Molecular Mechanism of Pasteurized Akkermansia muciniphila in Alleviating Type 2 Diabetes Symptoms.

Type 2 diabetes (T2DM) significantly diminishes people's quality of life and imposes a substantial economic burden. This pathological progression is intimately linked with specific gut microbiota, such as Akkermansia muciniphila. Pasteurized A. muciniphila (P-AKK) has been defined as a novel food by the European Food Safety Authority and exhibited significant hypoglycemic activity. However, current research on the hypoglycemic activity of P-AKK is limited to the metabolic level, neglecting systematic exploration at the pathological level. Consequently, its material basis and mechanism of action for hypoglycemia remain unclear. Drawing upon this foundation, we utilized high-temperature killed A. muciniphila (H-K-AKK) with insignificant hypoglycemic activity as the control research object. Assessments were conducted at pathological levels to evaluate the hypoglycemic functions of both P-AKK and H-K-AKK separately. Our study unveiled for the first time that P-AKK ameliorated symptoms of T2DM by enhancing the generation of glucagon-Like Peptide 1 (GLP-1), with pasteurized A. muciniphila total proteins (PP) being a pivotal component responsible for this activity. Utilizing SDS-PAGE, proteomics, and molecular docking techniques, we deeply analyzed the material foundation of PP. We scientifically screened and identified a protein weighing 77.85 kDa, designated as P5. P5 enhanced GLP-1 synthesis and secretion by activating the G protein-coupled receptor (GPCR) signaling pathway, with free fatty acid receptor 2 (FFAR-2) being identified as the pivotal target protein for P5's physiological activity. These findings further promote the widespread application of P-AKK in the food industry, laying a solid theoretical foundation for its utilization as a beneficial food ingredient or functional component.

Liver Resection Criteria for Patients with Hepatocellular Carcinoma and Multiple Tumors Based on Total Tumor Volume.

BACKGROUND: In many Asian hepatocellular carcinoma (HCC) guidelines, resection is an option for multiple HCCs. It is difficult to compare small but multiple tumors vs. fewer large tumors in terms of the traditional tumor burden definition. We aimed to evaluate the role of liver resection for multiple HCCs and determine factors associated with survival benefits. METHODS: We reviewed 160 patients with multiple HCCs who underwent liver resection between July 2003 and December 2018. The risk factors for tumor recurrence were assessed using Cox proportional hazards modeling, and survival was analyzed using the Kaplan-Meier method. RESULTS: In all 160 patients, 133 (83.1%) exceeded the Milan criteria. Total tumor volume (TTV) > 275 cm3 and serum alpha-fetoprotein (AFP) level > 20 ng/mL were associated with disease-free survival. Patients beyond the Milan criteria were grouped into three risk categories: no risk (TTV ≤ 275 cm3 and AFP ≤ 20 ng/mL, n = 39), one risk (either TTV > 275 cm3 or AFP > 20 ng/mL, n = 76), and two risks (TTV > 275 cm3 and AFP > 20 ng/mL, n = 18). No-risk group had comparable disease-free survival (p = 0.269) and overall survival (p = 0.215) to patients who met the Milan criteria. CONCLUSION: Patients with TTV ≤ 275 cm3 and AFP ≤ 20 ng/mL can have good outcomes even exceed the Milan criteria.

The Motivation for COVID-19 Vaccination and Preventive Behavior.

COVID-19, a viral infection that emerged in late 2019, induces a severe acute respiratory syndrome marked by significant clinical symptoms, and the potential for progressive respiratory failure and death. People facing the threat of COVID-19 not only feared being infected, but were also worried about the side-effects of vaccination. This conflict affected their epidemic prevention behavior. To understand this issue, the present study explored whether infection anxiety affected the psychological avoidance or approach to getting vaccinated and the intention to take epidemic prevention measures. The study implemented a cross-sectional, web-based survey. We created questionnaires using Surveycake, an online e-form questionnaire platform. We used the snowball sampling method via a social media app to recruit participants. If individuals were willing to participate in the research, we emailed the e-form questionnaire link to them to collect data. After questionnaire collection, 288 questionnaires were returned, and 277 valid questionnaires were obtained for structural equation modeling analysis. According to the statistical results, it was found that infection anxiety was positively related to avoidance-avoidance conflict, and the power of infection anxiety on avoidance conflict was 23.0%. Infection anxiety was negatively related to approach-approach conflict regarding vaccination, and the power of infection anxiety on approach-approach conflict was 22.0%. Approach-approach conflict regarding vaccination was negatively related to prevention behavior, while avoidance-avoidance conflict regarding vaccination was positively related to prevention behavior. The two conflicts explained 12.5% of the total variance in prevention behavior. The study results highlight the long-term importance of achieving vaccine goals in order to prepare for future health emergencies similar to the recent COVID-19 pandemic.

Atrophy patterns in hippocampal subregions and their relationship with cognitive function in fibromyalgia patients with mild cognitive impairment.

Objectives: Fibromyalgia (FM) has been associated with decreased hippocampal volume; however, the atrophy patterns of hippocampal subregions have not yet been identified. We therefore aimed to evaluate the volumes of hippocampal subregions in FM patients with mild cognitive impairment (MCI), and to explore the relationship between different subregional alterations and cognitive function. Methods: The study included 35 FM patients (21 with MCI and 14 without MCI) and 35 healthy subjects. All subjects performed the Montreal Cognitive Assessment (MoCA) to assess cognitive function. FreeSurfer V.7.3.2 was used to calculate hippocampal subregion volumes. We then compared hippocampal subregion volumes between the groups, and analyzed the relationship between hippocampal subregion volume and cognitive function using a partial correlation analysis method. Results: Compared with the healthy subjects, FM patients with MCI had smaller hippocampal volumes in the left and right CA1 head, Molecular layer head, GC-DG head, and CA4 head, and in the left Presubiculum head. Poorer executive function, naming ability, and attention were associated with left CA1 head and left Molecular layer head atrophy. By contrast, hippocampal subregion volumes in the FM patients without MCI were slightly larger than or similar to those in the healthy subjects, and were not significantly correlated with cognitive function. Conclusion: Smaller volumes of left CA1 head and left Molecular layer head were associated with poorer executive function, naming ability, and attention in FM patients with MCI. However, these results were not observed in the FM patients without MCI. These findings suggest that the hippocampal subregions of FM patients might present compensatory mechanisms before cognitive decline occurs.

Comprehensive landscape of junctional genes and their association with overall survival of patients with lung adenocarcinoma.

Objectives: Junctional proteins are involved in tumorigenesis. Therefore, this study aimed to investigate the association between junctional genes and the prognosis of patients with lung adenocarcinoma (LUAD). Methods: Transcriptome, mutation, and clinical data were retrieved from The Cancer Genome Atlas (TCGA). "Limma" was used to screen differentially expressed genes. Moreover, Kaplan-Meier survival analysis was used to identify junctional genes associated with LUAD prognosis. The junctional gene-related risk score (JGRS) was generated based on multivariate Cox regression analysis. An overall survival (OS) prediction model combining the JGRS and clinicopathological properties was proposed using a nomogram and further validated in the Gene Expression Omnibus (GEO) LUAD cohort. Results: To our knowledge, this study is the first to demonstrate the correlation between the mRNA levels of 14 junctional genes (CDH15, CDH17, CDH24, CLDN6, CLDN12, CLDN18, CTNND2, DSG2, ITGA2, ITGA8, ITGA11, ITGAL, ITGB4, and PKP3) and clinical outcomes of patients with LUAD. The JGRS was generated based on these 14 genes, and a higher JGRS was associated with older age, higher stage levels, and lower immune scores. Thus, a prognostic prediction nomogram was proposed based on the JGRS. Internal and external validation showed the good performance of the prediction model. Mechanistically, JGRS was associated with cell proliferation and immune regulatory pathways. Mutational analysis revealed that more somatic mutations occurred in the high-JGRS group than in the low-JGRS group. Conclusion: The association between junctional genes and OS in patients with LUAD demonstrated by our "TCGA filtrating and GEO validating" model revealed a new function of junctional genes.

Gut microbiota affects mPXR agonist PCN-induced hepatomegaly by regulating PXR and YAP activation.

Pregnane X receptor (PXR) is essential in the regulation of liver homeostasis and the gut microbiota is closely linked to liver physiological and pathological status. We previously found that activation of PXR significantly promotes liver enlargement through interaction with yes-associated protein (YAP). However, whether gut microbiota is contributed to PXR-induced hepatomegaly and the involved mechanisms remain unclear. In this study, C57BL/6 mice were administered the mouse-specific agonist PCN for 5 days. Depletion of gut microbiota was achieved using broad-spectrum antibiotics (ABX) and fecal microbiota transplantation (FMT) was performed to restore the gut microbial. The composition of gut microbiota was analyzed by 16S rRNA sequencing, while the expression of PXR, YAP and their downstream target genes and proteins were assessed. The results indicated that PCN treatment altered the composition and abundance of specific bacterial taxa. Furthermore, depletion of gut microbiota using ABX significantly attenuated PCN-induced hepatomegaly. FMT experiment further demonstrated that the fecal microbiota from PCN-treated mice could induce liver enlargement. Mechanistic studies revealed that ABX treatment impeded the PXR and YAP activation induced by PCN, as evidenced by decreased expression of PXR, YAP, and their downstream targets. Moreover, alterations in PXR and YAP activation were likely contributing to hepatomegaly in recipient mice following FMT from PCN-treated mice. Collectively, the current study demonstrated that gut microbiota is involved in PCN-induced hepatomegaly via regulating PXR and YAP activation, providing potential novel insights into the involvement of gut microbiota in PXR-mediated hepatomegaly. Significance Statement This work describes that the composition of gut microbiota is altered in mPXR agonist PCN-induced hepatomegaly. The treatment with an antibiotic cocktail (ABX) depletes the intestinal microbiota, leading to the impairment of liver enlargement caused by PCN. Besides, fecal microbiota transplantation (FMT) from PCN-treated mice induces liver enlargement. Further study revealed that gut microbiota is involved in hepatomegaly via regulating PXR and YAP activation.

MdARF3 switches the lateral root elongation to regulate dwarfing in apple plants.

Apple rootstock dwarfing and dense planting are common practices in apple farming. However, the dwarfing mechanisms are not understood. In our study, the expression of MdARF3 in the root system of dwarfing rootstock 'M9' was lower than in the vigorous rootstock from Malus micromalus due to the deletion of the WUSATAg element in the promoter of the 'M9' genotype. Notably, this deletion variation was significantly associated with dwarfing rootstocks. Subsequently, transgenic tobacco (Nicotiana tabacum) cv. Xanthi was generated with the ARF3 promoter from 'M9' and M. micromalus genotypes. The transgenic apple with 35S::MdARF3 was also obtained. The transgenic tobacco and apple with the highly expressed ARF3 had a longer root system and a higher plant height phenotype. Furthermore, the yeast one-hybrid, luciferase, electrophoretic mobility shift assays, and Chip-qPCR identified MdWOX4-1 in apples that interacted with the pMm-ARF3 promoter but not the pM9-ARF3 promoter. Notably, MdWOX4-1 significantly increased the transcriptional activity of MdARF3 and MdLBD16-2. However, MdARF3 significantly decreased the transcriptional activity of MdLBD16-2. Further analysis revealed that MdARF3 and MdLBD16-2 were temporally expressed during different stages of lateral root development. pMdLBD16-2 was mainly expressed during the early stage of lateral root development, which promoted lateral root production. On the contrary, pMmARF3 was expressed during the late stage of lateral root development to promote elongation. The findings in our study will shed light on the genetic causes of apple plant dwarfism and provide strategies for molecular breeding of dwarfing apple rootstocks.

Long-Term Follow-Up Defines the Population That Benefits from Early Interception in a High-Risk Smoldering Multiple Myeloma Clinical Trial Using the Combination of Ixazomib, Lenalidomide, and Dexamethasone.

Background: Early therapeutic intervention in high-risk SMM (HR-SMM) has demonstrated benefit in previous studies of lenalidomide with or without dexamethasone. Triplets and quadruplet studies have been examined in this same population. However, to date, none of these studies examined the impact of depth of response on long-term outcomes of participants treated with lenalidomide-based therapy, and whether the use of the 20/2/20 model or the addition of genomic alterations can further define the population that would benefit the most from early therapeutic intervention. Here, we present the results of the phase II study of the combination of ixazomib, lenalidomide, and dexamethasone in patients with HR-SMM with long-term follow-up and baseline single-cell tumor and immune sequencing that help refine the population to be treated for early intervention studies. Methods: This is a phase II trial of ixazomib, lenalidomide, and dexamethasone (IRD) in HR-SMM. Patients received 9 cycles of induction therapy with ixazomib 4mg on days 1, 8, and 15; lenalidomide 25mg on days 1-21; and dexamethasone 40mg on days 1, 8, 15, and 22. The induction phase was followed by maintenance with ixazomib 4mg on days 1, 8, and 15; and lenalidomide 15mg d1-21 for 15 cycles for 24 months of treatment. The primary endpoint was progression-free survival after 2 years of therapy. Secondary endpoints included depth of response, biochemical progression, and correlative studies included single-cell RNA sequencing and/or whole-genome sequencing of the tumor and single-cell sequencing of immune cells at baseline. Results: Fifty-five patients, with a median age of 64, were enrolled in the study. The overall response rate was 93%, with 31% of patients achieving a complete response and 45% achieving a very good partial response or better. The most common grade 3 or greater treatment-related hematologic toxicities were neutropenia (16 patients; 29%), leukopenia (10 patients; 18%), lymphocytopenia (8 patients; 15%), and thrombocytopenia (4 patients; 7%). Non-hematologic grade 3 or greater toxicities included hypophosphatemia (7 patients; 13%), rash (5 patients; 9%), and hypokalemia (4 patients; 7%). After a median follow-up of 50 months, the median progression-free survival (PFS) was 48.6 months (95% CI: 39.9 - not reached; NR) and median overall survival has not been reached. Patients achieving VGPR or better had a significantly better progression-free survival (p<0.001) compared to those who did not achieve VGPR (median PFS 58.2 months vs. 31.3 months). Biochemical progression preceded or was concurrent with the development of SLiM-CRAB criteria in eight patients during follow-up, indicating that biochemical progression is a meaningful endpoint that correlates with the development of end-organ damage. High-risk 20/2/20 participants had the worst PFS compared to low- and intermediate-risk participants. The use of whole genome or single-cell sequencing of tumor cells identified high-risk aberrations that were not identified by FISH alone and aided in the identification of participants at risk of progression. scRNA-seq analysis revealed a positive correlation between MHC class I expression and response to proteasome inhibition and at the same time a decreased proportion of GZMB+ T cells within the clonally expanded CD8+ T cell population correlated with suboptimal response. Conclusions: Ixazomib, lenalidomide and dexamethasone in HR-SMM demonstrates significant clinical activity with an overall favorable safety profile. Achievement of VGPR or greater led to significant improvement in time to progression, suggesting that achieving deep response is beneficial in HR-SMM. Biochemical progression correlates with end-organ damage. Patients with high-risk FISH and lack of deep response had poor outcomes. ClinicalTrials.gov identifier: (NCT02916771).

Targeting BMAL1 reverses drug resistance of acute myeloid leukemia cells and promotes ferroptosis through HMGB1-GPX4 signaling pathway.

PURPOSE: Acute myeloid leukemia (AML) is a refractory hematologic malignancy that poses a serious threat to human health. Exploring alternative therapeutic strategies capable of inducing alternative modes of cell death, such as ferroptosis, holds great promise as a viable and effective intervention. METHODS: We analyzed online database data and collected clinical samples to verify the expression and function of BMAL1 in AML. We conducted experiments on AML cell proliferation, cell cycle, ferroptosis, and chemotherapy resistance by overexpressing/knocking down BMAL1 and using assays such as MDA detection and BODIPY 581/591 C11 staining. We validated the transcriptional regulation of HMGB1 by BMAL1 through ChIP assay, luciferase assay, RNA level detection, and western blotting. Finally, we confirmed the results of our cell experiments at the animal level. RESULTS: BMAL1 up-regulation is an observed phenomenon in AML patients. Furthermore, there existed a strong correlation between elevated levels of BMAL1 expression and inferior prognosis in individuals with AML. We found that knocking down BMAL1 inhibited AML cell growth by blocking the cell cycle. Conversely, overexpressing BMAL1 promoted AML cell proliferation. Moreover, our research results revealed that BMAL1 inhibited ferroptosis in AML cells through BMAL1-HMGB1-GPX4 pathway. Finally, knocking down BMAL1 can enhance the efficacy of certain first-line cancer therapeutic drugs, including venetoclax, dasatinib, and sorafenib. CONCLUSION: Our research results suggest that BMAL1 plays a crucial regulatory role in AML cell proliferation, drug resistance, and ferroptosis. BMAL1 could be a potential important therapeutic target for AML.

MEK signaling represents a viable therapeutic vulnerability of KRAS-driven somatic brain arteriovenous malformations.

Brain arteriovenous malformations (bAVMs) are direct connections between arteries and veins that remodel into a complex nidus susceptible to rupture and hemorrhage. Most sporadic bAVMs feature somatic activating mutations within KRAS, and endothelial-specific expression of the constitutively active variant KRASG12D models sporadic bAVM in mice. By leveraging 3D-based micro-CT imaging, we demonstrate that KRASG12D-driven bAVMs arise in stereotypical anatomical locations within the murine brain, which coincide with high endogenous Kras expression. We extend these analyses to show that a distinct variant, KRASG12C, also generates bAVMs in predictable locations. Analysis of 15,000 human patients revealed that, similar to murine models, bAVMs preferentially occur in distinct regions of the adult brain. Furthermore, bAVM location correlates with hemorrhagic frequency. Quantification of 3D imaging revealed that G12D and G12C alter vessel density, tortuosity, and diameter within the mouse brain. Notably, aged G12D mice feature increased lethality, as well as impaired cognition and motor function. Critically, we show that pharmacological blockade of the downstream kinase, MEK, after lesion formation ameliorates KRASG12D-driven changes in the murine cerebrovasculature and may also impede bAVM progression in human pediatric patients. Collectively, these data show that distinct KRAS variants drive bAVMs in similar patterns and suggest MEK inhibition represents a non-surgical alternative therapy for sporadic bAVM.

Associated lifestyle factors of elevated plasma aldosterone concentration in community population, gender-stratified analysis of a cross-sectional survey.

BACKGROUND: Aldosterone plays important parts in development of cardio-metabolic diseases as end product of renin-angiotensin-aldosterone system. However, factors elevating circulating aldosterone are not clear, and lifestyle-related factors are suggested to be involved, whereas less studied. Therefore, we aimed to explore the association of lifestyle factors with plasma aldosterone concentration (PAC) in community population. METHODS: In this cross-sectional study, we recruited participants using multistage random sampling from Emin China in 2019, and collected data and fasting blood samples. The considered lifestyle factors included obesity parameters (neck circumference, abdominal circumference), alcohol consumption, blood pressure (BP), physical activity, sleep duration, sleep quality, mental state (depression and anxiety), fasting blood glucose (FBG), and lipid profiles (total cholesterol and triglyceride). PAC was measured using radioimmunoassay. We performed sex-stratified linear and logistic regressions to explore associated factors of PAC. Component analysis was further performed to identify the main factors affecting PAC. RESULTS: Twenty-seven thousand four hundred thirty-six participants with 47.1% men were included. Obesity parameters (neck circumference, abdominal circumference), glucose metabolism (FBG), psychological status (anxiety status in men and women, depression status in men), BP, liver function (in men), lipid metabolism (TC and TG in men), sleep parameters (sleep quality in women), and renal function (in women) are the main factors associated with elevated PAC. CONCLUSION: lower physical activity, alcohol consumption, higher BP, fat accumulation, dyslipidemia, higher fasting blood glucose, and presence of depression and anxiety were the main factors associated with eleveated PAC.

Nucleoporin Nup98 is an essential factor for ipo4 dependent protein import.

Nucleocytoplasmic transport of macromolecules is essential in eukaryotic cells. In this process, the karyopherins play a central role when they transport cargoes across the nuclear pore complex. Importin 4 belongs to the karyopherin ß family. Many studies have focused on finding substrates for importin 4, but no direct mechanism studies of its precise transport function have been reported. Therefore, this paper mainly aimed to study the mechanism of nucleoporins in mediating nuclear import and export of importin 4. To address this question, we constructed shRNAs targeting Nup358, Nup153, Nup98, and Nup50. We found that depletion of Nup98 resulted in a shift in the subcellular localization of importin 4 from the cytoplasm to the nucleus. Mutational analysis demonstrated that Nup98 physically and functionally interacts with importin 4 through its N-terminal phenylalanine-glycine (FG) repeat region. Mutation of nine of these FG motifs to SG motifs significantly attenuated the binding of Nup98 to importin 4, and we further confirmed the essential role of the six FG motifs in amino acids 121-360 of Nup98 in binding with importin 4. In vitro transport assay also confirmed that VDR, the substrate of importin 4, could not be transported into the nucleus after Nup98 knockdown. Overall, our results showed that Nup98 is required for efficient importin 4-mediated transport. This is the first study to reveal the mechanism of importin 4 in transporting substrates into the nucleus.

The YABBY Transcription Factor, SlYABBY2a, Positively Regulates Fruit Septum Development and Ripening in Tomatoes.

The tomato fruit is a complex organ and is composed of various structures from the inside out, such as columella, septum, and placenta. However, our understanding of the development and function of these internal structures remains limited. In this study, we identified a plant-specific YABBY protein, SlYABBY2a, in the tomato (Solanum lycopersicum). SlYABBY2a exhibits relatively high expression levels among the nine YABBY genes in tomatoes and shows specific expression in the septum of the fruit. Through the use of a gene-editing technique performed by CRISPR/Cas9, we noticed defects in septum development in the Slyabby2a mutant fruits, leading to the inward concavity of the fruit pericarp and delayed septum ripening. Notably, the expression levels of key genes involved in auxin (SlFZY4, SlFZY5, and SlFZY6) and ethylene (SlACS2) biosynthesis were significantly downregulated in the septum of the Slalkbh10b mutants. Furthermore, the promoter activity of SlYABBY2a was regulated by the ripening regulator, SlTAGL1, in vivo. In summary, these discoveries provide insights into the positive regulation of SlYABBY2a on septum development and ripening and furnish evidence of the coordinated regulation of the auxin and ethylene signaling pathways in the ripening process, which expands our comprehension of septum development in the internal structure of the fruit.

S-scheme electron transfer promoted by novel indium oxide quantum dot-loaded carbon nitride heterojunctions promoted using oxidized indium monomers.

The graphitic carbon nitride (g-C3N4) photocatalysis has emerged as a clean method for cleaving lignin-linked bonds due to its mild and sunlight-driven reaction conditions. The fast electron-hole pair complex of g-C3N4 constrains its degradation efficiency, making the heterojunction construction a popular solution. The conventional methods of preparing g-C3N4 heterojunctions by physical mixing destroy π-conjugations in g-C3N4, reducing the adsorption of lignin containing benzene rings. In this study, a novel indium oxide (In2O3) quantum dot-g-C3N4 0D/2D heterojunction was prepared through the high-temperature oxidation of pre-prepared indium-doped g-C3N4. The introduction of In2O3 at the quantum dot level minimizes the interference with lignin adsorption capacity. The strong combination of the two (In2O3 and g-C3N4) increases the intersection interface area, promoting the S-scheme transfer route of the photogenerated electrons. Consequently, this enhances the photoelectric conversion efficiency and carrier lifetime of the heterojunction, and inhibits the rapid recombination of photogenerated electron-hole pairs in g-C3N4. The proposed heterojunction was 3 times more efficient than g-C3N4 alone for selective cleavage of lignin ß-O-4 bonds after 2 h of sunlight irradiation. Combined with inhibitor experiments and gas chromatography-mass spectrometry analysis, this paper defines the reactive oxides and proposes a cleavage pathway for the lignin ß-O-4 bonds in In2O3-g-C3N4 heterojunction system.

Comparing Energy-Based Devices for Striae Improvement: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Striae distensae (SD) are cutaneous lesions that are caused by hormones or mechanical stress leading to rapid expansion of skin. Therefore, SD are now a cosmetic concern. However, improving SD is notoriously difficult. Among different treatments, energy-based devices (EBDs) are much more effective and controllable. OBJECTIVE: The aim of this review was to determine the most effective type of EBD for improving the appearance of striae. MATERIALS AND METHODS: The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The population comprised patients suffering from striae. Different types of EBDs used to improve striae were compared. The primary outcome of the reduction in the width of striae was evaluated. A random-effects model was performed. The means and standard deviations were extracted. RESULTS: Eighteen randomized controlled trials were included. The network meta-analysis revealed that after a comparison among the 4 types of EBDs, no significant differences were observed in the reduction of striae width. CONCLUSION: Radiofrequency, ablative lasers, nonablative lasers, and intense pulsed light are all effective treatments for reducing the striae width. None of them was superior to the others. However, radiofrequency and ablative lasers may have the highest chance of improving the appearance of striae.

Anti-inflammatory discovery of sesquiterpenoids and a jasmonic acid derivative from Artemisia stolonifera.

Eleven previously undescribed sesquiterpenoids (8-18), one undescribed jasmonic acid derivative (35) and 28 known compounds were isolated from the leaves of Artemisia stolonifera. Undescribed compounds with their absolute configurations were determined by extensive spectroscopic analysis, single-crystal X-ray diffraction and ECD calculation. Compound 8 was identified as a rare sesquiterpenoid featuring a rearranged 5/8 bicyclic ring system, whereas compound 17 was found to be an unprecedented monocyclic sesquiterpenoid with methyl rearrangement. Evaluation of biological activity showed that compounds 1-5 and 7 displayed cytotoxicity against six tumor cells. In the meantime, compounds 11, 12, 18 and 35 exhibited inhibitory effects against LPS-stimulated NO production in RAW 264.7 macrophage cells and reduced the transcription of IL-6 and IL-1ß in a dose-dependent manner at 25, 50 and 100 µM. Moreover, the anti-inflammatory-based network pharmacology and molecular docking analyses revealed potential target proteins of 11, 12, 18 and 35.

High-performance and frost-resistance MXene co-ionic liquid conductive hydrogel printed by electrohydrodynamic for flexible strain sensor.

Conductive hydrogels with high performance and frost resistance are essential for flexible electronics, electronic skin, and soft robots. Nonetheless, the preparation of hydrogel-based flexible strain sensors with rapid response, wide strain detection range, and high sensitivity remains a considerable challenge. Furthermore, the inevitable freezing and evaporation of water in sub-zero temperatures and dry environments lead to the loss of flexibility and conductivity in hydrogels, which seriously limits their practical application. In this work, ionic liquids (ILs) and MXene are introduced into gelatin/polyacrylamide (PAM) precursor solution, and a PAM/gelatin/ILs/MXene/glycerol (PGIMG) hydrogel-based flexible strain sensor with MXene co-ILs ion-electron composite conductive network is prepared by combining the electrohydrodynamic (EHD) printing method and in-situ photopolymerization. The introduction of ILs provides an ionic conductive channel for the hydrogel. The introduction of MXene nanosheets forms an interpenetrating network with gelatin and PAM, which not only provides a conductive channel, but also improves the mechanical and sensing properties of the hydrogel-based flexible strain sensor. The prepared PGIMG hydrogel with the MXene co-ILs ion-electron composite conductive network demonstrates a tensile strength of 0.21 MPa at 602.82 % strain, the conductivity of 1.636 × 10-3 S/cm, high sensitivity (Gauge Factor, GF = 4.17), a wide strain detection range (1-600 %), and the response/recovery times (73 ms and 74 ms). In addition, glycerol endows the hydrogel with excellent freezing (-60 °C) and water retention properties. The application of the hydrogel-based flexible strain sensor in the field of human motion detection and information transmission shows the great potential of wearable devices, electronic skin, and information encryption transmission.

Legionella effector LnaB is a phosphoryl-AMPylase that impairs phosphosignalling.

AMPylation is a posttranslational modification that generally modifies amino acid side chains of proteins with adenosine monophosphate (AMP)1,2. Here we report that with ATP as the ligand and actin as the host activator, the effector protein LnaB of Legionella pneumophila exhibits AMPylase activity toward the phosphoryl group of phosphoribose on PRR42-Ub that is generated by the SidE family effectors and deubiquitinases DupA/B in an E1/E2-independent ubiquitination process3-7. The product of LnaB is further hydrolyzed by an ADP-ribosyl hydrolase, MavL, to be Ub, thereby preventing accumulation of PRR42-Ub and ADPRR42-Ub and protecting the canonical ubiquitination in host cells. LnaB represents a large family of AMPylases adopting a common structural fold, which is distinct from those of the previously known AMPylases, in bacterial pathogens of more than 20 species. Moreover, LnaB also exhibits robust phosphoryl AMPylase activity toward phosphorylated residues and produces unique ADPylation modification in proteins. During infection, LnaB AMPylates the conserved phosphorylated tyrosine residues in the activation loop of the Src family kinases8,9, which dampens the host downstream phosphorylation signaling. Structural studies revealed the actin-dependent activation and catalytic mechanisms of the LnaB family of AMPylases. This study presents an unprecedented regulation and molecular mechanism in bacterial pathogenesis and protein phosphorylation.

Increasing CRISPR/Cas9-mediated gene editing efficiency in T7 phage by reducing the escape rate based on insight into the survival mechanism.

Bacteriophages have been used across various fields, and the utilization of CRISPR/Cas-based genome editing technology can accelerate the research and applications of bacteriophages. However, some bacteriophages can escape from the cleavage of Cas protein, such as Cas9, and decrease the efficiency of genome editing. This study focuses on the bacteriophage T7, which is widely utilized but whose mechanism of evading the cleavage of CRISPR/Cas9 has not been elucidated. First, we test the escape rates of T7 phage at different cleavage sites, ranging from 10 -2 to 10 -5. The sequencing results show that DNA point mutations and microhomology-mediated end joining (MMEJ) at the target sites are the main causes. Next, we indicate the existence of the hotspot DNA region of MMEJ and successfully reduce MMEJ events by designing targeted sites that bypass the hotspot DNA region. Moreover, we also knock out the ATP-dependent DNA ligase 1. 3 gene, which may be involved in the MMEJ event, and the frequency of MMEJ at 4. 3 is reduced from 83% to 18%. Finally, the genome editing efficiency in T7 Δ 1. 3 increases from 20% to 100%. This study reveals the mechanism of T7 phage evasion from the cleavage of CRISPR/Cas9 and demonstrates that the special design of editing sites or the deletion of key gene 1. 3 can reduce MMEJ events and enhance gene editing efficiency. These findings will contribute to advancing CRISPR/Cas-based tools for efficient genome editing in phages and provide a theoretical foundation for the broader application of phages.