Combining Flexible Region Design and Automatic Design to Enhance the Thermal Stability and Catalytic Efficiency of Leucine Dehydrogenase.

Leucine dehydrogenase (LeuDH, EC 1.4.1.9) can reversibly catalyze the oxidative deamination of l-leucine and some other specific α-amino acids to form the corresponding α-ketoacids. This reaction has great significance in the field of food additives and the pharmaceutical industry. The LeuDH from Exiguobacterium sibiricum (EsLeuDH) has high catalytic efficiency but limited thermal stability, hindering its widespread industrial application. In this study, a mutant N5F/I12L/A352Y of EsLeuDH (referred to as M2) was developed with enhanced thermal stability and catalytic activity through rational modification. The M2 mutant exhibits a half-life at 60 °C (t1/2(60 °C)) of 975.7 min and a specific activity of 69.6 U mg-1, which is 5.4 and 2.1 times higher than those of EsLeuDH, respectively. This research may facilitate the utilization of EsLeuDH at elevated temperatures, enhancing its potential for industrial applications. The findings offer a practical and efficient approach for optimizing LeuDH and other industrial enzymes.

Creating yellow seed Camelina sativa with enhanced oil accumulation by CRISPR-mediated disruption of Transparent Testa 8.

Camelina (Camelina sativa L.), a hexaploid member of the Brassicaceae family, is an emerging oilseed crop being developed to meet the increasing demand for plant oils as biofuel feedstocks. In other Brassicas, high oil content can be associated with a yellow seed phenotype, which is unknown for camelina. We sought to create yellow seed camelina using CRISPR/Cas9 technology to disrupt its Transparent Testa 8 (TT8) transcription factor genes and to evaluate the resulting seed phenotype. We identified three TT8 genes, one in each of the three camelina subgenomes, and obtained independent CsTT8 lines containing frameshift edits. Disruption of TT8 caused seed coat colour to change from brown to yellow reflecting their reduced flavonoid accumulation of up to 44%, and the loss of a well-organized seed coat mucilage layer. Transcriptomic analysis of CsTT8-edited seeds revealed significantly increased expression of the lipid-related transcription factors LEC1, LEC2, FUS3, and WRI1 and their downstream fatty acid synthesis-related targets. These changes caused metabolic remodelling with increased fatty acid synthesis rates and corresponding increases in total fatty acid (TFA) accumulation from 32.4% to as high as 38.0% of seed weight, and TAG yield by more than 21% without significant changes in starch or protein levels compared to parental line. These data highlight the effectiveness of CRISPR in creating novel enhanced-oil germplasm in camelina. The resulting lines may directly contribute to future net-zero carbon energy production or be combined with other traits to produce desired lipid-derived bioproducts at high yields.

Cavitation is the determining mechanism for the atomization of high-viscosity liquid.

Piezoelectric atomization is becoming mainstream in the field of inhalation therapy due to its significant advantages. With the rapid development of high-viscosity gene therapy drugs, the demand for piezoelectric atomization devices is increasing. However, conventional piezoelectric atomizers with a single-dimensional energy supply are unable to provide the energy required to atomize high-viscosity liquids. To address this problem, our team has designed a flow tube internal cavitation atomizer (FTICA). This study focuses on dissecting the atomization mechanism of FTICA. In contrast to the widely supported capillary wave hypothesis, our study provides evidence in favor of the cavitation hypothesis, proving that cavitation is the key to atomizing high-viscosity liquids with FTICA. In order to prove that the cavitation is the key to atomizing in the structure of FTICA, the performance of atomization is experimented after changing the cavitation conditions by heating and stirring of the liquids.

Pedigree Analysis of Nonclassical Cholesteryl Ester Storage Disease with Dominant Inheritance in a LIPA I378T Heterozygous Carrier.

BACKGROUND: Cholesterol ester storage disorder (CESD; OMIM: 278,000) was formerly assumed to be an autosomal recessive allelic genetic condition connected to diminished lysosomal acid lipase (LAL) activity due to LIPA gene abnormalities. CESD is characterized by abnormal liver function and lipid metabolism, and in severe cases, liver failure can occur leading to death. In this study, one Chinese nonclassical CESD pedigree with dominant inheritance was phenotyped and analyzed for the corresponding gene alterations. METHODS: Seven males and eight females from nonclassical CESD pedigree were recruited. Clinical features and LAL activities were documented. Whole genome Next-generation sequencing (NGS) was used to screen candidate genes and mutations, Sanger sequencing confirmed predicted mutations, and qPCR detected LIPA mRNA expression. RESULTS: Eight individuals of the pedigree were speculatively thought to have CESD. LAL activity was discovered to be lowered in four living members of the pedigree, but undetectable in the other four deceased members who died of probable hepatic failure. Three of the four living relatives had abnormal lipid metabolism and all four had liver dysfunctions. By liver biopsy, the proband exhibited diffuse vesicular fatty changes in noticeably enlarged hepatocytes and Kupffer cell hyperplasia. Surprisingly, only a newly discovered heterozygous mutation, c.1133T>C (p. Ile378Thr) on LIPA, was found by gene sequencing in the proband. All living family members who carried the p.I378T variant displayed reduced LAL activity. CONCLUSIONS: Phenotypic analyses indicate that this may be an autosomal dominant nonclassical CESD pedigree with a LIPA gene mutation.

Clinical phenotype and genetic function analysis of a family with hypomyelinating leukodystrophy-7 caused by POLR3A mutation.

Hypomyelinating leukodystrophy (HLD) is a rare genetic heterogeneous disease that can affect myelin development in the central nervous system. This study aims to analyze the clinical phenotype and genetic function of a family with HLD-7 caused by POLR3A mutation. The proband (IV6) in this family mainly showed progressive cognitive decline, dentin dysplasia, and hypogonadotropic hypogonadism. Her three old brothers (IV1, IV2, and IV4) also had different degrees of ataxia, dystonia, or dysarthria besides the aforementioned manifestations. Their brain magnetic resonance imaging showed bilateral periventricular white matter atrophy, brain atrophy, and corpus callosum atrophy and thinning. The proband and her two living brothers (IV2 and IV4) were detected to carry a homozygous mutation of the POLR3A (NM_007055.4) gene c. 2300G > T (p.Cys767Phe), and her consanguineous married parents (III1 and III2) were p.Cys767Phe heterozygous carriers. In the constructed POLR3A wild-type and p.Cys767Phe mutant cells, it was seen that overexpression of wild-type POLR3A protein significantly enhanced Pol III transcription of 5S rRNA and tRNA Leu-CAA. However, although the mutant POLR3A protein overexpression was increased compared to the wild-type protein overexpression, it did not show the expected further enhancement of Pol III function. On the contrary, Pol III transcription function was frustrated (POLR3A, BC200, and tRNA Leu-CAA expression decreased), and MBP and 18S rRNA expressions were decreased. This study indicates that the POLR3A p.Cys767Phe variant caused increased expression of mutated POLR3A protein and abnormal expression of Pol III transcripts, and the mutant POLR3A protein function was abnormal.

Antagonizing roles of SHP1 in the pathogenesis of Helicobacter pylori infection.

BACKGROUND: SHP1 has been documented as a tumor suppressor and it was thought to play an antagonistic role in the pathogenesis of Helicobacter pylori infection. In this study, the exact mechanism of this antagonistic action was studied. MATERIALS AND METHODS: AGS, MGC803, and GES-1 cells were infected with H. pylori, intracellular distribution changes of SHP1 were first detected by immunofluorescence. SHP1 overexpression and knockdown were then constructed in these cells to investigate its antagonistic roles in H. pylori infection. Migration and invasion of infected cells were detected by transwell assay, secretion of IL-8 was examined via ELISA, the cells with hummingbird-like alteration were determined by microexamination, and activation of JAK2/STAT3, PI3K/Akt, and ERK pathways were detected by immunoblotting. Mice infection model was established and gastric pathological changes were evaluated. Finally, the SHP1 activator sorafenib was used to analyze the attenuating effect of SHP1 activation on H. pylori pathogenesis in vitro and in vivo. RESULTS: The sub-localization of SHP1 changed after H. pylori infection, specifically that the majority of the cytoplasmic SHP1 was transferred to the cell membrane. SHP1 inhibited H. pylori-induced activation of JAK2/STAT3 pathway, PI3K/Akt pathway, nuclear translocation of NF-κB, and then reduced EMT, migration, invasion, and IL-8 secretion. In addition, SHP1 inhibited the formation of CagA-SHP2 complex by dephosphorylating phosphorylated CagA, reduced ERK phosphorylation and the formation of CagA-dependent hummingbird-like cells. In the mice infection model, gastric pathological changes were observed and increased IL-8 secretion, indicators of cell proliferation and EMT progression were also detected. By activating SHP1 with sorafenib, a significant curative effect against H. pylori infection was obtained in vitro and in vivo. CONCLUSIONS: SHP1 plays an antagonistic role in H. pylori pathogenesis by inhibiting JAK2/STAT3 and PI3K/Akt pathways, NF-κB nuclear translocation, and CagA phosphorylation, thereby reducing cell EMT, migration, invasion, IL-8 secretion, and hummingbird-like changes.

m 6 A reader IGF2BP1 reduces the sensitivity of nasopharyngeal carcinoma cells to Taxol by upregulation of AKT2.

Taxol is widely used in the treatment of nasopharyngeal carcinoma (NPC); nevertheless, the acquired resistance of NPC to Taxol remains one of the major obstacles in clinical treatment. In this study, we aimed to investigate the role and mechanism of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in Taxol resistance of NPC. Taxol-resistant NPC cell lines were established by exposing to gradually increased concentration of Taxol. Relative mRNA and protein levels were tested using qRT-PCR and western blot, respectively. NPC cell viability and apoptosis were assessed by cell counting kit-8 and flow cytometry analysis, respectively. Cell migration and invasion capacities were measured using transwell assay. Interaction between IGF2BP1 and AKT2 was examined by RNA immunoprecipitation assay. The N6-methyladenosine level of AKT2 was tested using methylated RNA immunoprecipitation-qPCR. IGF2BP1 expression was enhanced in Taxol-resistant NPC cell lines. Knockdown of IGF2BP1 strikingly enhanced the sensitivity of NPC cells to Taxol and repressed the migration and invasion of NPC cells. Mechanistically, IGF2BP1 elevated the expression of AKT2 by increasing its mRNA stability. Furthermore, overexpression of AKT2 reversed the inhibitory roles of IGF2BP1 silence on Taxol resistance and metastasis. Our results indicated that IGF2BP1 knockdown enhanced the sensitivity of NPC cells to Taxol by decreasing the expression of AKT2, implying that IGF2BP1 might be promising candidate target for NPC treatment.

Investigating the impact of remnant cholesterol on new-onset stroke across diverse inflammation levels: Insights from the China Health and Retirement Longitudinal Study (CHARLS).

BACKGROUND: Prior research underscores the significant impact of remnant cholesterol (RC) on stroke occurrence due to its proatherogenic and proinflammatory traits. This study aims to explore diverse risks of new-onset stroke associated with RC, considering distinct inflammation levels in the middle-aged and senior population in China. METHODS: We analyzed 6509 participants from the China Health and Retirement Longitudinal Study (CHARLS) across four waves (2011-2018). We employed a multivariable Cox proportional hazards regression model, incorporated restricted cubic spline techniques, and conducted sensitivity analyses to evaluate the association among RC, high-sensitivity C-reactive protein (hsCRP), and the risk of new-onset stroke. RESULTS: Over 7 years, 540 new-onset strokes occurred. Individuals in the highest quartile of RC levels exhibited a heightened risk of new-onset stroke, with a multivariable-adjusted hazard ratio (HR) peaking at 1.50 (95% confidence interval 1.12-2.00, P for trend = 0.021), showing a non-linear correlation (P nonlinearity = 0.049). High hsCRP alone had an adjusted HR of 1.10 (95% CI 0.87-1.39), compared to 1.40 (95% CI 1.00-1.96) for high RC alone. Additionally, concurrent high RC and hsCRP showed an adjusted HR of 1.43 (95% CI 1.05-1.96). Consistency persisted across various hsCRP thresholds, after adjusting for additional parameters, or excluding chronic diseases in the primary model, reinforcing result robustness. CONCLUSION: Our findings reveal a substantial and non-linear association between higher baseline RC levels and an elevated risk of new-onset stroke. Moreover, elevated levels of both RC and hsCRP jointly pose the highest risk for new-onset stroke, surpassing the risk associated with each factor individually.

CD93 regulates breast cancer growth and vasculogenic mimicry through the PI3K/AKT/SP2 signaling pathway activated by integrin ß1.

In women, breast cancer (BC) accounts for 7%-10% of all cancer cases and is one of the most common cancers. To identify a new method for treating BC, the role of CD93 and its underlying mechanism were explored. MDA-MB-231 cells were used in this study and transfected with si-CD93, si-MMRN2, oe-CD93, si-integrin ß1, or oe-SP2 lentivirus. After MDA-MB-231 cells were transfected with si-NC or si-CD93, they were injected into nude mice by subcutaneous injection at a dose of 5 × 106/mouse to construct a BC animal model. The expression of genes and proteins and cell migration, invasion and vasculogenic mimicry were detected by RT‒qPCR, western blot, immunohistochemistry, immunofluorescence, Transwell, and angiogenesis assays. In pathological samples and BC cell lines, CD93 was highly expressed. Functionally, CD93 promoted the proliferation, migration, and vasculogenic mimicry of MDA-MB-231 cells. Moreover, CD93 interacts with MMRN2 and integrin ß1. Knockdown of CD93 and MMRN2 can inhibit the activation of integrin ß1, thereby inhibiting the PI3K/AKT/SP2 signaling pathway and inhibiting BC growth and vasculogenic mimicry. In conclusion, the binding of CD93 to MMRN2 can activate integrin ß1, thereby activating the PI3K/AKT/SP2 signaling pathway and subsequently promoting BC growth and vasculogenic mimicry.

Engineering Escherichia coli for high-yielding 2,5-Dimethylpyrazine synthesis from L-Threonine by reconstructing metabolic pathways and enhancing cofactors regeneration.

2,5-Dimethylpyrazine (2,5-DMP) is important pharmaceutical raw material and food flavoring agent. Recently, engineering microbes to produce 2,5-DMP has become an attractive alternative to chemical synthesis approach. In this study, metabolic engineering strategies were used to optimize the modified Escherichia coli BL21 (DE3) strain for efficient synthesis of 2,5-DMP using L-threonine dehydrogenase (EcTDH) from Escherichia coli BL21, NADH oxidase (EhNOX) from Enterococcus hirae, aminoacetone oxidase (ScAAO) from Streptococcus cristatus and L-threonine transporter protein (EcSstT) from Escherichia coli BL21, respectively. We further optimized the reaction conditions for synthesizing 2,5-DMP. In optimized conditions, the modified strain can convert L-threonine to obtain 2,5-DMP with a yield of 2897.30 mg/L. Therefore, the strategies used in this study contribute to the development of high-level cell factories for 2,5-DMP.

Split-type photoelectrochemical immunoassay for sensitive quantification of carcinoembryonic antigen based on target-induced in situ formation of Z-type heterojunction.

Carcinoembryonic antigen (CEA), a vital biomarker, plays a significant role in the early diagnosis and prognostic estimation of malignant tumors. In this study, a split-type photoelectrochemical immunoassay for the sensitive quantification of CEA has been successfully developed based on the target-induced in situ formation of a Z-type heterojunction. First, gold nanoparticle-decorated ZnIn2S4 (AuNPs/ZnIn2S4) composites were synthesized and used for the fabrication of photoelectrodes. Then, the detection antibody labeled with Ag nanoparticles was formed and applied for the biorecognition of CEA and subsequent liberation of Ag+ ions to induce the in situ formation of Ag2S/AuNPs/ZnIn2S4, a Z-type heterojunction, on the photoelectrode. The Z-type Ag2S/AuNPs/ZnIn2S4 heterojunction with effectively promoted separation of photogenerated charge carriers could lead to a markedly enhanced photocurrent response and highly sensitive quantification of CEA. Moreover, the three-dimensional spatial structure of ZnIn2S4 provides abundant active sites for the reaction and exhibits non-enzymatic properties, which are conducive to the further improvement of the analytical performance of CEA. The developed split-type photoelectrochemical immunoassay with good sensitivity, satisfactory selectivity, reliable stability, wide dynamic linear range (0.01-20 ng mL-1), and low detection limit (7.3 pg mL-1) offers valuable insights into the development of novel PEC biosensing models for the detection of tumor biomarkers and holds potential application value in the field of disease diagnosis.

Immunogenicity and safety of boosting with a recombinant two-component SARS-CoV-2 vaccine: two randomized, parallel-controlled, phase 2 studies.

BACKGROUND: Recombinant protein vaccines are vital for broad protection against SARS-CoV-2 variants. This study assessed ReCOV as a booster in two Phase 2 trials. RESEARCH DESIGN AND METHODS: Study-1 involved subjects were randomized (1:1:1) to receive 20 µg ReCOV, 40 µg ReCOV, or an inactivated vaccine (COVILO®) in the United Arab Emirates. Study-2 participating individuals were randomized (1:1:1) to receive 20 µg ReCOV (pilot batch, ReCOV HA), 20 µg ReCOV (commercial batch, ReCOV TC), or 30 µg BNT162b2 (COMIRNATY®) in the Philippines. The primary immunogenicity objectives was to compare the geometric mean titer (GMT) and seroconversion rate (SCR) of neutralizing antibodies induced by one ReCOV booster dose with those of inactivated vaccine and BNT162b2, respectively, at 14 days post-booster. RESULTS: Heterologous ReCOV booster doses were safe and induced comparable immune responses to inactivated vaccines and BNT162b2 against Omicron variants and the prototype. They showed significant advantages in cross-neutralization against multiple SARS-CoV-2 variants, surpassing inactivated vaccines and BNT162b2, with good immune persistence. CONCLUSIONS: Heterologous ReCOV boosting was safe and effective, showing promise in combating COVID-19. The study highlights ReCOV's potential for enhanced protection, supported by strong cross-neutralization and immune persistence. CLINICAL TRIAL REGISTRATION: Study-1, www.clinicaltrials.gov, identifier is NCT05323435; Study-2, www.clinicaltrials.gov, identifier is NCT05084989.

Adult type I Gaucher disease with splenectomy caused by a compound heterozygous GBA1 mutation in a Chinese patient: a case report.

Gaucher disease (GD) is an autosomal recessive ailment resulting from glucocerebrosidase deficiency caused by a mutation in the GBA1 gene, leading to multi-organ problems in the liver, spleen, and bone marrow. In China, GD is extremely uncommon and has a lower incidence rate than worldwide. In this study, we report the case of an adult male with an enlarged spleen for 13 years who presented with abdominal distension, severe loss of appetite and weight, reduction of the three-line due to hypersplenism, frequent nosebleeds, and bloody stools. Regrettably, the unexpected discovery of splenic pathology suggestive of splenic Gaucher disease was only made after a splenectomy due to a lack of knowledge about rare disorders. Our patient's delayed diagnosis may have been due to the department where he was originally treated, but it highlights the need for multidisciplinary consultation in splenomegaly of unknown etiology. We then investigated the patient's clinical phenotypes and gene mutation features using genetically phenotypical analysis. The analysis of the GBA1 gene sequence indicated that the patient carried a compound heterozygous mutation consisting of two potentially disease-causing mutations: c.907C > A (p. Leu303Ile) and c.1448 T > C (p. Leu483Pro). While previous research has linked the p. Leu483Pro mutation site to neurologic GD phenotypes (GD2 and GD3), the patients in this investigation were identified as having non-neuronopathic GD1. The other mutation, p. Leu303Ile, is a new GD-related mutation not indexed in PubMed that enriches the GBA1 gene mutation spectrum. Biosignature analysis has shown that both mutations alter the protein's three-dimensional structure, which may be a pathogenic mechanism for GD1 in this patient.

Prognostic significance of IL-18 in acute coronary syndrome patients.

BACKGROUND: After acute coronary syndrome (ACS), inflammation aids healing but may harm the heart. Interleukin (IL)-18 and IL-1ß are pivotal proinflammatory cytokines released during pyroptosis, a process that initiates and sustains inflammation. This study aimed to evaluate the levels of circulating IL-18 and IL-1ß during the progression of ACS and to determine their association with subsequent clinical events in ACS patients. HYPOTHESIS: Circulating levels of IL-18 and IL-1ß are associated with subsequent clinical events in ACS patients. METHODS: Employing immunoassays, we examined plasma levels of IL-1ß and IL-18 in 159 ACS patients and matched them with 159 healthy controls. The primary composite endpoint included recurrent unstable angina, myocardial infarction, heart failure exacerbation, stroke, or cardiovascular death. RESULTS: ACS patients exhibited a significant increase in plasma IL-18 levels, measuring 6.36 [4.46-9.88] × 102 pg/mL, in contrast to the control group with levels at 4.04 [3.21-4.94] × 102 pg/mL (p < 0.001). Conversely, plasma levels of IL-1ß remained unchanged compared to the control group. Following a 25-month follow-up, IL-18 levels exceeding the median remained an important prognostic factor for adverse clinical events in ACS patients (hazard ratio = 2.37, 95% confidence interval: 1.14-4.91, p = 0.021). Besides, IL-18 displayed a nonlinear association with adverse clinical events (p nonlinear = 0.044). Subgroup analysis revealed that the correlation between IL-18 and the risk of adverse clinical events was not significantly affected by factors such as age, sex, history of diabetes, smoking, Gensini score, or ACS type (all p interaction >0.05). CONCLUSION: IL-18 appears to hold potential as a predictive marker for anticipating clinical outcomes in patients with ACS.

Pathophysiology of human mitochondrial tRNA metabolism.

Mitochondria play multiple critical roles in cellular activity. In particular, mitochondrial translation is pivotal in the regulation of mitochondrial and cellular homeostasis. In this forum article, we discuss human mitochondrial tRNA metabolism and highlight its tight connection with various mitochondrial diseases caused by mutations in aminoacyl-tRNA synthetases, tRNAs, and tRNA-modifying enzymes.

Gut microbiota and chronic rhinosinusitis: a two-sample Mendelian randomization study.

BACKGROUND: The nasal cavity and gut are interconnected, both housing a rich natural microbiome. Gut microbiota may interact with nasal microbiota and contribute to the development of chronic rhinosinusitis (CRS). However, the specific role of gut microbiota in CRS has not been fully investigated. Therefore, we conducted a two-sample Mendelian randomization study to reveal the potential genetic causal effect of gut microbiota on CRS. METHODS: We performed a two-sample Mendelian Randomization (MR) analysis using aggregated data from genome-wide association studies (GWAS) on gut microbiota and CRS. The primary method used to assess the causal relationship between gut microbiota and CRS was the inverse variance weighting (IVW) method. In addition, sensitivity analyses were conducted to evaluate the robustness of the MR results, including heterogeneity, pleiotropy, and leave-one-out tests. RESULTS: Genetically predicted twelve gut microbiota, including class Coriobacteriia, class Methanobacteria, family Coriobacteriaceae, family Methanobacteriaceae, family Pasteurellaceae, genus Haemophilus, genus Ruminococcus torques group, genus Subdoligranulum, order Coriobacteriales, order Methanobacteriales, order Pasteurellales, and phylum Proteobacteria, demonstrated a potential inhibitory effect on CRS risk (P < 0.05). In addition, four gut microbiota, including family Streptococcaceae, genus Clostridium innocuum group, genus Oscillospira, and genus Ruminococcaceae NK4A214 group, exhibited a causal role in increasing CRS risk (P < 0.05). Sensitivity analyses showed no evidence of heterogeneity or pleiotropy (P > 0.05). CONCLUSIONS: This study reveals the causal relationship between specific gut microbiota and CRS, which provides a new direction and theoretical foundation for the future development of interventions and prevention and treatment strategies for CRS.

METTL17 coordinates ferroptosis and tumorigenesis by regulating mitochondrial translation in colorectal cancer.

Ferroptosis, an iron-dependent lipid peroxidation-induced form of regulated cell death, shows great promise as a cancer therapy strategy. Despite the critical role of mitochondria in ferroptosis regulation, the underlying mechanisms remain elusive. This study reveals that the mitochondrial protein METTL17 governs mitochondrial function in colorectal cancer (CRC) cells through epigenetic modulation. Bioinformatic analysis establishes that METTL17 expression positively correlates with ferroptosis resistance in cancer cells and is up-regulated in CRC. Depletion of METTL17 sensitizes CRC cells to ferroptosis, impairs cell proliferation, migration, invasion, xenograft tumor growth, and AOM/DSS-induced CRC tumorigenesis. Furthermore, suppression of METTL17 disrupts mitochondrial function, energy metabolism, and enhances intracellular and mitochondrial lipid peroxidation and ROS levels during ferroptotic stress. Mechanistically, METTL17 inhibition significantly reduces mitochondrial RNA methylation, including m4C, m5C, m3C, m7G, and m6A, leading to impaired translation of mitochondrial protein-coding genes. Additionally, the interacting proteins associated with METTL17 are essential for mitochondrial gene expression, and their knockdown sensitizes CRC cells to ferroptosis and inhibits cell proliferation. Notably, combined targeting of METTL17 and ferroptosis in a therapeutic approach effectively suppresses CRC xenograft growth in vivo. This study uncovers the METTL17-mediated defense mechanism for cell survival and ferroptosis in mitochondria, highlighting METTL17 as a potential therapeutic target for CRC.

Association between blood volatile organic aromatic compound concentrations and hearing loss in US adults.

OBJECTIVE: Benzene, ethylbenzene, meta/para-xylene, and ortho-xylene, collectively referred to as benzene, ethylbenzene, and xylene (BEX), constitute the main components of volatile organic aromatic compounds (VOACs) and can have adverse effects on human health. The relationship between exposure to BEX and hearing loss (HL) in the adult U.S. population was aimed to be assessed. METHODS: Cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) for the years 2003-2004, 2011-2012, and 2015-2016 were analyzed. This dataset included complete demographic characteristics, pure-tone audiometry measurements, and volatile organic compound detection data from the NHANES database. A weighted multivariate logistic regression model was employed to investigate the associations between blood BEX concentrations HL, low-frequency hearing loss (SFHL), and high-frequency hearing loss (HFHL). RESULTS: 2174 participants were included, with weighted prevalence rates of HL, SFHL, and HFHL being 46.81%, 25.23%, and 45.86%, respectively. Exposure to benzene, ethylbenzene, meta/para-xylene, and ortho-xylene, and cumulative BEX concentrations increased the risk of hearing loss (odds ratios [ORs] were 1.36, 1.22, 1.42, 1.23, and 1.31, respectively; all P < 0.05). In the analysis with SFHL as the outcome, ethylbenzene, m-/p-xylene, o-xylene, benzene, and overall BEX increased the risk (OR 1.26, 1.21, 1.28, 1.20, and 1.25, respectively; all P < 0.05). For HFHL, exposure to ethylbenzene, m-/p-xylene, o-xylene, benzene, and overall BEX increased the risk (OR 1.36, 1.22, 1.42, 1.22, and 1.31, respectively; all P < 0.05). CONCLUSION: Our study indicated that a positive correlation between individual or cumulative exposure to benzene, ethylbenzene, meta/para-xylene, and ortho-xylene and the risk of HL, SFHL, and HFHL. Further research is imperative to acquire a more comprehensive understanding of the mechanisms by which organic compounds, notably BEX, in causing hearing loss and to validate these findings in longitudinal environmental studies.

Study on the preparation and enzyme inhibitory activity of polyphenols from Sargassum pallidum.

This study aimed to obtain a high yield and purity of Sargassum pallidum polyphenol extracts (SPPE) and study its enzyme activity. Fresh Sargassum pallidum seaweed was selected for optimization of ultrasound-assisted extraction (UAE) conditions and purification conditions using macroporous resin and Sephadex LH20 to obtain SPPE. The SPPE was characterized using UPLC-QTOF-MS/MS and α-amylase, α-glucosidase, tyrosinase, and AchE inhibitory activity were determined. The maximum extraction rate of SPPE was 7.56 mg GAE/g and the polyphenol purity reached 70.5% after macroporous resin and Sephadex LH-20 purification. A total of 50 compounds were identified by UPLC-QTOF-MS/MS. The IC50 values of SPPE were 334.9 µg/mL, 6.290 µg /mL, 0.834 mg /mL and 0.6538 mg /mL for α-amylase, α-glucosidase, tyrosinase and AchE, respectively. Molecular docking technology further revealed the effects of SPPE on the above enzymes. This study provided information on the potential hypoglycemic, whitening and anti-Alzheimer's disease biological activities of SPPE, which had guiding significance for the purification and development of other seaweed polyphenols.