PF-PEG@ASIV-EXO Hydrogel Accelerates Diabetic Wound Healing by Ferroptosis Resistance and Promoting Angiogenesis.

Astragaloside IV (ASIV) promotes the proliferation of key cells, endothelial progenitor cells (EPCs), during the wound healing process, while exosomes and hydrogels are ideal drug delivery carriers. This study aims to explore the mechanism of action of the "ROS-responsive hydrogel-engineered EPCs-targeted exosomes" composite ASIV delivery system (PF-PEG@ASIV-EXO) in diabetic wound healing. Surface markers of EPCs and PF-PEG@ASIV-EXO were detected separately. The degradation rate of PF-PEG@ASIV-EXO was assessed after coculturing with human dermal fibroblasts (HDF), immortalized human epidermal cells (HaCAT), and human EPCs, and the biocompatibility of EPCs and PF-PEG@ASIV-EXO was evaluated through exosome release and uptake. The effects of PF-PEG@ASIV-EXO on the viability, angiogenesis, ferroptosis, and mitochondria of high-glucose-treated EPCs (HS-EPCs) were investigated. A diabetic wound rat model was established, and the effects of PF-PEG@ASIV-EXO on diabetic wounds were evaluated through HE and Masson staining, as well as levels of VWF, CD31, and ferroptosis in the skin. EPCs were successfully isolated, and PF-PEG@ASIV-EXO was successfully constructed. PF-PEG@ASIV-EXO exhibited a high degradation rate within EPCs, and both EPCs and PF-PEG@ASIV-EXO showed good biocompatibility. PF-PEG@ASIV-EXO promoted the vitality and angiogenesis of EPCs, inhibited ferroptosis, and mitigated mitochondrial damage. Following treatment with PF-PEG@ASIV-EXO, the healing of diabetic rat skin accelerated, accompanied by elevated expression of VWF and CD31, and reduced ferroptosis levels. PF-PEG@ASIV-EXO hydrogel inhibits ferroptosis, promotes angiogenesis, and thereby accelerates the healing of diabetic wounds.

Synthesis of nicotinimidamides via a tandem CuAAC/ring-cleavage /cyclization/oxidation four-component reaction and their cytotoxicity.

Nicotinamide and its derivatives, recognized as crucial drug intermediates, have been a focal point of extensive chemical modifications and rigorous pharmacological studies. Herein, a series of novel nicotinamide derivatives, nicotinimidamides, were synthesized via a tandem CuAAC/ring-cleavage/cyclization/oxidation four-component reaction procedure from O-acetyl oximes, terminal ynones, sulfonyl azides, and NH4OAc. This strategy is significantly more efficient than previously reported, and the cytotoxicity of the nicotinimidamides is also tested. This project not only exhibits a sustainable and eco-friendly domino methodology for the creation of nicotinimidamides but also presents a promising candidate for liver cancer treatment.

Preoperative prediction model of lymph node metastasis in the inguinal and femoral region based on radiomics and artificial intelligence.

OBJECTIVE: To predict preoperative inguinal lymph node metastasis in vulvar cancer patients using a machine learning model based on imaging features and clinical data from pelvic magnetic resonance imaging (MRI). METHODS: 52 vulvar cancer patients were divided into a training set (n=37) and validation set (n=15). Clinical data and MRI images were collected, and regions of interest were delineated by experienced radiologists. A total of 1688 quantitative imaging features were extracted using the Radcloud platform. Dimensionality reduction and feature selection were applied, resulting in a radiomics signature. Clinical characteristics were screened, and a combined model integrating the radiomics signature and significant clinical features was constructed using logistic regression. Four machine learning classifiers (K nearest neighbor, random forest, adaptive boosting, and latent dirichlet allocation) were trained and validated. Model performance was evaluated using the receiver operating characteristic curve and the area under the curve (AUC), as well as decision curve analysis. RESULTS: The radiomics score significantly differentiated between lymph node metastasis positive and negative patients in both the training and validation sets. The combined model demonstrated excellent discrimination, with AUC values of 0.941 and 0.933 in the training and validation sets, respectively. The calibration curve and decision curve analysis confirmed the model's high predictive accuracy and clinical utility. Among the machine learning classifiers, latent dirichlet allocation and random forest models achieved AUC values >0.7 in the validation set. Integrating all four classifiers resulted in a total model with an AUC of 0.717 in the validation set. CONCLUSION: Radiomics combined with artificial intelligence can provide a new method for prediction of inguinal lymph node metastasis of vulvar cancer before surgery.

Effects of gossypol acetate on growth, serum biochemical parameters, and intestinal health of goslings.

Free gossypol (FG), the primary antinutritional component in cottonseed meal, can adversely affect the growth and health of poultry. Although younger geese are particularly sensitive to FG, the precise effects of FG on geese remain elusive. This study aimed to investigate the effects of gossypol acetate (GA), a form of FG, on the growth, serum biochemical parameters, and intestinal health of goslings. Seventy-two healthy male goslings, aged 7-day-old with similar body weight (BW), were randomly divided into 3 groups: a control group and 2 GA-treated groups (GA25 and GA50), which were orally administered GA (25 and 50 mg/kg BW) daily for 14 d. The results showed that oral administration of GA significantly suppressed BW, altered serum parameters, and impaired intestinal health in a dose- and time-dependent manner. Specifically, GA adversely affected intestinal morphology, induced oxidative stress, and inflammation, diminished immune function, and increased intestinal permeability and apoptosis of intestinal cells, consequently impairing nutrient absorption and utilization of goslings. Overall, these data indicate that GA adversely affects the growth, serum parameters, and intestinal health of goslings, providing valuable information further to understand the toxic effects of gossypol on goslings.

Synthesis of Pyridin-2(1H)-imines via the Transformation of Conjugated Ynones.

Conjugated ynones represent an important class of reactive species, useful synthetic intermediates, and synthons. However, the reactivity and synthetic applications of ynones are usually focused on the transformation of mono- or dual-functional groups. Herein, we developed a straightforward synthesis of pyridin-2(1H)-imines from the transformation of conjugated ynones. This cascade process probably began with a Michael addition of ynones and 2-aminopyridines, further underwent an intramolecular cyclization to generate the N,O-bidentate intermediates, and finally reacted with sulfonyl azides giving the pyridin-2(1H)-imines with accompanying loss of diazo.

Global distribution of zoonotic digenetic trematodes: a scoping review.

BACKGROUND: Digenetic trematodes, including blood flukes, intestinal flukes, liver flukes, lung flukes, and pancreatic flukes, are highly diverse and distributed widely. They affect at least 200 million people worldwide, so better understanding of their global distribution and prevalence are crucial for controlling and preventing human trematodiosis. Hence, this scoping review aims to conduct a comprehensive investigation on the spatio-temporal distribution and epidemiology of some important zoonotic digenetic trematodes. METHODS: We conducted a scoping review by searching PubMed, Web of Science, Google Scholar, China National Knowledge Infrastructure, and Wanfang databases for articles, reviews, and case reports of zoonotic digenetic trematodes, without any restrictions on the year of publication. We followed the inclusion and exclusion criteria to identify relevant studies. And relevant information of the identified studies were collected and summarized. RESULTS: We identified a total of 470 articles that met the inclusion criteria and were included in the review finally. Our analysis revealed the prevalence and global distribution of species in Schistosoma, Echinostoma, Isthmiophora, Echinochasmus, Paragonimus, Opisthorchiidae, Fasciolidae, Heterophyidae, and Eurytrema. Although some flukes are distributed worldwide, developing countries in Asia and Africa are still the most prevalent areas. Furthermore, there were some overlaps between the distribution of zoonotic digenetic trematodes from the same genus, and the prevalence of some zoonotic digenetic trematodes was not entirely consistent with their global distribution. The temporal disparities in zoonotic digenetic trematodes may attribute to the environmental changes. The gaps in our knowledge of the epidemiology and control of zoonotic digenetic trematodes indicate the need for large cohort studies in most countries. CONCLUSIONS: This review provides important insights into the prevalence and global distribution of some zoonotic digenetic trematodes, firstly reveals spatio-temporal disparities in these digenetic trematodes. Countries with higher prevalence rate could be potential sources of transmitting diseases to other areas and are threat for possible outbreaks in the future. Therefore, continued global efforts to control and prevent human trematodiosis, and more international collaborations are necessary in the future.

Esterification of black bean anthocyanins with unsaturated oleic acid, and application characteristics of the product.

Esterification of anthocyanins with saturated fatty acids have been widely investigated, while that with unsaturated fatty acids is little understood. In this study, crude extract (purity âˆ¼ 35 %) of cyanidin-3-O-glucoside (C3G) from black bean seed coat was utilized as reaction substrate, and enzymatically acylated with unsaturated fatty acid (oleic acid). Optimization of various reaction parameters finally resulted in the highest acylation rate of 54.3 %. HPLC-MS/MS and NMR analyses elucidated the structure of cyanidin-3-O-glucoside-oleic acid ester (C3G-OA) to be cyanidin-3-O-(6″-octadecene)-glucoside. Introduction of oleic acid into C3G improved the lipophilicity, antioxidant ability, and antibacterial activity. Further, the color and substance stability analyses showed that the susceptibility of C3G and C3G-OA to different thermal, peroxidative, and illuminant treatments were highly pH dependent, which suggested individual application guidelines. Moreover, C3G-OA showed lower toxicity to normal cell (QSG-7701) and better inhibitory effect on the proliferation of HepG2 cells than C3G, which indicated its potential anti-tumor bioactivity.

RNA modification-related genes illuminate prognostic signature and mechanism in esophageal squamous cell carcinoma.

Emerging studies have demonstrated the link between RNA modifications and various cancers, while the predictive value and functional mechanisms of RNA modification-related genes (RMGs) in esophageal squamous cell carcinoma (ESCC) remain unclear. Here we established a prognostic signature for ESCC based on five RMGs. The analysis of ESCC clinical samples further verified the prognostic power of the prognostic signature. Moreover, we found that the knockdown of NSUN6 promotes ESCC progression in vitro and in vivo, whereas the overexpression of NSUN6 inhibits the malignant phenotype of ESCC cells. Mechanically, NSUN6 mediated tRNA m5C modifications selectively enhance the translation efficiency of CDH1 mRNA in a codon dependent manner. Rescue assays revealed that E-cadherin is an essential downstream target that mediates NSUN6's function in the regulation of ESCC progression. These findings offer additional insights into the link between ESCC and RMGs, as well as provide potential strategies for ESCC management and therapy.

Exosomes Derived from Astragaloside IV-pretreated Endothelial Progenitor Cells (AS-IV-Exos) Alleviated Endothelial Oxidative Stress and Dysfunction Via the miR-210/ Nox2/ROS Pathway.

BACKGROUND: Chronic hyperglycemia in diabetes induces oxidative stress, leading to damage to the vascular system. In this study, we aimed to evaluate the effects and mechanisms of AS-IV-Exos in alleviating endothelial oxidative stress and dysfunction caused by high glucose (HG). METHODS: Histopathological changes were observed using HE staining, and CD31 expression was assessed through immunohistochemistry (IHC). Cell proliferation was evaluated through CCK8 and EDU assays. The levels of ROS, SOD, and GSH-Px in the skin tissues of each group were measured using ELISA. Cell adhesion, migration, and tube formation abilities were assessed using adhesion, Transwell, and tube formation experiments. ROS levels in HUVEC cells were measured using flow cytometry. The levels of miR-210 and Nox2 were determined through quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The expression of Nox2, SOD, GSH-Px, CD63, and CD81 was confirmed using WB. RESULTS: The level of miR-210 was reduced in diabetes-induced skin damage, while the levels of Nox2 and ROS increased. Treatment with AS-IV increased the level of miR-210 in EPC-Exos. Compared to Exos, AS-IV-Exos significantly reduced the proliferation rate, adhesion number, migration speed, and tube-forming ability of HGdamaged HUVEC cells. AS-IV-Exos also significantly decreased the levels of SOD and GSH-Px in HG-treated HUVEC cells and reduced the levels of Nox2 and GSH-Px. However, ROS levels and Nox2 could reverse this effect. CONCLUSION: AS-IV-Exos effectively alleviated endothelial oxidative stress and dysfunction induced by HG through the miR-210/Nox2/ROS pathway.

Chemoselectivity of the CuAAC/Ring Cleavage/Cyclization Reaction between Enaminones and α-Acylketenimine.

Ketenimines represent an important class of reactive species, useful synthetic intermediates, and synthons. However, in general, ketenimines preferentially undergoes nucleophilic addition reactions with hydroxyl and amino groups, and carbon functional groups remain a less studied subset of such systems. Herein, we develop a straightforward syntheses of pyridin-4(1H)-imines that is achieved by cyclization of a reacting enaminone unit with α-acylketenimine which is generated from the reactions of sulfonyl azides and terminal ynones in situ (CuAAC/Ring cleavage reaction). The cascade process preferentially starts with the nucleophilic α-C of the enaminone unit instead of an amino group, attacking the electron-deficient central carbon of ketenimine, and the chemoselectivity unconventional products pyridin-4(1H)-imines were formed by intramolecular cyclization.

Remdesivir inhibits Porcine epidemic diarrhea virus infection in vitro.

Porcine Epidemic Diarrhea Virus (PEDV) is a highly contagious and pathogenic virus that causes symptoms such as diarrhea, vomiting, weight loss, and even death in piglets. Due to its high transmission rate, PEDV has resulted in significant global losses. Although some vaccines have been developed and utilized to prevent PEDV, their effectiveness is limited due to the virus's mutations. Therefore, it is imperative to investigate new strategies to combat PEDV. Remdesivir, a classic antiviral drug for coronaviruses, has been proven in our experiment to effectively suppress PEDV replication in Vero and LLC-PK1 cells. Additionally, the cell experiment demonstrated its direct inhibition of PEDV RNA-dependent RNA polymerase (RdRp) enzyme activity. Molecular docking simulations were employed to predict the binding site of remdesivir and PEDV RdRp. Moreover, we observed that remdesivir does not impact the production of inflammatory factors and exhibits antagonistic effects with exogenous nucleosides. Furthermore, we conducted RNA-Seq analysis to investigate the global changes in transcriptome of infected cells treated with remdesivir. Overall, our findings indicate that remdesivir holds promise as a potential candidate for the treatment of PEDV infection.

In situ cyclodextrin metal-organic framework/electrospun composite fibers with biosafety for the removal of volatile organic compounds.

Volatile organic compounds (VOCs) are one of the most common air pollutants, which threaten human health seriously. Fibrous textile is one of the most popular matrices for VOC removal in daily life. In this study, biosafe cyclodextrin metal-organic framework/polycaprolactone (CD-MOF/PCL) electrospun fibers were prepared via a CD precursor doping method, followed by hydrothermal treatment in methanol vapor diffusion. In situ CD-MOF crystals with a high loading of more than 50 wt% densely covered the surface of the electrospun fibers. The CD-MOF/PCL composite fibers show similar stress-strain behavior to the electrospun PCL fibers. The analysis of the fractured zone indicated that the compatibility of CD-MOF/PCL fibers was excellent, and CD-MOF showed no obvious peeling-off, even at low temperatures. The hemolysis rate of less than 1% confirms the biosafety of the composite materials. Further, the CD-MOF crystals anchored onto the fibers promote their VOC uptakes significantly. The CD-MOF/PCL fibrous matrix, which demonstrated compatibility, excellent strength, and biosafety would be beneficial to develop novel equipment to purify air pollution.

Molnupiravir Inhibits Porcine Epidemic Diarrhea Virus Infection In Vitro.

Porcine epidemic diarrhea virus (PEDV) is a swine coronavirus that is highly infectious and prone to variation. Vaccines derived from traditional PEDV strains provide less protection against PEDV-variant strains. Furthermore; there is a complex diversity of sequences among various PEDV-variant strains. Therefore; there is an urgent need to develop alternative antiviral strategies to defend against PEDV. Molnupiravir is a nucleotide analogue that could replace natural nucleosides to restrain viral RNA replication. Our study provided evidence for the dose-dependent inhibition of PEDV replication by molnupiravir in Vero cells. Molnupiravir also exhibited a strong inhibitory effect on viral RNA and protein production. Our results demonstrated that molnupiravir inhibits PEDV RNA-dependent RNA polymerase (RdRp) activity and induces a high frequency of mutations in the PEDV genome. Further studies revealed that molnupiravir can reverse changes in the transcriptome caused by viral infection. In conclusion, our results indicated that molnupiravir has the potential to be an effective treatment for PEDV infection.

Nitrogen metabolism in mycobacteria: the key genes and targeted antimicrobials.

Nitrogen metabolism is an important physiological process that affects the survival and virulence of Mycobacterium tuberculosis. M. tuberculosis's utilization of nitrogen in the environment and its adaptation to the harsh environment of acid and low oxygen in macrophages are closely related to nitrogen metabolism. In addition, the dormancy state and drug resistance of M. tuberculosis are closely related to nitrogen metabolism. Although nitrogen metabolism is so important, limited research was performed on nitrogen metabolism as compared with carbon metabolism. M. tuberculosis can use a variety of inorganic or organic nitrogen sources, including ammonium salts, nitrate, glutamine, asparagine, etc. In these metabolic pathways, some enzymes encoded by key genes, such as GlnA1, AnsP2, etc, play important regulatory roles in the pathogenesis of TB. Although various small molecule inhibitors and drugs have been developed for different nitrogen metabolism processes, however, long-term validation is needed before their practical application. Most importantly, with the emergence of multidrug-resistant strains, eradication, and control of M. tuberculosis will still be very challenging.

State- and stimulus-specific dynamics of SMAD signaling determine fate decisions in individual cells.

SMAD-mediated signaling regulates apoptosis, cell cycle arrest, and epithelial-to-mesenchymal transition to safeguard tissue homeostasis. However, it remains elusive how the relatively simple pathway can determine such a broad range of cell fate decisions and how it differentiates between varying ligands. Here, we systematically investigate how SMAD-mediated responses are modulated by various ligands of the transforming growth factor ß (TGFß) family and compare these ligand responses in quiescent and proliferating MCF10A cells. We find that the nature of the phenotypic response is mainly determined by the proliferation status, with migration and cell cycle arrest being dominant in proliferating cells for all tested TGFß family ligands, whereas cell death is the major outcome in quiescent cells. In both quiescent and proliferating cells, the identity of the ligand modulates the strength of the phenotypic response proportional to the dynamics of induced SMAD nuclear-to-cytoplasmic translocation and, as a consequence, the corresponding gene expression changes. Interestingly, the proliferation state of a cell has little impact on the set of genes induced by SMAD signaling; instead, it modulates the relative cellular sensitivity to TGFß superfamily members. Taken together, diversity of SMAD-mediated responses is mediated by differing cellular states, which determine ligand sensitivity and phenotypic effects, while the pathway itself merely serves as a quantitative relay from the cell membrane to the nucleus.

Bile Acid Derivatives Effectively Prevented High-Fat Diet-Induced Colonic Barrier Dysfunction.

SCOPE: Bile acids (BAs) have recently emerged as important regulators of many physiological and pathological processes. However, the change of colonic BAs induced by high-fat diet (HFD) and their effects on colonic barrier function remain to be further elucidated. METHODS AND RESULTS: C57BL/6 mice are divided into two groups and feed 12 weeks with diets differing for fat content. Higher levels of serum diamine oxidase (DAO) activity, endotoxin (ET), and d-lactate (d-LA) are observed in HFD-fed mice, indicating an increase in intestinal permeability. Real-time quantitative PCR and western blot analyses demonstrate that HFD downregulates tight junction proteins (TJs, including zonula-occludens 1 [ZO-1], Occludin, and Claudin1) and Muc2 expression in the colon. The colonic BA profiles are analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). HFD induces an increase in primary BAs but a decrease in secondary BAs. In human colonic cell line Caco-2, secondary BAs (deoxycholic acid [DCA], lithocholic acid [LCA], their 3-oxo- and iso- derivates) upregulate the expression of TJs and counteract DSS-induced increase in intestinal permeability at physiological concentrations. IsoDCA and isoLCA are the most effective ones. Moreover, supplementation of isoDCA or isoLCA also effectively prevents HFD-induced colonic barrier dysfunction in mice. CONCLUSION: These results demonstrate that secondary BAs (especially isomerized derivatives) may be important protectors for the colonic barrier function.

Passivity and passification of fractional-order memristive neural networks with time delays.

A class of fractional-order memristive neural networks (FMNNs) with time delays is studied. At first, the original network system is converted to fractional-order uncertain one to simplify the analysis by a variable transformation. Successively, some new LMIs-based passivity criteria are derived by differential inclusions, set-valued maps, inequality techniques and linear matrix inequality approach. Furthermore, a feedback control protocol is designed to solve the passification problem for the considered system, whose feedback control effect on different neurons can be changed artificially, which can be better applied to neural networks. The obtained results include some existing ones as special cases. A numerical example is proposed to illustrate the theoretical results.

The value of dual-energy spectral CT in differentiating solitary pulmonary tuberculosis and solitary lung adenocarcinoma.

Background: To explore the value of dual-energy spectral CT in distinguishing solitary pulmonary tuberculosis (SP-TB) from solitary lung adenocarcinoma (S-LUAD). Methods: A total of 246 patients confirmed SP-TB (n = 86) or S-LUAD (n = 160) were retrospectively included. Spectral CT parameters include CT40keV value, CT70keV value, iodine concentration (IC), water concentration (WC), effective atomic number (Zeff), and spectral curve slope (λ70keV). Data were measured during the arterial phase (AP) and venous phase (VP). Chi-square test was used to compare categorical variables, Wilcoxon rank-sum test was used to compare continuous variables, and a two-sample t-test was used to compare spectral CT parameters. ROC curves were used to calculate diagnostic efficiency. Results: There were significant differences in spectral CT quantitative parameters (including CT40keV value [all P< 0.001] , CT70keV value [all P< 0.001], λ70keV [P< 0.001, and P = 0.027], Zeff [P =0.015, and P = 0.001], and IC [P =0.002, and P = 0.028]) between the two groups during the AP and VP. However, WC (P = 0.930, and P = 0.823) was not statistically different between the two groups. The ROC curve analysis showed that the AUC in the AP and VP was 90.9% (95% CI, 0.873-0.945) and 83.4% (95% CI, 0.780-0.887), respectively. The highest diagnostic performance (AUC, 97.6%; 95% CI, 0.961-0.991) was achieved when all spectral CT parameters were combined with clinical variables. Conclusion: Dual-energy spectral CT has a significant value in distinguishing SP-TB from S-LUAD.

Imaging Stars with Quantum Error Correction.

The development of high-resolution, large-baseline optical interferometers would revolutionize astronomical imaging. However, classical techniques are hindered by physical limitations including loss, noise, and the fact that the received light is generally quantum in nature. We show how to overcome these issues using quantum communication techniques. We present a general framework for using quantum error correction codes for protecting and imaging starlight received at distant telescope sites. In our scheme, the quantum state of light is coherently captured into a nonradiative atomic state via stimulated Raman adiabatic passage, which is then imprinted into a quantum error correction code. The code protects the signal during subsequent potentially noisy operations necessary to extract the image parameters. We show that even a small quantum error correction code can offer significant protection against noise. For large codes, we find noise thresholds below which the information can be preserved. Our scheme represents an application for near-term quantum devices that can increase imaging resolution beyond what is feasible using classical techniques.

Optical quantum super-resolution imaging and hypothesis testing.

Estimating the angular separation between two incoherent thermal sources is a challenging task for direct imaging, especially at lengths within the diffraction limit. Moreover, detecting the presence of multiple sources of different brightness is an even more severe challenge. We experimentally demonstrate two tasks for super-resolution imaging based on hypothesis testing and quantum metrology techniques. We can significantly reduce the error probability for detecting a weak secondary source, even for small separations. We reduce the experimental complexity to a simple interferometer: we show (1) our set-up is optimal for the state discrimination task, and (2) if the two sources are equally bright, then this measurement can super-resolve their angular separation. Using a collection baseline of 5.3 mm, we resolve the angular separation of two sources placed 15 µm apart at a distance of 1.0 m with a 1.7% accuracy - an almost 3-orders-of-magnitude improvement over shot-noise limited direct imaging.