE47681. MSigDB and KEGG datasets were searched for necroptosis-related genes (NRGs). Differentially expressed genes (DEGs) and NRGs were intersected to obtain NRDEGs. The MCC algorithm was employed to select the first 10 genes as hub genes. A protein-protein interaction (PPI) network related to NRDEGs was developed utilizing STRING. Several databases were searched to predict interactions between hub genes and miRNAs, transcription factors, potential drugs, and small molecules. Immunoassays were performed to identify DEGs using CIBERSORTx. Additionally, qRT-PCR was carried out to verify NRDEGs in an animal model of SCI. Combined analysis of all datasets identified 15 co-expressed DEGs and NRGs. GO and KEGG pathway analyses highlighted DEGs mostly belonged to pathways associated with necroptosis and apoptosis. Hub gene expression analysis showed high accuracy in SCI diagnosis was associated with the expression of CHMP7 and FADD. A total of two hub genes, i.e. CHMP7, FADD, were considered potential targets for SCI therapy.

[Characteristics of anion and cation in rhizosphere soil of saline grassland in North China under different nitrogen addition levels]. / ä¸åŒæ°´å¹³æ°®æ·»åŠ ä¸‹åŽåŒ—ç›æ¸åŒ–è‰åœ°æ ¹é™ åœŸå£¤é˜´é˜³ç¦»å­ç‰¹å¾.

We investigated the effects and mechanisms of nitrogen additions (0, 1, 2, 4, 8, 16, 24, 32 g N·m-2·a-1) on contents of anion and cation in rhizosphere soil, bulk soil, and mixed rhizosphere and bulk soil in the heavily salinized grassland in the agro-pastoral ecotone of North China. The results showed that pH of rhizosphere, mixed and bulk soils decreased significantly with the increases of nitrogen addition levels. Moreover, pH of three soil types under the 32 g N·m-2·a-1 treatment decreased by 1.2, 0.9, and 0.6, respectively, while pH of rhizosphere soil decreased by 0.44 compared with the bulk soil. Na+ content of rhizosphere, mixed and bulk soils significantly decreased, while the NO3- content significantly increased. The proportion of Na+ content in total soluble salt content in rhizosphere soil decreased by 14% and that in bulk soil decreased by 12% after the 32 g N·m-2·a-1 addition. NO3- content increased by 29% in rhizosphere soil and by 26% in bulk soil. There was significant negative correlation between pH and NO3- content, and significant positive correlation between pH and Na+ content. The total soluble salt content of rhizosphere soil under the 32 g N·m-2·a-1 treatment was significantly reduced by 31.5%. Collectedly, nitrogen deposition could reduce soil pH and total soluble salt content of rhizosphere soil and alleviate saline-alkali stress.

Insights into the fish protein degradation induced by the fish-borne spoiler Pseudomonas psychrophila and Shewanella putrefaciens: From whole genome sequencing to quality changes.

The aim of this study is evaluating the protein degradation capacity of specific spoilage organisms (SSOs) Pseudomonas psychrophila and Shewanella putrefaciens in fish flesh during chilled storage and revealing the underlying genes by whole-genome sequencing (WGS). Biochemical and physical tests were performed on fish flesh inoculated with P. psychrophila and S. putrefaciens individually, including textural properties, myofibrillar fragmentation index, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) profiles, free amino acid composition, total volatile basic nitrogen (TVB-N), trichloroacetic acid (TCA) soluble peptides, and muscle microstructure. Results showed that P. psychrophila and S. putrefaciens exhibited a strong capacity for decomposing the fish protein, and the deterioration of fish flesh texture was primarily attributed to P. psychrophila. The genes from SSOs associated with the production of proteases were identified by whole genome sequencing and serine protease may be the primary enzyme secreted by SSOs involved in the degradation of fish protein. Therefore, the present study has shed light on the mechanisms of protein degradation induced by SSOs, thereby offering valuable insights for the development of effective quality control strategies.

Fucoxanthin induces human melanoma cytotoxicity by thwarting the JAK2/STAT3/BCL-xL signaling axis.

Melanoma is the most lethal skin malignancy. Fucoxanthin is a marine carotenoid with significant anticancer activities. Intriguingly, Fucoxanthin's impact on human melanoma remains elusive. Signal Transducer and Activator of Transcription 3 (STAT3) represents a promising target in cancer therapy due to its persistent activation in various cancers, including melanoma. Herein, we revealed that Fucoxanthin is cytotoxic to human melanoma cell lines A2758 and A375 while showing limited cytotoxicity to normal human melanocytes. Apoptosis is a primary reason for Fucoxanthin's melanoma cytotoxicity, as the pan-caspase inhibitor z-VAD-fmk drastically abrogated Fucoxanthin-elicited clonogenicity blockage. Besides, Fucoxanthin downregulated tyrosine 705-phosphorylated STAT3 (p-STAT3 (Y705)), either inherently present in melanoma cells or inducible by interleukin 6 (IL-6) stimulation. Notably, ectopic expression of STAT3-C, a dominant-active STAT3 mutant, abolished Fucoxanthin-elicited melanoma cell apoptosis and clonogenicity inhibition, supporting the pivotal role of STAT3 blockage in Fucoxanthin's melanoma cytotoxicity. Moreover, Fucoxanthin lowered BCL-xL levels by blocking STAT3 activation, while ectopic BCL-xL expression rescued melanoma cells from Fucoxanthin-induced killing. Lastly, Fucoxanthin was found to diminish the levels of JAK2 with dual phosphorylation at tyrosine residues 1007 and 1008 in melanoma cells, suggesting that Fucoxanthin impairs STAT3 signaling by blocking JAK2 activation. Collectively, we present the first evidence that Fucoxanthin is cytotoxic selectively against human melanoma cells while sparing normal melanocytes. Mechanistically, Fucoxanthin targets the JAK2/STAT3/BCL-xL antiapoptotic axis to provoke melanoma cell death. This discovery implicates the potential application of Fucoxanthin as a chemopreventive or therapeutic strategy for melanoma management.