Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion.

Tumor cells and surrounding immune cells undergo metabolic reprogramming, leading to an acidic tumor microenvironment. However, it is unclear how tumor cells adapt to this acidic stress during tumor progression. Here we show that carnosine, a mobile buffering metabolite that accumulates under hypoxia in tumor cells, regulates intracellular pH homeostasis and drives lysosome-dependent tumor immune evasion. A previously unrecognized isoform of carnosine synthase, CARNS2, promotes carnosine synthesis under hypoxia. Carnosine maintains intracellular pH (pHi) homeostasis by functioning as a mobile proton carrier to accelerate cytosolic H+ mobility and release, which in turn controls lysosomal subcellular distribution, acidification and activity. Furthermore, by maintaining lysosomal activity, carnosine facilitates nuclear transcription factor X-box binding 1 (NFX1) degradation, triggering galectin-9 and T-cell-mediated immune escape and tumorigenesis. These findings indicate an unconventional mechanism for pHi regulation in cancer cells and demonstrate how lysosome contributes to immune evasion, thus providing a basis for development of combined therapeutic strategies against hepatocellular carcinoma that exploit disrupted pHi homeostasis with immune checkpoint blockade.

OXCT1 functions as a succinyltransferase, contributing to hepatocellular carcinoma via succinylating LACTB.

Metabolic reprogramming is an important feature of cancers that has been closely linked to post-translational protein modification (PTM). Lysine succinylation is a recently identified PTM involved in regulating protein functions, whereas its regulatory mechanism and possible roles in tumor progression remain unclear. Here, we show that OXCT1, an enzyme catalyzing ketone body oxidation, functions as a lysine succinyltransferase to contribute to tumor progression. Mechanistically, we find that OXCT1 functions as a succinyltransferase, with residue G424 essential for this activity. We also identified serine beta-lactamase-like protein (LACTB) as a main target of OXCT1-mediated succinylation. Extensive succinylation of LACTB K284 inhibits its proteolytic activity, resulting in increased mitochondrial membrane potential and respiration, ultimately leading to hepatocellular carcinoma (HCC) progression. In summary, this study establishes lysine succinyltransferase function of OXCT1 and highlights a link between HCC prognosis and LACTB K284 succinylation, suggesting a potentially valuable biomarker and therapeutic target for further development.

A Clinically Feasible Diagnostic Typing of Breast Cancer Built on a Homogeneous Electrochemical Biosensor for Simultaneous Multiplex Detection.

Simultaneous detection of multiple tumor markers is of great significance for an accurate diagnosis and early treatment of cancer. Electrochemical homogeneous biosensing strategies have been shown to have advantages, such as high sensitivity and no electrode modification, but they are still a challenge in the field of simultaneous detection of multiple tumor markers. The ER, PR, HER2, and Ki67 proteins are the standard biomarkers for the clinical molecular typing of breast cancer. Precise, sensitive, and simultaneous detection of these four biomarkers is of great importance in the molecular typing of breast cancer, which helps in the creation of personalized treatment plans. In the present study, we developed an electrochemical homogeneous electrochemical bioplatform based on metal ions/SiO2NPs/magnetic beads for detection of the four biomarkers and simultaneous diagnosis of the 10 types of breast cancer directly in human serum at one system by a single electrode. The electrochemical bioplatform has a short detection time of 140 min; however, the current clinical tissue testing time takes about 1 week. Also, the electrochemical bioplatform selectively detects HER2, ER, Ki67, and PR in a range of 0-1000 pg/mL with detection limits of 2, 1.8, 10.36, and 1.33 pg/mL, respectively.

Protocol for identifying OXCT1-mediated LACTB succinylation sites in vitro.

OXCT1 acts as a succinyltransferase to promote serine beta-lactamase-like protein (LACTB) K284 succinylation. Here, we present a protocol for detecting OXCT1-mediated LACTB succinylation levels and sites. We describe steps for using western blotting (WB) and mass spectrometry to determine OXCT1-mediated LACTB succinylation levels and sites in vitro. This protocol can be applied to detect and identify succinylation levels and sites on other proteins. For complete details on the use and execution of this protocol, please refer to Ma et al.1.

Investigating the impact of ultrasound-assisted cellulase pretreatment on the nutrients, phytic acid, and phenolics bioaccessibility in sprouted brown rice.

This study aimed to elucidate the impact of ultrasound-assisted cellulase (UC) pretreatment on nutrients, phytic acid, and the bioavailability of phenolics during brown rice sprouting. It sought to unveil the underlying mechanisms by quantifying the activity of key enzymes implicated in these processes. The sprouted brown rice (SBR) surface structure was harmed by the UC pretreatment, which also increased the amount of γ-oryzanol and antioxidant activity in the SBR. Concurrently, the UC pretreatment boosted the activity of phytase, glutamate decarboxylase, succinate semialdehyde dehydrogenase, Gamma-aminobutyric acid (GABA) transaminase, chalcone isomerase, and phenylalanine ammonia lyase, thereby decreasing the phytic acid content and increasing the GABA, flavonoid, and phenolic content in SBR. In addition, UC-pretreated SBR showed increased phenolic release and bioaccessibility during in vitro digestion when compared to the treated group. These findings might offer theoretical direction for using SBR to maximize value.

Diagnosis Framework for Probable Alzheimer's Disease and Mild Cognitive Impairment Based on Multi-Dimensional Emotion Features.

BACKGROUND: Emotion and cognition are intercorrelated. Impaired emotion is common in populations with Alzheimer's disease (AD) and mild cognitive impairment (MCI), showing promises as an early detection approach. OBJECTIVE: We aim to develop a novel automatic classification tool based on emotion features and machine learning. METHODS: Older adults aged 60 years or over were recruited among residents in the long-term care facilities and the community. Participants included healthy control participants with normal cognition (HC, n = 26), patients with MCI (n = 23), and patients with probable AD (n = 30). Participants watched emotional film clips while multi-dimensional emotion data were collected, including mental features of Self-Assessment Manikin (SAM), physiological features of electrodermal activity (EDA), and facial expressions. Emotional features of EDA and facial expression were abstracted by using continuous decomposition analysis and EomNet, respectively. Bidirectional long short-term memory (Bi-LSTM) was used to train classification model. Hybrid fusion was used, including early feature fusion and late decision fusion. Data from 79 participants were utilized into deep machine learning analysis and hybrid fusion method. RESULTS: By combining multiple emotion features, the model's performance of AUC value was highest in classification between HC and probable AD (AUC = 0.92), intermediate between MCI and probable AD (AUC = 0.88), and lowest between HC and MCI (AUC = 0.82). CONCLUSIONS: Our method demonstrated an excellent predictive power to differentiate HC/MCI/AD by fusion of multiple emotion features. The proposed model provides a cost-effective and automated method that can assist in detecting probable AD and MCI from normal aging.

Obesity and septic patient outcomes: Shaping the puzzle through age and sex perspectives.

BACKGROUND & AIMS: While obesity has been reported as a protective factor in septic patients, little is known about the potential modifying effects of age and sex. The objective of this study is to investigate age and sex-specific associations between obesity and the prognosis of septic patients. METHODS: A retrospective analysis was conducted on a cohort of 15,464 septic patients, categorized by body mass index (BMI) into four groups: underweight (<18.5 kg/m2, n = 483), normal (18.5-24.9 kg/m2, n = 4344), overweight (25-29.9 kg/m2, n = 4949) and obese (≥30 kg/m2, n = 5688). Multivariable logistic regression and inverse probability weighting were employed to robustly confirm the protective effect of a higher BMI on 28-day mortality, with normal weight serving as the reference category. Subgroup analyses based on age (young: 18-39, middle-aged: 40-64 and elderly: ≥65) and sex were performed. RESULTS: The findings demonstrate that high BMI independently confers a protective effect against 28-day mortality in septic patients. However, the relationship between BMI and 28-day mortality exhibits a non-linear trend, with a BMI of 34.5 kg/m2 displaying the lowest odds ratio. Notably, the survival benefits associated with a high BMI were not observed in the young group. Moreover, being underweight emerges as an independent risk factor for middle-aged and elderly female patients, while in males it is only a risk factor in the elderly group. Interestingly, being overweight and obese were identified as independent protective factors in middle-aged and elderly male patients, but not in females. CONCLUSIONS: The effect of BMI on mortality in septic patients varies according to age and sex. Elderly individuals with sepsis may derive more prognostic benefits from obesity.

The combination of DNA nanostructures and materials for highly sensitive electrochemical detection.

Due to the wide range of electrochemical devices available, DNA nanostructures and material-based technologies have been greatly broadened. They have been actively used to create a variety of beautiful nanostructures owing to their unmatched programmability. Currently, a variety of electrochemical devices have been used for rapid sensing of biomolecules and other diagnostic applications. Here, we provide a brief overview of recent advances in DNA-based biomolecular assays. Biosensing platform such as electrochemical biosensor, nanopore biosensor, and field-effect transistor biosensors (FET), which are equipped with aptamer, DNA walker, DNAzyme, DNA origami, and nanomaterials, has been developed for amplification detection. Under the optimal conditions, the proposed biosensor has good amplification detection performance. Further, we discussed the challenges of detection strategies in clinical applications and offered the prospect of this field.

Bright light therapy-induced improvements of mood, cognitive functions and cerebellar functional connectivity in subthreshold depression: A randomized controlled trial.

Background: The efficacy of bright light therapy (BLT) in ameliorating depression has been validated. The present study is to investigate the changes of depressive symptoms, cognitive function and cerebellar functional connectivity (FC) following BLT in individuals with subthreshold depression (StD). Method: Participants were randomly assigned to BLT group (N = 47) or placebo (N = 41) in this randomized controlled trial between March 2020 and June 2022. Depression severity and cognitive function were assessed, as well as resting-state functional MRI scan was conducted before and after 8-weeks treatment. Seed-based whole-brain static FC (sFC) and dynamic FC (dFC) analyses of the bilateral cerebellar subfields were conducted. Besides, a multivariate regression model examined whether baseline brain FC was associated with changes of depression severity and cognitive function during BLT treatment. Results: After 8-week BLT treatment, individuals with StD showed improved depressive symptoms and attention/vigilance cognitive function. BLT also increased sFC between the right cerebellar lobule IX and left temporal pole, and decreased sFC within the cerebellum, and dFC between the right cerebellar lobule IX and left medial prefrontal cortex. Moreover, the fusion of sFC and dFC at baseline could predict the improvement of attention/vigilance in response to BLT. Conclusions: The current study identified that BLT improved depressive symptoms and attention/vigilance, as well as changed cerebellum-DMN connectivity, especially in the cerebellar-frontotemporal and cerebellar internal FC. In addition, the fusion features of sFC and dFC at pre-treatment could serve as an imaging biomarker for the improvement of attention/vigilance cognitive function after BLT in StD.

How do carbon emissions trading impact the financialization of non-financial companies? Evidence from a quasi-natural experiment in China.

This study examines whether and how carbon trading policy impacts the financialization of non-financial firms, using China emission trading scheme as a quasi-natural experiment. We find that the carbon trading policy exerts a substantial and enduring inhibitory effect on corporate financialization. Our findings are robust to possible result bias and more precise control group. Additionally, we explore potential channels through which carbon trading policy can affect financialization, and find that it curbs financialization by reducing financing constraints. Finally, we demonstrate that the relationship between carbon trading policy and financialization of non-financial companies is moderated by company's ownership, region, and industry competition.

The effects of esketamine on the intestinal microenvironment and intestinal microbiota in mice.

OBJECTIVE: This study aimed to investigate the impact of esketamine on the intestinal flora and microenvironment in mice using mRNA transcriptome sequencing and 16S rRNA sequencing. METHODS: Ten female mice were randomly assigned to two groups. One group received daily intramuscular injections of sterile water, while the other group received esketamine. After 24 days, the mice were sacrificed, and their intestinal tissues and contents were collected for 16S rRNA sequencing and mRNA transcriptome sequencing. The intergroup differences in the mouse intestinal flora were analyzed. Differentially expressed genes were utilized to construct ceRNA networks and transcription factor regulatory networks to assess the effects of esketamine on the intestinal flora and intestinal tissue genes. RESULTS: Esketamine significantly altered the abundance of intestinal microbiota, including Adlercreutzia equolifaciens and Akkermansia muciniphila. Differential expression analysis revealed 301 significantly upregulated genes and 106 significantly downregulated genes. The ceRNA regulatory network consisted of 6 lncRNAs, 44 miRNAs, and 113 mRNAs, while the regulatory factor network included 13 transcription factors and 53 target genes. Gene Ontology enrichment analysis indicated that the differentially expressed genes were primarily associated with immunity, including B-cell activation and humoral immune response mediation. The biological processes in the ceRNA regulatory network primarily involved transport, such as organic anion transport and monocarboxylic acid transport. The functional annotation of target genes in the TF network was mainly related to epithelial cells, including epithelial cell proliferation and regulation. CONCLUSION: Esketamine induces changes in gut microbiota and the intestinal microenvironment, impacting the immune environment and transport modes.