IDENTIFICATION OF MUC1-C AS A TARGET FOR SUPPRESSING PROGRESSION OF HEAD AND NECK SQUAMOUS CELL CARCINOMAS.

The MUC1-C protein is aberrantly expressed in adenocarcinomas of epithelial barrier tissues and contributes to their progression. Less is known about involvement of MUC1-C in the pathogenesis of squamous cell carcinomas (SCCs). Here, we report that the MUC1 gene is upregulated in advanced head and neck SCCs (HNSCCs). Studies of HNSCC cell lines demonstrate that the MUC1-C subunit regulates expression of (i) RIG-I and MDA5 pattern recognition receptors, (ii) STAT1 and interferon (IFN) regulatory factors, and (iii) downstream IFN-stimulated genes (ISGs). MUC1-C integrates chronic activation of the STAT1 inflammatory pathway with induction of the ∆Np63 and SOX2 genes that are aberrantly expressed in HNSCCs. In extending those dependencies, we demonstrate that MUC1-C is necessary for NOTCH3 expression, self-renewal capacity and tumorigenicity. The findings that MUC1 associates with ∆Np63, SOX2 and NOTCH3 expression by scRNA-seq analysis further indicate that MUC1-C drives the HNSCC stem cell state and is a target for suppressing HNSCC progression.

Association of vitamin B1 intake with geriatric cognitive function: An analysis of the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014.

Background: The association between dietary vitamin B1 intake and cognitive performance in the noninstitutionalized older adult population of the United States remains unclear. Purpose: This study aimed to investigate the association between vitamin B1 intake and cognitive performance in older adults in the United States. Methods: Vitamin B1 intake was assessed through two 24-h dietary recalls. Weighted logistic regression was used to evaluate the association between vitamin B1 intake and three cognitive scores (immediate recall test [IRT], animal fluency test [AFT], and digit symbol substitution test [DSST]). Cognitive performance was measured by these three tests, and individuals scoring below the lowest quartile were categorized as cognitive impairment. Sensitivity analysis, including dose-response curves, subgroup analyses, interaction effects, per 1 SD, and quartiles, were performed to ensure the accuracy of the conclusion. Results: A total of 2896 participants over the age of 60 were included in this study. In the adjusted final model, the association between vitamin B1 intake and low cognitive performance in old age was statistically significant, with the following odds ratios (ORs) and 95% confidence intervals (CIs): IRT, 0.75 (0.57, 0.97), P = 0.018; AFT, 0.68 (0.50, 0.92), P = 0.007; DSST, 0.71 (0.54, 0.92), P = 0.005. Subgroup analyses showed that this association was statistically significant among males, white, low-education, and no memory impairment. The results of the sensitivity analyses confirmed the association between VB1 and cognitive function in old age and the absence of interactions in the final calibrated model. Conclusion: Dietary vitamin B1 intake is negatively associated with cognitive performance in older adults.

Single-cell disulfidptosis regulator patterns guide intercellular communication of tumor microenvironment that contribute to kidney renal clear cell carcinoma progression and immunotherapy.

Background: Disulfidptosis, an emerging type of programmed cell death, plays a pivotal role in various cancer types, notably impacting the progression of kidney renal clear cell carcinoma (KIRC) through the tumor microenvironment (TME). However, the specific involvement of disulfidptosis within the TME remains elusive. Methods: Analyzing 41,784 single cells obtained from seven samples of KIRC through single-cell RNA sequencing (scRNA-seq), this study employed nonnegative matrix factorization (NMF) to assess 24 disulfidptosis regulators. Pseudotime analysis, intercellular communication mapping, determination of transcription factor activities (TFs), and metabolic profiling of the TME subgroup in KIRC were conducted using Monocle, CellChat, SCENIC, and scMetabolism. Additionally, public cohorts were utilized to predict prognosis and immune responses within the TME subgroup of KIRC. Results: Through NMF clustering and differential expression marker genes, fibroblasts, macrophages, monocytes, T cells, and B cells were categorized into four to six distinct subgroups. Furthermore, this investigation revealed the correlation between disulfidptosis regulatory factors and the biological traits, as well as the pseudotime trajectories of TME subgroups. Notably, disulfidptosis-mediated TME subgroups (DSTN+CD4T-C1 and FLNA+CD4T-C2) demonstrated significant prognostic value and immune responses in patients with KIRC. Multiple immunohistochemistry (mIHC) assays identified marker expression within both cell clusters. Moreover, CellChat analysis unveiled diverse and extensive interactions between disulfidptosis-mediated TME subgroups and tumor epithelial cells, highlighting the TNFSF12-TNFRSF12A ligand-receptor pair as mediators between DSTN+CD4T-C1, FLNA+CD4T-C2, and epithelial cells. Conclusion: Our study sheds light on the role of disulfidptosis-mediated intercellular communication in regulating the biological characteristics of the TME. These findings offer valuable insights for patients with KIRC, potentially guiding personalized immunotherapy approaches.

AI and Knowledge-Based Method for Rational Design of Escherichia coli Sigma70 Promoters.

Expanding sigma70 promoter libraries can support the engineering of metabolic pathways and enhance recombinant protein expression. Herein, we developed an artificial intelligence (AI) and knowledge-based method for the rational design of sigma70 promoters. Strong sigma70 promoters were identified by using high-throughput screening (HTS) with enhanced green fluorescent protein (eGFP) as a reporter gene. The features of these strong promoters were adopted to guide promoter design based on our previous reported deep learning model. In the following case study, the obtained strong promoters were used to express collagen and microbial transglutaminase (mTG), resulting in increased expression levels by 81.4% and 33.4%, respectively. Moreover, these constitutive promoters achieved soluble expression of mTG-activating protease and contributed to active mTG expression in Escherichia coli. The results suggested that the combined method may be effective for promoter engineering.

Bacteria-targeted magnolol-loaded multifunctional nanocomplexes for antibacterial and anti-inflammatory treatment.

Natural plant-derived small molecules have shown great potential for their antimicrobial and anti-inflammatory properties. In this study, we successfully developed a nanocomplex consisting of magnolol (Mag), a surfactant with an 18 carbon hydrocarbon chain and multi-amine head groups (C18N3), and a peptide (cyclic 9-amino acid peptide (CARG)) with targeting capabilities forStaphylococcus aureus(S. aureus). The obtained Mag/C18N3/CARG nanocomplexes exhibited strong antibacterial activity againstS. aureus. Furthermore, they demonstrated anti-inflammatory effects by reducing the secretion of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1ßfrom macrophage inflammatory cells. This was achieved through downregulating the activation of NF-κB, KEAP1, and NRF2 signaling pathways. In a murine skin infection model, the Mag/C18N3/CARG nanocomplexes effectively suppressed the growth ofS. aureusin the infected area and promoted wound healing. Additionally, in a mouse model of acute kidney injury (AKI), the nanocomplexes significantly reduced the levels of blood urea nitrogen and creatinine, leading to a decrease in mortality rate. These findings demonstrate the potential of combining natural plant-derived small molecules with C18N3/CARG assemblies as a novel approach for the development of effective and safe antibacterial agents.

Crown Ether Electrolyte Additive Enables High-Rate and Stable Polyviologen Cathode Material for Chloride Ion Batteries.

A variety of inorganic and inorganic cathode materials for chloride ion storage are reported. However, their application in chloride ion batteries (CIB) is hindered by poor rate capability and cycling stability. Herein, an organic poly(butyl viologen dichloride) (PBVCl2 ) cathode material with significantly enhanced rate and cycling performance in the CIB is achieved using a crown ether (18-Crown-6) additive in the tributylmethylammonium chloride-based electrolyte. The as-prepared PBVCl2 cathodes exhibit impressive capacity increases from 149.4 to 179.1 mAh g-1 at 0.1 C and from 57.8 to 111.9 mAh g-1 at 10 C, demonstrating the best rate performance with the highest energy density among those of various reported cathodes for CIBs. This impressive performance improvement is a result of the great boosts in charge transfer, ion transport, and interface stability of the battery by the use of 18-Crown-6, which also contributes to a more than twofold increase in capacity retention after 120 cycles. The electrode reaction mechanism of the CIB based on highly reversible chloride ion transfer is revealed by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy.

Deep Learning-Assisted Design of Novel Promoters in Escherichia coli.

Deep learning (DL) approaches have the ability to accurately recognize promoter regions and predict their strength. Here, the potential for controllably designing active Escherichia coli promoter is explored by combining multiple deep learning models. First, "DRSAdesign," which relies on a diffusion model to generate different types of novel promoters is created, followed by predicting whether they are real or fake and strength. Experimental validation showed that 45 out of 50 generated promoters are active with high diversity, but most promoters have relatively low activity. Next, "Ndesign," which relies on generating random sequences carrying functional -35 and -10 motifs of the sigma70 promoter is introduced, and their strength is predicted using the designed DL model. The DL model is trained and validated using 200 and 50 generated promoters, and displays Pearson correlation coefficients of 0.49 and 0.43, respectively. Taking advantage of the DL models developed in this work, possible 6-mers are predicted as key functional motifs of the sigma70 promoter, suggesting that promoter recognition and strength prediction mainly rely on the accommodation of functional motifs. This work provides DL tools to design promoters and assess their functions, paving the way for DL-assisted metabolic engineering.

Arsenic Exposure Induces Neuro-immune Toxicity in the Cerebral Cortex and the Hippocampus via Neuroglia and NLRP3 Inflammasome Activation in C57BL/6 Mice.

This study aimed to examine the immuntoxic effects of arsenic in the nervous system. Our results showed that arsenic increased corticocerebral and hippocampal weights (p < 0.05). Morris water maze tests revealed that arsenic significantly increased the time spent in latency to platform on the fourth day in 50 mg/L arsenic exposure and the fifth day in 25 and 50 mg/L arsenic exposure, as well as reduced the path length in target quadrant, time spent in target quadrant, and crossing times of the platform (p < 0.05). Hematoxylin-eosin staining showed that the vacuolated degeneration and pyknosis was found in the cerebral cortex and hippocampus of arsenic-treated mice. The mRNA levels of corticocerebral and hippocampal brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were decreased in the 50 mg/L arsenic-treated group (p < 0.05). In addition, immunofluorescence staining showed that 25 and 50 mg/L arsenic all increased the expression of CD11b and glial fibrillary acidic protein (GFAP) in the cerebral cortex and hippocampus (p < 0.05). Arsenic markedly raised antigen-presenting molecule MHCII and CD40 mRNA levels in the cerebral cortex and hippocampus and upregulated the cell chemokine receptor 5 (CCR5) and CCR7 mRNA levels in the cerebral cortex at the 50 mg/L arsenic group, and increased the CCR7 mRNA levels in the hippocampus at the 25 and 50 mg/L arsenic groups (p < 0.05). Arsenic activated the nucleotide-binding domain-like receptor protein-3 (NLRP3) inflammasome, and enhanced its upstream promoter NF-κB protein level and downstream regulators IL-18 mRNA levels. Collectively, these results provide new evidences for the neuro-immune toxicity of arsenic.

A systematical review on antimicrobial peptides and their food applications.

Food safety issues are a major concern in food processing and packaging industries. Food spoilage is caused by microbial contamination, where antimicrobial peptides (APs) provide solutions by eliminating microorganisms. APs such as nisin have been successfully and commonly used in food processing and preservation. Here, we discuss all aspects of the functionalization of APs in food applications. We briefly review the natural sources of APs and their native functions. Recombinant expression of APs in microorganisms and their yields are described. The molecular mechanisms of AP antibacterial action are explained, and this knowledge can further benefit the design of functional APs. We highlight current utilities and challenges for the application of APs in the food industry, and address rational methods for AP design that may overcome current limitations.

Homogalacturonan enriched pectin based hydrogel enhances 6-gingerol's colitis alleviation effect via NF-κB/NLRP3 axis.

A nanolipidcarrier (NLC) loaded homogalacturonan enriched pectin (citrus modified pectin, MCP4) hydrogel was designed as a novel colon inflammation site-specific oral delivery system for 6-gingerol (6G) (6G-NLC/MCP4 hydrogel) administration, and its colitis alleviation effect were investigated. 6G-NLC/MCP4 exhibited typical "cage-like" ultrastructure with 6G-NLC embedded in the hydrogel matrix as observed by cryoscanning electron microscope. And due to the homogalacturonan (HG) domain in MCP4 specifically combined with Galectin-3, which is overexpressed in the inflammatory region, the 6G-NLC/MCP4 hydrogel targeted to severe inflammatory region. Meanwhile, the prolonged-release characteristics of 6G-NLC provided sustained release of 6G in severe inflammatory regions. The matrix of hydrogel MCP4 and 6G achieved synergistic alleviation effects for colitis through NF-κB/NLRP3 axis. Specifically, 6G mainly regulated the NF-κB inflammatory pathway and inhibited the activity of NLRP3 protein, while MCP4 regulated the expression of Galectin-3 and peripheral clock gene Rev-Erbα/ß to prevent the activation of inflammasome NLRP3.

Rosmarinic Acid Restores Colonic Mucus Secretion in Colitis Mice by Regulating Gut Microbiota-Derived Metabolites and the Activation of Inflammasomes.

Maintaining a steady state of mucus barrier is an important potential target for polyphenol to exert its anticolitis activity. This study elucidates the pivotal role of polyphenol rosmaric acid (RA) in regulating the mucus barrier function and alleviating inflammation by identifying its gut microbiota-derived metabolites and evaluating its inhibitory effect on inflammasomes in colitis mice. Results demonstrated that RA treatment promoted the proliferation of goblet cells and restored the level of mucus secretion, especially Muc2. RA reshaped the microbiota of colitis mice, particularly the boost of core probiotics, such as p. Bacteroidaceae, f. Muribaculaceae, g. Muribaculaceae, g. Alistipes, and g. Clostridia_UCG-014. Nontargeted metabonomics and targeted metabonomics confirmed a significant increase in the bile acids and their metabolites (7-sulfocholic acid, stercobilin, chenodeoxycholic acid 3-sulfate, chenodeoxycholic acid sulfate, and ursodeoxycholic acid 3-sulfate), indole metabolites ((R)-2,3-dihydro-3,5-dihydroxy-2-oxo-3-indoleacetic acid, frovatriptan, 3-formyl-6-hydroxyindole, and brassicanal A), and short-chain fatty acids (SCFAs) (acetic acid, butyric acid, isobutyric acid, isovaleric acid, and valeric acid) that contributed to the strengthened mucus barrier function. In addition, being absorbed mainly in the lower digestive tract, RA inhibited the overexpression of inflammasomes (especially NLRP6) that occurred in colitis mice to promote the mucus secretion of goblet cells. These data confirmed that RA, as a promising candidate to enhance gut health, restored colonic mucus secretion in colitis mice by mediating the production of gut microbiota-derived metabolites and the overexpression of inflammasomes. The presented study provides scientific evidence explaining the apparent paradox of low bioavailability and high bioactivity in polyphenols.

Possibilities of Using De Novo Design for Generating Diverse Functional Food Enzymes.

Food enzymes have an important role in the improvement of certain food characteristics, such as texture improvement, elimination of toxins and allergens, production of carbohydrates, enhancing flavor/appearance characteristics. Recently, along with the development of artificial meats, food enzymes have been employed to achieve more diverse functions, especially in converting non-edible biomass to delicious foods. Reported food enzyme modifications for specific applications have highlighted the significance of enzyme engineering. However, using direct evolution or rational design showed inherent limitations due to the mutation rates, which made it difficult to satisfy the stability or specific activity needs for certain applications. Generating functional enzymes using de novo design, which highly assembles naturally existing enzymes, provides potential solutions for screening desired enzymes. Here, we describe the functions and applications of food enzymes to introduce the need for food enzymes engineering. To illustrate the possibilities of using de novo design for generating diverse functional proteins, we reviewed protein modelling and de novo design methods and their implementations. The future directions for adding structural data for de novo design model training, acquiring diversified training data, and investigating the relationship between enzyme-substrate binding and activity were highlighted as challenges to overcome for the de novo design of food enzymes.

Arsenic Induces Blood‒Brain Barrier Disruption and Regulates T Lymphocyte Subpopulation Differentiation in the Cerebral Cortex and Hippocampus Associated with the Nrf2 Pathway In Vivo.

Increasing evidence has confirmed that the nervous system shows innate and adaptive immunity, which also participates in nerve damage. This study aimed to explore the neuroimmune imbalance induced by arsenic and its possible mechanism. Mice were exposed to NaAsO2 (0, 5, 10, 25, and 50 mg/L) for 1 month by drinking water. Y-maze and Morris water maze tests revealed that arsenic impaired learning and memory. The optical density of Evans blue showed a marked dose-dependent increase in the brain, and the mRNA and protein levels of the BBB tight junctions (TJs), occludin at 25 and 50 mg/L arsenic, and claudin-5 at 50 mg/L arsenic, were markedly decreased in the cerebral cortex. Arsenic downregulated occludin and claudin-5 mRNA expression at 50 mg/L and protein expression at 25 and 50 mg/L in the hippocampus. Immunohistochemical staining showed that 50 mg/L arsenic increased corticocerebral and hippocampal CD3+ T, CD4+ T, and CD8+ T cells; CD4 and CD8 proteins were increased with 25 and 50 mg/L arsenic. Arsenic decreased the corticocerebral and hippocampal Th1, Th17, and regulatory Treg transcription factors T-bet, Rorγt, and Foxp3 and the cytokine IFN-γ, IL-17, and TGF-ß mRNA levels and increased the Th2 transcription factor GATA3 and cytokine IL-4 mRNA levels. Moreover, arsenic enhanced the expression of nuclear factor E2-related factor (Nrf2) and its downstream enzymes heme oxygenase-1 (HO-1) and glutathione-S-transferase (GST). In conclusion, these results demonstrate that arsenic exposure induces BBB dysfunction and T lymphocyte infiltration and affects CD4+ T lymphocyte differentiation, which may be associated with Nrf2 activation.

Arsenic Activates the NLRP3 Inflammasome and Disturbs the Th1/Th2/Th17/Treg Balance in the Hippocampus in Mice.

Arsenic exerts neurotoxicity and immunomodulatory effects. Studies have shown that the nervous system is not considered to be an immune-privileged site. However, the effect of arsenic-induced neuroimmune toxicity has rarely been reported. We aimed to investigate the toxic effects of arsenic on the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and the Th1/Th2/Th17/Treg balance in the brain tissue of mice. Mice were exposed to NaAsO2 (0, 2.5, 5, and 10 mg/kg) for 24 h. Our results showed that 10 mg/kg arsenic exposure significantly decreased brain and hippocampal indices (p < 0.05). The mRNA and protein levels of the blood‒brain barrier (BBB) tight junction protein occludin were decreased in the 5 and 10 mg/kg arsenic-treated groups. Compared with those in the control group, NLRP3 protein levels in 10 mg/kg arsenic-treated mice, caspase-1 protein levels in 2.5, 5, and 10 mg/kg arsenic-treated mice, and IL-1ß protein levels in 5 and 10 mg/kg arsenic-treated mice were increased in the hippocampus (p < 0.05). In addition, arsenic induced a hippocampal inflammatory response by upregulating the mRNA levels of the proinflammatory factors IL-6 and TNF-α and downregulating the mRNA level of the anti-inflammatory factor IL-10. Moreover, arsenic decreased the mRNA levels of the Th1 and Th2 transcription factors T-bet and GATA3 and the cytokines IFN-γ and IL-4 and increased the mRNA levels of the Th17 transcription factor RORγt and the cytokine IL-22 (p < 0.05). Collectively, our study demonstrated that arsenic could induce immune-inflammatory responses by regulating the NLRP3 inflammasome and CD4+ T lymphocyte differentiation. These results provide a novel strategy to block the arsenic-induced impairment of neuroimmune responses.

Comparison of Hypertension in Migrant and Local Patients with Atherosclerotic Diseases: A Cross-Sectional Study in Shanghai, China.

Background: Hypertension and its complications represent major health problems worldwide and are distributed differently in different populations. This study aimed to reveal the differences between two populations of patients with hypertension who had atherosclerotic complications: local residents in and migrants to the city of Shanghai, China. Methods: We conducted a cross-sectional study among hospitalized patients with hypertension age 21-65 years in Pudong District. We compared the characteristics of local and migrant patients with hypertension, and analyzed the distribution and risk factors of atherosclerotic complications between these groups. Results: The proportion of young and uninsured patients with hypertension was higher among migrant than local participants. The rates of stroke (15.4% vs. 25.0%, p < 0.05) and coronary heart disease (8.6% vs. 11.7%, p < 0.05) were lower and the rates of other atherosclerotic diseases higher (8.5% vs. 7.9%, p = 0.429) among migrant than local participants. According to logistic regression analysis, age was an important risk factor in both the migrant and local groups for all three atherosclerotic complications investigated. Insurance, diabetes, and frequency of hospitalization could influence the incidence of atherosclerotic complications among local patients with hypertension. Among migrant patients, differences for sex, insurance, marital status, diabetes history, and frequency of hospitalization were not significant. Conclusions: Our study demonstrated differences in the characteristics, distribution, and risk factors of atherosclerotic complications among migrant and local patients with hypertension. Greater attention in needed for the increasing population of migrants.

Diagnostic efficacy of b value (2000 s/mm2) diffusion-weighted imaging for prostate cancer: Comparison of a reduced field of view sequence and a conventional technique.

OBJECTIVES: To compare high b value (2000 s/mm2) reduced field-of-view (rFOV) diffusion-weighted imaging (DWI) with a conventional DWI sequence in terms of image quality, as well as diagnostic performance concerning prostate cancer (PCa) detection and tumor staging at 3 T. METHODS: Sixty-one patients underwent rFOV DWI and conventional DWI due to clinical suspicious of PCa were retrospectively recruited. Imaging qualities were evaluated qualitatively and quantitatively by two blinded radiologists. Thirty-two subjects with detailed pathology reports were further analyzed for diagnostic efficacy using the Prostate Imaging Reporting and Data System (PI-RADS) version 2. The PCa detection rate, sensitivity, specificity, and PI-RADS staging changes were compared between the DWI sequences. RESULTS: Qualitative evaluation regarding image quality was significantly better in rFOV DWI than in the conventional DWI (all P < 0.05). ADC contrast with rFOV DWI was rated significantly higher than the conventional DWI in both peripheral zone (PZ) and transition zone (TZ) (P = 0.001 for PZ, and P = 0.003 for TZ). Regarding diagnostic efficacy, rFOV DWI yielded higher tumor detection, sensitivity and the area under the curve (AUC) than the conventional DWI (all P < 0.05), except the AUC in the PZ for one reader (P = 0.262). Conventional DWI achieved slightly higher specificity for the PZ and TZ but with no significant difference except for one reader in the PZ (P = 0.009). CONCLUSION: The rFOV DWI could offer improved image quality and yielded better diagnostic performance in terms of higher tumor detection rate and relatively precise staging for PCa compared to the conventional sequence.