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PD-L1-positive extracellular vesicles (PD-L1+ EVs) play a pivotal role as predictive biomarkers in cancer immunotherapy. These vesicles, originating from immune cells (I-PD-L1+ EVs) and tumor cells (T-PD-L1+ EVs), hold distinct clinical predictive values, emphasizing the importance of deeply differentiating the PD-L1+ EV subtypes for effective liquid biopsy analyses. However, current methods such as ELISA lack the ability to differentiate their cellular sources. In this study, a novel step-wedge microfluidic chip that combines magnetic microsphere separation with single-layer fluorescence counting is developed. This chip integrates magnetic microspheres modified with anti-PD-L1 antibodies and fluorescent nanoparticles targeting EpCAM (tumor cell marker) or CD45 (immunocyte marker), enabling simultaneous quantification and sensitive analysis of PD-L1+ EV subpopulations in oral squamous cell carcinoma (OSCC) patients' saliva without background interference. Analysis results indicate reduced levels of I-PD-L1+ EVs in OSCC patients compared to those in healthy individuals, with varying levels of heterogeneous PD-L1+ EVs observed among different patient groups. During immunotherapy, responders exhibit decreased levels of total PD-L1+ EVs and T-PD-L1+ EVs, accompanied by reduced levels of I-PD-L1+ EVs. Conversely, nonresponders show increased levels of I-PD-L1+ EVs. Utilizing the step-wedge microfluidic chip allows for simultaneous detection of PD-L1+ EV subtypes, facilitating the precise prediction of oral cancer immunotherapy outcomes.

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Heteromeric pore-forming proteins often contain recognition patterns or stereospecific selection filters. However, the construction of heteromeric pore-forming proteins for single-molecule sensing is challenging due to the uncontrollability of producing position isomers and difficulties in purification of regio-defined products. To overcome these preparation obstacles, we present an in situ strategy involving single-molecule chemical modification of a heptameric pore-forming protein to build a stereo- and regio-specific heteromeric nanopore (hetero-nanopore) with a subunit stoichiometric ratio of 3:4. The steric hindrance inherent in the homo-nanopore of K238C aerolysin directs the stereo- and regio-selective modification of maleimide derivatives. Our method utilizes real-time ionic current recording to facilitate controlled voltage manipulation for stoichiometric modification and position-based side-isomer removal. Single-molecule experiments and all-atom molecular dynamics simulations revealed that the hetero-nanopore features an asymmetric stereo- and regio-defined residue structure. The hetero-nanopore produced was characterized by mass spectrometry and single-particle cryogenic electron microscopy. In a proof-of-concept single-molecule sensing experiment, the hetero-nanopore exhibited 95% accuracy for label-free discrimination of four peptide stereoisomers with single-amino-acid structural and chiral differences in the mixtures. The customized hetero-nanopores could advance single-molecule sensing.

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Although the desulfurization of thiols is a topic of great importance and has received significant attention, most efforts have focused on the hydrodesulfurization of thiols. In this work, we describe the desulfurization of thiols for nucleophilic substitution. This process occurs rapidly, promoted by the Ph3P/ICH2CH2I system, and can be extended to a wide range of nucleophiles. Notably, free amines can be employed as nucleophiles to synthesize various secondary and tertiary amines. This method tolerates a wide array of functional groups, including hydroxyl groups in amination reactions. Benzyl thiols are particularly reactive and can be completely converted at room temperature within 15 min. Although alkyl thiols show lower reactivity, they can also be converted smoothly at a reaction temperature of 70 °C overnight.

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The tumor microenvironment (TME) plays a pivotal role in the onset, progression, and treatment response of cancer. Among the various components of the TME, cancer-associated fibroblasts (CAFs) are key regulators of both immune and non-immune cellular functions. Leveraging single-cell RNA sequencing (scRNA) data, we have uncovered previously hidden and promising roles within this specific CAF subgroup, paving the way for its clinical application. However, several critical questions persist, primarily stemming from the heterogeneous nature of CAFs and the use of different fibroblast markers in various sample analyses, causing confusion and hindrance in their clinical implementation. In this groundbreaking study, we have systematically screened multiple databases to identify the most robust marker for distinguishing CAFs in lung cancer, with a particular focus on their potential use in early diagnosis, staging, and treatment response evaluation. Our investigation revealed that COL1A1, COL1A2, FAP, and PDGFRA are effective markers for characterizing CAF subgroups in most lung adenocarcinoma datasets. Through comprehensive analysis of treatment responses, we determined that COL1A1 stands out as the most effective indicator among all CAF markers. COL1A1 not only deciphers the TME signatures related to CAFs but also demonstrates a highly sensitive and specific correlation with treatment responses and multiple survival outcomes. For the first time, we have unveiled the distinct roles played by clusters of CAF markers in differentiating various TME groups. Our findings confirm the sensitive and unique contributions of CAFs to the responses of multiple lung cancer therapies. These insights significantly enhance our understanding of TME functions and drive the translational application of extensive scRNA sequence results. COL1A1 emerges as the most sensitive and specific marker for defining CAF subgroups in scRNA analysis. The CAF ratios represented by COL1A1 can potentially serve as a reliable predictor of treatment responses in clinical practice, thus providing valuable insights into the influential roles of TME components. This research marks a crucial step forward in revolutionizing our approach to cancer diagnosis and treatment.

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Low selenium levels are closely associated with reduced cognitive performance and lipid dysregulation, yet the mechanism of action remains unclear. The physiological function of selenium is primarily mediated by selenoproteins. Selenoprotein H (SELENOH), as one of the selenium-containing proteins, has an unelucidated role in regulating cognitive status and lipid metabolism. In this study, we established a Selenoh gene knockout (HKO) mouse model to investigate whether Selenoh mediates the impact of selenium on cognitive function. We found that HKO mice showed a significant decline in cognition compared with the wild-type (HWT) littermates, and were not affected by deficient or excessive selenium, while no differences in anxiety and depression behavior were observed. HKO mice showed reduced myelin basic protein expression in hippocampal oligodendrocytes, with decreased glycolipid levels and increased phospholipid and sphingolipid levels in the hippocampus. Furthermore, the high-fat diet (HFD) exerted no effect on cognition and limited impact on the gene profile in the hippocampus of HKO mice. Compared with those of HWT mice, the myelination pathways in the hippocampus of HKO mice were downregulated as revealed by RNA-seq, which was further confirmed by the reduced expression levels of myelin-related proteins. Finally, HKO increased the expression of hippocampal fatty acid transporter (FATP) 4, and HFD increased the FATP4 expression in HWT mice but not in HKO mice. In summary, our study demonstrated that HKO induced cognitive decline by impairing myelination in oligodendrocytes with disrupted hippocampal lipid metabolism, which provided a novel viewpoint on the selenoprotein-mediated neurodegenerative diseases of selenium.

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The arginyl-transferase ATE1 is a tRNA-dependent enzyme that covalently attaches an arginine molecule to a protein substrate. Conserved from yeast to humans, ATE1 deficiency in mice correlates with defects in cardiovascular development and angiogenesis and results in embryonic lethality, while conditional knockouts exhibit reproductive, developmental, and neurological deficiencies. Despite the recent revelation of the tRNA binding mechanism and the catalytic cycle of yeast ATE1, the structure-function relationship of ATE1 in higher organisms is not well understood. In this study, we present the three-dimensional structure of human ATE1 in an apo-state and in complex with its tRNA cofactor and a peptide substrate. In contrast to its yeast counterpart, human ATE1 forms a symmetric homodimer, which dissociates upon binding of a substrate. Furthermore, human ATE1 includes a unique and extended loop that wraps around tRNAArg, creating extensive contacts with the T-arm of the tRNA cofactor. Substituting key residues identified in the substrate binding site of ATE1 abolishes enzymatic activity and results in the accumulation of ATE1 substrates in cells.

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BACKGROUND: Previous observational studies have suggested a possible association between periodontal disease and gastric cancer (GC); however, a causal relationship has not yet been established. This study aimed to explore the causal relationship between the 2 through a 2-sample bidirectional Mendelian randomization (MR) study. METHODS: Genome-wide association studies (GWAS) summary statistics were obtained from publicly available GWAS and relevant databases. Two-sample bidirectional MR analysis was conducted to investigate the causal relationship between periodontal disease and GC using the inverse-variance weighted (IVW) method selected as the primary analytical approach. Cochran Q test, MR-PRESSO, MR-pleiotropy, and leave-one-out analyses were performed to assess heterogeneity, pleiotropy, and sensitivity. RESULTS: In European ancestry, IVW analysis revealed no causal relationship between periodontal disease and GC (OR = 1.873; 95% CI [4.788e-10, 7.323e + 09]; P = .956), or between loose teeth and GC (OR = 1.064; 95% CI [0.708, 1.598]; P = .765). In East Asian ancestry, there was no causal relationship between periodontitis and GC according to IVW (OR = 0.948; 95% CI [0.886, 1.015]; P = .126). Conversely, according to the results of the IVW analysis, there was no causal relationship between GC and periodontal disease, regardless of European or East Asian ancestry. Furthermore, there was no heterogeneity or pleiotropy in the causal relationships between these variables (all P > .05), suggesting a certain level of reliability in our results. CONCLUSION: Within the limitations of this MR study, we found no mutual causal relationship between periodontal disease and GC. This finding can prevent overtreatment by clinical physicians and alleviate the psychological burden on patients.

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OBJECTIVES: To observe the activation state and neuronal types of somatosensory cortex and the primary motor cortex induced by electroacupuncture (EA) stimulation of "Sibai" (ST2) and "Quanliao" (SI18) acupoints in mice. METHODS: Male C57BL/6J mice were randomly divided into blank control and EA groups, with 6 mice in each group. Rats of the EA group received EA stimulation (2 Hz, 0.6 mA) at ST2 and SI18 for 30 minutes. Samples were collected after EA intervention, and immunofluorescence staining was performed to quantify the expression of the c-Fos gene (proportion of c-Fos positive cells) in the somatosensory cortex and primary motor cortex. The co-labelled cells of calcium/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) and gamma-aminobutyric acid (GABA) in the somatosensory cortex and primary motor cortex were observed and counted by using microscope after immunofluorescence staining. Another 10 mice were used to detect the calcium activity of excitatory neurons in the somatosensory cortex and primary motor cortex by fiber photometry. RESULTS: In comparison with the blank control group, the number of c-Fos positive cells, and the proportion of c-Fos and CaMKⅡ co-labelled cells in both the somatosensory cortex and primary motor cortex were significantly increased after EA stimulation (P<0.05). No significant changes were found in the proportion of c-Fos and GABA co-labeled cells in both the somatosensory cortex and primary motor cortex after EA. Results of fiber optic calcium imaging technology showed that the spontaneous calcium activity of excitatory neurons in both somatosensory cortex and primary motor cortex were obviously increased during EA compared with that before EA (P<0.01), and strikingly reduced after cessation of EA compared with that during EA (P<0.05). CONCLUSIONS: Under physiological conditions, EA of ST2 and SI18 can effectively activate excitatory neurons in the somatosensory cortex and primary motor cortex.

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Glucose and lipid metabolic disorders (GLMDs), such as diabetes, dyslipidemia, metabolic syndrome, nonalcoholic fatty liver disease, and obesity, are significant public health issues that negatively impact human health. The endoplasmic reticulum (ER) plays a crucial role at the cellular level for lipid and sterol biosynthesis, intracellular calcium storage, and protein post-translational modifications. Imbalance and dysfunction of the ER can affect glucose and lipid metabolism. As an essential trace element, selenium contributes to various human physiological functions mainly through 25 types of selenoproteins (SELENOs). At least 10 SELENOs, with experimental and/or computational evidence, are predominantly found on the ER membrane or within its lumen. Two iodothyronine deiodinases (DIOs), DIO1 and DIO2, regulate the thyroid hormone deiodination in the thyroid and some external thyroid tissues, influencing glucose and lipid metabolism. Most of the other eight members maintain redox homeostasis in the ER. Especially, SELENOF, SELENOM, and SELENOS are involved in unfolded protein responses; SELENOI catalyzes phosphatidylethanolamine synthesis; SELENOK, SELENON, and SELENOT participate in calcium homeostasis regulation; and the biological significance of thioredoxin reductase 3 in the ER remains unexplored despite its established function in the thioredoxin system. This review examines recent research advances regarding ER SELENOs in GLMDs and aims to provide insights on ER-related pathology through SELENOs regulation.

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Resting-state functional magnetic resonance imaging (rs-fMRI) has gained attention as a reliable technique for investigating the intrinsic function patterns of the brain. It facilitates the extraction of functional connectivity networks (FCNs) that capture synchronized activity patterns among regions of interest (ROIs). Analyzing FCNs enables the identification of distinctive connectivity patterns associated with mild cognitive impairment (MCI). For MCI diagnosis, various sparse representation techniques have been introduced, including statistical- and deep learning-based methods. However, these methods face limitations due to their reliance on supervised learning schemes, which restrict the exploration necessary for probing novel solutions. To overcome such limitation, prior work has incorporated reinforcement learning (RL) to dynamically select ROIs, but effective exploration remains challenging due to the vast search space during training. To tackle this issue, in this study, we propose an advanced RL-based framework that utilizes a divide-and-conquer approach to decompose the FCN construction task into smaller sub-problems in a subject-specific manner, enabling efficient exploration under each sub-problem condition. Additionally, we leverage the learned value function to determine the sparsity level of FCNs, considering individual characteristics of FCNs. We validate the effectiveness of our proposed framework by demonstrating its superior performance in MCI diagnosis on publicly available cohort datasets.

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The role of vitamin D (VD) in non-alcoholic fatty liver disease (NAFLD) remains controversial, possibly due to the differential effects of various forms of VD. In our study, Sod1 gene knockout (SKO) mice were utilized as lean NAFLD models, which were administered 15 000 IU VD3 per kg diet, or intraperitoneally injected with the active VD analog calcipotriol for 12 weeks. We found that VD3 exacerbated hepatic steatosis in SKO mice, with an increase in the levels of Cd36, Fatp2, Dgat2, and CEBPA. However, calcipotriol exerted no significant effect on hepatic steatosis. Calcipotriol inhibited the expression of Il-1a, Il-1b, Il-6, Adgre1, and TNF, with a reduction of NFκB phosphorylation in SKO mice. No effect was observed by either VD3 or calcipotriol on hepatocyte injury and hepatic fibrosis. Co-immunofluorescence stains of CD68, a liver macrophage marker, and VDR showed that calcipotriol reduced CD68 positive cells, and increased the colocalization of VDR with CD68. However, VD3 elevated hepatocyte VDR expression, with no substantial effect on the colocalization of VDR with CD68. Finally, we found that VD3 increased the levels of serum 25(OH)D3 and 24,25(OH)2D3, whereas calcipotriol decreased both. Both VD3 and calcipotriol did not disturb serum calcium and phosphate levels. In summary, our study found that VD3 accentuated hepatic steatosis, while calcipotriol diminished inflammation levels in SKO mice, and the difference might stem from their distinct cellular selectivity in activating VDR. This study provides a reference for the application of VD in the treatment of lean NAFLD.

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The adsorption-type molecular switch exhibits bistable states with an equivalently long lifetime at the organic/inorganic interface, promising reliable switching behavior and superior assembly ability in the electronic circuits at the molecular scale. However, the number of reported adsorption-type molecular switches is currently less than 10, and exploring these molecular switches poses a formidable challenge due to the intricate interplay occurring at the interface. To address this challenge, we have developed a model enabling the identification of diverse molecular switches on metal surfaces based on easily accessible physical characteristics. These characteristics primarily include the metal valency electron concentration, the work function of metal surfaces, and the electronegativity difference of molecules. Using this model, we identified 56 new molecular switches. Employing the gradient descent algorithm and statistical linear discriminant analysis, we constructed an explicit descriptor that establishes a relationship between the interfacial structure and chemical environment and the stability of molecular switches. The model's accuracy was validated through density functional theory calculations, achieving a 90% accuracy for aromatic molecular switches. The conductive switching behaviors were further confirmed by nonequilibrium Green's function transport calculations.

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Putrescine and cadaverine are significant volatile indicators used to assess the degree of food spoilage. Herein, we propose a micro-nano multi cavity structure for surface-enhanced Raman spectroscopy (SERS) to analyze the volatile gas putrescine and cadaverine in decomposing food. The MoS2 nano-flowers are inserted into a PVDF micro-cavity through in-situ growth, followed by vacuum evaporation technology of Ag nanoparticles to form an Ag/MoS2 nano-flower cavity/PVDF micron-bowl cavity (FIB) substrate. The micro-nano multi cavity structure can improve the capture capacity of both light and gas, thereby exhibiting high sensitivity (EF = 7.71 × 107) and excellent capability for gas detection of 2-naphthalenethiol. The SERS detections of the putrescine and cadaverine are achieved in the spoiled pork samples with the FIB substrate. Therefore, this substrate can provide an efficient, accurate, and feasible method for the specific and quantitative detection in the food safety field.

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It is generally believed that at-Γ bound states in the continuum (BICs) are enclosed by a linearly polarized vortex in momentum space when the structures have mirror (σz) symmetry, in-plane inversion (I) symmetry, and time reversal symmetry (T). Here, we reveal an anomalous situation in which at-Γ BICs can be enclosed by linearly and elliptically polarized far-field even when the σz, I, and T symmetries are all maintained in non-Bravais lattices, which is radically different from previous cognition. Asymmetric, diatomic structures are designed to elaborate this intriguing phenomenon. By controlling the geometric parameters or refractive indexes of the two meta-atoms, the far-field polarization around the at-Γ BICs gradually deviates from linear polarization and approaches circular polarization. Our findings reveal that non-Bravais lattices can provide a novel platform to manipulate the far-field polarization, showing important applications in quantum entanglement, structured light, and radiation modulation.

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Efforts to develop alternatives to triflic anhydride (Tf2O) as a trifluoromethylation reagent continue due to its limitations, including volatility, corrosiveness, and moisture sensitivity. Described herein is the use of a trifluoromethylsulfonylpyridinium salt (TFSP), easily obtained by a one-step reaction of Tf2O with 4-dimethylaminopyridine, as a reagent for the trifluoromethylative difunctionalization of alkenes by photoredox catalysis. DMSO and CH3CN are suitable solvents for achieving keto- and amino-trifluoromethylation of alkenes, respectively, with good functional group tolerance.

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China has adopted a national carbon emissions trading market to promote emission reductions, but until now, overallocation of allowances suffer low carbon prices and thus to unfulfilled emission reduction goals. We report a general equilibrium modeling that indicates the flexible compliance and price adjustment mechanism of the carbon market, along with explores the solution to the oversupply of allowances in the China's national carbon market. We find that, under the current policy, the initial loose allowance allocation decreases the overall carbon price, and simultaneously the total amount of banked carbon allowances reaches 4.880 billion tons in 2030, resulting in the level of carbon price cannot achieve NDC (Nationally Determined Contribution) targets. However, by introducing carbon market price adjustment schemes, we observe that the cumulative amount of allowances can effectively reduce, enabling the carbon price rising. Importantly, the amount of the supply of allowances decreases most under the benchmark decrease scenario, which increases the emission reduction pressure of the enterprises from the beginning, leading to the largest economic losses, the price-based adjustment mechanism raises the carbon price to expected level at the minimize economic losses, and the quantity-based adjustment mechanism is more sensitive to policy parameters compared to the price -based adjustment mechanism. These findings offer a promising avenue for selecting cost-effective price adjustment mechanism to improve price mechanism design for national carbon markets.

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BACKGROUND: With the rapidly increasing prevalence of metabolic diseases such as type 2 diabetes mellitus (T2DM), neuronal complications associated with these diseases have resulted in significant burdens on healthcare systems. Meanwhile, effective therapies have remained insufficient. A novel fatty acid called S-9-PAHSA has been reported to provide metabolic benefits in T2DM by regulating glucose metabolism. However, whether S-9-PAHSA has a neuroprotective effect in mouse models of T2DM remains unclear. METHODS: This in vivo study in mice fed a high-fat diet (HFD) for 5 months used fasting blood glucose, glucose tolerance, and insulin tolerance tests to examine the effect of S-9-PAHSA on glucose metabolism. The Morris water maze test was also used to assess the impact of S-9-PAHSA on cognition in the mice, while the neuroprotective effect of S-9-PAHSA was evaluated by measuring the expression of proteins related to apoptosis and oxidative stress. In addition, an in vitro study in PC12 cells assessed apoptosis, oxidative stress, and mitochondrial membrane potential with or without CAIII knockdown to determine the role of CAIII in the neuroprotective effect of S-9-PAHSA. RESULTS: S-9-PAHSA reduced fasting blood glucose levels significantly, increased insulin sensitivity in the HFD mice and also suppressed apoptosis and oxidative stress in the cortex of the mice and PC12 cells in a diabetic setting. By suppressing oxidative stress and apoptosis, S-9-PAHSA protected both neuronal cells and microvascular endothelial cells in in vivo and in vitro diabetic environments. Interestingly, this protective effect of S-9-PAHSA was reduced significantly when CAIII was knocked down in the PC12 cells, suggesting that CAIII has a major role in the neuroprotective effect of S-9-PAHSA. However, overexpression of CAIII did not significantly enhance the protective effect of S-9-PAHSA. CONCLUSION: S-9-PAHSA mediated by CAIII has the potential to exert a neuroprotective effect by suppressing apoptosis and oxidative stress in neuronal cells exposed to diabetic conditions. Furthermore, S-9-PAHSA has the capability to reduce fasting blood glucose and LDL levels and enhance insulin sensitivity in mice fed with HFD.

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Actively controlling surface-enhanced Raman scattering (SERS) performance plays a vital role in highly sensitive detection or in situ monitoring. Nevertheless, it is still challenging to achieve further modulation of electromagnetic enhancement and chemical enhancement simultaneously in SERS detection. In this study, a silver nanocavity structure with graphene as a spacer layer is coupled with thermoelectric semiconductor P-type gallium nitride (GaN) to form an electric-field-induced SERS (E-SERS) for dual enhancement. After applying the electric field, the intensity of SERS signals is further enhanced by over 10 times. The thermoelectric field enables fast and reproducible doping of graphene, thereby modulating its Fermi level over a wide range. The thermoelectric field also regulates the position of the plasmon resonance peak of the silver nanocavity structure, rendering synchronous dual electromagnetic and chemical regulation. Additionally, the method enables the trace detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A detailed theoretical analysis is performed based on the experimental results and finite-element calculations, paving the way for the fabrication of high-efficient E-SERS substrates.

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Microbe-produced secondary metabolite phenazine-1-carboxylic acid (PCA) facilitates pathogen virulence and defense mechanisms against competitors. Magnaporthe oryzae, a causal agent of the devastating rice blast disease, needs to compete with other phyllosphere microbes and overcome host immunity for successful colonization and infection. However, whether M. oryzae produces PCA or it has any other functions remains unknown. Here, we found that the MoPHZF gene encodes the phenazine biosynthesis protein MoPhzF, synthesizes PCA in M. oryzae, and regulates appressorium formation and host virulence. MoPhzF is likely acquired through an ancient horizontal gene transfer event and has a canonical function in PCA synthesis. In addition, we found that PCA has a role in suppressing the accumulation of host-derived reactive oxygen species (ROS) during infection. Further examination indicated that MoPhzF recruits both the endoplasmic reticulum membrane protein MoEmc2 and the regulator of G-protein signaling MoRgs1 to the plasma membrane (PM) for MoRgs1 phosphorylation, which is a critical regulatory mechanism in appressorium formation and pathogenicity. Collectively, our studies unveiled a canonical function of MoPhzF in PCA synthesis and a noncanonical signaling function in promoting appressorium formation and host infection.

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Reactions involving sulfhydryl groups play a critical role in maintaining the structure and function of proteins. However, traditional mechanistic studies have mainly focused on reaction rates and the efficiency in bulk solutions. Herein, we have designed a cysteine-mutated nanopore as a biological protein nanoreactor for electrochemical visualization of the thiol substitute reaction. Statistical analysis of characteristic current signals shows that the apparent reaction rate at the single-molecule level in this confined nanoreactor reached 1400 times higher than that observed in bulk solution. This substantial acceleration of thiol substitution reactions within the nanopore offers promising opportunities for advancing the design and optimization of micro/nanoreactors. Moreover, our results could shed light on the understanding of sulfhydryl reactions and the thiol-involved signal transduction mechanisms in biological systems.