Constructing network structures to enhance stability and target deposition of selenium nanoparticles via amphiphilic sodium alginate and alkyl glycosides.

Dietary selenium (Se) supplementation has recently received increasing attention; however, Selenium nanoparticles (SeNPs) exhibit poor stability and tend to aggregate in aqueous solution. Therefore, enhancing the stability of SeNPs and their effective delivery to plants remain challenging. In this study, sodium alginate (SA) and lysozyme (LZ) were reacted via the wet-heat Maillard reaction (MR) to obtain amphiphilic alginate-based polymers (SA-LZ). Alkyl glycosides (APG) were introduced into SA-LZ to enhance the deposition of SeNPs in leaves. Thus, a renewable and degradable polysaccharide-based material (SA-LZ/APG) loaded with Se formed an amphiphilic alginate-based-based shell with a Se core. Notably, the encapsulation of SeNPs into a polysaccharide base (SA-LZ/APG) increased the stabilization of SeNPs and resulted in orange-red, zero-valent, monoclinic and spherical SeNPs with a mean diameter of approximately 43.0 nm. In addition, SA-LZ/APG-SeNPs reduced the interfacial tension of plant leaves and increased the Se content of plants compared to the blank group. In vitro studies have reported that SA-LZ/APG-SeNPs and SA-LZ-SeNPs have significantly better clearance of DDPH and ABTS than that of APG-SeNPs. Thus, we believe that SA-LZ/APG is a promising smart delivery system that can synergistically enhance the stability of SeNPs in aqueous solutions and improve the bioavailability of Se nutrient solutions.

Ursolic acid targets secreted phosphoprotein 1 to regulate Th17 cells against non-alcoholic fatty liver disease.

Background/Aims: Non-alcoholic fatty liver disease (NAFLD) has become an increasingly important health challenge, with a substantial rise linked to changing lifestyles and global obesity. Ursolic acid, a natural pentacyclic triterpenoid, has been explored for its potential therapeutic effects. Given its multifunctional bioactive properties, this research further revealed the pharmacological mechanisms of ursolic acid on NAFLD. Methods: Drug target chips and bioinformatics analysis were combined in this study to explore the potential therapeutic effects of ursolic acid on NAFLD. Molecular docking simulations, surface plasmon resonance analyses, pull-down experiments, and co-immunoprecipitation assays were used to verify the direct interactions. Gene knockdown mice were generated, and high-fat diets were used to validate drug efficacy. Furthermore, initial CD4+ T cells were isolated and stimulated to demonstrate our findings. Results: In this study, the multifunctional extracellular matrix phosphorylated glycoprotein secreted phosphoprotein 1 (SPP1) was investigated, highlighting its capability to induce Th17 cell differentiation, amplifying inflammatory cascades, and subsequently promoting the evolution of NAFLD. In addition, this study revealed that in addition to the canonical TGF-ß/IL-6 cytokine pathway, SPP1 can directly interact with ITGB1 and CD44, orchestrating Th17 cell differentiation via their joint downstream ERK signaling pathway. Remarkably, ursolic acid intervention notably suppressed the protein activity of SPP1, suggesting a promising avenue for ameliorating the immunoinflammatory trajectory in NAFLD progression. Conclusions: Ursolic acid could improve immune inflammation in NAFLD by modulating SPP1-mediated Th17 cell differentiation via the ERK signaling pathway, which is orchestrated jointly by ITGB1 and CD44, emerging as a linchpin in this molecular cascade.

The value of speckle-tracking stratified strain combined with myocardial work measurement in evaluating left ventricular function in patients with heart failure with preserved ejection fraction.

Background: Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent progressive disease accompanied by poor quality of life, high utilization of medical resources, morbidity, and mortality. However, the role of left ventricular (LV) systolic dysfunction has yet to be well elaborated despite the preservation of the LV ejection fraction. This study aimed to explore the diagnostic value of speckle-tracking stratified strain combined with myocardial work (MW) measurement in evaluating LV systolic dysfunction in patients with HFpEF. Methods: A total of 125 study consecutive individuals, 64 HFpEF patients, and 61 controls were prospectively enrolled in the Fourth Affiliated Hospital of Harbin Medical University. In addition to the conventional echocardiographic parameters, LV stratified strain and MW parameters were statistically compared between the HFpEF and control groups. The global longitudinal strain (GLS) of the subendocardium, myocardium, and subepicardium (GLSendo, GLSmyo, and GLSepi); the transmural gradient (ΔGLS); the global myocardial work index (GWI), global myocardial work efficiency (GWE), global myocardial constructive work (GCW), and the global myocardial wasted work (GWW) were included. Area under the receiver operating characteristic curve analysis was used to evaluate the diagnostic performance of these univariate and multivariable logistic models in detecting impaired LV systolic function in HFpEF. Ten-fold cross-validation was used to evaluate the generalizability of the predictive model. Results: Stratified strains values showed a gradient decline from GLSendo to GLSepi in both control and HFpEF patients. Compared with the control group, HFpEF patients had a significantly reduced GLSepi, GLSmyo, GLSendo, ΔGLS, GWI, GWE, and GCW and a significantly increased GWW (all P<0.001). In the derivation set, the optimal logistic model (combined stratified strain and MW variables) demonstrated the highest performance in predicting LV systolic function impairment in HFpEF patients. The best-performing model with a mean area under the curve (AUC) of 0.966 [95% confidence interval (CI): 0.88 to 1] accessed by 10-fold cross-validation. In the validation set, the AUC of the optimal logistic model was 0.933 (95% CI: 0.85 to 1), the sensitivity was 87%, and the specificity was 93%. Conclusions: Both speck-tracking stratified strain and MW measurement may sensitively detect impairment of LV myocardial function at an early stage for patients with HFpEF. Combining the two techniques may improve the quality of HFpEF diagnosis and may provide a reference value for the early diagnosis of HFpEF in the future.

Differential Microbial Composition and Interkingdom Interactions in the Intestinal Microbiota of Holstein and German Simmental × Holstein Cross F1 Calves: A Comprehensive Analysis of Bacterial and Fungal Diversity.

Calf intestines are colonized by rich and complex microbial communities, playing a crucial role in animal physiology, metabolism, nutrition, and immune function. In this study, we provide insight into the composition of fecal microbial bacteria and fungi, respectively, as well as the cross-kingdom interactions. We investigated the intestinal microbiota of different breeds of calves by characterizing the bacterial and fungal communities in the rectal feces of Holstein calves and German Simmental × Holstein cross F1 generation (GXH) using 16S rRNA and ITS amplicon sequencing techniques. PICRUSt2 (version 2.2.0) were used to determine microbial diversity and function and explore the reasons why Holstein calves are more susceptible to diarrhea. The results revealed no significant difference in the diversity of fecal microbiota among the groups (p > 0.05). We identified Firmicutes, Bacteroidetes, and Proteobacteria as the dominant bacterial phyla in the fecal bacterial communities of the two breeds of calves. Ascomycota and Basidiomycota play important roles in the fungal community but differ in relative abundance. Bacteroides was the dominant genus at the group level for calf fecal microbiota in both breeds. The relative abundance of Prevotella, Escherichia-Shigella, Peptostreptococcus, and Butyricicoccus was higher in Holstein calves, and the relative abundance of Faecalibacterium, Megamonas, Butyricicoccus, and Alloprevotella was lower than GXH group. Aspergillus and Cladosporium were the dominating genera of fecal fungi in both groups of calves. LEfSe analysis revealed 33 different bacteria and 23 different fungi between the two groups, with more differential strains found in GXH. In addition, the feces fungi-bacteria interkingdom interactions varied among breeds. Thus, the composition and structure of bacterial and fungal communities in calf feces varied by breed, indicating a potential association between breed and microbial communities. We also found differences in the network between bacterial-fungal kingdoms. We explain the reasons for Holstein calves being more prone to diarrhea. This indicated that breed makes differences in calf diarrhea rates by influencing gut microbial composition and interactions.

B ← N coordination bond reinforced dynamic fluorescence of pH-responsive amphiphile alginate aggregates for anti-counterfeiting.

High quantum yield polysaccharide-based materials are significative for the dynamic anti-counterfeiting, while that are limited by weak fluorescence. However, natural polysaccharides with weak fluorescence are not suitable for anti-counterfeiting. Herein, alginate derivatives (SA-PBA) exhibiting aggregation-induced emission with high-quantum yields were synthesized by grafting phenylboronic acid (PBA) onto a sodium alginate (SA) chain. As the concentration increases, polymer assembly can be induced to form more compact soft colloidal aggregates, which enhances the fluorescence properties of alginate derivatives by introducing B â† N coordination bonds in the hydrophobic microregions. Interestingly, the clustered aggregates of SA-PBA can be dynamically controlled by pH, realizing the reversible adjustment of fluorescence. The corresponding mechanism is revealed by the combination of coarse-grained simulations and experiments. It is found that SA-PBA uses a hydrophobic driving force and hydrogen bond interaction to self-assemble in an aqueous solution and promote fluorescence emission. Moreover, the fluorescence quantum yield of SA-PBA can reach 14.4 % and can be reversibly altered by tuning soft colloidal microstructures. Therefore, a reversible information encryption system of SA-PBA is developed for anti-counterfeiting. This work shed some light on how to design novel anti-counterfeit materials based on natural polysaccharides and optimize the dynamic fluorescence conditions.

Uncovering PROTAC Sensitivity and Efficacy by Multidimensional Proteome Profiling: A Case for STAT3.

Proteolysis-targeting chimera (PROTAC) is a powerful technology that can effectively trigger the degradation of target proteins. The intricate interplay among various factors leads to a heterogeneous drug response, bringing about significant challenges in comprehending drug mechanisms. Our study applied data-independent acquisition-based mass spectrometry to multidimensional proteome profiling of PROTAC (DIA-MPP) to uncover the efficacy and sensitivity of the PROTAC compound. We profiled the signal transducer and activator of transcription 3 (STAT3) PROTAC degrader in six leukemia and lymphoma cell lines under multiple conditions, demonstrating the pharmacodynamic properties and downstream biological responses. Through comparison between sensitive and insensitive cell lines, we revealed that STAT1 can be regarded as a biomarker for STAT3 PROTAC degrader, which was validated in cells, patient-derived organoids, and mouse models. These results set an example for a comprehensive description of the multidimensional PROTAC pharmacodynamic response and PROTAC drug sensitivity biomarker exploration.

Pyruvate kinase deficiency and PKLR gene mutations: Insights from molecular dynamics simulation analysis.

Pyruvate kinase deficiency is a rare hereditary erythrocyte enzyme disease caused by mutations in the pyruvate kinase liver and red blood cell gene. The clinical presentations of pyruvate kinase deficiency are significantly heterogeneous, ranging from just mild anemia to hemolytic crisis or even death. The proband in our study was a 2-year-old girl for severe skin and scleral icterus with progressive aggravation. We collected the family's data for further analysis. Whole exome genome sequencing of the pedigree revealed a novel compound heterozygous mutation, c.1097del (p.P366Lfs*12) and c.1493G > A (p.R498H), in the pyruvate kinase liver and red blood cell gene. Furthermore, molecular dynamics simulations were employed to uncover differences between the wild type and mutant pyruvate kinase liver and red blood cell proteins, focusing on structural stability, protein flexibility, secondary structure, and overall conformation. The combined bioinformatic tools were also utilised to assess the effects of the missense mutation on protein function. Thereafter, wild type and mutant plasmids were constructed and transfected into 293T cells, and Western blot assay was conducted to validate the impact of the mutations on the expression of pyruvate kinase liver and red blood cell protein. The data presented in our study enriches the genotype database and provides evidence for genetic counseling and molecular diagnosis of pyruvate kinase deficiency.

Fluorophore Label-Free Light-up Near Infrared Deoxyribonucleic Acid Nanosensor for Monitoring Extracellular Potassium Levels.

Fluorescent DNA nanosensors have been widely used due to their unique advantages, among which the near-infrared (NIR) imaging mode can provide deeper penetration depth and lower biological background for the nanosensors. However, efficient NIR quenchers require ingenious design, complex synthesis, and modification, which severely limit the development of NIR DNA nanosensors. Label-free strategies based on G-quadruplex (G4) and NIR G4 dyes were first introduced into in situ extracellular imaging, and a novel NIR sensing strategy for the specific detection of extracellular targets is proposed. The strategy avoids complex synthesis and site-specific modification by controlling the change of the NIR signal through the formation of a G4 nanostructure. A light-up NIR DNA nanosensor based on potassium ion (K+)-sensitive G4 chain PS2.M was constructed to verify the strategy. PS2.M forms a stable G4 nanostructure in the presence of K+ and activates the NIR G4 dye CSTS, thus outputting NIR signals. The nanosensor can rapidly respond to K+ with a linear range of 5-50 mM and has good resistance to interference. The nanosensor with cholesterol can provide feedback on the changes in extracellular K+ concentration in many kinds of cells, serving as a potential tool for the study of diseases such as epilepsy and cancer, as well as the development of related drugs. The strategy can be potentially applied to the NIR detection of a variety of extracellular targets with the help of functional DNAs such as aptamer and DNAzyme.

Research progress, challenges and perspectives of phospholipids metabolism in the LXR­LPCAT3 signaling pathway and its relation to NAFLD (Review).

Phospholipids (PLs) are principle constituents of biofilms, with their fatty acyl chain composition significantly impacting the biophysical properties of membranes, thereby influencing biological processes. Recent studies have elucidated that fatty acyl chains, under the enzymatic action of lyso­phosphatidyl­choline acyltransferases (LPCATs), expedite incorporation into the sn­2 site of phosphatidyl­choline (PC), profoundly affecting pathophysiology. Accumulating evidence suggests that alterations in LPCAT activity are implicated in various diseases, including non­alcoholic fatty liver disease (NAFLD), hepatitis C, atherosclerosis and cancer. Specifically, LPCAT3 is instrumental in maintaining systemic lipid homeostasis through its roles in hepatic lipogenesis, intestinal lipid absorption and lipoprotein secretion. The liver X receptor (LXR), pivotal in lipid homeostasis, modulates cholesterol, fatty acid (FA) and PL metabolism. LXR's capacity to modify PL composition in response to cellular sterol fluctuations is a vital mechanism for protecting biofilms against lipid stress. Concurrently, LXR activation enhances LPCAT3 expression on cell membranes and elevates polyunsaturated PL levels. This activation can ameliorate saturated free FA effects in vitro or endoplasmic reticulum stress in vivo due to lipid accumulation in hepatic cells. Pharmacological interventions targeting LXR, LPCAT and membrane PL components could offer novel therapeutic directions for NAFLD management. The present review primarily focused on recent advancements in understanding the LPCAT3 signaling pathway's role in lipid metabolism related to NAFLD, aiming to identify new treatment targets for the disease.

Crosstalk between endothelial progenitor cells and HCC through periostin/CCL2/CD36 supports formation of the pro-metastatic microenvironment in HCC.

Metastasis causes most cancer-related deaths, and the role and mechanism of periostin (POSTN) in the metastasis of hepatocellular carcinoma (HCC) remain undiscovered. In this study, DEN and HTVi HCC models were performed in hepatic-specific Postn ablation and Postn knock-in mouse to reveal the role of POSTN in HCC metastasis. Furthermore, POSTN was positively correlated with circulating EPCs level and promoted EPC mobilization and tumour infiltration. POSTN also mediated the crosstalk between HCC and EPCs, which promoted metastasis ability and upregulated CD36 expression in HCC through indirect crosstalk. Chemokine arrays further revealed that hepatic-derived POSTN induced elevated CCL2 expression and secretion in EPCs, and CCL2 promoted prometastatic traits in HCC. Mechanistic studies showed that POSTN upregulated CCL2 expression in EPCs via the αvß3/ILK/NF-κB pathway. CCL2 further induced CD36 expression via the CCR2/STAT3 pathway by directly binding to the promoter region of CD36. Finally, CD36 was verified to have a prometastatic role in vitro and to be correlated with POSTN expression, metastasis and recurrence in HCC in clinical samples. Our findings revealed that crosstalk between HCC and EPCs is mediated by periostin/CCL2/CD36 signalling which promotes HCC metastasis and emphasizes a potential therapeutic strategy for preventing HCC metastasis.

Blockade of pan-viral propagation by inhibition of host cell PNPT1.

For successful viral propagation within infected cells, the virus needs to overcome the cellular integrated stress response (ISR), triggered during viral infection, which, in turn, inhibits general protein translation. This paper reports a tactic employed by viruses to suppress the ISR by upregulating host cell polyribonucleotide nucleotidyltransferase 1 (PNPT1). The propagation of adenovirus, murine cytomegalovirus and hepatovirus within their respective host cells induces PNPT1 expression. Notably, when PNPT1 is knocked down, the propagation of all three viruses is prevented. Mechanistically, the inhibition of PNPT1 facilitates the relocation of mitochondrial double-stranded RNAs (mt-dsRNAs) to the cytoplasm, where they activate RNA-activated protein kinase (PKR). This activation leads to eukaryotic initiation factor 2α (eIF2α) phosphorylation, resulting in the suppression of translation. Furthermore, by scrutinizing the PNPT1 recognition element and screening 17,728 drugs and bioactive compounds approved by the US Food and Drug Administration, lanatoside C was identified as a potent PNPT1 inhibitor. This compound impedes the propagation of adenovirus, murine cytomegalovirus and hepatovirus, and suppresses production of the severe acute respiratory syndrome coronavirus-2 spike protein. These discoveries shed light on a novel strategy to impede pan-viral propagation by activating the host cell mt-dsRNA-PKR-eIF2α signalling axis.

A Novel Zero-Velocity Interval Detection Algorithm for a Pedestrian Navigation System with Foot-Mounted Inertial Sensors.

The zero-velocity update (ZUPT) algorithm is a pivotal advancement in pedestrian navigation accuracy, utilizing foot-mounted inertial sensors. Its key issue hinges on accurately identifying periods of zero-velocity during human movement. This paper introduces an innovative adaptive sliding window technique, leveraging the Fourier Transform to precisely isolate the pedestrian's gait frequency from spectral data. Building on this, the algorithm adaptively adjusts the zero-velocity detection threshold in accordance with the identified gait frequency. This adaptation significantly refines the accuracy in detecting zero-velocity intervals. Experimental evaluations reveal that this method outperforms traditional fixed-threshold approaches by enhancing precision and minimizing false positives. Experiments on single-step estimation show the adaptability of the algorithm to motion states such as slow, fast, and running. Additionally, the paper demonstrates pedestrian trajectory localization experiments under a variety of walking conditions. These tests confirm that the proposed method substantially improves the performance of the ZUPT algorithm, highlighting its potential for pedestrian navigation systems.

Liensinine inhibits progression of intrahepatic cholangiocarcinoma by regulating TGF-ß1 /P-smad3 signaling through HIF-1a.

Intrahepatic cholangiocarcinoma (ICC) is a high-grade malignant digestive system tumor with an insidious onset and unfavorable prognosis. Liensinine, a small molecule derived from plants, has been proven to have significant tumor suppressor activity in other cancers. However, there are no reports on whether liensinine can inhibit the proliferation or metastasis of ICC. This study aimed to explore the tumor-suppressive activity of liensinine in ICC and its underlying mechanisms. The phenotypic changes in ICC cells were monitored in vitro using cell function tests. Western blot and immunofluorescence analyses verified the efficacy of liensinine. Tumor-bearing nude mice were used to explore the effect of liensinine on tumors and its toxicity and side effects in vivo. Liensinine suppressed ICC cell proliferation and arrested the cell cycle at the G1 phase. The epithelial-mesenchymal transition (EMT) of ICC cells was also inhibited, thereby restraining their invasion and migration of tumor cells. In addition, this study found that the potential mechanism of liensinine inhibiting EMT may be via suppression of the TGF-ß1/P-smad3 signaling pathway through hypoxia-inducible factor 1 alpha (HIF-1a). In vivo experiments showed that liensinine inhibited the growth of Hucc-T1 transplanted tumors in nude mice. Liensinine restrained the proliferation of ICC cells and suppressed EMT in ICC via the HIF-1a-mediated TGF-ß1/P-smad3 signaling pathway.

Highly active electroreduction of nitrates to ammonia over a zeolitic imidazolium framework-derived Fe single-atom catalyst with sulfur-modified asymmetric active centers.

The electroreduction of aqueous nitrate (NO3-) to ammonium is an energy-efficient process that helps protect the environment and facilitates ammonia production. However, a fine optimization of the catalyst structure containing active centers should be performed to improve the efficiencies of NO3- reduction and NH4+ production. Herein, a zeolitic imidazolate framework (ZIF)-derived sulfur-modified Fe single-atom catalyst is developed as an efficient and durable cathode material. Experimental and theoretical studies confirm the role of S-doping in modifying the electron density distribution of Fe centers, promoting the interaction between the Fe 3d orbital and O 2p orbital of NO3- and thereby enhancing its catalytic performance. A Faradaic efficiency of 93.9% for NH4+ production at - 0.47 V vs. the reversible hydrogen electrode is achieved, which remains at 91.0% even after six cycles. A synergistic effect between a defect-rich support and metal atom centers can be utilized to develop a new strategy for the facile design and implementation of high-performance electrocatalysts.

NRAS Mutant Dictates AHCYL1-Governed ER Calcium Homeostasis for Melanoma Tumor Growth.

Calcium homeostasis is critical for cell proliferation, and emerging evidence shows that cancer cells exhibit altered calcium signals to fulfill their need for proliferation. However, it remains unclear whether there are oncogene-specific calcium homeostasis regulations that can expose novel therapeutic targets. Here, from RNAi screen, we report that adenosylhomocysteinase like protein 1 (AHCYL1), a suppressor of the endoplasmic reticulum (ER) calcium channel protein inositol trisphosphate receptor (IP3R), is selectively upregulated and critical for cell proliferation and tumor growth potential of human NRAS-mutated melanoma, but not for melanoma expressing BRAF V600E. Mechanistically, AHCYL1 deficiency results in decreased ER calcium levels, activates the unfolded protein response (UPR), and triggers downstream apoptosis. In addition, we show that AHCYL1 transcription is regulated by activating transcription factor 2 (ATF2) in NRAS-mutated melanoma. Our work provides evidence for oncogene-specific calcium regulations and suggests AHCYL1 as a novel therapeutic target for RAS mutant-expressing human cancers, including melanoma. IMPLICATIONS: Our findings suggest that targeting the AHCYL1-IP3R axis presents a novel therapeutic approach for NRAS-mutated melanomas, with potential applicability to all cancers harboring RAS mutations, such as KRAS-mutated human colorectal cancers.

Game-Based Approximate Optimal Motion Planning for Safe Human-Swarm Interaction.

Safety as a fundamental requirement for human-swarm interaction has attracted a lot of attention in recent years. Most existing approaches solve a constrained optimization problem at each time step, which has a high real-time requirement. To deal with this challenge, this article formulates the safe human-swarm interaction problem as a Stackerberg-Nash game, in which the optimization is performed over the entire time domain. The leader robot is supposed to be in a dominant position, interacting directly with the human operator to realize trajectory tracking and responsible for guiding the swarm to avoid obstacles. The follower robots always take their best responses to leader's behavior with the purpose of achieving the desired formation. Following the bottom-up principle, we first design the best-response controllers, that is, Nash equilibrium strategies, for the followers. Then, a Lyapunov-like control barrier function-based safety controller and a learning-based formation tracking controller for the leader are designed to realize safe and robust cooperation. We show that the designed controllers can make the robotic swarms move in a desired geometric formation following the human command and modify their motion trajectories autonomously when the human command is unsafe. The effectiveness of the proposed approach is verified through simulation and experiments. The experiment results further show that safety can still be guaranteed even when there exists a dynamic obstacle.

MK8722 initiates early-stage autophagy while inhibiting late-stage autophagy via FASN-dependent reprogramming of lipid metabolism.

Background and objective: Epithelial ovarian cancer (EOC) is associated with latent onset and poor prognosis, with drug resistance being a main concern in improving the prognosis of these patients. The resistance of cancer cells to most chemotherapeutic agents can be related to autophagy mechanisms. This study aimed to assess the therapeutic effect of MK8722, a small-molecule compound that activates AMP-activated protein kinase (AMPK), on EOC cells and to propose a novel strategy for the treatment of EOC. Purpose: To explore the therapeutic effects of MK8722 on EOC cells, and to elucidate the underlying mechanism. Methods and results: It was found that MK8722 effectively inhibited the malignant biological behaviors of EOC cells. In vitro experiments showed that MK8722 targeted and decreased the lipid metabolic pathway-related fatty acid synthase (FASN) expression levels, causing the accumulation of lipid droplets. In addition, transmission electron microscopy revealed the presence of autophagosome-affected mitochondria. Western blotting confirmed that MK8722 plays a role in activating autophagy upstream (PI3K/AKT/mTOR) and inhibiting autophagy downstream via FASN-dependent reprogramming of lipid metabolism. Plasmid transient transfection demonstrated that MK8722 suppressed late-stage autophagy by blocking autophagosome-lysosome fusion. Immunofluorescence and gene silencing revealed that this effect was achieved by inhibiting the interaction of FASN with the SNARE complexes STX17-SNP29-VAMP8. Furthermore, the antitumor effect of MK8722 was verified using a subcutaneous xenograft mouse model. Conclusion: The findings suggest that using MK8722 may be a new strategy for treating EOC, as it has the potential to be a new autophagy/mitophagy inhibitor. Its target of action, FASN, is a molecular crosstalk between lipid metabolism and autophagy, and exploration of the underlying mechanism of FASN may provide a new research direction.

Cas13b-mediated RNA targeted therapy alleviates genetic dilated cardiomyopathy in mice.

BACKGROUND: Recent advances in gene editing technology have opened up new avenues for in vivo gene therapy, which holds great promise as a potential treatment method for dilated cardiomyopathy (DCM). The CRISPR-Cas13 system has been shown to be an effective tool for knocking down RNA expression in mammalian cells. PspCas13b, a type VI-B effector that can be packed into adeno-associated viruses and improve RNA knockdown efficiency, is a potential treatment for diseases characterized by abnormal gene expression. RESULTS: Using PspCas13b, we were able to efficiently and specifically knockdown the mutant transcripts in the AC16 cell line carrying the heterozygous human TNNT2R141W (hTNNT2R141W) mutation. We used adeno-associated virus vector serotype 9 to deliver PspCas13b with specific single guide RNA into the hTNNT2R141W transgenic DCM mouse model, effectively knocking down hTNNT2R141W transcript expression. PspCas13b-mediated knockdown significantly increased myofilament sensitivity to Ca2+, improved cardiac function, and reduced myocardial fibrosis in hTNNT2R141W DCM mice. CONCLUSIONS: These findings suggest that targeting genes through Cas13b is a promising approach for in vivo gene therapy for genetic diseases caused by aberrant gene expression. Our study provides further evidence of Cas13b's application in genetic disease therapy and paves the way for future applicability of genetic therapies for cardiomyopathy.

Loading Mode-Induced Enhancement in Friction for Microscale Graphite/Hexagonal Boron Nitride Heterojunction.

Classical friction laws traditionally assume that the friction between solid pairs remains constant with a given normal load. However, our study has unveiled a remarkable deviation from conventional wisdom. In this paper, we discovered that altering the loading mode of micro graphite flakes led to significant changes in the lateral friction under identical normal loads. By adding a cap onto a single graphite flake to disperse the normal load applied by an atomic force microscope (AFM) tip, we were able to distribute the concentrated force. Astonishingly, our results demonstrated a notable 4-7 times increase in friction as a consequence of load dispersion. Finite element analysis (FEA) further confirmed that the increase in compressive stress at the edges of the graphite flake, resulting from load dispersion, led to a significant increase in friction. This study underscores the critical role of the loading mode in microscale friction dynamics, challenging the prevailing notion that friction remains static with a given normal force. Importantly, our research sheds light on the potential for achieving macroscale structural superlubricity (SSL) by assembling microscale SSL graphite flakes by using a larger cap.