Spermidine-eIF5A axis is essential for muscle stem cell activation via translational control.

Adult skeletal muscle stem cells, also known satellite cells (SCs), are quiescent and activate in response to injury. However, the activation mechanisms of quiescent SCs (QSCs) remain largely unknown. Here, we investigated the metabolic regulation of SC activation by identifying regulatory metabolites that promote SC activation. Using targeted metabolomics, we found that spermidine acts as a regulatory metabolite to promote SC activation and muscle regeneration in mice. Mechanistically, spermidine activates SCs via generating hypusinated eIF5A. Using SC-specific eIF5A-knockout (KO) and Myod-KO mice, we further found that eIF5A is required for spermidine-mediated SC activation by controlling MyoD translation. More significantly, depletion of eIF5A in SCs results in impaired muscle regeneration in mice. Together, the findings of our study define a novel mechanism that is essential for SC activation and acts via spermidine-eIF5A-mediated MyoD translation. Our findings suggest that the spermidine-eIF5A axis represents a promising pharmacological target in efforts to activate endogenous SCs for the treatment of muscular disease.

Development of STING probes and visualization of STING in multiple tumor types.

PURPOSE: The stimulator of interferon genes (STING) is a critical component of the innate immune system and plays a pivotal role in tumor immunotherapy. Developing non-invasive in vivo diagnostic methods for visualizing STING is highly valuable for STING-related immunotherapy. This work aimed to build a noninvasive imaging platform that can dynamically and quantitatively monitor tumor STING expression. METHODS: We investigated the in vivo positron emission tomography (PET) imaging of STING-expressing tumors (B16F10, MC38, and Panc02) with STING-targeted radioprobe ([18F]F-CRI1). The expression of STING in tumors was quantified, and correlation analysis was performed between these results and the outcomes of PET imaging. Furthermore, we optimized the structure of [18F]F-CRIn with polyethylene glycol (PEG) to improve the pharmacokinetic characteristics in vivo. A comprehensive comparison of the imaging and biodistribution results obtained with the optimized probes was conducted in the B16F10 tumors. RESULTS: The PET imaging results showed that the uptake of [18F]F-CRI1 in tumors was positively correlated with the expression of STING in tumors (r = 0.9184, P < 0.001 at 0.5 h). The lipophilicity of the optimized probes was significantly reduced. As a result of employing optimized probes, B16F10 tumor-bearing mice exhibited significantly improved tumor visualization in PET imaging, along with a marked reduction in retention within non-target areas such as the gallbladder and intestines. Biodistribution experiments further validated the efficacy of probe optimization in reducing uptake in non-target areas. CONCLUSION: In summary, this work demonstrated a promising pathway for the development of STING-targeted radioprobes, advancing in vivo PET imaging capabilities.

Clinical characteristics, in-hospital management, and outcomes among patients hospitalized for acute ischemic stroke in rural vs. urban hospitals in China: a nationwide hospital-based study.

BACKGROUND: Efforts to improve rural stroke care have intensified in China. However, high-quality comprehensive data on the differences in care and outcomes between urban and rural hospitals are limited. METHODS: We analyzed data on patients with acute ischemic stroke hospitalized in the China Stroke Center Alliance hospitals from 2015 to 2022. The in-hospital management measures assessed included nine acute and five discharge management measures. Outcomes evaluated included death or discharge against medical advice (DAMA), major adverse cardiovascular events (MACE), disability at discharge, and in-hospital complications. RESULTS: We enrolled 1,583,271 patients with acute ischemic stroke from 1,930 hospitals, comprising 1 086 (56.3%) rural sites with 735 452 patients and 844 (43.7%) urban sites with 847 891 patients. Patients in rural hospitals demonstrate suboptimal management measures compared to those in urban hospitals, including lower rates of intravenous recombinant tissue plasminogen activator within 4.5 h (26.0% vs. 28.3%; difference, -2.3% [-2.5% to -2.0%]), endovascular treatment (0.6% vs. 1.9%; difference, -1.3% [-1.3% to -1.2%]), vessel assessment (88.5% vs. 92.0%; difference, -3.5% [95% CI, -3.6% to -3.4%]), and anticoagulants for atrial fibrillation at discharge (42.9% vs. 47.7%; difference, -4.8% [95% CI, -5.4% to -4.2%]). Overall, the rural-urban disparity in in-hospital outcomes was small. Rural patients had a slightly higher rate of in-hospital death/DAMA (9.0% vs. 8.0%; aOR, 1.22 [95% CI, 1.20-1.23]; aRD, 1.3% [95% CI, 1.2%-1.4%]) and a slightly lower rate of complications (10.9% vs. 13.0%; aOR, 0.83 [95% CI, 0.82-0.84]; aRD, -1.3% [95% CI, -1.3%-1.3%]). No notable rural-urban differences were observed in MACE and disability at discharge. CONCLUSIONS: Patients in rural hospitals demonstrated suboptimal management measures and had higher rates of in-hospital death/DAMA compared to those in urban hospitals. Prioritizing the allocation of health resources to rural hospitals is essential to improve healthcare quality and outcomes. DATA ACCESS STATEMENT: The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Development and Evaluation of [68Ga]Ga-Labeled Riboflavin Derivative for RFVT3-Targeted PET Imaging of Melanoma in Mice.

The limited progress in treatment options and the alarming survival rates in advanced melanoma emphasize the significant research importance of early melanoma diagnosis. RFVT3, a crucial protein at the core of energy metabolism reprogramming in melanoma, might play a pivotal role in early detection. In this study, [68Ga]Ga-NOTA-RF, based on riboflavin (RF), was rationally developed and validated, serving as an innovative tool for positron emission tomography (PET) imaging of RFVT3 expression in melanoma. The in vitro assays of RFVT3 specificity of [68Ga]Ga-NOTA-RF were performed on B16F10 melanoma cells. Then, PET imaging of melanoma was investigated in B16F10 allograft mouse models with varying volumes. Biodistribution studies are used to clarify the behavior of [68Ga]Ga-NOTA-RF in vivo. [68Ga]Ga-NOTA-RF was obtained with high radiochemical purity (>95%). A significant uptake (37.79 ± 6.86%, n = 4) of [68Ga]Ga-NOTA-RF was observed over time in B16F10 melanoma cells, which was significantly inhibited by RFVT3 inhibitors RF or methylene blue (MB), demonstrating the specific binding of [68Ga]Ga-NOTA-RF. At 60 min postinjection, the tumor-to-muscle (T/M) ratio of [68Ga]Ga-NOTA-RF was 4.03 ± 0.34, higher than that of the RF-blocked group (2.63 ± 0.19) and MB-blocked group (2.14 ± 0.20). The T/M ratios for three distinct tumor volumes-small (5 mm), medium (10 mm), and large (15 mm) were observed to be 5.25 ± 0.28, 4.03 ± 0.34, and 3.19 ± 0.55, respectively. The expression of RFVT3 was validated by immunohistochemical staining in various tumor models, with small B16F10 tumors exhibiting the highest expression. [68Ga]Ga-NOTA-RF demonstrates promising properties for the early diagnosis of melanoma and the examination of minute metastatic lesions, indicating its potential to assist in guiding clinical treatment decisions.

The KEAP1/PGAM5/AIFM1-Mediated oxeiptosis pathway in Alzheimer's disease.

BACKGROUND: Alzheimer's Disease (AD) is a neurodegenerative disease with mitochondrial dysfunction and oxidative stress. Oxeiptosis is a cell death pathway sensitive to reactive oxygen species (ROS). This study investigates the role of oxeiptosis pathway and mitochondrial damage in AD. METHODS: An AD model was developed in C57BL/6 mice by injecting Aß1-42 oligomers into the brain. Cognitive function was tested using the Morris water maze. Exposure of HT22 mouse hippocampal neurons to H2O2 induces oxidative stress. Protein levels of KEAP1, PGAM5 and AIFM1 were analyzed by western blot, and mitochondrial damage was observed with electron microscopy. Cell survival rates were using the CCK8 assay and flow cytometry after knocking down KEAP1, PGAM5 and AIFM1. RESULTS: The protein concentrations of KEAP1, PGAM5 and AIFM1 were found to be elevated in the hippocampal tissues of AD mice compared to control group, accompanied by mitochondrial damage in the hippocampal neurons of the AD group. Similarly, in the HT22 oxidative stress model, there was an increase in the protein levels of KEAP1, PGAM5 and AIFM1, along with observed mitochondrial damage. Following individual and combined knockdown of KEAP1, PGAM5 and AIFM1, cell survival rates under oxidative stress conditions were higher compared to H2O2 group, with no significant difference in cell survival rates among the knockdown groups. CONCLUSION: This research underscores the critical role of the KEAP1/PGAM5/AIFM1-mediated oxeiptosis pathway in neuronal cell death, offering insights into potential therapeutic targets for mitigating neurodegeneration in AD.

MicroPET Imaging of Riboflavin Transporter 3 Expression in Myocardial Infarction/Reperfusion Rat Models with Radiofluorinated Riboflavin.

Riboflavin transporter 3 (RFVT3) represents a potential cardioprotective biotarget in energetic metabolism reprogramming after myocardial infarction/reperfusion (MI/R). This study investigated the feasibility of noninvasive real-time quantification of RFVT3 expression after MI/R with an radiolabeled probe 18F-RFTA in a preclinical rat model of MI/R. The tracer 18F-RFTA was radio-synthesized manually and characterized on the subjects of radiolabeling yield, radiochemical purity, and stability in vivo. MI/R and sham-operated rat models were confirmed by cardiac magnetic resonance imaging (cMRI) and single-photon-emission computed tomography (SPECT) myocardial perfusion imaging (MPI) with technetium-99m sestamibi (99mTc-MIBI). Positron emission tomography (PET) imaging of MI/R and sham-operated rat models were conducted with 18F-RFTA. Ex vivo autoradiography and RFVT3 immunohistochemical (IHC) staining were conducted to verify the RFVT3 expression in infarcted and normal myocardium. 18F-RFTA injection was prepared with high radiochemical purity (>95%) and kept stable in vitro and in vivo. 18F-RFTA PET revealed significant uptake in the infarcted myocardium at 8 h after reperfusion, as confirmed by lower 99mTc-MIBI perfusion and decreased intensity of cMRI. Conversely, there were only the tiniest uptakes in the normal myocardium and blocked infarcted myocardium, which was further corroborated by ex vivo autoradiography. The RFVT3 expression was further confirmed by IHC staining in the infarcted and normal myocardium. We first demonstrate the feasibility of imaging RFVT3 in infarcted myocardium. 18F-RFTA is an encouraging PET probe for imaging cardioprotective biotarget RFVT3 in mitochondrial energetic metabolism reprogramming after myocardial infarction. Noninvasive imaging of cardioprotective biotarget RFVT3 has potential value in the diagnosis and therapy of patients with MI.

Alternative localization of HEME OXYGENASE 1 in plant cells regulates cytosolic heme catabolism.

Heme, an organometallic tetrapyrrole, is widely engaged in oxygen transport, electron delivery, enzymatic reactions, and signal transduction. In plants, it is also involved in photomorphogenesis and photosynthesis. HEME OXYGENASE 1 (HO1) initiates the first committed step in heme catabolism, and it has generally been thought that this reaction takes place in chloroplasts. Here, we show that HO1 in both Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) has 2 transcription start sites (TSSs), producing long (HO1L) and short (HO1S) transcripts. Their products localize to the chloroplast and the cytosol, respectively. During early development or de-etiolation, the HO1L/HO1S ratio gradually increases. Light perception via phytochromes (Phys) and cryptochromes elevates the HO1L/HO1S ratio in the whole seedling through the functions of ELONGATED HYPOCOTYL 5 (HY5) and HY5 HOMOLOG and through the suppression of DE-ETIOLATED 1, CONSTITUTIVE PHOTOMORPHOGENESIS 1, and PHYTOCHROME INTERACTING FACTORs. HO1L introduction complements the HO1-deficient mutant; surprisingly, HO1S expression also restores the short hypocotyl phenotype and high pigment content and helps the mutant recover from the genomes uncoupled (gun) phenotype. This indicates the assembly of functional Phys within these lines. Furthermore, our findings support the hypothesis that a mobile heme signal is involved in retrograde signaling from the chloroplast. Altogether, our work clarifies the molecular mechanism of HO1 TSS regulation and highlights the presence of a cytosolic bypass for heme catabolism in plant cells.

Novel microbial fermentation for the preparation of iron-chelating scallop skirts peptides-its profile, identification, and possible binding mode.

Iron chelating peptides have been widely utilized as iron supplements due to their excellent absorption capacity, However, the high cost and cumbersome manufacturing process of these peptides significantly limit their industrial application. In this study, fermentation was used for the first time to prepare iron chelating peptides. Bacillus altitudinis 3*1-3 was selected as the most suitable strain from 50 strains. The hydrolysates of fermented scallop skirts showed excellent iron-chelating capacity (9.39 mg/g). Aspartic acid, glutamic acid, and histidine are crucial for the binding of peptides to ferrous ions. The heptapeptide (FEDPEFE) forms six binding bonds with ferrous irons. Compared with ferrous sulfate, peptide-ferrous chelate showed more stability in salt solution and simulated gastrointestinal juice (p < 0.05). Furthermore, the fermentation method could save >50% of the cost compared with the enzymatic method. The results can provide a theoretical basis for the preparation of ferrous-chelated peptides using the fermentation method.

Lactiplantibacillus plantarum A72, a Strain with Antioxidant Properties, Obtained through ARTP Mutagenesis, Affects Caenorhabditis elegans Anti-Aging.

This research endeavored to elucidate the antioxidant attributes of lactic acid bacteria, specifically their impact on anti-aging and lifespan augmentation in Caenorhabditis elegans. The study focused on Lactiplantibacillus plantarum A72, identified through ARTP mutagenesis for its potent antioxidant properties. In vitro analysis affirmed its free radical neutralizing capacity. In C. elegans, the strain not only extended the lifespan by 25.13% and amplified motility 2.52-fold, but also maintained reproductive capabilities. Remarkably, Lpb. plantarum A72 diminished reactive oxygen species (ROS) and malondialdehyde (MDA) levels in C. elegans by 34.86% and 69.52%, respectively, while concurrently enhancing its antioxidant enzyme activities. The strain also bolstered C. elegans survival rates by 46.33% and 57.78% under high temperature and H2O2 conditions, respectively. Transcriptomic scrutiny revealed that Lpb. plantarum A72 could retard C. elegans aging and extend lifespan by upregulating the sod-5 and hsp-16.1 genes and downregulating the fat-6 and lips-17 genes. These findings propose Lpb. plantarum A72 as a potential antioxidant and anti-aging lactic acid bacteria.

The role of NLRP6 in the development and progression of neurological diseases.

The nervous system possesses the remarkable ability to undergo changes in order to store information; however, it is also susceptible to damage caused by invading pathogens or neurodegenerative processes. As a member of nucleotide-binding oligomerization domain-like receptor (NLR) family, the NLRP6 inflammasome serves as a cytoplasmic innate immune sensor responsible for detecting microbe-associated molecular patterns. Upon activation, NLRP6 can recruit the adapter protein apoptosis-associated speck-like protein (ASC) and the inflammatory factors caspase-1 or caspase-11. Consequently, inflammasomes are formed, facilitating the maturation and secretion of pro-inflammatory cytokines such as inflammatory factors-18 (IL-18) and inflammatory factors-1ß (IL-1ß). Precise regulation of NLRP6 is crucial for maintaining tissue homeostasis, as dysregulated inflammasome activation can contribute to the development of various diseases. Furthermore, NLRP6 may also play a role in the regulation of extraintestinal diseases. In cells of the brain, such as astrocytes and neurons, NLRP6 inflammasome are also present. Here, the assembly and subsequent activation of caspase-1 mediated by NLRP6 contribute to disease progression. This review aims to discuss the structure and function of NLRP6, explain clearly the mechanisms that induce and activate NLRP6, and explore its role within the central and peripheral nervous system.

Severe housing cost burden and premature mortality from cancer.

Unaffordable housing has been associated with poor health. We investigated the relationship between severe housing cost burden and premature cancer mortality (death before 65 years of age) overall and by Medicaid expansion status. County-level severe housing cost burden was measured by the percentage of households that spend 50% or more of their income on housing. States were classified on the basis of Medicaid expansion status (expanded, late-expanded, nonexpanded). Mortality-adjusted rate ratios were estimated by cancer type across severe housing cost burden quintiles. Compared with the lowest quintile of severe housing cost burden, counties in the highest quintile had a 5% greater cancer mortality rate (mortality-adjusted rate ratio = 1.05, 95% confidence interval = 1.01 to 1.08). Within each severe housing cost burden quintile, cancer mortality rates were greater in states that did not expand Medicaid, though this association was significant only in the fourth quintile (mortality-adjusted rate ratio = 1.08, 95% confidence interval = 1.03 to 1.13). Our findings demonstrate that counties with greater severe housing cost burden had higher premature cancer death rates, and rates are potentially greater in non-Medicaid-expanded states than Medicaid-expanded states.

Mechanism of thermal oxidation into volatile compounds from (E)-4-decenal: A density functional theory study.

Unsaturated aliphatic aldehyde oxidation plays a significant role in the deep oxidation of fatty acids to produce volatile chemicals. Exposing the oxidation process of unsaturated aliphatic aldehydes is crucial to completely comprehend how food flavor forms. In this study, thermal desorption cryo-trapping in conjunction with gas chromatography-mass spectrometry was used to examine the volatile profile of (E)-4-decenal during heating, and 32 volatile compounds in all were detected and identified. Meanwhile, density functional theory (DFT) calculations were used, and 43 reactions were obtained in the 24 pathways, which were summarized into the peroxide reaction mechanism (ROOH), the peroxyl radical reaction mechanism (ROO·) and the alkoxy radical reaction mechanism (RO·). Moreover, the priority of these three oxidative mechanisms was the RO· mechanism > ROOH mechanism > ROO· mechanism. Furthermore, the DFT results and experimental results agreed well, and the oxidative mechanism of (E)-4-decenal was finally illuminated.

Poor oral health and the risk of esophageal squamous cell carcinoma in Malawi.

Esophageal squamous cell carcinoma (ESCC) is the second most common cancer in Malawi. Risk factors for this cancer in Malawi are poorly understood. Poor oral health has previously been linked to increased ESCC risk in other high-incidence regions, including parts of Eastern and Southern Africa. We assessed the relationship between oral health and ESCC risk in a sex, age and location frequency-matched case-control study based at two hospitals in Lilongwe, Malawi from 2017 to 2020. Trained interviewers used a structured questionnaire and direct observation to collect data on demographics; behaviors; oral hygiene habits; the sum of decayed, missing or filled teeth (DMFT score); oral mucosa status; lip depigmentation and dental fluorosis via a visual scale. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI), adjusted for known and suspected ESCC risk factors. During the study period, 300 cases and 300 controls were enrolled. Subjects in the highest tertile of DMFT score (≥7) had an increased risk of ESCC with an adjusted OR of 1.96 (95% CI: 1.16-3.36) compared to those with a DMFT score of 0. Severe dental fluorosis was associated with a statistically nonsignificant increased risk of ESCC (adjusted OR = 2.24, 95% CI: 0.97-5.49) compared to individuals with no fluorosis. Associations with oral mucosa status, lip depigmentation and toothbrushing method and frequency were mostly null or uncertain. Poor oral health, indicated by a higher DMFT score, was associated with increased ESCC risk in Malawi. Dental fluorosis is another possible risk factor in this population, but further evaluation is necessary to clarify any effects of fluorosis on ESCC risk.

Inoculation of Yarrowia lipolytica promotes the growth of lactic acid bacteria, Debaryomyces udenii and the formation of ethyl esters in sour meat.

Yarrowia lipolytica N12 and A13 with high lipase activity obtained by mutagenesis were inoculated into sour meat, and their effects on physicochemical properties, microbial community succession, free amino acids, and volatile compounds of sour meat were investigated. Inoculation fermentation increased the contents of free amino acids observably, rapidly reduced pH, promoted the accumulation of total acids, decreased 2-thiobarbituric acid reactive substances (TBARS) values. In addition, the addition of Y. lipolytica might contribute to the growth of lactic acid bacteria, Candida spp., and Debaryomyces udenii, which play an important role in production of volatile compounds. It was shown that inoculation promoted the production of esters, aldehydes, and alcohols, especially ethyl esters, giving sour meat a better meat flavor. Besides, it was found that Y. lipolytica A13 had better fermenting property. Sample of A13 group had higher contents of ethyl esters, free amino acids and dominant microorganisms. The results may help to provide new strains for sour meat fermentation.

Survival After Diagnosis of Esophageal Squamous Cell Carcinoma in Malawi.

PURPOSE: Esophageal cancer (EC) is the second most common cancer in Malawi, with esophageal squamous cell carcinoma (ESCC) representing >90% of all ECs. Despite significant morbidity and mortality, little is known about disease outcomes. In this study, we assess survival after ESCC diagnosis in Malawi. METHODS: We report on ESCC cases enrolled in a case-control study at Kamuzu Central Hospital in Lilongwe from August 2017 to April 2020. Suspected cases completed a questionnaire interview; provided blood, urine, and saliva specimens; and underwent a tumor biopsy for histologic confirmation. Cases were followed up by phone biweekly from enrollment to the study end date (December 31, 2020), date of death, or loss to follow-up. Survival was assessed using Kaplan-Meier analysis with the log-rank test. We also examined associations between treatment and ESCC mortality using Cox regression models. RESULTS: There were 300 patients with ESCC enrolled in this study, of whom 290 (97%) had known vital status at the end of follow-up and 10 (3%) were lost to follow-up. Among the 290 patients, 282 (97%) died during follow-up. The median age at enrollment was 55 years (IQR, 48-66), and the median time to death was 106 days (95% CI, 92 to 127). The 1-year, 2-year, and 3-year survival rates were 11% (95% CI, 8 to 15), 3% (95% CI, 1 to 6), and 0.9% (95% CI, 0.8 to 4), respectively. Palliative chemotherapy significantly improved the overall survival of patients with ESCC (Plog-rank = .038) and was significantly associated with reduced mortality (adjusted hazard ratio, 0.71 [95% CI, 0.51 to 0.99]). No significant association was observed between tobacco use, alcohol consumption, or HIV status and mortality. CONCLUSION: Survival after diagnosis of ESCC was poor in Malawi. Although palliative chemotherapy was associated with improved survival, prevention and earlier detection remain key priorities to improve ESCC mortality at a population level.

Chemical Composition and Flavor Characteristics of Cider Fermented with Saccharomyces cerevisiae and Non-Saccharomyces cerevisiae.

Cider flavor has a very important impact on the quality. Solid-phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS) combined with gas chromatography-ion mobility spectrometry (GC-IMS) tested different kinds of non-Saccharomyces yeasts and Saccharomyces cerevisiae (S. cerevisiae) co-inoculated for the fermentation of cider to determine differences in aroma material, and the determination of odor activity value (OAV) is applied less frequently in research. Through Rhodotorula mucilaginosa, Debaryomyces hansenii, Zygosaccharomyces bailii, and Kluyveromyces Marxianus, four different strains of non-Saccharomyces yeast fermented cider, and it was found that, in both the chemical composition and flavor of material things, compared with monoculture-fermented cider using S. cerevisiae, all differences were significant. Co-inoculated fermentation significantly improved the flavor and taste of cider. As in the volatile compounds of OVA > 1, octanoic acid (Sc 633.88 µg/L, co-inoculation fermented group 955.49 µg/L) provides vegetable cheese fragrance and decanoic acid, ethyl ester (Sc 683.19 µg/L, co-inoculation fermented group 694.98 µg/L) a creamy fruity fragrance, etc., and the average content increased after co-inoculated fermentation. Phenylethyl alcohol, which can produce a rose scent, was relatively abundant in cider samples and varied greatly among the groups. Moreover, the contents of ethyl lactate and 1-butanol in the Sc+Rm (ciders fermented by S. cerevisiae and R. mucilaginosa) were the highest of all of the cider samples. Different types of non-Saccharomyces yeast produced cider with different flavor characteristics. This study demonstrates that different species of non-Saccharomyces yeast do have an important impact on the characteristics of cider and that co-inoculation with non-Saccharomyces yeast and S. cerevisiae for cider fermentation may be a strategy to improve the flavor of cider.

Inhibition Mechanism of Lactiplantibacillus plantarum on the Growth and Biogenic Amine Production in Morganella morganii.

Morganella morganii, a spoilage bacterium in fermented foods, produces harmful biogenic amines (BAs). Although Lactiplantibacillus plantarum is widely used to inhibit spoilage bacteria, the inhibition pattern and inhibition mechanism of M. morganii by Lpb. plantarum are not well studied. In this study, we analysed the effects of the addition of Lpb. plantarum cell-free supernatant (CFS) on the growth and BA accumulation of M. morganii and revealed the mechanisms of changes in different BAs by using RNA sequencing transcriptome analysis. The results showed that Lpb. plantarum CFS could significantly inhibit M. morganii BAs in a weak acid environment (pH 6), and the main changes were related to metabolism. Carbohydrate and energy metabolism were significantly down-regulated, indicating that Lpb. plantarum CFS inhibited the growth activity and decreased the BA content of M. morganii. In addition, the change in histamine content is also related to the metabolism of its precursor amino acids, the change in putrescine content may also be related to the decrease in precursor amino acid synthesis and amino acid transporter, and the decrease in cadaverine content may also be related to the decrease in the cadaverine transporter. The results of this study help to inhibit the accumulation of harmful metabolites in fermented foods.

CTCF coordinates cell fate specification via orchestrating regulatory hubs with pioneer transcription factors.

CCCTC-binding factor (CTCF), a ubiquitously expressed architectural protein, has emerged as a key regulator of cell identity gene transcription. However, the precise molecular mechanism underlying specialized functions of CTCF remains elusive. Here, we investigate the mechanism through integrative analyses of primary hepatocytes, myocytes, and B cells from mouse and human. We demonstrate that CTCF cooperates with lineage-specific pioneer transcription factors (TFs), including MyoD, FOXA, and PU.1, to control cell identity at 1D and 3D levels. At the 1D level, pioneer TFs facilitate lineage-specific CTCF occupancy via opening chromatin. At the 3D level, CTCF and pioneer TFs form regulatory hubs to govern the expression of cell identity genes. This mechanism is validated using MyoD-null mice, CTCF knockout mice, and CRISPR editing during myogenic differentiation. Collectively, these findings uncover a general mechanism whereby CTCF acts as a cell identity cofactor to control cell identity genes via orchestrating regulatory hubs with pioneer TFs.

The Screening and Isolation of Ethyl-Carbamate-Degrading Strains from Fermented Grains and Their Application in the Degradation of Ethyl Carbamate in Chinese Baijiu.

Ethyl carbamate (EC), a 2A carcinogen produced during the fermentation of foods and beverages, primarily occurs in distilled spirits. Currently, most studies focus on strategies for EC mitigation. In the present research, we aimed to screen strains that can degrade EC directly. Here, we report two Candida ethanolica strains (J1 and J116), isolated from fermented grains, which can reduce EC concentrations directly. These two yeasts were grown using EC as the sole carbon source, and they grew well on different carbon sources. Notably, after immobilization with chitosan, the two strains degraded EC in Chinese Baijiu by 42.27% and 27.91% in 24 h (from 253.03 ± 9.89 to 146.07 ± 1.67 and 182.42 ± 5.05 µg/L, respectively), which was better than the performance of the non-immobilized strains. Furthermore, the volatile organic compound content, investigated using gas chromatography-mass spectrometry, did not affect the main flavor substances in Chinese Baijiu. Thus, the yeasts J1 and J116 may be potentially used for the treatment and commercialization of Chinese Baijiu.

Trends in Mortality From Poisonings, Firearms, and All Other Injuries by Intent in the US, 1999-2020.

Importance: Although deaths due to external causes are a leading cause of mortality in the US, trends over time by intent and demographic characteristics remain poorly understood. Objective: To examine national trends in mortality rates due to external causes from 1999 to 2020 by intent (homicide, suicide, unintentional, and undetermined) and demographic characteristics. External causes were defined as poisonings (eg, drug overdose), firearms, and all other injuries, including motor vehicle injuries and falls. Given the repercussions of the COVID-19 pandemic, US death rates for 2019 and 2020 were also compared. Design, Setting, and Participants: Serial cross-sectional study using national death certificate data obtained from the National Center for Health Statistics and including all external causes of 3 813 894 deaths among individuals aged 20 years or older from January 1, 1999, to December 31, 2020. Data analysis was conducted from January 20, 2022, to February 5, 2023. Exposures: Age, sex, and race and ethnicity. Main Outcomes and Measures: Trends in age-standardized mortality rates and average annual percentage change (AAPC) in rates calculated by intent (suicide, homicide, unintentional, and undetermined), age, sex, and race and ethnicity for each external cause. Results: Between 1999 and 2020, there were 3 813 894 deaths due to external causes in the US. From 1999 to 2020, poisoning death rates increased annually (AAPC, 7.0%; 95% CI, 5.4%-8.7%). From 2014 to 2020, poisoning death rates increased the most among men (APC, 10.8%; 95% CI, 7.7%-14.0%). During the study period, poisoning death rates increased in all the racial and ethnic groups examined; the most rapid increase was among American Indian and Alaska Native individuals (AAPC, 9.2%; 95% CI, 7.4%-10.9%). During the study period, death rates for unintentional poisoning had the most rapid rate of increase (AAPC, 8.1%; 95% CI, 7.4%-8.9%). From 1999 to 2020, firearm death rates increased (AAPC, 1.1%; 95% CI, 0.7%-1.5%). From 2013 to 2020, firearm mortality increased by an average of 4.7% annually (95% CI, 2.9%-6.5%) among individuals aged 20 to 39 years. From 2014 to 2020, mortality from firearm homicides increased by an average of 6.9% annually (95% CI, 3.5%-10.4%). From 2019 to 2020, mortality rates from external causes accelerated further, largely from increases in unintentional poisoning, and homicide due to firearms and all other injuries. Conclusions and Relevance: Results of this cross-sectional study suggest that from 1999 to 2020, death rates due to poisonings, firearms, and all other injuries increased substantially in the US. The rapid increase in deaths due to unintentional poisonings and firearm homicides is a national emergency that requires urgent public health interventions at the local and national levels.