Deficiency of SLC26A3 promotes jejunal barrier damage in metabolic disease-susceptible transgenic pigs.

Intestinal disorders are common in metabolic syndrome. However, their pathogenesis is still not fully understood. Pig and human intestines are highly similar in terms of associated metabolic processes. Here, we successfully constructed a metabolic disease-susceptible transgenic (TG) Bama pig model by knocking in three humanized disease risk genes with the CRISPR/Cas9 technique to assess its potential as a model for human intestinal diseases and explore the possible pathological mechanisms involved. We found that jejunal barrier integrity was disrupted and that the infiltration of inflammatory cells increased in TG pigs after high-fat and high-sucrose diet (HFHSD) treatment. We revealed significant differences in the transcriptome, associated microbiome profiles and microbial metabolite short-chain fatty acid (SCFA) content of the jejunum of TG pigs. Notably, we found that SLC26A3 was significantly downregulated in TG pigs. Knockdown or overexpression of the SLC26A3 gene in IPEC-J2 cells significantly affected the expression of MUC2, MUC13 and occludin. Furthermore, in vitro experiments further verified that CDX2 directly regulated the expression of SLC26A3. Mechanistically, CDX2 mediated intestinal barrier function by enhancing the expression of SLC26A3 by binding to its promoter region between -1120 and - 1070 bp. TG pigs represent a promising model that provides new insights into preclinical research on human intestinal metabolic diseases associated with metabolic disorders and revealed that SLC26A3 may be a potential therapeutic target for intestinal metabolic diseases.

A one-stop integrated natural antimicrobial microneedles with anti-inflammatory, pro-angiogenic and long-term moisturizing properties to accelerate diabetic wound healing.

Diabetic ulcers present a formidable obstacle in diabetes management, typically leading to high mortality and amputation rates. To overcome traditional monotherapy drawbacks, We developed a novel microneedle strategy for combined antimicrobial action: ingeniously integrating quercetin with Platelet-derived Growth Factor-BB(PDGF-BB) and Sucrose Octasulfate(SOS) into the microneedle system(QPS MN). This method allows to penetrate through biofilms, administering quercetin nanocrystals and PDGF-BB deep into the tissue to combat microbial infection, mitigate inflammation, and promote angiogenesis. The accompanying backing material contains SOS, which absorbs wound exudate and forms a dressing that provides a moist environment for wound healing In an in vitro wound-scratch assay demonstrated that co-cultivating Human Umbilical Vein Endothelial Cells(HUVEC) with QPS MN for 48 h (90.3 ± 2.51 %) significantly enhanced cell migration compared to the control group (20.2 ± 1.41 %). Moreover, treatment of streptozotocin-induced diabetic wounds in rats with QPS MN for 14 days resulted in a wound healing rate of 96.56 ± 3.44 %, far surpassing the healing rate of only 40.34 ± 7.26 % observed in the untreated control group. Furthermore, the QPS MN treated wounds exhibited a notable increase in skin appendages and neovascularisation, indicating promising potential for achieving complete wound healing. These results suggest that QPS MN may offer substantial therapeutic benefits for addressing diabetic wounds.

Exploring blood transcriptomic signatures in patients with herpes zoster and postherpetic neuralgia.

Postherpetic neuralgia (PHN) is a common, severe, and hard-to-treat chronic pain condition in clinics. Although PHN is developed from herpes zoster (HZ), the developing mechanism is unknown. A previous study investigated blood metabolomic and proteomic profiling in patients with PHN and HZ. The current study aims to explore the blood transcriptomic signature of PHN compared to HZ patients. Whole blood from eight PHN and 15 HZ patients was used for RNA-Seq analysis. There were 82 and 1,788 genes detected specifically in the PHN and HZ groups, respectively. PHN-specific genes are involved in viral infection, lipid and carbohydrate metabolism, and immune response. For genes coexpressed in PHN and HZ patients, there were 407 differential expression genes (DEGs), including 205 upregulated (UP DEGs) and 202 downregulated (DOWN DEGs) in PHN compared to HZ groups. DEGs are involved in viral infection, type I interferon (IFN), and hemoglobin and oxygen carrier activity. UP DEGs are associated with regulatory T cells (Tregs), activated NK cells, and neutrophils, while DOWN DEGs are associated with Tregs, resting NK cells, and monocytes. The results suggest that the metabolism of lipid, glycan, and nucleotides, type I IFN signaling, and altered neutrophil activation are associated with and might contribute to the development of PHN in HZ. It is also suggested that persistent or altered activation of nonspecific immunity may contribute to the development of PHN from HZ.

Fe-Catalyzed Fluorosulfonylation of Alkenes via Sulfur Dioxide Insertion: Synthesis of Lactam-Functionalized Alkyl Sulfonyl Fluorides.

A novel Fe-catalyzed fluorosulfonylation of alkenes with Na2S2O4 and N-fluorobenzenesulfonimide (NFSI) for assembling various lactam-functionalized alkyl sulfonyl fluorides is disclosed. In this reaction, Na2S2O4 acts as both an SO2 source and a reductant. Furthermore, the resulting products can be efficiently transformed into valuable chemicals, including sulfonyl esters and sulfonamides, via the sulfur(VI) fluoride exchange (SuFEx) click reaction. Preliminary mechanistic studies suggest that the transformation proceeds through intramolecular radical cyclization, SO2 insertion, sulfite anion formation, and fluorination.

Peripheral blood eosinophils: an important reference for radiologists to distinguish between pulmonary paragonimiasis and tuberculous pleurisy in children.

OBJECTIVE: In this study, we examined the value of chest CT signs combined with peripheral blood eosinophil percentage in differentiating between pulmonary paragonimiasis and tuberculous pleurisy in children. METHODS: Patients with pulmonary paragonimiasis and tuberculous pleurisy were retrospectively enrolled from January 2019 to April 2023 at the Kunming Third People's Hospital and Lincang People's Hospital. There were 69 patients with pulmonary paragonimiasis (paragonimiasis group) and 89 patients with tuberculous pleurisy (tuberculosis group). Clinical symptoms, chest CT imaging findings, and laboratory test results were analyzed. Using binary logistic regression, an imaging model of CT signs and a combined model of CT signs and eosinophils were developed to calculate and compare the differential diagnostic performance of the two models. RESULTS: CT signs were used to establish the imaging model, and the receiver operating characteristic (ROC) curve was plotted. The area under the curve (AUC) was 0.856 (95% CI: 0.799-0.913), the sensitivity was 66.7%, and the specificity was 88.9%. The combined model was established using the CT signs and eosinophil percentage, and the ROC was plotted. The AUC curve was 0.950 (95% CI: 0.919-0.980), the sensitivity was 89.9%, and the specificity was 90.1%. The differential diagnostic efficiency of the combined model was higher than that of the imaging model, and the difference in AUC was statistically significant. CONCLUSION: The combined model has a higher differential diagnosis efficiency than the imaging model in the differentiation of pulmonary paragonimiasis and tuberculous pleurisy in children. The presence of a tunnel sign on chest CT, the absence of pulmonary nodules, and an elevated percentage of peripheral blood eosinophils are indicative of pulmonary paragonimiasis in children.

Single-nucleus transcriptomics reveal cardiac cell type-specific diversification in metabolic disease transgenic pigs.

Cardiac damage is widely present in patients with metabolic diseases, but the exact pathophysiological mechanisms involved remain unclear. The porcine heart is an ideal material for cardiovascular research due to its similarities to the human heart. This study evaluated pathological features and performed single-nucleus RNA sequencing (snRNA-seq) on myocardial samples from both wild-type and metabolic disease-susceptible transgenic pigs (previously established). We found that transgenic pigs exhibited lipid metabolism disturbances and myocardial injury after a high-fat high-sucrose diet intervention. snRNA-seq reveals the cellular landscape of healthy and metabolically disturbed pig hearts and identifies the major cardiac cell populations affected by metabolic diseases. Within metabolic disorder hearts, metabolically active cardiomyocytes exhibited impaired function and reduced abundance. Moreover, massive numbers of reparative LYVE1+ macrophages were lost. Additionally, proinflammatory endothelial cells were activated with high expression of multiple proinflammatory cytokines. Our findings provide insights into the cellular mechanisms of metabolic disease-induced myocardial injury.

Non-professional efferocytosis of Salmonella-infected intestinal epithelial cells in the neonatal host.

The intestinal epithelium is the first line of defense against enteric pathogens. Removal of infected cells by exfoliation prevents mucosal translocation and systemic infection in the adult host, but is less commonly observed in the neonatal intestine. Instead, here, we describe non-professional efferocytosis of Salmonella-infected enterocytes by neighboring epithelial cells in the neonatal intestine. Intestinal epithelial stem cell organoid cocultures of neonatal and adult cell monolayers with damaged enterocytes replicated this observation, confirmed the age-dependent ability of intestinal epithelial cells for efferocytosis, and identified the involvement of the "eat-me" signals and adaptors phosphatidylserine and C1q as well as the "eat-me" receptors integrin-αv (CD51) and CD36 in cellular uptake. Consistent with this, massive epithelial cell membrane protrusions and CD36 accumulation at the contact site with apoptotic cells were observed in the infected neonatal host in vivo. Efferocytosis of infected small intestinal enterocytes by neighboring epithelial cells may represent a previously unrecognized mechanism of neonatal antimicrobial host defense to maintain barrier integrity.

Glucose restriction enhances oxidative fiber formation: A multi-omic signal network involving AMPK and CaMK2.

Skeletal muscle is a highly plastic organ that adapts to different metabolic states or functional demands. This study explored the impact of permanent glucose restriction (GR) on skeletal muscle composition and metabolism. Using Glut4m mice with defective glucose transporter 4, we conducted multi-omics analyses at different ages and after low-intensity treadmill training. The oxidative fibers were significantly increased in Glut4m muscles. Mechanistically, GR activated AMPK pathway, promoting mitochondrial function and beneficial myokine expression, and facilitated slow fiber formation via CaMK2 pathway. Phosphorylation-activated Perm1 may synergize AMPK and CaMK2 signaling. Besides, MAPK and CDK kinases were also implicated in skeletal muscle protein phosphorylation during GR response. This study provides a comprehensive signaling network demonstrating how GR influences muscle fiber types and metabolic patterns. These insights offer valuable data for understanding oxidative fiber formation mechanisms and identifying clinical targets for metabolic diseases.

Device-independent quantum randomness-enhanced zero-knowledge proof.

Zero-knowledge proof (ZKP) is a fundamental cryptographic primitive that allows a prover to convince a verifier of the validity of a statement without leaking any further information. As an efficient variant of ZKP, noninteractive zero-knowledge proof (NIZKP) adopting the Fiat-Shamir heuristic is essential to a wide spectrum of applications, such as federated learning, blockchain, and social networks. However, the heuristic is typically built upon the random oracle model that makes ideal assumptions about hash functions, which does not hold in reality and thus undermines the security of the protocol. Here, we present a quantum solution to the problem. Instead of resorting to a random oracle model, we implement a quantum randomness service. This service generates random numbers certified by the loophole-free Bell test and delivers them with postquantum cryptography (PQC) authentication. By employing this service, we conceive and implement NIZKP of the three-coloring problem. By bridging together three prominent research themes, quantum nonlocality, PQC, and ZKP, we anticipate this work to inspire more innovative applications that combine quantum information science and the cryptography field.

A Leaf-Patchable Reflectance Meter for In Situ Continuous Monitoring of Chlorophyll Content.

Plant wearable sensors facilitate the real-time monitoring of plant physiological status. In situ monitoring of the plant chlorophyll content over days can provide valuable information on the photosynthetic capacity, nitrogen content, and general plant health. However, it cannot be achieved by current chlorophyll measuring methods. Here, a miniaturized and plant-wearable chlorophyll meter for rapid, non-destructive, in situ, and long-term chlorophyll monitoring is developed. The reflectance-based chlorophyll sensor with 1.5 mm thickness and 0.2 g weight (1000 times lighter than the commercial chlorophyll meter), includes a light emitting diode (LED) and two symmetric photodetectors (PDs) on a flexible substrate, and is patched onto the leaf upper epidermis with a conformal light guiding layer. A chlorophyll content index (CCI) calculated based on the sensor shows a better linear relationship with the leaf chlorophyll content (r2 > 0.9) than the traditional chlorophyll meter. This meter can wirelessly communicate with a smartphone to monitor the leaf chlorophyll change under various stresses and indicate the unhealthy status of plants for long-term application of plants under various stresses earlier than chlorophyll meter and naked-eye observation. This wearable chlorophyll sensing patch is promising in smart and precision agriculture.

Pd-Catalyzed Multicomponent Cross-Coupling of Allyl Esters with Alkyl Bromides and Potassium Metabisulfite: Access to Allylic Sulfones.

A Pd-catalyzed multicomponent cross-coupling of allyl esters with alkyl bromides to synthesize allylic sulfones by using K2S2O5 as a connector is first reported. The reaction displays a broad range of substrate generality along with excellent functional group compatibility and produces the products with high regioselectivity (only E). Furthermore, the biologically active molecules with a late-stage modification, including aspirin, menthol, borneol, and estrone, are also highly compatible with the multicomponent cross-coupling reaction. Mechanistic studies indicate that the process of SO2 insertion into the C-Pd bond was involved in this transformation.

SnRNA-Seq of Pancreas Revealed the Dysfunction of Endocrine and Exocrine Cells in Transgenic Pigs with Prediabetes.

Diabetes poses a significant threat to human health. Exocrine pancreatic dysfunction is related to diabetes, but the exact mechanism is not fully understood. This study aimed to describe the pathological phenotype and pathological mechanisms of the pancreas of transgenic pigs (PIGinH11) that was constructed in our laboratory and to compare it with humans. We established diabetes-susceptible transgenic pigs and subjected them to high-fat and high-sucrose dietary interventions. The damage to the pancreatic endocrine and exocrine was evaluated using histopathology and the involved molecular mechanisms were analyzed using single-nucleus RNA-sequencing (SnRNA-seq). Compared to wild-type (WT) pigs, PIGinH11 pigs showed similar pathological manifestations to type 2 diabetes patients, such as insulin deficiency, fatty deposition, inflammatory infiltration, fibrosis tissue necrosis, double positive cells, endoplasmic reticulum (ER) and mitochondria damage. SnRNA-seq analysis revealed 16 clusters and cell-type-specific gene expression characterization in the pig pancreas. Notably, clusters of Ainar-M and Endocrine-U were observed at the intermediate state between the exocrine and endocrine pancreas. Beta cells of the PIGinH11 group demonstrated the dysfunction with insulin produced and secret decreased and ER stress. Moreover, like clinic patients, acinar cells expressed fewer digestive enzymes and showed organelle damage. We hypothesize that TXNIP that is upregulated by high glucose might play an important role in the dysfunction of endocrine to exocrine cells in PIGinH11 pigs.

Multicomponent Sulfonylation of Alkenes to Access ß-Substituted Arylsulfones.

A novel multicomponent sulfonylation of alkenes is described for the assembly of various ß-substituted arylsulfones using cheap and easily available K2S2O5 as a sulfur dioxide source. Of note, the procedure does not need any extra oxidants and metal catalysts and exhibits a relatively wide substrate scope and good functional group compatibility. Mechanistically, an initial arylsulfonyl radical is formed involving the insertion of sulfur dioxide with aryl diazonium salt, followed by alkoxyarylsulfonylation or hydroxysulfonylation of alkenes.

Target Netgrams: An Annulus-Constrained Stress Model for Radial Graph Visualization.

We present Target Netgrams as a visualization technique for radial layouts of graphs. Inspired by manually created target sociograms, we propose an annulus-constrained stress model that aims to position nodes onto the annuli between adjacent circles for indicating their radial hierarchy, while maintaining the network structure (clusters and neighborhoods) and improving readability as much as possible. This is achieved by having more space on the annuli than traditional layout techniques. By adapting stress majorization to this model, the layout is computed as a constrained least square optimization problem. Additional constraints (e.g., parent-child preservation, attribute-based clusters and structure-aware radii) are provided for exploring nodes, edges, and levels of interest. We demonstrate the effectiveness of our method through a comprehensive evaluation, a user study, and a case study.

Decreased Hyocholic Acid and Lysophosphatidylcholine Induce Elevated Blood Glucose in a Transgenic Porcine Model of Metabolic Disease.

(1) Background: This work aims to investigate the metabolomic changes in PIGinH11 pigs and investigate differential compounds as potential therapeutic targets for metabolic diseases. (2) Methods: PIGinH11 pigs were established with a CRISPR/Cas9 system. PNPLA3I148M, hIAPP, and GIPRdn were knocked in the H11 locus of the pig genome. The differential metabolites between and within groups were compared at baseline and two months after high-fat-high-sucrose diet induction. (3) Results: 72.02% of the 815 detected metabolites were affected by the transgenic effect. Significantly increased metabolites included isoleucine, tyrosine, methionine, oxoglutaric acid, acylcarnitine, glucose, sphinganines, ceramides, and phosphatidylserines, while fatty acids and conjugates, phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins were decreased. Lower expression of GPAT3 and higher expression of PNPLA3I148M decreased the synthesis of diacylglycerol and phosphatidylcholines. Accumulated ceramides that block Akt signaling and decrease hyocholic acid and lysophosphatidylcholines might be the main reason for increased blood glucose in PIGinH11 pigs, which was consistent with metabolomic changes in patients. (4) Conclusions: Through serum metabolomics and lipidomics studies, significant changes in obesity and diabetes-related biomarkers were detected in PIGinH11 pigs. Excessive fatty acids ß-oxidation interfered with glucose and amino acids catabolism and reduced phosphatidylcholines. Decreased hyocholic acid, lysophosphatidylcholine, and increased ceramides exacerbated insulin resistance and elevated blood glucose. Phosphatidylserines were also increased, which might promote chronic inflammation by activating macrophages.

Copper(I)-Catalyzed Cross-Coupling of Arylsulfonyl Radicals with Diazo Compounds: Assembly of Arylsulfones.

A novel copper-catalyzed cross-coupling of arylsulfonyl radicals with diazo compounds is described for the synthesis of various arylsulfones under mild conditions. In this reaction, the cheap, environmentally friendly, and readily available inorganic K2S2O5 is employed as the sulfur dioxide source for providing arylsulfonyl radicals. In addition, a radical mechanism involving the insertion of sulfur dioxide with aryl radicals followed by the coupling of arylsulfonyl radicals with copper carbenes is proposed.

Radical-Mediated Cascade Spirocyclization of N-Benzylacrylamides with Polyhaloalkanes: Access to Polyhalo-Substituted Azaspirocyclohexadienones.

A novel and mild metal-free catalyzed radical-mediated cascade spirocyclization of N-benzylacrylamides with polyhaloalkanes is proposed for the preparation of polyhalo-substituted azaspirocyclohexadienones. Notably, polyhaloalkanes are employed as efficient alkyl radical sources via the cleavage of C(sp3)-H bonds. This protocol undergoes a cascade radical addition and intramolecular cyclization/dearomatization process, and enables the easy construction of multiple chemical bonds and a spiro ring in a single reaction.

Stabilization but No Functional Influence of HIF-1α Expression in the Intestinal Epithelium during Salmonella Typhimurium Infection.

Hypoxia-inducible transcription factor 1 (HIF-1) has been shown to enhance microbial killing and ameliorate the course of bacterial infections. While the impact of HIF-1 on inflammatory diseases of the gut has been studied intensively, its function in bacterial infections of the gastrointestinal tract remains largely elusive. With the help of a publicly available gene expression data set, we inferred significant activation of HIF-1 after oral infection of mice with Salmonella enterica serovar Typhimurium. Immunohistochemistry and Western blot analyses confirmed marked HIF-1α protein stabilization, especially in the intestinal epithelium. This prompted us to analyze conditional Hif1a-deficient mice to examine cell type-specific functions of HIF-1 in this model. Our results demonstrate enhanced noncanonical induction of HIF-1 activity upon Salmonella infection in the intestinal epithelium as well as in macrophages. Surprisingly, Hif1a deletion in intestinal epithelial cells did not impact inflammatory gene expression, bacterial spread, or disease outcomes. In contrast, Hif1a deletion in myeloid cells enhanced intestinal Cxcl2 expression and reduced the cecal Salmonella load. In vitro, HIF-1α-deficient macrophages showed overall impaired transcription of mRNA encoding proinflammatory factors; however, the intracellular survival of Salmonella was not impacted by HIF-1α deficiency.

All optical metropolitan quantum key distribution network with post-quantum cryptography authentication.

Quantum key distribution (QKD) provides information theoretically secure key exchange requiring authentication of the classic data processing channel via pre-sharing of symmetric private keys to kick-start the process. In previous studies, the lattice-based post-quantum digital signature algorithm Aigis-Sig, combined with public-key infrastructure (PKI), was used to achieve high-efficiency quantum security authentication of QKD, and we have demonstrated its advantages in simplifying the MAN network structure and new user entry. This experiment further integrates the PQC algorithm into the commercial QKD system, the Jinan field metropolitan QKD network comprised of 14 user nodes and 5 optical switching nodes, and verifies the feasibility, effectiveness and stability of the post-quantum cryptography (PQC) algorithm and advantages of replacing trusted relays with optical switching brought by PQC authentication large-scale metropolitan area QKD network. QKD with PQC authentication has potential in quantum-secure communications, specifically in metropolitan QKD networks.