Endophilin A2 controls touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking.

BACKGROUND: Tactile and mechanical pain are crucial to our interaction with the environment, yet the underpinning molecular mechanism is still elusive. Endophilin A2 (EndoA2) is an evolutionarily conserved protein that is documented in the endocytosis pathway. However, the role of EndoA2 in the regulation of mechanical sensitivity and its underlying mechanisms are currently unclear. METHODS: Male and female C57BL/6 mice (8-12 weeks) and male cynomolgus monkeys (7-10 years old) were used in our experiments. Nerve injury-, inflammatory-, and chemotherapy-induced pathological pain models were established for this study. Behavioral tests of touch, mechanical pain, heat pain, and cold pain were performed in mice and nonhuman primates. Western blotting, immunostaining, co-immunoprecipitation, proximity ligation and patch-clamp recordings were performed to gain insight into the mechanisms. RESULTS: The results showed that EndoA2 was primarily distributed in neurofilament-200-positive (NF200+) medium-to-large diameter dorsal root ganglion (DRG) neurons of mice and humans. Loss of EndoA2 in mouse NF200+ DRG neurons selectively impaired the tactile and mechanical allodynia. Furthermore, EndoA2 interacted with the mechanically sensitive ion channel Piezo2 and promoted the membrane trafficking of Piezo2 in DRG neurons. Moreover, as an adaptor protein, EndoA2 also bound to kinesin family member 5B (KIF5B), which was involved in the EndoA2-mediated membrane trafficking process of Piezo2. Loss of EndoA2 in mouse DRG neurons damaged Piezo2-mediated rapidly adapting mechanically activated currents, and re-expression of EndoA2 rescued the MA currents. In addition, interference with EndoA2 also suppressed touch sensitivity and mechanical hypersensitivity in nonhuman primates. CONCLUSIONS: Our data reveal that the KIF5B/EndoA2/Piezo2 complex is essential for Piezo2 trafficking and for sustaining transmission of touch and mechanical hypersensitivity signals. EndoA2 regulates touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking in sensory neurons. Our findings identify a potential new target for the treatment of mechanical pain.

Exploration of signature based on T cell-related genes in stomach adenocarcinoma by analysis of single cell sequencing data.

BACKGROUND: Gastric cancer (GC) is a leading reason for the death of cancer around the world. The immune microenvironment counts a great deal in immunotherapy of advanced tumors, in which T cells exert an indispensable function. METHODS: Single-cell RNA sequencing data were utilized to characterize the expression profile of T cells, followed by T cell-related genes (TCRGs) to construct signature and measure differences in survival time, enrichment pathways, somatic mutation status, immune status, and immunotherapy between groups. RESULTS: The complex tumor microenvironment was analyzed by scRNA-seq data of GC patients. We screened for these T cell signature expression genes and the TCRGs-based signature was successfully constructed and relied on the riskscore grouping. In gene set enrichment analysis, it was shown that pro-tumor and suppressive immune pathways were more abundant in the higher risk group. We also found different infiltration of immune cells in two groups, and that the higher risk samples had a poorer response to immunotherapy. CONCLUSION: Our study established a prognostic model, in which different groups had different prognosis, immune status, and enriched features. These results have provided additional insights into prognostic evaluation and the development of highly potent immunotherapies in GC.

Construction of a gene model related to the prognosis of patients with gastric cancer receiving immunotherapy and exploration of COX7A1 gene function.

BACKGROUND: GC is a highly heterogeneous tumor with different responses to immunotherapy, and the positive response depends on the unique interaction between the tumor and the tumor microenvironment (TME). However, the currently available methods for prognostic prediction are not satisfactory. Therefore, this study aims to construct a novel model that integrates relevant gene sets to predict the clinical efficacy of immunotherapy and the prognosis of GC patients based on machine learning. METHODS: Seven GC datasets were collected from the Gene Expression Omnibus (GEO) database, The Cancer Genome Atlas (TCGA) database and literature sources. Based on the immunotherapy cohort, we first obtained a list of immunotherapy related genes through differential expression analysis. Then, Cox regression analysis was applied to divide these genes with prognostic significancy into protective and risky types. Then, the Single Sample Gene Set Enrichment Analysis (ssGSEA) algorithm was used to score the two categories of gene sets separately, and the scores differences between the two gene sets were used as the basis for constructing the prognostic model. Subsequently, Weighted Correlation Network Analysis (WGCNA) and Cytoscape were applied to further screen the gene sets of the constructed model, and finally COX7A1 was selected for the exploration and prediction of the relationship between the clinical efficacy of immunotherapy for GC. The correlation between COX7A1 and immune cell infiltration, drug sensitivity scoring, and immunohistochemical staining were performed to initially understand the potential role of COX7A1 in the development and progression of GC. Finally, the differential expression of COX7A1 was verified in those GC patients receiving immunotherapy. RESULTS: First, 47 protective genes and 408 risky genes were obtained, and the ssGSEA algorithm was applied for model construction, showing good prognostic discrimination ability. In addition, the patients with high model scores showed higher TMB and MSI levels, and lower tumor heterogeneity scores. Then, it is found that the COX7A1 expressions in GC tissues were significantly lower than those in their corresponding paracancerous tissues. Meanwhile, the patients with high COX7A1 expression showed higher probability of cancer invasion, worse clinical efficacy of immunotherapy, worse overall survival (OS) and worse disease-free survival (DFS). CONCLUSIONS: The ssGSEA score we constructed can serve as a biomarker for GC patients and provide important guidance for individualized treatment. In addition, the COX7A1 gene can accurately distinguish the prognosis of GC patients and predict the clinical efficacy of immunotherapy for GC patients.

Gastric cancer with enhanced myogenesis is associated with less cell proliferation, enriched epithelial-to-mesenchymal transition and angiogenesis, and poor clinical outcomes.

Gastric cancer (GC) remains a lethal disease, with over 26,000 new cases and more than 11,000 deaths annually in the US. Thus, a deeper understanding of GC biology is critical to improve survival. Myogenesis is the formation of muscle fibers, which is a mesodermal tissue. In cancer, epithelial-to-mesenchymal transition (EMT) is a known phenomenon that promotes metastasis and poor survival. Given that myogenesis produces mesenchymal cells, we hypothesized that GC with increased myogenesis is linked to aggressive tumor behaviors and less favorable outcomes. In this study, three GC patient cohorts: TCGA (n=375), GSE26253 (n=432), and GSE84437 (n=482), were analyzed. The "MYOGENESIS" set in the Hallmark collection which comprises 200 myogenesis-related genes was analyzed to perform gene set variation analysis to create a score to quantify the myogenesis activity. Our results showed that T category of AJCC cancer staging that reflects the tumor invasion to stomach wall consistently correlated with myogenesis activity in two GC cohorts. High myogenesis GC was associated with lower cell proliferation, evidenced by reduced proliferation scores, decreased Ki67 gene expression, and less enrichment of E2F Targets, G2M checkpoint, MYC Targets V1, and V2 gene sets. High myogenesis tumors showed increased stromal cells (fibroblasts and adipocytes) infiltration within the tumor microenvironment, as well as less silent and non-silent mutation rates and copy number alterations. Higher lymphocyte infiltration, leukocyte fraction, T-cell receptor richness, and B-cell receptor richness were associated with high myogenesis GC. However, infiltration of CD4 cells, T helper type 1 and 2 cells, Natural Killer cells, regulatory T cells, and plasma cells was lower, with increased infiltration of dendritic cells in high myogenesis GC. High myogenesis GC enriched EMT, Hedgehog, TGF-ß, and KRAS gene sets. Furthermore, it was associated with enhanced angiogenesis, evidenced by enrichment of Angiogenesis, Coagulation, and Hypoxia gene sets, and increased infiltration of microvascular and lymphatic endothelial cells and pericytes. High myogenesis GC consistently correlated with worse overall survival in all three cohorts, and worse disease-specific and progression-free survival in the TCGA cohort. Hence, our findings suggest that GC with enhanced myogenesis is associated with decreased cell proliferation, increased EMT and angiogenesis, and worse prognosis.

Biodegradable bio-film based on Cordyceps militaris and metal-organic frameworks for fruit preservation.

In this study, Cordyceps militaris matrix was employed for the first time to fabricate a biodegradable food packaging. Carmine and Ag@CuBTC were introduced to cross-link with mycelium and were uniformly dispersed within the matrix to enhance the water resistance, antimicrobial, and antioxidant properties of the bio-films. The bio-film displayed high biodegradability, with nearly 100 % degradation achieved after three weeks. The bio-film exhibited exceptional resistance to oxidation (49.30 % DPPH and 93.94 % ABTS•+), as well as effective inhibitory capabilities against E. coli and S. aureus, respectively. The composite film maintained a high CO2/O2 selective permeability, which was advantageous for mitigating fruit metabolism and extending shelf life. Simultaneously, food preservation experiments confirmed that these bio-films can decelerate the spoilage of fruits and effectively prolong the shelf-life of food. The experimental findings indicated that the prepared Bio-R-Ag@Cu film held promise as an environmentally friendly biodegradable material for food packaging.

ATF4 inhibits TRPV4 function and controls itch perception in rodents and nonhuman primates.

ABSTRACT: Acute and chronic itch are prevalent and incapacitating, yet the neural mechanisms underlying both acute and chronic itch are just starting to be unraveled. Activated transcription factor 4 (ATF4) belongs to the ATF/CREB transcription factor family and primarily participates in the regulation of gene transcription. Our previous study has demonstrated that ATF4 is expressed in sensory neurons. Nevertheless, the role of ATF4 in itch sensation remains poorly understood. Here, we demonstrate that ATF4 plays a significant role in regulating itch sensation. The absence of ATF4 in dorsal root ganglion (DRG) neurons enhances the itch sensitivity of mice. Overexpression of ATF4 in sensory neurons significantly alleviates the acute and chronic pruritus in mice. Furthermore, ATF4 interacts with the transient receptor potential cation channel subfamily V member 4 (TRPV4) and inhibits its function without altering the expression or membrane trafficking of TRPV4 in sensory neurons. In addition, interference with ATF4 increases the itch sensitivity in nonhuman primates and enhances TRPV4 currents in nonhuman primates DRG neurons; ATF4 and TRPV4 also co-expresses in human sensory neurons. Our data demonstrate that ATF4 controls pruritus by regulating TRPV4 signaling through a nontranscriptional mechanism and identifies a potential new strategy for the treatment of pathological pruritus.

Higher Inflammatory Response in Hepatocellular Carcinoma is Associated with Immune Cell Infiltration and a Better Outcome.

Background & Aims: Hepatocellular carcinoma (HCC) often develops from chronic liver inflammation. Inflammation within a tumor can either promote cancer progression or activate an immune response against it. This study aims to determine the clinical significance of enhanced inflammation in HCC. Methods: Data from 655 HCC patients across four cohorts (TCGA, GSE6764, GSE76427, GSE89377) were examined. Inflammatory response was quantified using a scoring system derived from the gene set variation analysis of the "INFLAMMATORY_RESPONSE" gene set. Results: A stepwise increase in inflammatory response was noted from normal liver to cirrhosis, with consistently lower levels in HCC across both GSE6764 and GSE89377 cohorts (both p<0.001). Similar trends were observed in interferon response, pathways such as IL6/JAK/STAT3 and complement signaling, coagulation cascade, and allograft rejection (all p<0.02). HCCs with high inflammatory response were associated with increased immune cell infiltrations (p<0.01) and cytolytic activity (p<0.001). Interestingly, these HCCs had reduced mutation rates, no relationship with cell proliferation, and displayed both immune responses and pro-cancerous signals including epithelial-mesenchymal transition, KRAS, and hypoxia. Further, a high inflammatory score correlated with improved disease-free survival in TCGA (p=0.034) and overall survival in GSE76427 (p=0.008). Conclusion: HCC with higher levels of inflammatory response demonstrated increased immune cell infiltration, enhanced immune-related and other pro-cancerous-related signaling, and better patient prognosis.

Eight Weeks of Bifidobacterium lactis BL-99 Supplementation Improves Lipid Metabolism and Sports Performance through Short-Chain Fatty Acids in Cross-Country Skiers: A Preliminary Study.

(1) Background: Probiotics in the form of nutritional supplements are safe and potentially useful for strategic application among endurance athletes. Bifidobacterium animalis lactis BL-99 (BL-99) was isolated from the intestines of healthy Chinese infants. We combined plasma-targeted metabolomics and fecal metagenomics to explore the effect of 8 weeks of BL-99 supplementation on cross-country skiers' metabolism and sports performance. (2) Methods: Sixteen national top-level male cross-country skiers were recruited and randomly divided into a placebo group (C) and a BL-99 group (E). The participants took the supplements four times/day (with each of three meals and at 21:00) consistently for 8 weeks. The experiment was conducted in a single-blind randomized fashion. The subject's dietary intake and total daily energy consumption were recorded. Blood and stool samples were collected before and after the 8-week intervention, and body composition, muscle strength, blood biochemical parameters, plasma-targeted metabolomic data, and fecal metagenomic data were then analyzed. (3) Results: The following changes occurred after 8 weeks of BL-99 supplementation: (a) There was no significant difference in the average total daily energy consumption and body composition between the C and E groups. (b) The VO2max and 60°/s and 180°/s knee joint extensor strength significantly increased in both the C and E groups. By the eighth week, the VO2max and 60 s knee-joint extensor strength were significantly higher in the E group than in the C group. (c) The triglyceride levels significantly decreased in both the C and E groups. In addition, the LDL-C levels significantly decreased in the E group. (d) The abundance of Bifidobacterium animalis increased two-fold in the C group and forty-fold in the E group. (e) Plasma-targeted metabolomic analysis showed that, after eight weeks of BL-99 supplementation, the increases in DHA, adrenic acid, linoleic acid, and acetic acid and decreases in glycocholic acid and glycodeoxycholic acid in the E group were significantly higher than those in the C group. (f) Spearman correlation analysis showed that there was a significant positive correlation between Bifidobacterium animalis' abundance and SCFAs, PUFAs, and bile acids. (g) There was a significant correlation between the most significantly regulated metabolites and indicators related to sports performance and lipid metabolism. (4) Conclusions: Eight weeks of BL-99 supplementation combined with training may help to improve lipid metabolism and sports performance by increasing the abundance of Bifidobacterium, which can promote the generation of short-chain fatty acids and unsaturated fatty acids, and inhibit the synthesis of bile acids.

Effects of dietary intervention combined with insulin aspart on serum nesfatin-1 and CTRP12 levels and pregnancy outcomes in pregnant women with gestational diabetes mellitus.

To analyze the effects of dietary intervention combined with insulin aspart on the serum levels of nesfatin-1, C1q/TNF related protein-12 (CTRP12), and pregnancy outcomes in pregnant women with gestational diabetes mellitus (GDM). In this retrospective cohort study, 513 women with GDM admitted to Tangshan Central Hospital (Tangshan, China) between January 2019 and December 2022 were selected and divided into an observation group (dietary intervention combined with insulin aspart therapy; n = 284) and a control group (insulin aspart therapy, n = 229). The general characteristics, clinical outcomes, serum nesfatin-1 and CTRP12 levels, 2-hour postprandial blood glucose levels, pregnancy outcomes, and perinatal outcomes of the 2 groups were compared. After treatment, the total effective rate in the observation group was significantly higher than that of the control group (97.54% vs 86.03%, respectively; P < .001). Compared with the pretreatment levels, nesfatin-1 and CTRP12 levels were decreased in both groups; nesfatin-1 and CTRP12 levels in the observation group were significantly higher than those in the control group. After treatment, the preprandial and 2-hour postprandial blood glucose levels in the observation group were significantly lower than those in the control group. Compared with the control group, the observation group had significantly fewer cesarean sections, and a significantly lower incidence of postpartum hemorrhage, premature rupture of membranes, and other adverse pregnancy outcomes. After treatment, the risks of preterm birth, macrosomia, fetal distress, neonatal asphyxia, neonatal hypoglycemia, and other adverse perinatal outcomes were significantly lower in the observation group than in the control group. In pregnant women with GDM, dietary intervention combined with insulin aspart can improve clinical outcomes; reduce nesfatin-1, CTRP12, and blood glucose levels; and reduce the incidence of adverse pregnancy outcomes.

Supplementation with food-derived oligopeptides promotes lipid metabolism in young male cyclists: a randomized controlled crossover trial.

BACKGROUND: Accumulation of body fat and dyslipidemia are associated with the development of obesity and cardiometabolic diseases. Moreover, the degree to which lipids can be metabolized has been cited as a determinant of cardiometabolic health and prolonged endurance capacity. In the backdrop of increasing obesity and cardiometabolic diseases, lipid metabolism and its modulation by physical activity, dietary adjustments, and supplementation play a significant role in maintaining health and endurance. Food-derived oligopeptides, such as rice and soybean peptides, have been shown to directly regulate abnormal lipid metabolism or promote hypolipidemia and fat oxidation in cell culture models, animal models, and human studies. However, whether supplementation with oligopeptides derived from multiple food sources can promote lipid degradation and fat oxidation in athletes remains unclear. Therefore, in a randomized controlled crossover trial, we investigated the impact of food-derived oligopeptide supplementation before and during exercise on lipid metabolism in young male cyclists. METHODS: Sixteen young male cyclists (age: 17.0 ± 1.0 years; height: 178.4 ± 6.9 cm; body mass: 68.7 ± 12.7 kg, body mass index: 21.5 ± 3.4 kg/m2; maximum oxygen uptake: 56.3 ± 5.8 mL/min/kg) participated in this randomized controlled crossover trial. Each participant drank two beverages, one containing a blend of three food-derived oligopeptides (treatment, 0.5 g/kg body weight in total) and the other without (control), with a 2-week washout period between two experiments. The cyclists completed a one-day pattern protocol that consisted of intraday fasting, 30 min of sitting still, 85 min of prolonged exercise plus a 5-min sprint (PE), a short recovery period of 60 min, a 20-min time trial (TT), and recovery till next morning. Blood samples were collected for biochemical analyses of serum lipids and other biomarkers. We analyzed plasma triglyceride species (TGs), free amino acids (FAAs), and tricarboxylic acid (TCA) cycle intermediates using omics methods. In addition, exhaled gas was collected to assess the fat oxidation rate. RESULTS: Five of 20 plasma FAAs were elevated pre-exercise (pre-Ex) only 20 min after oligopeptide ingestion, and most FAAs were markedly increased post PE and TT. Serum levels of TG and non-esterified fatty acids were lower in the experimental condition than in the control condition at the post PE and TT assessments, respectively. Further, the omics analysis of plasma TGs for the experimental condition demonstrated that most TGs were lower post PE and at the next fasting when compared with control levels. Simultaneously, the fat oxidation rate began to increase only 20 min after ingestion and during the preceding 85 min of PE. Levels of TCA cycle intermediates did not differ between the conditions. CONCLUSIONS: The study noted that continuous ingestion of food-derived oligopeptides accelerated total body triglyceride breakdown, non-esterified fatty acid uptake, and fat oxidation during both sedentary and exercise states. Elevated circulating and intracellular FAA flux may modulate the selection of substrates for metabolic pathways in conjunction with the release of neuroendocrinological factors that slow down carbohydrate metabolism via acetyl coenzyme A feedback inhibition. This may increase the availability of fatty acids for energy production, with FAAs supplying more substrates for the TCA cycle. The findings of this study provide novel insight into strategies for promoting lipid metabolism in populations with dyslipidemia-related metabolic disorders such as obesity and for improving physiological functioning during endurance training. However, the absence of a non-exercising control group and verification of long-term supplementation effects was a limitation. Future studies will emphasize the impacts of whole protein supplementation as a control and of combined food-derived peptides or oligopeptides with probiotics and healthy food components on lipid metabolism in individuals who exercise.

Biomimetic Structural Protein Based Magnetic Responsive Scaffold for Enhancing Bone Regeneration by Physical Stimulation on Intracellular Calcium Homeostasis.

The bone matrix has distinct architecture and biochemistry which present a barrier to synthesizing bone-mimetic regenerative scaffolds. To mimic the natural structures and components of bone, biomimetic structural decellularized extracellular matrix (ECM)/regenerated silk fibroin (RSF) scaffolds incorporated with magnetic nanoparticles (MNP) are prepared using a facile synthetic methodology. The ECM/RSF/MNP scaffold is a hierarchically organized and interconnected porous structure with silk fibroin twined on the collagen nanofibers. The scaffold demonstrates saturation magnetization due to the presence of MNP, along with good cytocompatibility. Moreover, the ß-sheet crystalline domain of RSF and the chelated MNP could mimic the deposition of hydroxyapatite and enhance compressive modulus of the scaffold by ≈20%. The results indicate that an external static magnetic field (SMF) with a magnetic responsive scaffold effectively promotes cell migration, osteogenic differentiation, neogenesis of endotheliocytes in vitro, and new bone formation in a critical-size femur defect rat model. RNA sequencing reveals that the molecular mechanisms underlying this osteogenic effect involve calsequestrin-2-mediated Ca2+ release from the endoplasmic reticulum to activate Ca2+ /calmodulin/calmodulin-dependent kinase II signaling axis. Collectively, bionic magnetic scaffolds with SMF stimulation provide a potent strategy for bone regeneration through internal structural cues, biochemical composition, and external physical stimulation on intracellular Ca2+ homeostasis.

Realistic three-layer head phantom for optically pumped magnetometer-based magnetoencephalography.

The advent of optically pumped magnetometer-based magnetoencephalography (OPM-MEG) has introduced new tools for neuroscience and clinical research. As it is still under development, the achievable performance of OPM-MEG remains to be tested, particularly in terms of source localization accuracy, which can be influenced by various factors, including software and hardware aspects. A feasible approach to comprehensively test the performance of the OPM-MEG system is to utilize a phantom that simulates the actual electrophysiological properties of the head while ensuring the precise locations of dipole sources. However, conventional water or dry phantoms can only simulate a single-sphere head model. In this work, a more realistic three-layer phantom was designed and fabricated. The proposed phantom included the scalp, skull, and cortex tissues of the head, as well as the simulated dipole sources. The scalp and cortex tissues were simulated using an electrolyte solution, while the dipole source was constructed from a coaxial cable. All main structures in the phantom were produced using 3D printing techniques, making the phantom easy to manufacture. The fabricated phantom was tested on a 36-channel OPM-MEG system, and the results showed that the dipole source inside the phantom could generate a magnetic field distribution on the scalp that was close to its theoretical values. The average source localization accuracy of 5.51 mm verified the effectiveness of the designed phantom and the performance of our OPM-MEG system. This work provides an effective test platform for OPM-MEG.

Separation of C2H2/C2H4/C2H6 and C2H2/CO2 in a Nitrogen-Rich Copper-Based Microporous Metal-Organic Framework.

The purification of industrially valuable C2H2 and C2H4 from multicomponent mixtures represents a crucial process in the chemical industry. In this study, we present a copper-based metal-organic framework (L-py-Cu) built on a nitrogen-rich organic linker that is capable of separating C2H2/C2H4/C2H6 and C2H2/CO2 mixtures, therefore producing highly pure C2H4 and C2H2, respectively. L-py-Cu exhibits favorable adsorption of C2H2 and C2H6 over C2H4 and thus achieves one-step C2H4 purification from C2H2/C2H4/C2H6 ternary mixtures, as verified by multicomponent breakthrough measurements. In addition, it can also extract C2H2 from C2H2/CO2 binary mixtures.

Inflammatory factors and risk of meningiomas: a bidirectional mendelian-randomization study.

Background: Meningiomas are one of the most common intracranial tumors, and the current understanding of meningioma pathology is still incomplete. Inflammatory factors play an important role in the pathophysiology of meningioma, but the causal relationship between inflammatory factors and meningioma is still unclear. Method: Mendelian randomization (MR) is an effective statistical method for reducing bias based on whole genome sequencing data. It's a simple but powerful framework, that uses genetics to study aspects of human biology. Modern methods of MR make the process more robust by exploiting the many genetic variants that may exist for a given hypothesis. In this paper, MR is applied to understand the causal relationship between exposure and disease outcome. Results: This research presents a comprehensive MR study to study the association of genetic inflammatory cytokines with meningioma. Based on the results of our MR analysis, which examines 41 cytokines in the largest GWAS datasets available, we were able to draw the relatively more reliable conclusion that elevated levels of circulating TNF-ß, CXCL1, and lower levels of IL-9 were suggestive associated with a higher risk of meningioma. Moreover, Meningiomas could cause lower levels of interleukin-16 and higher levels of CXCL10 in the blood. Conclusion: These findings suggest that TNF-ß, CXCL1, and IL-9 play an important role in the development of meningiomas. Meningiomas also affect the expression of cytokines such as IL-16 and CXCL10. Further studies are needed to determine whether these biomarkers can be used to prevent or treat meningiomas.

Self-powered enzyme-linked microneedle patch for scar-prevention healing of diabetic wounds.

Diabetic wounds with complex pathological features and a difficult-to-heal nature remain a formidable challenge. To address this challenge, we design and fabricate a self-powered enzyme-linked microneedle (MN) patch composed of anode and cathode MN arrays, which respectively contain glucose oxidase (GOx) and horseradish peroxidase (HRP) encapsulated in ZIF-8 nanoparticles. The enzymatic cascade reaction in the MN patch can effectively reduce local hyperglycemia in diabetic wounds while generating stable microcurrents to promote rapid healing of diabetic wounds. Therefore, the diabetic wounds treated with this MN patch exhibit rapid, complete, and scar-preventative healing, which can be attributed to the synergistic actions of hypoglycemic, antibacterial, anti-inflammatory, and bioelectrical stimulation. In brief, the self-powered MN patch is an effective method to rapidly promote diabetic wound healing and prevent scar formation.

Boosting Water Evaporation by Construction of Photothermal Materials with a Biomimetic Black Soil Aggregate Structure.

Solar-driven interfacial evaporation is considered an efficient way to get fresh water from seawater. However, the low evaporation rate, surface salt crystallization, and low energy collection of the photothermal evaporation layer limit its further application in an outdoor freshwater field. And the aggregate structure design of the material itself is often ignored in solar-driven water evaporation. Black soil (BS), with a unique soil aggregate structure, is rich in tubular pores, which can be used for multilevel sunlight utilization and good capillary water transport. Based on the extraordinary photothermal properties and pumping capacity of BS, a reasonable unidirectional salt-collecting device is designed, which can realize long-term collection of mineral salts and continuous evaporation of seawater and generate electric energy in the continuous evaporation. Inspired by the unique aggregate structure, the photothermal material doping of halloysite and nigrosin will simulate the generation of this aggregate structure and retain a good water transport effect while obtaining multistage utilization of sunlight. The solar-driven evaporation rate of a nigrosin-halloysite solar steam generator is 1.75 kg m-2 h-1 under 1 kW m-2 mimic solar radiation; it can achieve stable salt leaching-induced voltage generation of 240 mV. This work demonstrates not only a solar evaporator that can continuously achieve desalination but also the design strategy of BS-like aggregate photothermal materials, which promotes the development of low-cost resource recovery and energy generation for practical outdoor seawater desalination.

Metabolic regulation and antihyperglycemic properties of diet-derived PGG through transcriptomic and metabolomic profiling.

Diabetes has become a significant disease threatening human health and social development. Food intervention is considered an essential strategy to prevent early diabetes development sustainably. The natural product, 1,2,3,4,6-penta-O-galloyl-ß-D-glucose (PGG), commonly found in fruits and diets, has many potential antihypoglycemic, antibacterial, and antitumor activities. We found that PGG can promote glucose uptake in whole-organism zebrafish screening, which help in downregulating the glucose levels. We investigated the metabolome and transcriptome changes in zebrafish exposed to high glucose and PGG intervention. The differential genes and metabolites were screened out based on the comparisons of blank, hyperglycemic, and the PGG-exposed groups of zebrafish larvae. Combined with RT-qPCR validation, we found that PGG mainly restored four genes (fthl27, LOC110438965, plat, and aacs) and six metabolites abnormally invoked by high glucose. These validated genes are related with the key metabolites sphingosine and (R)-3-hydroxybutanoate involving the pathways of apelin, apoptosis, necroptosis, and butanoate metabolism. Our findings provided a new mechanistic basis for understanding the hypoglycaemic function of the commonly present dietary molecule (PGG) and offered a new perspective for the rational utilization of PGG to regulate metabolic disorders.

Construction and validation of a prognostic prediction model for gastric cancer using a series of genes related to lactate metabolism.

Background: Gastric cancer (GC) is one of the most common clinical malignant tumors worldwide, with high morbidity and mortality. The commonly used tumor-node-metastasis (TNM) staging and some common biomarkers have a certain value in predicting the prognosis of GC patients, but they gradually fail to meet the clinical demands. Therefore, we aim to construct a prognostic prediction model for GC patients. Methods: A total of 350 cases were included in the STAD (Stomach adenocarcinoma) entire cohort of TCGA (The Cancer Genome Atlas), including the STAD training cohort of TCGA (n = 176) and the STAD testing cohort of TCGA (n = 174). GSE15459 (n = 191), and GSE62254 (n = 300) were for external validation. Results: Through differential expression analysis and univariate Cox regression analysis in the STAD training cohort of TCGA, we screened out five genes among 600 genes related to lactate metabolism for the construction of our prognostic prediction model. The internal and external validations showed the same result, that is, patients with higher risk score were associated with poor prognosis (all p < 0.05), and our model works well without regard of patients' age, gender, tumor grade, clinical stage or TNM stage, which supports the availability, validity and stability of our model. Gene function analysis, tumor-infiltrating immune cells analysis, tumor microenvironment analysis and clinical treatment exploration were performed to improve the practicability of the model, and hope to provide a new basis for more in-depth study of the molecular mechanism for GC and for clinicians to formulate more reasonable and individualized treatment plans. Conclusions: We screened out and used five genes related to lactate metabolism to develop a prognostic prediction model for GC patients. The prediction performance of the model is confirmed by a series of bioinformatics and statistical analysis.

A triple amplification strategy using GR-5 DNAzyme as a signal medium for ultrasensitive detection of trace Pb2+ based on CRISPR/Cas12a empowered electrochemical biosensor.

Lead ions (Pb2+) are a well-known toxic heavy metal that poses a significant threat to human health. Therefore, the development of a simple and ultrasensitive technique for detecting Pb2+ is essential. With their trans-cleavage properties, the newly discovered CRISPR-V effectors have become a potential high-precision biometric tool. In this regard, a CRISPR/Cas12a-based electrochemical biosensor (E-CRISPR) has been developed, which is combined with the GR-5 DNAzyme that can specifically recognize Pb2+. In this strategy, the GR-5 DNAzyme acts as a signal-mediated intermediary, which can convert Pb2+ into nucleic acid signals, thereby becoming single-stranded DNA that triggers strand displacement amplification (SDA) reaction. This is coupled with following activated CRISPR/Cas12a cleavage of the electrochemical signal probe, enabling cooperative signal amplification for ultrasensitive Pb2+ detection. The proposed method has a detection limit as low as 0.02 pM. Therefore, we have developed an E-CRISPR detection platform with GR-5 DNAzyme as a signal medium (called SM-E-CRISPR biosensor). This provides a method for the CRISPR system to specifically detect non-nucleic substances by converting the signal using a medium.