Decreased IgA binding levels were accompanied by increased IgG sialylation in IgA nephropathy.

INTRODUCTION: IgA nephropathy (IgAN) is a kidney disorder characterized by the deposition of circulating immune complexes of IgG bound to galactose-deficient IgA1 (Gd-IgA1) in the mesangial glomeruli. However, limited research has been conducted on the levels of IgA binding in relation to the various sialylation profiles of IgG in IgAN. MATERIALS AND METHODS: Sialylated IgG (SA-IgG) and desialylated IgG (DSA-IgG) were isolated from IgAN patients. The IgG-IgA immune complex (IgG-IgA-IC) was detected using two customized commercial ELISA kits. Additionally, IgG was enzymatically digested with neuraminidase to produce DSA-IgG. Subsequently, the binding capacities of both intact IgG and the neuraminidase-digested DSA-IgG with Gd-IgA1 were determined using ELISA kits. RESULTS: Our research revealed that SA-IgG levels were negatively correlated with Gd-IgA1 (R = -0.16, p = 0.03) in IgAN patients. The optical density (OD) levels of IgG-IgA complexes in SA-IgG samples were significantly lower (0.58 ± 0.09) compared to those in DSA-IgG samples (0.78 ± 0.12) when using the Gd-IgA1 assay kit. These results were confirmed using an IgG assay kit, which showed that the SA-IgG groups had significantly lower IgA indices (0.31 ± 0.12) compared to the DSA-IgG groups (0.57 ± 0.19). Furthermore, we investigated the binding capacity of IgG with different sialic acid levels to Gd-IgA1. The results revealed that neuraminidase digestion of IgG increased its propensity to bind to Gd-IgA1. Additionally, we examined the binding capacity of both intact IgG and DSA-IgG to Gd-IgA1 at different mix ratios (IgG 1.5 µg and Gd-IgA1 1.5 µg, IgG 1.5 µg and Gd-IgA1 3 µg, IgG 3 µg and Gd-IgA1 1.5 µg). Interestingly, DSA-IgG demonstrated significantly higher binding capacity to Gd-IgA1 compared to intact IgG at all mix ratios tested. CONCLUSION: The preliminary findings from our present study indicate that the binding level of IgA in purified sialylated IgG is lower than that in desialylated IgG.

Combating Atherosclerosis with Chirality/Phase Dual-Engineered Nanozyme Featuring Microenvironment-Programmed Senolytic and Senomorphic Actions.

Senescence plays a critical role in the development and progression of various diseases. This study introduces an amorphous, high-entropy alloy (HEA)-based nanozyme designed to combat senescence. By adjusting the nanozyme's composition and surface properties, this work analyzes its catalytic performance under both normal and aging conditions, confirming that peroxide and superoxide dismutase (SOD) activity are crucial for its anti-aging therapeutic function. Subsequently, the chiral-dependent therapeutic effect is validated and the senolytic performance of D-handed PtPd2CuFe across several aging models is confirmed. Through multi-Omics analyses, this work explores the mechanism underlying the senolytic action exerted by nanozyme in depth. It is confirm that exposure to senescent conditions leads to the enrichment of copper and iron atoms in their lower oxidation states, disrupting the iron-thiol cluster in mitochondria and lipoic acid transferase, as well as oxidizing unsaturated fatty acids, triggering a cascade of cuproptosis and ferroptosis. Additionally, the concentration-dependent anti-aging effects of nanozyme is validated. Even an ultralow dose, the therapeutic can still act as a senomorphic, reducing the effects of senescence. Given its broad-spectrum action and concentration-adjustable anti-aging potential, this work confirms the remarkable therapeutic capability of D-handed PtPd2CuFe in managing atherosclerosis, a disease involving various types of senescent cells.

Macrophage MCT4 inhibition activates reparative genes and protects from atherosclerosis by histone H3 lysine 18 lactylation.

Macrophage activation is a hallmark of atherosclerosis, accompanied by a switch in core metabolism from oxidative phosphorylation to glycolysis. The crosstalk between metabolic rewiring and histone modifications in macrophages is worthy of further investigation. Here, we find that lactate efflux-associated monocarboxylate transporter 4 (MCT4)-mediated histone lactylation is closely related to atherosclerosis. Histone H3 lysine 18 lactylation dependent on MCT4 deficiency activated the transcription of anti-inflammatory genes and tricarboxylic acid cycle genes, resulting in the initiation of local repair and homeostasis. Strikingly, histone lactylation is characteristically involved in the stage-specific local repair process during M1 to M2 transformation, whereas histone methylation and acetylation are not. Gene manipulation and protein hydrolysis-targeted chimerism technology are used to confirm that MCT4 deficiency favors ameliorating atherosclerosis. Therefore, our study shows that macrophage MCT4 deficiency, which links metabolic rewiring and histone modifications, plays a key role in training macrophages to become repair and homeostasis phenotypes.

Oscillatory shear stress promotes endothelial senescence and atherosclerosis via STING activation.

Endothelial dysfunction is an initiating factor in atherosclerosis. Endothelial cells (ECs) are constantly subject to blood flow shear stress, and atherosclerotic plaques tend to occur in aortic bends or bifurcations impaired by low oscillatory shear stress (OSS). However, the mechanism that how OSS affects the initiation and progression of atherosclerosis remains to be explored. Here, we first reported that OSS can promote endothelial dysfunction and atherogenesis in vivo and in vitro by activating STING pathway. Mechanistically, at atherosclerosis-prone areas, OSS caused mitochondria damage in ECs, leading to the leakage of mitochondrial DNA (mtDNA) into the cytoplasm. The cytoplasmic mtDNA was recognized by cGAS to produce cGAMP, activating the STING pathway and leading to endothelial senescence, which resulted in endothelial dysfunction and atherosclerosis. We found that STING was activated in plaques of atherosclerotic patients and in aortic arch ECs of high-fat diet (HFD)-fed ApoeKO mice, as well as in ECs exposed to OSS. STING-specific deficiency in ECs attenuates endothelial senescence and resulted in a significant reduction in aortic arch plaque area in HFD-fed ApoeKO mice. Consistently, specific deficiency or pharmacological inhibition of STING attenuated OSS-induced senescence and endothelial dysfunction. Pharmacological depletion of mtDNA ameliorated OSS-induced senescence and endothelial dysfunction. Taken together, our study linked hemodynamics and endothelial senescence, and revealed a novel mechanism by which OSS leads to endothelial dysfunction. Our study provided new insights into the development of therapeutic strategies for endothelial senescence and atherosclerosis.

High-power 100 W Kerr-lens mode-locked ring-cavity femtosecond Yb:YAG thin-disk oscillator.

High-power femtosecond pulses delivered at a high-repetition rate will aid machining throughput and improve signal-to-noise ratios for sensitive measurements. Here we demonstrate a Kerr-lens mode-locked femtosecond Yb:YAG ring-cavity thin-disk oscillator with a multi-pass scheme for the laser beam. With four passes through the thin disk, 175-fs pulses were delivered from the oscillator at an average power of 71.5 W and a repetition rate of 65.3 MHz. The corresponding intra-cavity peak power of 110 MW is ample for intra-cavity nonlinear conversion into more exotic wavelength ranges. With six passes, the average output power reached 101.3 W. To the best of our knowledge, this is the highest average output power of any mode-locked ring laser. These results confirm the viability of using multi-pass configuration on a thin-disk ring oscillator for high-throughput femtosecond applications.

Uncovering the potential of APOD as a biomarker in gastric cancer: A retrospective and multi-center study.

Gastric cancer (GC) poses a significant health challenge worldwide, necessitating the identification of predictive biomarkers to improve prognosis. Dysregulated lipid metabolism is a well-recognized hallmark of tumorigenesis, prompting investigation into apolipoproteins (APOs). In this study, we focused on apolipoprotein D (APOD) following comprehensive analyses of APOs in pan-cancer. Utilizing data from the TCGA-STAD and GSE62254 cohorts, we elucidated associations between APOD expression and multiple facets of GC, including prognosis, tumor microenvironment (TME), cancer biomarkers, mutations, and immunotherapy response, and identified potential anti-GC drugs. Single-cell analyses and immunohistochemical staining confirmed APOD expression in fibroblasts within the GC microenvironment. Additionally, we independently validated the prognostic significance of APOD in the ZN-GC cohort. Our comprehensive analyses revealed that high APOD expression in GC patients was notably associated with unfavorable clinical outcomes, reduced microsatellite instability and tumor mutation burden, alterations in the TME, and diminished response to immunotherapy. These findings provide valuable insights into the potential prognostic and therapeutic implications of APOD in GC.

lncRNA JPX-Enriched Chromatin Microenvironment Mediates Vascular Smooth Muscle Cell Senescence and Promotes Atherosclerosis.

BACKGROUND: Senescence is a series of degenerative changes in the structure and physiological function of an organism. Whether JPX (just proximal to XIST)-a newly identified age-related noncoding RNA by us-is associated with atherosclerosis is still unknown. Our study was to investigate the role of JPX and provide insights into potential therapies targeting atherosclerosis. METHODS: We analyzed clinical data from multiple tissues including meniscus tissue, leukemia cells, and peripheral blood monocytes to identify age-related noncoding RNAs in senescent vascular smooth muscle cells (VSMCs). The molecular mechanism of JPX was investigated by capture hybridization analysis of RNA targets and chromatin immunoprecipitation. IGVTools and real-time quantitative polymerase chain reaction were used to evaluate the JPX expression during phenotype regulation in age-related disease models. The therapeutic potential of JPX was evaluated after establishing an atherosclerosis model in smooth muscle-specific Jpx knockout mice. RESULTS: JPX expression was upregulated in activated ras allele (H-rasV12)-induced senescent VSMCs and atherosclerotic arteries. JPX knockdown substantially reduced the elevation of senescence-associated secretory phenotype (SASP) genes in senescent VSMCs. Cytoplasmic DNA leaked from mitochondria via mitochondrial permeability transition pore formed by VDAC1 (voltage-dependent anion channel 1) oligomer activates the STING (stimulator of interferon gene) pathway. JPX could act as an enhancer for the SASP genes and functions as a scaffold molecule through interacting with phosphorylated p65/RelA and BRD4 (bromodomain-containing protein 4) in chromatin remodeling complex, promoting the transcription of SASP genes via epigenetic regulation. Smooth muscle knockout of Jpx in ApoeKO mice resulted in a decrease in plaque area, a reduction in SASP gene expression, and a decrease in senescence compared with controls. CONCLUSIONS: As an enhancer RNA, JPX can integrate p65 and BRD4 to form a chromatin remodeling complex, activating SASP gene transcription and promoting cellular senescence. These findings suggest that JPX is a potential therapeutic target for the treatment of age-related atherosclerosis.

Non-canonical STING-PERK pathway dependent epigenetic regulation of vascular endothelial dysfunction via integrating IRF3 and NF-κB in inflammatory response.

Inflammation-driven endothelial dysfunction is the major initiating factor in atherosclerosis, while the underlying mechanism remains elusive. Here, we report that the non-canonical stimulator of interferon genes (STING)-PKR-like ER kinase (PERK) pathway was significantly activated in both human and mice atherosclerotic arteries. Typically, STING activation leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF-κB)/p65, thereby facilitating IFN signals and inflammation. In contrast, our study reveals the activated non-canonical STING-PERK pathway increases scaffold protein bromodomain protein 4 (BRD4) expression, which encourages the formation of super-enhancers on the proximal promoter regions of the proinflammatory cytokines, thereby enabling the transactivation of these cytokines by integrating activated IRF3 and NF-κB via a condensation process. Endothelium-specific STING and BRD4 deficiency significantly decreased the plaque area and inflammation. Mechanistically, this pathway is triggered by leaked mitochondrial DNA (mtDNA) via mitochondrial permeability transition pore (mPTP), formed by voltage-dependent anion channel 1 (VDAC1) oligomer interaction with oxidized mtDNA upon cholesterol oxidation stimulation. Especially, compared to macrophages, endothelial STING activation plays a more pronounced role in atherosclerosis. We propose a non-canonical STING-PERK pathway-dependent epigenetic paradigm in atherosclerosis that integrates IRF3, NF-κB and BRD4 in inflammatory responses, which provides emerging therapeutic modalities for vascular endothelial dysfunction.

The effect of fibrinoid necrosis on the clinical features and outcomes of primary IgA nephropathy.

BACKGROUND: To explore the clinicopathologic features and outcomes of IgAN patients who presented with fibrinoid necrosis (FN) lesions or not and the effect of immunosuppressive (IS) treatment in IgAN patients with FN lesions as well. METHODS: This was a retrospective cohort study with 665 patients diagnosed with primary IgAN from January 2010 to December 2020 in Tianjin Medical University General Hospital and having detailed baseline and follow-up characteristics. Patients were divided into two groups depending on the appearance of FN lesions. Patients with FN lesions were recruited into Group FN1, while patients who were not found FN lesions in their renal biopsy specimens were recruited into Group FN0. Compare the differences between Group FN0 and Group FN1 in baseline clinicopathologic features, treatment solutions and follow-up data as well. To evaluate the impact of different fractions of FN lesions on baseline characteristics and prognosis of IgAN, we subdivided patients in Group FN1 into 3 groups depending on the FN lesions distribution, Mild Group: 0 < FN% < 1/16; Moderate Group: 1/16 < FN% < 1/10; Severe Group: FN% > 1/10. Furthermore, we compared the differences in baseline clinicopathologic features, treatment solutions and follow-up data among these three groups. Kidney endpoint event was defined as patients went into end-stage kidney disease (ESKD), which estimated glomerular filtration rate (eGFR) < 15 ml/min/1.73 m^2, regularly chronic dialysis over 6 months or received renal transplantation surgery. The kidney composite endpoint was defined by a ≥ 30% reduction in eGFR, double Scr increase than on-set, ESKD, chronic dialysis over 6 months or renal transplantation. Compare the survival from a composite endpoint rate in different groups by Kaplan-Meier survival curve. The univariate and multivariate Cox models were used to establish the basic model for renal outcomes in patients with FN lesions. RESULTS: (1) A total of 230 patients (34.59%) were found FN lesions in all participants. Patients with FN lesions suffered more severe hematuria than those without. On the hand of pathological characteristic, patients with FN lesions showed higher proportions of M1, E1, C1/C2 and T1/T2 lesions compared with those without FN lesions. (2) The 1-year, 3-year, and 5-year survival of the composite endpoint were lower in the FN1 group than FN0 group. (3) After adjusting for clinicopathological variables, the presence of FN lesions was a significantly independent risk factor for composite endpoint. By using multivariate Cox regression analyses, we also found when the fraction of FN lesions exceeded 10%, the risk of progression into composite endpoint increased 3.927 times. CONCLUSION: Fibrinoid necrosis of capillary loops is an independent risk factor of poor renal outcomes. More effective treatment should be considered for those who had FN lesions.

Generation of femtosecond optical vortices with multiple separate phase singularities from a Kerr-lens mode-locked Yb:KGW oscillator.

Femtosecond optical vortices with a phase singular point have diverse applications such as microscopic particles manipulation, special-structure micro-processing and quantum information. Raising the number of singularity points can provide additional dimensions of control. Here we report for what we believe is the first time the generation of femtosecond optical vortices with multiple (two and five) singularities directly from a laser oscillator. The average powers and pulse durations of the resulting vortex pulses are several hundred milliwatts and less than 300 fs, respectively. This work represents an innovate way for obtaining femtosecond multi-vortices, opening the way to the further studies of optical vortex crystals and their applications.

Self-started Kerr-lens mode-locked thin-disk oscillator.

Kerr-lens mode-locking (KLM) has been widely used in thin-disk oscillators to generate high-power femtosecond pulses. Here we demonstrate a Kerr-lens mode-locked Yb:YAG thin-disk oscillator that can be self-started under two configurations. The first can deliver 13-W, 235-fs pulses at a repetition rate of 103 MHz; the second delivers 49 W at a repetition rate of 46.5 MHz, whose corresponding pulse energy of 1.05 µJ is, to the best of our knowledge, the highest energy ever obtained in self-started Kerr-lens mode-locked oscillators. A new method to initiate KLM in the form of optical perturbation in a thin-disk oscillator has also been demonstrated.

Granule Dendrobii suppresses chronic atrophic gastritis induced by N-methyl-N'-nitro-N-nitrosoguanidine by modulating the gastrointestinal bacteria in rats.

Chronic atrophic gastritis (CAG) is an important stage in the transformation of the normal gastric mucosa into gastric cancer. Granule Dendrobii (GD), a proprietary Chinese medicine, has proven clinical efficacy in treating CAG. GD might promote the reversal of precancerous lesions by improving them in CAG patients. However, the mechanism of GD in CAG treatment is relatively less understood. Here, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced CAG rats were treated with GD and its efficacy was evaluated by observing the changes in the rats' weight and the pathology of gastric tissues. The potential effect of GD on the bacteria was predicted and verified in the large and small intestines and stomachs of CAG rats using amplicon sequencing and RT-qPCR. The results showed that GD could ameliorate the symptoms of body weight loss in CAG rats. Hematoxylin-Eosin (HE) and Alcian Blue (AB) staining showed that GD significantly improved the pathological state of the gastric mucosa in CAG rats. The relative abundance (RA) of Lactobacillus and Turicibacter significantly decreased after GD intervention compared with that of the model group (P < 0.05), indicating that GD might improve CAG by regulating the RA of Lactobacillus and Turicibacter. These findings revealed that Lactobacillus and Turicibacter as bacteria agents associated with gastritis, have the potential to inhibit gastric cancer, especially Turicibacter maybe another pathogen of CAG besides Helicobacter pylori (HP), which is worthy of further study. Meanwhile, the findings provided new ideas and materials for the research and development of new CAG drugs.

Modulating the organic photovoltaic properties of non-fullerene acceptors by molecular modification based on Y6: a theoretical study.

Developing non-fullerene acceptors (NFAs) by modifying the backbone, side chains and end groups is the most important strategy to improve the power conversion efficiency of organic solar cells (OSCs). Among numerous developed NFAs, Y6 and its derivatives are famous NFAs in the OSC field due to their good performance. Herein, in order to understand the mechanism of tuning the photovoltaic performance by modifying the Y6's center backbone, π-spacer and side-chains, we selected the PM6:Y6 OSC as a reference and systematically studied PM6:AQx-2, PM6:Y6-T, PM6:Y6-2T, PM6:Y6-O, PM6:Y6-1O and PM6:Y6-2O OSC systems based on extensive quantum chemistry calculations. The results indicate that introducing quinoxaline to substitute thiadiazole in the backbone induces a blue-shift of absorption spectra, reduces the charge transfer (CT) distance (Δd) and average electrostatic potential (ESP), and increases the singlet-triplet energy gap (ΔEST), CT excitation energy and the number of CT states in low-lying excitations. Inserting thienyl and dithiophenyl as π spacers generates a red-shift of absorption spectra, enlarges Δd and average ESP, and reduces ΔEST and the number of CT states. Introducing furo[3,2-b]furan for substituting one thieno[3,2-b]thiophene unit in the Y6's backbone causes a red-shift of absorption spectra and increases ΔEST, Δd and average ESP as well as CT excitation energy. Introducing alkoxyl as a side chain results in a blue-shift of absorption spectra, and increases ΔEST, Δd, average ESP, CT excitation energy and the number of CT states. The rate constants calculated using Marcus theory suggest that all the molecular modifications of Y6 reduce the exciton dissociation and charge recombination rates at the heterojunction interface, while introducing furo[3,2-b]furan and alkoxyl enlarges CT rates.

High-order femtosecond vortices up to the 30th order generated from a powerful mode-locked Hermite-Gaussian laser.

Femtosecond vortex beams are of great scientific and practical interest because of their unique phase properties in both the longitudinal and transverse modes, enabling multi-dimensional quantum control of light fields. Until now, generating femtosecond vortex beams for applications that simultaneously require ultrashort pulse duration, high power, high vortex order, and a low cost and compact laser source has been very challenging due to the limitations of available generation methods. Here, we present a compact apparatus that generates powerful high-order femtosecond vortex pulses via astigmatic mode conversion from a mode-locked Hermite-Gaussian Yb:KGW laser oscillator in a hybrid scheme using both the translation-based off-axis pumping and the angle-based non-collinear pumping techniques. This hybrid scheme enables the generation of femtosecond vortices with a continuously tunable vortex order from the 1st up to the 30th order, which is the highest order obtained from any femtosecond vortex laser source based on a mode-locked oscillator. The average powers and pulse durations of all resulting vortex pulses are several hundred milliwatts and <650 fs, respectively. In particular, 424-fs 11th-order vortex pulses have been achieved with an average power of 1.6 W, several times more powerful than state-of-the-art oscillator-based femtosecond vortex sources.

Effect of hematuria on the kidney disease progression in IgA nephropathy patients with mild proteinuria and well-preserved renal function.

OBJECTIVE: To investigate whether hematuria is a risk factor in IgA nephropathy (IgAN) patients with mild proteinuria and well-preserved renal function. METHODS: This retrospective study included a total of 63 IgAN patients, with complete clinical data available for 50 patients. Hematuria assessment was conducted using two methods: 1) an automated method using a urine particle analyzer, and 2) a manual method performed by a skilled examiner to examine microscopic urine sediment. RESULTS: The results of hematuria measurement using both automated and manual methods showed a strong linear correlation (r = 0.78, P < 0.001). In IgAN patients, those with high urinary red blood cell count (U-RBCs) exhibited higher serum IgA levels compared to patients with low U-RBCs. Additionally, patients with crescent formation had higher levels of proteinuria compared to those without crescents. Patients who received immunosuppressive treatment displayed higher levels of systolic blood pressure (SBP) and mean arterial pressure (MAP), as well as lower levels of serum hemoglobin and albumin. They also had a higher prevalence of T1 lesions compared to patients who did not undergo immunosuppression. Furthermore, among patients with crescent formation, those who received immunosuppressive agents exhibited higher levels of SBP, diastolic blood pressure (DBP), MAP, and U-RBCs, as well as lower levels of albumin and proteinuria at the time of renal biopsy. No composite kidney endpoint events were observed in these groups of patients. The U-RBCs level was not identified as a risk factor influencing the decline of estimated glomerular filtration rate (eGFR) in IgAN. CONCLUSIONS: The presence of hematuria at the time of biopsy was not found to be associated with kidney disease progression in IgAN patients who had mild proteinuria and well-preserved renal function. This suggests that it is possible that these patients may not derive significant benefits from immunosuppressive therapy.

Mitochondrial GSNOR Alleviates Cardiac Dysfunction via ANT1 Denitrosylation.

BACKGROUND: The cardiac-protective role of GSNOR (S-nitrosoglutathione reductase) in the cytoplasm, as a denitrosylase enzyme of S-nitrosylation, has been reported in cardiac remodeling, but whether GSNOR is localized in other organelles and exerts novel effects remains unknown. We aimed to elucidate the effects of mitochondrial GSNOR, a novel subcellular localization of GSNOR, on cardiac remodeling and heart failure (HF). METHODS: GSNOR subcellular localization was observed by cellular fractionation assay, immunofluorescent staining, and colloidal gold particle staining. Overexpression of GSNOR in mitochondria was achieved by mitochondria-targeting sequence-directed adeno-associated virus 9. Cardiac-specific knockout of GSNOR mice was used to examine the role of GSNOR in HF. S-nitrosylation sites of ANT1 (adenine nucleotide translocase 1) were identified using biotin-switch and liquid chromatography-tandem mass spectrometry. RESULTS: GSNOR expression was suppressed in cardiac tissues of patients with HF. Consistently, cardiac-specific knockout mice showed aggravated pathological remodeling induced by transverse aortic constriction. We found that GSNOR is also localized in mitochondria. In the angiotensin II-induced hypertrophic cardiomyocytes, mitochondrial GSNOR levels significantly decreased along with mitochondrial functional impairment. Restoration of mitochondrial GSNOR levels in cardiac-specific knockout mice significantly improved mitochondrial function and cardiac performance in transverse aortic constriction-induced HF mice. Mechanistically, we identified ANT1 as a direct target of GSNOR. A decrease in mitochondrial GSNOR under HF leads to an elevation of S-nitrosylation ANT1 at cysteine 160 (C160). In accordance with these findings, overexpression of either mitochondrial GSNOR or ANT1 C160A, non-nitrosylated mutant, significantly improved mitochondrial function, maintained the mitochondrial membrane potential, and upregulated mitophagy. CONCLUSIONS: We identified a novel species of GSNOR localized in mitochondria and found mitochondrial GSNOR plays an essential role in maintaining mitochondrial homeostasis through ANT1 denitrosylation, which provides a potential novel therapeutic target for HF.

Sub-100-fs Kerr-lens mode-locked Yb:YAG ring-cavity thin-disk oscillator.

Ultrafast ring-cavity thin-disk oscillators combine high output power with the flexibility of generating output either unidirectionally or bidirectionally. Here, we report a Kerr-lens mode-locked ring-cavity Yb:YAG thin-disk oscillator delivering unidirectional 89-fs pulses by inducing additional spectral broadening with nonlinear plates. This is the shortest pulse duration for a ring-cavity mode-locked thin-disk oscillator. Bidirectional mode-locking was also realized. These results lay the foundation for the more efficient generation of high-order harmonics at MHz repetition rates and high-power dual frequency combs.

High-power femtosecond vortices generated from a Kerr-lens mode-locked solid-state Hermite-Gaussian oscillator.

We report the generation of high-order transverse modes from a Kerr-lens mode-locked femtosecond laser. Two different orders of Hermite-Gaussian modes were realized by non-collinear pumping, which were converted into the corresponding Laguerre-Gaussian vortex modes using a cylindrical lens mode converter. The mode-locked vortex beams, with an average power of 1.4 W and 0.8 W, contained pulses as short as 126 fs and 170 fs at the first and second Hermite-Gaussian mode orders, respectively. This work demonstrates the possibility of developing Kerr-lens mode-locked bulk lasers with various pure high-order modes and paves the way for generating ultrashort vortex beams.

Cathepsin B S-nitrosylation promotes ADAR1-mediated editing of its own mRNA transcript via an ADD1/MATR3 regulatory axis.

Genetic information is generally transferred from RNA to protein according to the classic "Central Dogma". Here, we made a striking discovery that post-translational modification of a protein specifically regulates the editing of its own mRNA. We show that S-nitrosylation of cathepsin B (CTSB) exclusively alters the adenosine-to-inosine (A-to-I) editing of its own mRNA. Mechanistically, CTSB S-nitrosylation promotes the dephosphorylation and nuclear translocation of ADD1, leading to the recruitment of MATR3 and ADAR1 to CTSB mRNA. ADAR1-mediated A-to-I RNA editing enables the binding of HuR to CTSB mRNA, resulting in increased CTSB mRNA stability and subsequently higher steady-state levels of CTSB protein. Together, we uncovered a unique feedforward mechanism of protein expression regulation mediated by the ADD1/MATR3/ADAR1 regulatory axis. Our study demonstrates a novel reverse flow of information from the post-translational modification of a protein back to the post-transcriptional regulation of its own mRNA precursor. We coined this process as "Protein-directed EDiting of its Own mRNA by ADAR1 (PEDORA)" and suggest that this constitutes an additional layer of protein expression control. "PEDORA" could represent a currently hidden mechanism in eukaryotic gene expression regulation.

Autophagy-Related Gene WD Repeat Domain 45B Promotes Tumor Proliferation and Migration of Hepatocellular Carcinoma through the Akt/mTOR Signaling Pathway.

Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor. It has been found that autophagy plays a role both as a tumor promoter and inhibitor in HCC carcinogenesis. However, the mechanism behind is still unveiled. This study aims to explore the functions and mechanism of the key autophagy-related proteins, to shed light on novel clinical diagnoses and treatment targets of HCC. Bioinformation analyses were performed by using data from public databases including TCGA, ICGC, and UCSC Xena. The upregulated autophagy-related gene WDR45B was identified and validated in human liver cell line LO2, human HCC cell line HepG2 and Huh-7. Immunohistochemical assay (IHC) was also performed on formalin-fixed paraffin-embedded (FFPE) tissues of 56 HCC patients from our pathology archives. By using qRT-PCR and Western blots we found that high expression of WDR45B influenced the Akt/mTOR signaling pathway. Autophagy marker LC3- II/LC3-I was downregulated, and p62/SQSTM1 was upregulated after knockdown of WDR45B. The effects of WDR45B knockdown on autophagy and Akt/mTOR signaling pathways can be reversed by the autophagy inducer rapamycin. Moreover, proliferation and migration of HCC can be inhibited after the knockdown of WDR45B through the CCK8 assay, wound-healing assay and Transwell cell migration and invasion assay. Therefore, WDR45B may become a novel biomarker for HCC prognosis assessment and potential target for molecular therapy.