The combination of SHP099 inhibits the malignant biological behavior of L-OHP/5-FU-resistant colorectal cancer cells by regulating energy metabolism reprogramming.

BACKGROUND AND OBJECTIVE: Colorectal cancer (CRC) is one of the most common malignancies in China. At present, there is a problem that the CRC treatment drugs SHP099, L-OHP and 5-FU are insensitive to tumor cells. Combination medication is an important means to solve the insensitivity of medication alone. The purpose of this project was to explore the effect and molecular mechanism of SHP099 combination on the malignant biological behavior of L-OHP/5-FU resistant strains of CRC. METHODS: HT29 and SW480 cells were cultured in media supplemented with L-OHP or 5-FU to establish drug-resistant strains. HT29 and SW480 drug-resistant cells were subcutaneously injected into the ventral nerves of nude mice at a dose of 5 × 106 to establish CRC drug-resistant animal models. CCK-8, Western blot, flow cytometry, Transwell and kit detection were used to detect the regulatory mechanism of energy metabolism reprogramming in drug-resistant CRC cells. RESULTS: Compared with nonresistant strains, L-OHP/5-FU-resistant strains exhibited greater metabolic reprogramming. Functionally, SHP099 can restrain the metabolic reprogramming of L-OHP/5-FU-resistant strains and subsequently restrain the proliferation, colony formation, migration and spheroid formation of L-OHP/5-FU-resistant strains. Downstream mechanistic studies have shown that SHP099 interferes with the metabolic reprogramming of L-OHP/5-FU drug-resistant strains by suppressing the PI3K/AKT pathway, thereby restraining the malignant biological behavior of L-OHP/5-FU drug-resistant strains and alleviating CRC. CONCLUSION: The combination of SHP099 can restrain the malignant biological behavior of L-OHP/5-FU-resistant CRC cells and alleviate the progression of CRC by interfering with the reprogramming of energy metabolism. This study explored the effect of SHP099 combination on dual-resistant CRC cells for the first time, and provided a new therapeutic idea for solving the problem of SHP099 insensitivity to CRC cells.

Magnetic-navigable silk fibroin microneedles for oral drug delivery: Ensuring long-lasting helicobacter pylori eradication and rapid hemostasis in the stomach.

The Helicobacter pylori infection in the stomach is the key reason for gastric mucosal bleeding. Eliminating gastric Helicobacter pylori by oral treatment remains difficult due to the presence of the gastric mucosal layer, which acts as a physical barrier to drugs via oral administration. In this study, a magnetic-navigable microneedle drug delivery platform (MNsD) for oral administration, featuring differential dual-mode drug release rate, was designed to fulfil rapid gastric hemostasis and overcome the gastric barriers for long-lasting Helicobacter pylori inhibition in stomach. MNs-D was created by rationally loading the carrier substrate, which was composed of silk fibroin with variable solubility, with antibiotics and hemostats. In vitro experiments showed MNs-D may sustainably eradicate Helicobacter pylori in stimulated gastric juices with long-lasting drug release (79 % in 24 h) and quickly establish hemostasis with instant drug release (92 % within 60 s). Most importantly, in vivo studies demonstrated MNs-D overcame the unsettling gastric mucosal barrier in traditional therapies of oral administration by insertion into the GML under magnetic navigation, resulting in sustained antibiotic release for long-lasting Helicobacter pylori eradiation (99 %). For differential dual-mode medication release against gastric Helicobacter pylori infections, this study may have firstly examined the effects of magnetic navigated microneedles administered orally.

Prevalence, clinical characteristics, and long-term outcomes of new diabetes diagnosis in elderly patients undergoing percutaneous coronary intervention.

Previous studies have reported associations between newly diagnosed diabetes and poor outcomes after percutaneous coronary intervention (PCI), but there is limited data focusing on elderly patients (age ≥ 65). This study aimed to analyze the prevalence and clinical implications of newly diagnosed diabetes in elderly patients who underwent PCI. From 2004 to 2021, a total of 2456 elderly patients who underwent invasive PCI at Korea University Guro Hospital were prospectively enrolled and followed up for a median of five years. The primary endpoint was five-year major adverse cardiovascular events (MACE). Cox regression was used to evaluate whether newly diagnosed diabetes impacted on long-term clinical outcomes. Newly diagnosed diabetes was presented in approximately 8.1% to 10.9% of elderly patients who underwent PCI. Those who had a new diagnosis of diabetes had a higher risk of MACE than previously known diabetes (25.28% vs. 19.15%, p = 0.039). After adjusting for significant factors, newly diagnosed diabetes remained an independent predictor of MACE (HR [hazard ratio] 1.64, 95% confidence interval [CI] 1.24-2.17, p < 0.001), cardiac death (HR 2.15, 95% CI 1.29-3.59, p = 0.003) and repeat revascularization (HR 1.52, 95% CI 1.09-2.11, p = 0.013), but not for non-fatal myocardial infarction (HR 1.66, 95% CI 0.94-2.12, p = 0.081). Newly diagnosed diabetes was associated with an increased risk of 5-year MACE compared with non-diabetes and previously diagnosed diabetes in elderly patients underwent PCI. More attention should be given to those elderly newly diagnosed diabetes population.

Metabolic differences in MSTN and FGF5 dual-gene edited sheep muscle cells during myogenesis.

Dynamic metabolic reprogramming occurs at different stages of myogenesis and contributes to the fate determination of skeletal muscle satellite cells (MuSCs). Accumulating evidence suggests that mutations in myostatin (MSTN) have a vital role in regulating muscle energy metabolism. Here, we explored the metabolic reprogramming in MuSCs and myotube cells in MSTN and FGF5 dual-gene edited sheep models prepared previously, and also focused on the metabolic alterations during myogenic differentiation of MuSCs. Our study revealed that the pathways of nucleotide metabolism, pantothenate and CoA biosynthesis were weakened, while the unsaturated fatty acids biosynthesis were strengthened during myogenic differentiation of sheep MuSCs. The MSTN and FGF5 dual-gene editing mainly inhibited nucleotide metabolism and biosynthesis of unsaturated fatty acids in sheep MuSCs, reduced the number of lipid droplets in per satellite cell, and promoted the pentose phosphate pathway, and the interconversion of pentose and glucuronate. The MSTN and FGF5 dual-gene editing also resulted in the inhibition of nucleotide metabolism and TCA cycle pathway in differentiated myotube cells. The differential metabolites we identified can be characterized as biomarkers of different cellular states, and providing a new reference for MSTN and FGF5 dual-gene editing in regulation of muscle development. It may also provide a reference for the development of muscle regeneration drugs targeting biomarkers.

C-H functionalization reactions catalyzed by artificial metalloenzymes.

CH functionalization, a promising frontier in modern organic chemistry, facilitates the direct conversion of inert CH bonds into many valuable functional groups. Despite its merits, traditional homogeneous catalysis, often faces challenges in efficiency, selectivity, and sustainability towards this transformation. In this context, artificial metalloenzymes (ArMs), resulting from the incorporation of a catalytically-competent metal cofactor within an evolvable protein scaffold, bridges the gap between the efficiency of enzymatic transformations and the versatility of transition metal catalysis. Accordingly, ArMs have emerged as attractive tools for various challenging catalytic transformations. Additionally, the coming of age of directed evolution has unlocked unprecedented avenues for optimizing enzymatic catalysis. Taking advantage of their genetically-encoded protein scaffold, ArMs have been evolved to catalyze various CH functionalization reactions. This review delves into the recent developments of ArM-catalyzed CH functionalization reactions, highlighting the benefits of engineering the second coordination sphere around a metal cofactor within a host protein.

Endangered status and threatened population ecological factors in Salvia daiguii, an endemic species from Hunan, China.

Many species of Salvia have excellent ornamental, culinary, and medicinal values. Salvia daiguii, is an ornamental and highly medicinal perennial herb endemic to the prefecture-level city of Zhangjiajie in Hunan Province, China, with a narrow geographical distribution. However, currently, it has only been assessed as a Critically Endangered species according to the IUCN classification criteria, but its conservation has not yet been studied. This study investigated the distribution and niche characteristics of S. daiguii, and compared the differences in growth, flowering characteristics, and soil nutrients between the wild and ex situ populations. We also analyzed the effects of soil nutrients on plant growth and flowering characteristics. During the survey, we found 274 individuals on a rock approximately 200 m from ZEFR1. Nevertheless, S. daiguii were still restricted in three populations, TNFP, TGM, and ZEFR in Zhangjiajie City, with a total of about 500 plants and less than 250 mature individuals. Our results show that aspects such as adverse environmental conditions, low seedling renewal rate, a lack of soil nutrients, and competition for the characteristic niche of this and other dominant plants in the natural community are the main ecological factors affecting the growth, flowering, and geographic distribution of S. daiguii. Based on the results of field surveys, we recommend that (1) S. daiguii be classified as Critically Endangered C2b and China's List of Plant Species with Extremely Small Populations. (2) Comprehensive conservation strategies were developed, such as the establishment of nature reserves, reintroduction, public education, and institutional development to provide management recommendations related to the conservation of S. daiguii and other endangered plants.

Additional PD-1 inhibitor improves complete response to induction chemotherapy in locally advanced nasopharyngeal carcinoma.

Purpose: To investigate the treatment response and toxicity of the combination of induction chemotherapy (IC) and PD-1 inhibitor in locally advanced nasopharyngeal carcinoma (LANPC). Methods: Patients with stage III-IVA NPC who received IC or IC + PD-1 inhibitor were included. The chi-square test and multivariate logistic regression analysis were used for statistical analysis. Results: A total of 225 patients were identified, including 193 (85.8%) and 32 (14.2%) who received IC alone and IC + PD-1 inhibitor, respectively. The addition of PD-1 inhibitor to IC significantly improved the tumor response than those treated with IC alone. The complete response (CR), partial response, stable disease, and progressive disease rates of 4.7% vs. 31.3%, 69.4% vs. 62.5%, 24.9% vs. 6.3%, and 1.0% vs. 0% in patients receiving IC alone and IC + PD-1 inhibitor, respectively (P<0.001). The results of the multivariate logistic regression showed that receiving PD-1 inhibitor was an independent predictor influencing the CR rate of patients (odds ratio 9.814, P<0.001). The most common toxicity by using IC and PD-1 inhibitor was hematological toxicity. In terms of non-hematological toxicity, 7 (21.9%) patients experienced thyroid dysfunction and all of them were hyperthyroidism. No grade 5 toxicities were found. In those who received IC and PD-1 inhibitor, the one-year locoregional recurrence-free survival, distant metastasis-free survival, disease-free survival, and overall survival were 100%, 96.9%, 96.9%, and 100%, respectively. Conclusion: The addition of PD-1 inhibitor to IC has promise as an effective treatment approach for LANPC. More studies are expected to provide further insights into the optimal use of this treatment strategy, paving the way for more personalized and effective treatment options for patients with LANPC.

Organocatalytic Enantioselective Synthesis of Inherently Chiral Calix[4]arenes.

Inherently chiral calix[4]arenes are an excellent structural scaffold for asymmetric synthesis, chiral recognition, sensing, and circularly polarized luminescence. However, their catalytic asymmetric synthesis remains challenging. Herein, we report an efficient synthesis of inherently chiral calix[4]arene derivatives via cascade asymmetric cyclization and oxidation reactions. The three-component reaction features a broad substrate scope (33 examples), high efficiency (up to 90% yield), and excellent enantioselectivity (>95% ee on average). The potential applications of calix[4]arene derivatives are highlighted by their synthetic transformation and a detailed investigation of their photophysical and chiroptical properties.

Limited effects of xylem anatomy on embolism resistance in cycad leaves.

Drought-induced xylem embolism is a primary cause of plant mortality. Although c. 70% of cycads are threatened by extinction and extant cycads diversified during a period of increasing aridification, the vulnerability of cycads to embolism spread has been overlooked. We quantified the vulnerability to drought-induced embolism, pressure-volume curves, in situ water potentials, and a suite of xylem anatomical traits of leaf pinnae and rachises for 20 cycad species. We tested whether anatomical traits were linked to hydraulic safety in cycads. Compared with other major vascular plant clades, cycads exhibited similar embolism resistance to angiosperms and pteridophytes but were more vulnerable to embolism than noncycad gymnosperms. All 20 cycads had both tracheids and vessels, the proportions of which were unrelated to embolism resistance. Only vessel pit membrane fraction was positively correlated to embolism resistance, contrary to angiosperms. Water potential at turgor loss was significantly correlated to embolism resistance among cycads. Our results show that cycads exhibit low resistance to xylem embolism and that xylem anatomical traits - particularly vessels - may influence embolism resistance together with tracheids. This study highlights the importance of understanding the mechanisms of drought resistance in evolutionarily unique and threatened lineages like the cycads.

Ultra-high Q resonances based on zero group-velocity modes accompanied by bound states in the continuum in 2D photonic crystal slabs.

Optical resonators made of 2D photonic crystal (PhC) slabs provide efficient ways to manipulate light at the nanoscale through small group-velocity modes with low radiation losses. The resonant modes in periodic photonic lattices are predominantly limited by nonleaky guided modes at the boundary of the Brillouin zone below the light cone. Here, we propose a mechanism for ultra-high Q resonators based on the bound states in the continuum (BICs) above the light cone that have zero-group velocity (ZGV) at an arbitrary Bloch wavevector. By means of the mode expansion method, the construction and evolution of avoided crossings and Friedrich-Wintgen BICs are theoretically investigated at the same time. By tuning geometric parameters of the PhC slab, the coalescence of eigenfrequencies for a pair of BIC and ZGV modes is achieved, indicating that the waveguide modes are confined longitudinally by small group-velocity propagation and transversely by BICs. Using this mechanism, we engineer ultra-high Q nanoscale resonators that can significantly suppress the radiative losses, despite the operating frequencies above the light cone and the momenta at the generic k point. Our work suggests that the designed devices possess potential applications in low-threshold lasers and enhanced nonlinear effects.

Increasing GSH-Px Activity and Activating Wnt Pathway Promote Fine Wool Growth in FGF5-Edited Sheep.

Fibroblast growth factor 5 (FGF5) plays key roles in promoting the transition from the anagen to catagen during the hair follicle cycle. The sheep serves as an excellent model for studying hair growth and is frequently utilized in various research processes related to human skin diseases. We used the CRISPR/Cas9 system to generate four FGF5-edited Dorper sheep and only low levels of FGF5 were detected in the edited sheep. The density of fine wool in GE sheep was markedly increased, and the proportion of fine wool with a diameter of 14.4-20.0 µm was significantly higher. The proliferation signal in the skin of gene-edited (GE) sheep was stronger than in wild-type (WT) sheep. FGF5 editing decreased cortisol concentration in the skin, further activated the activity of antioxidant enzymes such as Glutathione peroxidase (GSH-Px), and regulated the expression of Wnt signaling pathways containing Wnt agonists (Rspondins, Rspos) and antagonists (Notum) in hair regeneration. We suggest that FGF5 not only mediates the activation of antioxidant pathways by cortisol, which constitutes a highly coordinated microenvironment in hair follicle cells, but also influences key signals of the Wnt pathway to regulate secondary hair follicle (SHF) development. Overall, our findings here demonstrate that FGF5 plays a significant role in regulating SHF growth in sheep and potentially serves as a molecular marker of fine wool growth in sheep breeding.

The correlation of orthostatic hypotension in Parkinson disease with the disease course and severity and its impact on quality of life.

We investigated the correlation of orthostatic hypotension (OH) in Parkinson disease (PD) with the disease course and severity, and its possible impact on quality of life. 171 PD patients were recruited and divided into the PD-NOH (n = 91) and PD-OH groups (n = 80). Clinical data were collected. The severity and quality of life of PD patients were evaluated. The impact of disease severity was analyzed using logistic regression analysis. The ROC curve was plotted. There were significant differences (P < .05) between PD-NOH and PD-OH groups in terms of the disease course, non-motor symptoms (somnipathy), Hoehn&Yahr stage, LEDD score, RBDSQ score, PDQ-39 score, MMSE score, MoCA, MDS-UPDRS Part III scores during off- and on-periods, and NMSS score. Hoehn&Yahr stage (OR 4.950, 95% CI 1.516-16.157, P = .008) was closely associated with the risk of OH in PD. PDQ-39 score (OR 1.079, 95% CI 1.033-1.127, P = .001) in PD patients with OH further decreased. Patients with PD-OH experienced severe impairment in 4 dimensions of quality of life, including motor function, cognitive function, physical discomfort, and activities of daily living. Different clinical symptoms of PD-OH were positively correlated with PDQ39 subscales. The area under the ROC curve of the Hoehn&Yahr stage in predicting the occurrence of OH was 0.679 (95% CI 0.600-0.758), and that of the Hoehn&Yahr stage combined with levodopa equivalent dose, and MDS-UPDRS Part III score during off-period was 0.793 (95% CI 0.727-0.862). Higher Hoehn&Yahr stage is associated with increased risk of OH in PD patients, and deteriorated quality of life of PD patients. Patients with different OH symptoms are affected in different dimensions of their quality of life. The Hoehn & Yahr stage can independently predict the risk of OH in PD patients.

Zeolitic imidazolate framework-encapsulated zinc porphyrin photoresponsive nanozyme for colorimetric/fluorescent dual-mode sensing of glyphosate.

A novel zeolitic imidazolate framework-encapsulated zinc porphyrin (ZnTCPP@ZIF-90) photoresponsive nanozyme is proposed for the colorimetric/fluorescent dual-mode visual sensing of glyphosate (Gly). ZnTCPP@ZIF-90 exhibits photoresponsive oxidase-like activity and fluorescence quenching behavior. Meanwhile, the outer ZIF-90 layer can be selectively destroyed by Gly, causing the release of free ZnTCPP, resulting in the enhanced enzyme-like activity as well as fluorescence emission. The constructed ZnTCPP@ZIF-90 was successfully used for the colorimetric/fluorescent dual-mode detection of Gly. Additionally, the colorimetric and fluorescent images information captured by the smartphone were converted to color intensity (HSV/RGB values), with limits of detection of 0.27 µg/mL and 0.19 µg/mL, respectively. The proposed dual-mode sensor exhibits excellent selectivity and reliability for detecting Gly, and can be successfully applied to the analysis of real samples such as tap water, lake water, and fruit washing water. The current research efforts are expected to provide new perspectives for designing highly active photoresponsive nanozymes and their stimuli-responsive sensing systems, paving the way for their applications in portable dual-mode chemical sensing and environmental monitoring.

Quality characteristics and cooking-induced changes on phenolic compounds of dried green tea noodles.

Incorporating green tea powder (GTP) into wheat flour-based noodles can significantly improve nutritional value. So, this study investigated the effects of GTP (0%, 0.5%, 1%, 1.5%, and 2.0%) on the quality properties of dried green tea noodles (DGTN) and cooking-induced changes to phenolic compounds. Mixolab analysis of wheat flour with GTP showed more water absorption of dough, and the developed dough had a firmer structure. GTP markedly increased the toughness of the noodle sheet. DGTN fortified with GTP showed more stable textural properties during cooking and storage, representing higher hardness and tensile strength. The viscosity and thermal properties of DGTN showed that GTP affected the gelatinization and retrogradation behavior of starch, which were closely related to the textural properties. Overall, DGTN prepared with 1.5% GTP showed better quality properties. However, ultra-performance liquid chromatography-time (UPLC/Q-TOF-mass spectrometry [MS]/MS) analysis showed that cooking by boiling significantly decreased phenolic content in 1.5% DGTN; further analysis revealed that the thermal degradation is a key factor in the loss of polyphenols. Therefore, further studies are necessary to focus on the mechanism of cooking-induced polyphenol loss, which is of great significance for improving the nutritional value of cooked DGTN.

Atomic physics on a 50-nm scale: Realization of a bilayer system of dipolar atoms.

Controlling ultracold atoms with laser light has greatly advanced quantum science. The wavelength of light sets a typical length scale for most experiments to the order of 500 nanometers (nm) or greater. In this work, we implemented a super-resolution technique that localizes and arranges atoms on a sub-50-nm scale, without any fundamental limit in resolution. We demonstrate this technique by creating a bilayer of dysprosium atoms and observing dipolar interactions between two physically separated layers through interlayer sympathetic cooling and coupled collective excitations. At 50-nm distance, dipolar interactions are 1000 times stronger than at 500 nm. For two atoms in optical tweezers, this should enable purely magnetic dipolar gates with kilohertz speed.

Experimental Generation of Spin-Photon Entanglement in Silicon Carbide.

A solid-state approach for quantum networks is advantageous, as it allows the integration of nanophotonics to enhance the photon emission and the utilization of weakly coupled nuclear spins for long-lived storage. Silicon carbide, specifically point defects within it, shows great promise in this regard due to the easy of availability and well-established nanofabrication techniques. Despite of remarkable progresses made, achieving spin-photon entanglement remains a crucial aspect to be realized. In this Letter, we experimentally generate entanglement between a silicon vacancy defect in silicon carbide and a scattered single photon in the zero-phonon line. The spin state is measured by detecting photons scattered in the phonon sideband. The photonic qubit is encoded in the time-bin degree of freedom and measured using an unbalanced Mach-Zehnder interferometer. Photonic correlations not only reveal the quality of the entanglement but also verify the deterministic nature of the entanglement creation process. By harnessing two pairs of such spin-photon entanglement, it becomes straightforward to entangle remote quantum nodes at long distance.

Pseudorabies virus hijacks the Rab6 protein to promote viral assembly and egress.

Pseudorabies virus (PRV) is recognized as the aetiological agent responsible for Aujeszky's disease, or pseudorabies, in swine populations. Rab6, a member of the small GTPase family, is implicated in various membrane trafficking processes, particularly exocytosis regulation. Its involvement in PRV infection, however, has not been documented previously. In our study, we observed a significant increase in the Rab6 mRNA and protein levels in both PK-15 porcine kidney epithelial cells and porcine alveolar macrophages, as well as in the lungs and spleens of mice infected with PRV. The overexpression of wild-type Rab6 and its GTP-bound mutant facilitated PRV proliferation, whereas the GDP-bound mutant form of Rab6 had no effect on viral propagation. These findings indicated that the GTPase activity of Rab6 was crucial for the successful spread of PRV. Further investigations revealed that the reduction in Rab6 levels through knockdown significantly hampered PRV proliferation and disrupted virus assembly and egress. At the molecular level, Rab6 was found to interact with the PRV glycoproteins gB and gE, both of which are essential for viral assembly and egress. Our results collectively suggest that PRV exploits Rab6 to expedite its assembly and egress and identify Rab6 as a promising novel target for therapeutic treatment for PRV infection.