Integrated single-cell and bulk RNA sequencing revealed an epigenetic signature predicts prognosis and tumor microenvironment colorectal cancer heterogeneity.

BACKGROUND: Colorectal cancer (CRC) prognosis prediction is currently a major challenge. Epigenetic regulation has been widely reported for its role in cancer development. AIM: To construct a robust prognostic signature, we used developed and validated across datasets. METHODS: After constructing the signature, the prognostic value of the signature was evaluated in the TCGA cohort and six independent datasets (GSE17526, GSE17537, GSE33113, GSE37892, GSE39048 and GSE39582). The clinical, genomic and transcriptomic features related to the signature were identified. The correlations of the signature score with immune cell infiltration and cell-cell interactions were analyzed. The correlations between the signature score and the sensitivity to different drugs were also predicted. RESULTS: In the TCGA cohort, patients in the low-risk group according to the signature score had longer survival than those in the high-risk group, and this finding was validated in the validation datasets. The signature was a prognostic factor independent of age and sex and was correlated with stage and PD-1/PD-L1 expression. Area under the receiving operating characteristic curve was 0.72. Genomic association analyses revealed that samples from high-risk patients exhibited chromosomal instability. Transcriptomic analyses revealed that the signature score was significantly associated with multiple cellular pathways. Bulk RNA-seq and single-cell sequencing data revealed that the signature reflected differences in infiltrating immune cell-tumor cell interactions, especially for macrophages. The signature also predicted the putative drug sensitivity of CRC samples. CONCLUSION: The signature is a valuable biomarker for predicting CRC prognosis and reflects multiple features of CRC, especially macrophage infiltration in the microenvironment.

Coupled Effects of High Temperature and Steel Fiber Content on Energy Absorption Properties of Concrete.

The associated effects of temperature and steel fiber content on the energy absorption properties of concrete were examined using quasi-static uniaxial compression tests of concrete materials with varied steel fiber contents (0%, 0.5%, 1%, and 1.5%) at various temperatures (20 °C, 200 °C, 400 °C, and 520 °C). The experimental findings demonstrate that steel fibers can greatly boost concrete's ability to absorb energy and that the toughness index rises with steel fiber concentration. The energy absorption capacity of concrete under high-temperature conditions also significantly decreases as temperature rises, and the energy absorption ability of steel fiber concrete under the same temperature is superior to that of plain concrete. The coupled influence factor K of temperature-steel fiber percentage characterizing the energy-absorbing ability of concrete was determined, and the coupled influence law of temperature and steel fiber content on the energy-absorbing capacity of concrete materials was summarized and analyzed on the basis of the experimental data of high-temperature compression. Equivalent equations for steel fiber reinforcing and temperature weakening effects when they are comparable (K = 1) are developed and equivalent parameters for concrete materials are given.

Ponytail Left Anterior Descending Artery: A Case Report.

Division of the anterior descending branch into many small arteries is a rare coronary anomaly. We report the case of a 64-year-old female with severe stenosis (>75%) in the proximal region of the anterior descending branch as indicated by coronary computed tomography angiography (CCTA). In addition, coronary angiography showed that the anterior descending branch of the coronary artery split into numerous small arteries, an anomaly that can confound clinical examination.

Clinical Course, Therapy, and Long-Term Outcomes of Children With Moyamoya Disease and Posterior Cerebral Artery Involvement.

BACKGROUND AND OBJECTIVES: Posterior cerebral artery involvement (PCAi) has been identified as an important factor related to poor prognosis in moyamoya disease (MMD). This study summarized the characteristics of children with MMD and PCAi, clarified the clinical course, identified prognostic predictors, and investigated the long-term effect of encephaloduroarteriosynangiosis for posterior circulation (EDAS-p). METHODS: We retrospectively reviewed all our pediatric MMD cases with follow-up angiograms from November 2003 to December 2016. PCAi was classified as early-onset at initial diagnosis and delayed-onset after anterior circulation revascularization. Multivariable data including clinical features, radiographic findings, and surgical outcomes were analyzed. RESULTS: Among 570 children with MMD, 246 (43.2%) had PCAi, with 176 (30.9%) classified as early-onset PCAi. During a median follow-up period of 10 years, 17.8% (70/394) of patients without initial PCAi developed delayed-onset PCAi. The median time to detection of a new PCA lesion was 15.5 (range 7-110) months from initial diagnosis, with a median age of 10.5 (3-22). Younger age at onset, familial occurrence, advanced Suzuki stages, and preoperative infarctions were predictors of delayed-onset PCAi. EDAS-p was performed on 294 hemispheres of 195 patients with PCAi. Stroke-free survival was significantly higher in the EDAS-p group than in the non-EDAS-p group (99.0% vs 90.2%; p < 0.001 [Breslow test]; p = 0.001 [log-rank test]; median follow-up: 101 months). DISCUSSION: PCAi is not uncommon in children with MMD, underscoring the need for long-term close clinical monitoring, especially in patients with high-risk factors for PCA progression. EDAS-p may be a safe and effective procedure for preventing subsequent stroke in children with MMD and PCAi.

Effects of CYP3A4 genetic polymorphisms on the pharmacokinetics and efficacy of perampanel in Chinese pediatric patients with epilepsy.

OBJECTIVE: This study was the first to evaluate the effect of CYP3A4 gene polymorphisms on the plasma concentration and effectiveness of perampanel (PER) in Chinese pediatric patients with epilepsy. METHODS: We enrolled 102 patients for this investigation. The steady-state concentration was determined after patients maintained a consistent PER dosing regimen for at least 21 days. Plasma PER concentrations were measured using liquid chromatography-tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final check-up. RESULTS: The CYP3A4×10 GC phenotype exhibited the highest average plasma concentration of PER at 491.1 ±â€¯328.1 ng/mL, in contrast to the CC phenotype at 334.0 ±â€¯161.1 ng/mL. The incidence of adverse events was most prominent in the CYP3A4×1 G TT and CYP3A4×10 GC groups, with rates of 77.8 % (7 of 9 patients) and 50.0 % (46 of 92 patients), respectively. Moreover, the percentage of patients for whom PER was deemed ineffective was least in the CYP3A4×1 G TT and CYP3A4×10 CC groups, recorded at 11.1 % (1 of 9 patients) and 10.0 % (1 of 10 patients), respectively. There was a significant correlation between PER plasma concentration and either exposure or toxicity (both with p < 0.05). We suggest a plasma concentration range of 625-900 ng/mL as a suitable reference for PER in Chinese patients with epilepsy. CONCLUSION: The CYP3A4×10 gene's genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A4 genetic phenotype should be factored in when prescribing PER to patients with epilepsy.

Alanine aminotransferase as a risk marker for new-onset metabolic dysfunction-associated fatty liver disease.

In this editorial, we comment on the article by Chen et al. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a global public health burden whose incidence has risen concurrently with overweight and obesity. Given its detrimental health impact, early identification of at-risk individuals is crucial. MAFLD diagnosis is based on evidence of hepatic steatosis indicated by liver biopsy, imaging, or blood biomarkers, and one of the following conditions: Overweight/ obesity, type 2 diabetes mellitus, or metabolic dysregulation. However, in large-scale epidemiological studies, liver biopsies are not feasible. The application of techniques such as ultrasonography, computed tomography, magnetic resonance imaging, and magnetic resonance spectroscopy is restricted by their limited sensitivity, low effectiveness, high costs, and need for specialized software. Blood biomarkers offer several advantages, particularly in large-scale epidemiological studies or clinical scenarios where traditional imaging techniques are impractical. Analysis of cumulative effects of excess high-normal blood alanine aminotransferase (ALT) levels of blood ALT levels could facilitate identification of at-risk patients who might not be detected through conventional imaging methods. Accordingly, investigating the utility of blood biomarkers in MAFLD should enhance early detection and monitoring, enabling timely intervention and management and improving patient outcomes.

Rigid-Flexible Coupled Dendritic Molecule Doping: General Approach to Activate Commercial Polymers into Harsh Condition- Tolerant Multi-Reusable Strong Supramolecular Adhesives.

Developing functional adhesives combining strong adhesion, good recyclability and diverse harsh-condition adaptability is a grand challenge. Here, we introduce a general dendritic molecule doping strategy to activate commercial polymers into a new family of supramolecular adhesives integrating high adhesion strength, ultralow temperature, water resistant and multi-reusable properties. Our method involves rational design of a new rigid-flexible coupled dendritic molecule - M4C8OH as a versatile dopant, while simple M4C8OH doping into commercial polymers can modulate internal and external non-covalent interaction to enable H-bonding enhanced interchain cross-linking for tough cohesion along with enhanced interphase interaction. This endows 20 wt% M4C8OH-doped polycaprolactone (PCL) adhesives (PCL-M4C8OH) with improved adhesion strength on various substrates with the maximum increase up to 2.87 times that of PCL. In particular, the adhesion strengths of PCL-M4C8OH on polymethyl methacrylate at 25 °C and -196 °C reach 4.67 and 3.58 MPa - 1.9 and 2.3 times those of PCL and superior to diverse commercial adhesives and most reported adhesives. PCL-M4C8OH also displays markedly-improved multi-usability and tolerance against ultralow temperature and diverse wet environments. Mechanism studies reveal the crucial role of  M4C8OH molecular structures toward superior adhesion. Our method can be expanded to other polymer matrices, yielding diverse new supramolecular adhesives.

NAD+ metabolic enzyme inhibitor as radiosensitizer for malignant meningioma and its modulation of P53 expression.

Surgical resection followed by radiotherapy (RT) is recommended for malignant meningioma but poor outcome is unavoidable. To improve the efficacy of RT in malignant meningioma, a targeted radiosensitizer could be added. Nicotinamide phosphoribosyltransferase (NAMPT), highly expressed in high-grade meningiomas may have a role in determining the radioresponse. Here, we evaluated the impact of NAMPT inhibition on radiosensitivity in malignant meningioma in vivo and in vitro. IOMM-Lee and TTMM705 cells were treated with NAMPT inhibition (FK866 or shRNA NAMPT) before irradiation. The subsequent clonogenic assay demonstrated significantly increased radiosensitivity. Combination treatment with FK866 and irradiation significantly increased the number of G2/M-phase cells, the percentage of apoptotic cells and the γ-H2A.X level compared to FK866 or RT alone. We examined the effect of NAMPT inhibition on NMI and p53 expression in IOMM-Lee and TTMM705 cells. NAMPT inhibition by FK866 and shRNA treatment increased NMI, p53, CDKN1A and BAX expression. Additionally, we assessed the efficacy of FK866/RT combination treatment in vivo. The combination treatment exhibited increased antitumor efficacy compared to either treatment alone. The Ki-67 level was significantly lower and the p53 and γ-H2A.X level was significantly higher in the combination treatment group than in any of the other three groups. In conclusion, these results indicate that FK866 improves radiosensitivity in malignant meningioma, an effect that may be attributed to the increase in p53 expression.

A bibliometric study related to the treatment of myocardial ischemia-reperfusion Injury.

BACKGROUND: Myocardial ischemia-reperfusion injury (MIRI) is defined as the restoration of blood flow to the myocardium after a brief interruption of blood supply, causing more severe damage to the ischemic myocardium. However, currently, reperfusion therapy is the preferred therapy for ischemic cardiomyopathy, which undoubtedly causes MIRI, and thus it has become a challenging issue affecting the prognosis of coronary artery disease. METHODS: A search was conducted in the Web of Science Core Collection database for papers relevant to MIRI therapy published between 1 January 2000 and 1 October 2023. Bibliometric analyses were performed using VOSviewer and CiteSpace to elucidate the progress and hotspots. RESULTS: 3304 papers from 64 countries, 2134 research institutions and 13,228 authors were enrolled in the study. Of these, China contributed the most papers and had the biggest impact, while the United States had the most extensive partnership. The Fourth Military Medical University was the primary research institution. The most valuable authors include Chattipakorn, Nipon, Chattipakorn, Siriporn c, Yang, Jian and Yang, Yang. CONCLUSION: Over the past 20 years, research on MIRI therapies has made significant strides. Further studies are necessary to explore the interactions between various therapeutic options. Future investigations will emphasize nanocarriers, cardiac regeneration, and stem cell therapies. Our study identifies MIRI research hotspots from a bibliometric perspective, forecasts future trends, and offers fresh insights into MIRI therapy research.

A strategy of "adding fuel to the flames" enables a self-accelerating cycle of ferroptosis-cuproptosis for potent antitumor therapy.

Cuproptosis in antitumor therapy faces challenges from copper homeostasis efflux mechanisms and high glutathione (GSH) levels in tumor cells, hindering copper accumulation and treatment efficacy. Herein, we propose a strategy of "adding fuel to the flames" for potent antitumor therapy through a self-accelerating cycle of ferroptosis-cuproptosis. Disulfiram (DSF) loaded hollow mesoporous copper-iron sulfide (HMCIS) nanoparticle with conjugation of polyethylene glycol (PEG) and folic acid (FA) (i.e., DSF@HMCIS-PEG-FA) was developed to swiftly release DSF, H2S, Cu2+, and Fe2+ in the acidic tumor microenvironment (TME). The hydrogen peroxide (H2O2) levels and acidity within tumor cells enhanced by the released H2S induce acceleration of Fenton (Fe2+) and Fenton-like (Cu2+) reactions, enabling the powerful tumor ferroptosis efficacy. The released DSF acts as a role of "fuel", intensifying catalytic effect ("flame") in tumor cells through the sustainable Fenton chemistry (i.e., "add fuel to the flames"). Robust ferroptosis in tumor cells is characterized by serious mitochondrial damage and GSH depletion, leading to excess intracellular copper that triggers cuproptosis. Cuproptosis disrupts mitochondria, compromises iron-sulfur (Fe-S) proteins, and elevates intracellular oxidative stress by releasing free Fe3+. These interconnected processes form a self-accelerating cycle of ferroptosis-cuproptosis with potent antitumor capabilities, as validated in both cancer cells and tumor-bearing mice.

Hollow mesoporous calcium peroxide nanoparticles for drug-free tumor calcicoptosis therapy.

Calcium ions (Ca2+) participate in the regulation of cellular apoptosis as a second messenger. Calcium overload, which refers to the abnormal elevation of intracellular Ca2+ concentration, is a factor that can lead to cell death. Here, based on the unique biological effects of Ca2+, hollow mesoporous calcium peroxide nanoparticles (HMCPN) were developed by a facile hydrolysis-precipitation method for drug-free tumor calcicoptosis therapy. The average pore size of the optimized HMCPN17 is 6.4 nm, and the surface area is 81.3 m2/g, which enables HMCPN17 with high drug loading capability. The Ca2+ release from HMCPN17 is much faster at pH 6.8 than that at pH 7.4, which can be ascribed to the acid-triggered conversion of HMCPN17 to Ca2+ and H2O2, indicating a pH-responsive decomposition behavior of HMCPN17. The high drug loading contents of doxorubicin (DOX) and/or sorafenib (SFN) indicate that HMCPN17 can be employed as a generic drug delivery system (DDS). The in vitro and in vivo results reinforce the high calcicoptosis therapeutic efficacy of tumors by our HMCPN17 without drug loading, which can be attributed to the efficient accumulation in tumors and the ability of H2O2 and Ca2+ production at acidic TME. Our HMCPN17 has broad application prospect for construction of multi-drug-loaded composite nanomaterials with diversified functions for the treatment of tumors. STATEMENT OF SIGNIFICANCE: The combination of hollow mesoporous nanomaterials and calcium peroxide nanoparticles has a wide range of applications in the synergistic treatment of tumors. In this study, hollow mesoporous calcium peroxide nanoparticles (HMCPN) were developed based on a simple hydrolysis-precipitation method for tumor calcicoptosis therapy without drug loading. The high drug loading contents of DOX and/or SFN indicate that our HMCPN can serve as a generic DDS. The experimental results demonstrated the high calcicoptosis therapeutic efficacy of HMCPN on tumors even without drug loading.

CRABP2 promotes cell migration and invasion by activating PI3K/AKT and MAPK signaling pathways via up-regulating LAMB3 in prostate cancer.

Prostate cancer (PCa) has become a worldwide health burden among men. Previous studies have suggested that Cellular Retinoic Acid Binding Protein 2 (CRABP2) significantly affects the regulation of cell proliferation, motility, and apoptosis in multiple cancers, yet the effect of CRABP2 on PCa is poorly reported. The CRABP2 expression in different PCa cell lines and its effect on different cellular functions were various. While CRABP2 promotes cell migration and invasion, it appears to inhibit cell proliferation specifically in PC-3 cells. However, the proliferation of DU145 and 22RV1 cells did not appear to be significantly affected by CRABP2. Besides, CRABP2 had no influence on the cell cycle distribution of PCa cells. RNA-seq assay showed that overexpressing CRABP2 up-regulated Laminin subunit beta-3 (LAMB3) mRNA expression, and the enrichment analyses revealed that the differentially expressed genes were enriched in PI3K/AKT and MAPK signaling pathway. The following WB experiments also confirmed the up-regulated LAMB3 protein level and the activation of PI3K/AKT and MAPK signaling pathways. Moreover, overexpressing CRABP2 inhibited tumor growth significantly in vivo. In conclusion, CRABP2 facilitates cell migration and invasion by activating PI3K/AKT and MAPK signaling pathways through upregulating LAMB3 in PCa.

Liquid-Phase Adsorption Behavior of ß-D-Glucooligosaccharides When Using Activated Carbon for Separation, and the Antioxidant Stress Activity of Purified Fractions.

The adsorption characteristics of ß-glucooligosaccharides on activated carbon and the purification were systematically investigated. The maximum adsorption capacity of activated carbon reached 0.419 g/g in the optimal conditions. The adsorption behavior was described to be monolayer, spontaneous, and exothermic based on several models' fitting results. Five fractions with different degrees of polymerization (DPs) and structures of ß-glucooligosaccharides were obtained by gradient ethanol elution. 10E mainly contained disaccharides with dp2a (G1→6G) and dp2b (G1→3G). 20E possessed trisaccharides with dp3a (G1→6G1→3G) and dp3b (G1→3G1→3G). 30E mainly consisted of dp3a and dp4a (G1→3G1→3(G1→6)G), dp4b (G1→6G1→3G1→3G), and dp4c (G1→3G1→3G1→3G). In addition to tetrasaccharides, 40E and 50E also contained pentasaccharides and hexasaccharides with ß-(1→3)-linked or ß-(1→6)-linked glucose residues. All fractions could inhibit the accumulation of intracellular reactive oxygen species (ROS) in H2O2-induced Caco-2 cells, and they could improve oxidative stress damage by increasing the activity of superoxide dismutase (SOD) and reduced glutathione (GSH), which were related to their DPs and structures. 50E with high DPs showed better anti-oxidative stress activity.

Establishment and validation of a 3-month prediction model for poor functional outcomes in patients with acute cardiogenic cerebral embolism related to non-valvular atrial fibrillation.

Objectives: Cardiogenic cerebral embolism (CCE) poses a significant health risk; however, there is a dearth of published prognostic prediction models addressing this issue. Our objective is to establish prognostic prediction models (PM) for predicting poor functional outcomes at 3 months in patients with acute CCE associated with non-valvular atrial fibrillation (NVAF) and perform both internal and external validations. Methods: We included a total of 730 CCE patients in the development cohort. The external regional validation cohort comprised 118 patients, while the external time-sequential validation cohort included 63 patients. Multiple imputation by chained equations (MICE) was utilized to address missing values and the least absolute shrink and selection operator (LASSO) regression was implemented through the glmnet package, to screen variables. Results: The 3-month prediction model for poor functional outcomes, denoted as N-ABCD2, was established using the following variables: NIHSS score at admission (N), Age (A), Brain natriuretic peptide (BNP), C-reactive protein (CRP), D-dimer polymers (D), and discharge with antithrombotic medication (D). The model's Akaike information criterion (AIC) was 637.98, and the area under Curve (AUC) for the development cohort, external regional, and time-sequential cohorts were 0.878 (95% CI, 0.854-0.902), 0.918 (95% CI, 0.857-0.979), and 0.839 (95% CI, 0.744-0.934), respectively. Conclusion: The N-ABCD2 model can accurately predict poor outcomes at 3 months for CCE patients with NVAF, demonstrating strong prediction abilities. Moreover, the model relies on objective variables that are readily obtainable in clinical practice, enhancing its convenience and applicability in clinical settings.

Understanding the rapid spread of antimicrobial resistance genes mediated by IS26.

Insertion sequences (ISs) promote the transmission of antimicrobial resistance genes (ARGs) across bacterial populations. However, their contributions and dynamics during the transmission of resistance remain unclear. In this study, we selected IS26 as a representative transposable element to decipher the relationship between ISs and ARGs and to investigate their transfer features and transmission trends. We retrieved 2656  translocatable  IS 26 -bounded  units with  ARGs (tIS26-bUs-ARGs) in complete bacterial genomes from the NCBI RefSeq database. In total, 124 ARGs spanning 12 classes of antibiotics were detected, and the average contribution rate of IS26 to these genes was 41.2%. We found that  IS 26 -bounded  units (IS26-bUs) mediated extensive ARG dissemination within the bacteria of the Gammaproteobacteria class, showing strong transfer potential between strains, species, and even phyla. The IS26-bUs expanded in bacterial populations over time, and their temporal expansion trend was significantly correlated with antibiotic usage. This wide dissemination could be due to the nonspecific target site preference of IS26. Finally, we experimentally confirmed that the introduction of a single copy of IS26 could lead to the formation of a composite transposon mediating the transmission of "passenger" genes. These observations extend our knowledge of the IS26 and provide new insights into the mediating role of ISs in the dissemination of antibiotic resistance.

Complete mitochondrial genomes of edible mushrooms: features, evolution, and phylogeny.

Edible mushrooms are an important food source with high nutritional and medicinal value. They are a useful source for studying phylogenetic evolution and species divergence. The exploration of the evolutionary relationships among these species conventionally involves analyzing sequence variations within their complete mitochondrial genomes, which range from 31,854 bp (Cordyceps militaris) to 197,486 bp (Grifolia frondosa). The study of the complete mitochondrial genomes of edible mushrooms has emerged as a critical field of research, providing important insights into fungal genetic makeup, evolution, and phylogenetic relationships. This review explores the mitochondrial genome structures of various edible mushroom species, highlighting their unique features and evolutionary adaptations. By analyzing these genomes, robust phylogenetic frameworks are constructed to elucidate mushrooms lineage relationships. Furthermore, the exploration of different variations of mitochondrial DNA presents novel opportunities for enhancing mushroom cultivation biotechnology and medicinal applications. The mitochondrial genomic features are essential for improving agricultural practices and ensuring food security through improved crop productivity, disease resistance, and nutritional qualities. The current knowledge about the mitochondrial genomes of edible mushrooms is summarized in this review, emphasising their significance in both scientific research and practical applications in bioinformatics and medicine.

Enhancement of ionospheric heating effect by chemical release.

The ionosphere can be artificially modified by employing ground-based high-power high-frequency electromagnetic waves to irradiate the ionosphere. This modification is achieved through the nonlinear interaction between the electromagnetic waves and the ionospheric plasma, leading to changes in the physical properties and structure of the ionosphere. The degree of artificial modification of the ionosphere is closely related to the heating energy density of high-frequency pump waves. Due to the high density of neutral constituents in the lower ionosphere and the high frequency of electron-neutral collisions, the energy of heating pump waves will be absorbed and attenuated during the penetration of the low ionosphere, seriously affecting the heating effect. This paper proposes a method to reduce the absorption of ionospheric heating pump waves by releasing electron attachment chemicals into low ionosphere to form a large-scale electron density hole. A model for mitigating pump waves absorption based on SF6 release is established, and the absorption at different frequencies is quantitatively calculated. The propagation characteristics of high-frequency signals in ionospheric holes are studied using a three-dimensional ray tracing method, and the results demonstrate that the chemical release method not only reduces the absorption attenuation of heating pump waves but also forms spherical electron density holes, which exhibit a focusing effect on the heating beam and enhance the heating effect. The results are of great significance for understanding the nonlinear interaction between electromagnetic wave and ionospheric plasma and improving the ionospheric heating efficiency.

Heterogeneous metabolic changes of brown and white adipose tissues are associated with metabolic adaptations in periparturient mice.

Pregnancy requires metabolic adaptations in order to meet support fetal growth with nutrient availability. In this study, the influence of pregnancy on metabolically active organs (adipose tissues in particular) was investigated. Our results showed that maternal weight and adipose mass presented dynamic remodeling in the periparturient mice. Meanwhile, pregnancy mice displayed obvious glucose intolerance and insulin resistance in late pregnancy as compared to non-pregnancy, which were partially reversed at parturition. Further analyses revealed that different fat depots exhibited site-specific adaptions of morphology and functionality as pregnancy advanced. Brown and inguinal white adipose tissue (BAT and IngWAT) exhibited obviously decreased thermogenic activity; by contrast, gonadal white adipose tissue (GonWAT) displayed remarkably increased lipid mobilization. Notably, we found that mammary gland differentiation was enhanced in IngWAT, followed by BAT but not in GonWAT. These result indicated that brown and white adipose tissues might synergistically play a crucial role in maintaining the maximum of energy supply for mother and fetus, which facilitates the mammary duct luminal epithelium development as well as the growth and development of fetus. Accompanied with adipose adaptation, however, our results revealed that the liver and pancreas also displayed significant metabolic adaptability, which together tended to trigger the risk of maternal metabolic diseases. Importantly, pregnancy-dependent obesity in our mice model resembled the disturbed metabolic phenotypes of pregnant women such as hyperglyceridemia and hypercholesterolemia. Our findings in this study could provide valuable clues for better understanding the underlying mechanisms of metabolic maladaptation and facilitate the development of the prevention and treatment of metabolic diseases.

Silver(I) Complexes with Mefenamic Acid and Nitrogen Heterocyclic Ligands: Synthesis, Characterization, and Biological Evaluation.

Four Ag(I) complexes with mefenamato and nitrogen heterocyclic ligands, [Ag(2-apy)(mef)]2 (1), [Ag(3-apy)(mef)] (2), [Ag2(tmpyz)(mef)2] (3), and {[Ag(4,4'-bipy)(mef)]2(CH3CN)1.5(H2O)2}n (4), (mef = mefenamato, 2-apy = 2-aminopyridine, 3-apy = 3-aminopyridine, tmpyz = 2,3,5,6-tetramethylpyrazine, 4,4'-bipy = 4,4'-bipyridine), were synthesized and characterized. The interactions of these complexes with BSA were investigated by fluorescence spectroscopy, which indicated that these complexes quench the fluorescence of BSA by a static mechanism. The fluorescence data also indicated that the complexes showed good affinity for BSA, and one binding site on BSA was suitable for the complexes. The in vitro cytotoxicity of the four complexes against human cancer cell lines (MCF-7, HepG-2, A549, and MDA-MB-468) and one normal cell line (HTR-8) was evaluated by the MTT assay. Complex 1 displayed high cytotoxic activity against A549 cells. Further studies revealed that complex 1 could enhance the intracellular levels of ROS (reactive oxygen species) in A549 cells, cause cell cycle arrest in the G0/G1 phase, and induce apoptosis in A549 cells in a dose-dependent manner.

Photothermal Particle-Loaded Panax Notoginseng Polysaccharide Cryogels As Personalized Tumor Vaccines.

Combination immunotherapy is being increasingly explored for cancer treatment, leading to various vector materials for the codelivery of immune agents and drugs. However, current tumor vaccines exhibit poor immunogenicity, severely compromising their therapeutic efficacy. Herein, an injectable hydrogel was developed based on dopamine (DA) and Panax notoginseng polysaccharide (PNPS) loaded with hair microparticles (HMPs) to enhance the immunogenicity of tumor vaccines. Photothermal effects of incorporated HMPs can trigger immunogenic cancer cell death and the release of abundant autologous tumor antigens, which are captured by catechol groups. Concomitant breakdown of PNPS recruits and activates dendritic cells (DCs). The macroporous structure of cryogels allows immune cell infiltration and interaction with antigens adsorbed on PNPS and DA cryogels (PD cryogels), thereby provoking potent cytotoxic T-cell responses. Hence, PD cryogels enabling cell infiltration and accelerated DC maturation may serve as a therapeutic vaccination platform against cancer.