Clinical characteristics and outcome of double-seropositive patients with anti-glomerular basement membrane antibodies and anti-neutrophil cytoplasmic antibodies.

OBJECTIVE: To explore the clinical characteristics of double-seropositive patients (DPPs) with anti-glomerular basement membrane (Anti-GBM) antibodies and anti-neutrophil cytoplasmic antibodies (ANCA). METHODS: We collected patients with both ANCA and anti-GBM positive glomerulonephritis who were hospitalized in the Department of Nephrology at the First Affiliated Hospital of Nanjing Medical University from January 2010 to August 2022. Retrospective analysis of the baseline clinical characteristics of patients and follow-up to explore relevant factors affecting renal and patient survival. RESULTS: A total of 386 patients, including 69 ANCA negative anti-GBM glomerulonephritis patients, 296 anti-GBM negative ANCA associated vasculitis (AAV) patients, and 21 DPPs were enrolled in this study. Among the 21 DPPs aged 68.0 years (59.5, 74.0), there were 11 males and 10 females. The median serum creatinine at diagnosis was 629.0 (343.85, 788.75) µmol/L, and the median eGFR (CKD-EPI) was 7.58 (4.74, 13.77) mL/min. Fifteen cases (71.4 %) underwent initial RRT. After a follow-up of 40.0 (11.0, 73.0) months, 13 out of 21 DPPs (61.9 %) received maintenance RRT, while 49 out of 69 (71.0 %) ANCA negative anti-GBM-GN patients and 124 out of 296 (41.9 %) anti-GBM negative AAV patients received maintenance RRT (P < 0.001). Kaplan-Meier survival analysis showed that DPPs and ANCA negative anti-GBM-GN patients were more likely to progress to ESRD than anti-GBM negative AAV patients (P = 0.001). Among the 21 patients with DPPs, renal survival was significantly better in patients with better initial renal function, including those who did not receive initial RRT (P = 0.003), with lower serum creatinine levels (Cr < 629.0 µmol/L, P = 0.004) and higher eGFR levels (eGFR ≥ 7.60 ml/min, P = 0.005) than those with poor initial renal function. At the end of follow-up, 14 out of 21 DPPs (66.7 %) survived. Survival analysis showed no significant difference among patients in DPPs group, ANCA negative anti-GBM-GN group, and anti-GBM negative AAV group. CONCLUSIONS: DPPs and ANCA negative anti-GBM-GN patients were more likely to progress to ESRD than anti-GBM negative AAV patients. In DPPs, the poor renal function at diagnosis might be a risk factor associated with poor renal survival.

Plasma Deoxycholic Acid Levels are Associated with Hemodynamic and Clinical Outcomes in Acute Pulmonary Embolism Patients.

This study aimed to evaluate the correlation of plasma deoxycholic acid (DCA) levels with clinical and hemodynamic parameters in acute pulmonary embolism (APE) patients. Total 149 APE adult patients were prospectively recruited. Plasma DCA levels were measured using rapid resolution liquid chromatography-quadrupole time-of-flight mass spectrometry. Baseline clinical and hemodynamic parameters were evaluated according to plasma DCA levels. The plasma DCA levels were significantly lower in APE patients than in those without APE (P < 0.001). APE patients with adverse events had lower plasma DCA levels (P < 0.001). Low DCA group patients presented more adverse cardiac function, higher NT-proBNP levels (P = 0.010), and higher WHO functional class levels (P = 0.023). Low DCA group also presented with an adverse hemodynamic status, with higher pulmonary vascular resistance levels (P = 0.027) and lower cardiac index levels (P = 0.024). Both cardiac function and hemodynamic parameters correlated well with plasma DCA levels. Kaplan-Meier survival analysis demonstrated that APE patients with lower plasma DCA levels had a significantly higher event rate (P = 0.009). In the univariate and multivariate Cox regression analyses, the plasma DCA level was an independent predictor of clinical worsening events after adjusting for age, sex, WHO functional class, NT-proBNP level, pulmonary vascular resistance, and cardiac index (HR 0.370, 95% CI 0.161, 0.852; P = 0.019). Low plasma DCA levels predicted adverse cardiac function and hemodynamic collapse. A low DCA level was correlated with a higher clinical worsening event rate and could be an independent predictor of clinical outcomes in multivariate analysis.

Tumor suppressor KEAP1 promotes HSPA9 degradation, controlling mitochondrial biogenesis in breast cancer.

The oxidative-stress-related protein Kelch-like ECH-associated protein 1 (KEAP1) is a substrate articulator of E3 ubiquitin ligase, which plays an important role in the ubiquitination modification of proteins. However, the function of KEAP1 in breast cancer and its impact on the survival of patients with breast cancer remain unclear. Our study demonstrates that KEAP1, a positive prognostic factor, plays a crucial role in regulating cell proliferation, apoptosis, and cell cycle transition in breast cancer. We investigate the underlying mechanism using human tumor tissues, high-throughput detection technology, and a mouse xenograft tumor model. KEAP1 serves as a key regulator of cellular metabolism, the reprogramming of which is one of the hallmarks of tumorigenesis. KEAP1 has a significant effect on mitochondrial biogenesis and oxidative phosphorylation by regulating HSPA9 ubiquitination and degradation. These results suggest that KEAP1 could serve as a potential biomarker and therapeutic target in the treatment of breast cancer.

Autophagy regulates age-related delayed jawbone regeneration and decreased osteoblast osteogenesis by degrading FABP3.

The regenerative ability of limb bones after injury decreases during aging, but whether a similar phenomenon occurs in jawbones and whether autophagy plays a role in this process remain unclear. Through retrospective analysis of clinical data and studies on a mouse model of jawbone defects, we confirmed the presence of delayed or impaired bone regeneration in the jawbones of old individuals and mice. Subsequently, osteoblasts (OBs) derived from mouse jawbones were isolated, showing reduced osteogenesis in senescent osteoblasts (S-OBs). We observed a reduction in autophagy within both aged jawbones and S-OBs. Additionally, pharmacological inhibition of autophagy in normal OBs (N-OBs) led to cell aging and decreased osteogenesis, while autophagic activation reversed the aging phenotype of S-OBs. The activator rapamycin (RAPA) increased the autophagy level and bone regeneration in aged jawbones. Finally, we found that fatty acid-binding protein 3 (FABP3) was degraded by autolysosomes through its interaction with sequestosome 1 (P62/SQSTM1). Autophagy inhibition within senescent jawbones and S-OBs led to the excessive accumulation of FABP3, and FABP3 knockdown partially rescued the decreased osteogenesis in S-OBs and alleviated age-related compromised jawbone regeneration. In summary, we confirmed that autophagy inhibition plays an important role in delaying bone regeneration in aging jawbones. Autophagic activation or FABP3 knockdown can partially rescue the osteogenesis of S-OBs and the regeneration of aging jawbones, providing insight into jawbone aging.

Discovery of sesquiterpene lactones with anti-inflammatory effect from Youngia japonica.

The preliminary study revealed that the ethyl acetate eluate of Youngia japonica (YJ-E) could inhibit the expression of key proteins of p-p65, p-IκBα, p-IKKα/ß, and p-AKT in LPS stimulated BV2 cell. Further phytochemical study led to the isolation of eight compounds from YJ-E, including one new sesquiterpene lactone. Their structures were elucidated by several spectroscopic data, and comparing the NMR data of known compound. In addition, all of the isolates were evaluated for the anti-inflammatory effect. As a result, compounds 3 and 4 distinctly attenuated the expressions of p-IκBα, p-p65, and p-AKT in LPS stimulated BV2 cell, respectively.

GSK3 regulation Wnt/ß-catenin signaling affects adipogenesis in bovine skeletal muscle fibro/adipogenic progenitors.

Clarifying the cellular origin and regulatory mechanisms of intramuscular fat (IMF) deposition is crucial for improving beef quality. Here, we used single-nucleus RNA sequencing to analyze the structure and heterogeneity of skeletal muscle cell populations in different developmental stages of Yanbian cattle and identified eight cell types in two developmental stages of calves and adults. Among them, fibro/adipogenic progenitors (FAPs) expressing CD29 (ITGA7)pos and CD56 (NCAM1)neg surface markers were committed to IMF deposition in beef cattle and expressed major Wnt ligands and receptors. LY2090314/XAV-939 was used to activate/inhibit Wnt/ß-catenin signal. The results showed that the blockade of Glycogen Synthase Kinase 3 (GSK3) by LY2090314 promoted the stabilization of ß-catenin and reduced the expression of genes related adipogenic differentiation (e.g., PPARγ and C/EBPα) in bovine FAPs, confirming the anti-adipogenic effect of GSK3. XAV-939 inhibition of the Wnt/ß-catenin pathway promoted the lipid accumulation capacity of FAPs. Furthermore, we found that blocking GSK3 enhanced the paracrine effects of FAPs-MuSCs and increased myotube formation in muscle satellite cells (MuSCs). Overall, our results outline a single-cell atlas of skeletal muscle development in Yanbian cattle, revealed the role of Wnt/GSK3/ß-catenin signaling in FAPs adipogenesis, and provide a theoretical basis for further regulation of bovine IMF deposition.

Flow dynamics and turbulent coherent structures around sediment reduction plates of a sewer system.

In the management of urban drainage networks, great interest has been generated in the removal of sediments from sewer systems. The unsteady three-dimensional (3D) flow and turbulent coherent structures surrounding sediment reduction plates in a sewer system are investigated by means of the detached-eddy simulation (DES). Particular emphasis is given to detailing the instantaneous velocity and vorticity fields within the grooves, along with an examination of the three-dimensional, long-term, average flow structure at a Reynolds number of approximately 105. Velocity vectors demonstrate continuous flapping of the flow on the groove wall, periodically interacting with ejections of positive and negative vorticity originating from the grooves. The interaction between the three-dimensional groove flow and the shear flow leads to the downstream transport of patches of positive and negative vorticity, which significantly influence sediment transport. The high-velocity shear flows and strong vortices generated in undulating topography, as identified by the Q-criteria, are the key factors contributing to the efficient sediment reduction capabilities of the sediment reduction plates. The sediment reduction plates with partially enclosed structures exhibit low sedimentation rates in grooves on the plate, a broader acceleration region, and a lesser impact on the flow capacity. The results improve the understanding of the hydrodynamics and turbulent coherent structures surrounding the sediment reduction plates while elucidating the driving factors behind the enhancement of sediment scouring and suspension capacities. These results indicate that the redesign of the plates as partially enclosed structures contributes to further improving their sediment reduction performance.

Delineation of the phenotypes and genotypes of PIK3CA-related overgrowth spectrum in East asians.

PIK3CA-related overgrowth spectrum (PROS) is an umbrella term to describe a diverse range of developmental disorders. Research to date has predominantly emerged from Europe and North America, resulting in a notable scarcity of studies focusing on East Asian populations. Currently, the prevalence and distribution of PIK3CA variants across various genetic loci and their correlation with distinct phenotypes in East Asian populations remain unclear. This study aims to elucidate the phenotype-genotype correlations of PROS in East Asian populations. We presented the phenotypes and genotypes of 82 Chinese patients. Among our cohort, 67 individuals carried PIK3CA variants, including missense, frameshift, and splice variants. Six patients presented with both PIK3CA and an additional variant. Seven PIK3CA-negative patients exhibited overlapping PROS manifestations with variants in GNAQ, AKT1, PTEN, MAP3K3, GNA11, or KRAS. An integrative review of the literature pertaining to East Asian populations revealed that specific variants are uniquely associated with certain PROS phenotypes. Some rare variants were exclusively identified in cases of megalencephaly and diffuse capillary malformation with overgrowth. Non-hotspot variants with undefined oncogenicity were more common in CNS phenotypes. Diseases with vascular malformation were more likely to have variants in the helical domain, whereas phenotypes involving adipose/muscle overgrowth without vascular abnormalities predominantly presented variants in the C2 domain. Our findings underscore the unique phenotype-genotype patterns within the East Asian PROS population, highlighting the necessity for an expanded cohort to further elucidate these correlations. Such endeavors would significantly facilitate the development of PI3Kα selective inhibitors tailored for the East Asian population in the future.

Evaluating research waste and traits among randomized controlled trials of scars over the past 20 years: a cross-sectional study.

PURPOSE: To analyze the changes in the characteristics of randomized controlled trials (RCTs) in the field of scarring over the last two decades, unveil the components of research waste (RW) within these RCTs, and identify targets for improvement. METHODS: A search was conducted on ClinicalTrials.gov for RCTs registered from January 2000 to December 2023, using "scar" as the keyword. The search was carried out in January 2024. RESULTS: 391 RCTs were included in this analysis. The global registration of RCTs in scarring has exhibited a consistent increase annually, with the proportion in Asia gradually rising, while the shares in North America and Europe have demonstrated a declining trend. In the analysis of RW, 232 RCTs were included, of which 96 (41.4%) have been published. Among the published RCTs, 56 (58.3%) were evaluated to have sufficient reporting, while 47 RCTs (48.9%) were identified as having avoidable design flaws. Ultimately, 183 RCTs (78.9%) exhibited at least one form of RW. Multicenter design (OR: 3.324, 95%CI: 1.385-7.975, P = 0.018), non-pharmacological interventions (OR: 2.61, 95%CI: 1.253-5.435, P = 0.010), the absence of external funding (OR: 0.325, 95%CI: 0.144-0.732, P = 0.031), and participant numbers exceeding 50 (OR: 3.269, 95%CI: 1.573-6.794, P = 0.002) were identified as independent protective factors against waste. CONCLUSIONS: This study delineates the changes in the characteristics of scar RCTs globally over the past two decades, uncovering a substantial burden of RW in scarring research. It provides an evidential reference for more rational planning of future scar-related RCTs and for minimizing RW.

[Ce3+-OV-Ce4+] Located Surface-Distributed Sheet Cu-Zn-Ce Catalysts for Methanol Production by CO2 Hydrogenation.

The metal-support interaction is crucial for the performance of Cu-based catalysts. However, the distinctive properties of the support metal element itself are often overlooked in catalyst design. In this paper, a sheet Cu-Zn-Ce with [Ce3+-OV-Ce4+] located on the surface was designed by the sol-gel method. Through EPR and X-ray photoelectron spectroscopy (XPS), the relationship between the content of oxygen vacancies and Ce was revealed. Ce itself induces the generation of [Ce3+-OV-Ce4+]. Through ICP-MS, XPS, and SEM-mapping, the Ce-induced formation of [Ce3+-OV-Ce4+] located on the catalyst surface was demonstrated. CO2-TPD and DFT calculations further revealed that [Ce3+-OV-Ce4+] enhanced CO2 adsorption, leading to a 10% increase in methanol selectivity compared to Cu-Zn-Ce synthesized via the coprecipitation method.

Design, Synthesis, and Activity Evaluation of Novel Benzazole Bifunctional Antifungal Inhibitors with an LDH Carrier.

Fungal infections maintain a close relation with the body's immune function. In this study, three series of benzazole compounds were designed as dual-target (PD-L1/CYP51) inhibitors using the skeleton splicing approach; their molecular structures were synthesized and evaluated accordingly. Among them, the compounds 9a-2, 12a-2, and 12b-1 exhibited potent antifungal activity and dual-target inhibition ability. Especially, the compound 12a-2 simultaneously exerted excellent bifunctional effects of fungal inhibition and immune activation. Moreover, a layered double hydroxide (LDH) carrier was also successfully constructed based on an infection microenvironment to improve the bioavailability and the targeting of compound 12a-2. This significantly accelerated the recovery process of deep and shallow fungal infections. In conclusion, this study expanded the development horizon of antifungal drugs and provided a novel drug delivery route for treating fungal infections.

High sodium intake and fluid overhydration predict cardiac structural and functional impairments in chronic kidney disease.

Background: High sodium intake and fluid overhydration are common factors of and strongly associated with adverse outcomes in chronic kidney disease (CKD) patients. Yet, their effects on cardiac dysfunction remain unclear. Aims: The study aimed to explore the impact of salt and volume overload on cardiac alterations in non-dialysis CKD. Methods: In all, 409 patients with CKD stages 1-4 (G1-G4) were enrolled. Daily salt intake (DSI) was estimated by 24-h urinary sodium excretion. Volume status was evaluated by the ratio of extracellular water (ECW) to total body water (TBW) measured by body composition monitor. Recruited patients were categorized into four groups according to DSI (6 g/day) and median ECW/TBW (0.439). Echocardiographic and body composition parameters and clinical indicators were compared. Associations between echocardiographic findings and basic characteristics were performed by Spearman's correlations. Univariate and multivariate binary logistic regression analysis were used to determine the associations between DSI and ECW/TBW in the study groups and the incidence of left ventricular hypertrophy (LVH) and elevated left ventricular filling pressure (ELVFP). In addition, the subgroup effects of DSI and ECW/TBW on cardiac abnormalities were estimated using Cox regression. Results: Of the enrolled patients with CKD, the median urinary protein was 0.94 (0.28-3.14) g/d and estimated glomerular filtration rate (eGFR) was 92.05 (IQR: 64.52-110.99) mL/min/1.73 m2. The distributions of CKD stages G1-G4 in the four groups was significantly different (p = 0.020). Furthermore, compared to group 1 (low DSI and low ECW/TBW), group 4 (high DSI and high ECW/TBW) showed a 2.396-fold (95%CI: 1.171-4.902; p = 0.017) excess risk of LVH and/or ELVFP incidence after adjusting for important CKD and cardiovascular disease risk factors. Moreover, combined with eGFR, DSI and ECW/TBW could identify patients with higher cardiac dysfunction risk estimates with an AUC of 0.704 (sensitivity: 75.2%, specificity: 61.0%). The specificity increased to 85.7% in those with nephrotic proteinuria (AUC = 0.713). The magnitude of these associations was consistent across subgroups analyses. Conclusion: The combination of high DSI (>6 g/d) and high ECW/TBW (>0.439) independently predicted a greater risk of LVH or ELVFP incidence in non-dialysis CKD patients. Moreover, the inclusion of eGFR and proteinuria improved the risk stratification ability of DSI and ECW/TBW in cardiac impairments in CKD.

Scytinostromabambusinum sp. nov. (Russulales, Basidiomycota) in China evidenced by morphological characteristics and phylogenetic analyses.

Background: Wood-rotting fungi as an important group within the Basidiomycota are known for their ecological role in the forest ecosystem in terms of decaying living and dead trees and recycling nutrients in forest ecosystems. Many new species were revealed in the last five years. In the present study, during an ongoing study on Scytinostroma, a new species of Scytinostroma was found from China. It is described and illustrated on the basis of the morphological and phylogenetic evidence. New information: Scytinostromabambusinum sp. nov. is described as a new species, based on morphological and molecular evidence. It is characterised by annual, resupinate and broadly ellipsoid basidiomata with white to cream hymenophore, a dimitic hyphal structure with generative hyphae bearing simple septa, the presence of cystidioles and amyloid basidiospores measuring 5.5-7 × 4-5.3 µm. Phylogeny, based on molecular data of ITS and nLSU sequences, shows that the new species forms an independent lineage and is different in morphology from the existing species of Scytinostroma.

[Expert consensus on the diagnosis and treatment of respiratory diseases exacerbated by nonsteroidal anti-inflammatory drugs （2024, Chengdu）].

Non-steroidal anti-inflammatory drugs-exacerbated respiratory disease （N-ERD） is a chronic respiratory disease characterized by eosinophilic inflammation, featuring chronic rhinosinusitis （CRS）, asthma, and intolerance to cyclooxygenase 1 （COX-1） inhibitors. The use of these medications can lead to an acute worsening of rhinitis and asthma symptoms. This condition has not yet received sufficient attention in China, with a high rate of misdiagnosis and a lack of related research. The Chinese Rhinology Research Group convened a group of leading young experts in otolaryngology from across the country, based on the latest domestic and international evidence-based medical practices to formulate this consensus.The consensus covers the epidemiology, pathogenesis, clinical manifestations, diagnostic methods, and treatment strategies for N-ERD, including pharmacotherapy, surgery, biologic treatments, and desensitization therapy. The goal is to improve recognition of N-ERD, reduce misdiagnosis, and enhance treatment outcomes.

Membrane-based optical fiber Bragg grating pressure sensor for health monitoring of pile foundations.

A fiber Bragg grating (FBG) pressure sensor is proposed, designed, and fabricated for lateral earth pressure sensing, in which the FBG sensor is mounted on a 3D printed trestle structure combined with a membrane. The applied pressure can cause a deformation on the membrane, and then this deformation applied on the trestle structure causes tensile strain on the FBG. The proposed sensor is functionalized as a high-sensitive pressure transducer capable of converting the pressure into strain on the FBG. Here, the performance of the proposed sensor is numerically and experimentally investigated. The results show that the pressure sensitivity at 30°C is 10.62 pm/kPa within a range of 0-0.6 MPa. Due to the thermal expansion of the structure, the pressure sensitivity coefficient decreases with the increase of temperature; however, the cross effect between the temperature and strain on the sensing sensitivity is investigated and can be eliminated. The fabricated sensor has advantages of high sensitivity, good stability, and high pressure resolution, so it has potential in the field of structural health monitoring.

Scalable Compliant Graphene Fiber-Based Thermal Interface Material with Metal-Level Thermal Conductivity via Dual-Field Synergistic Alignment Engineering.

High-performance thermal interface materials (TIMs) are highly desired for high-power electronic devices to accelerate heat dissipation. However, the inherent trade-off conflict between achieving high thermal conductivity and excellent compliance of filler-enhanced TIMs results in the unsatisfactory interfacial heat transfer efficiency of existing TIM solutions. Here, we report the graphene fiber (GF)-based elastic TIM with metal-level thermal conductivity via mechanical-electric dual-field synergistic alignment engineering. Compared with state-of-the-art carbon fiber (CF), GF features both superb high thermal conductivity of ∼1200 W m-1 K-1 and outstanding flexibility. Under dual-field synergistic alignment regulation, GFs are vertically aligned with excellent orientation (0.88) and high array density (33.5 mg cm-2), forming continuous thermally conductive pathways. Even at a low filler content of ∼17 wt %, GF-based TIM demonstrates extraordinarily high through-plane thermal conductivity of up to 82.4 W m-1 K-1, exceeding most CF-based TIMs and even comparable to commonly used soft indium foil. Benefiting from the low stiffness of GF, GF-based TIM shows a lower compressive modulus down to 0.57 MPa, an excellent resilience rate of 95% after compressive cycles, and diminished contact thermal resistance as low as 7.4 K mm2 W-1. Our results provide a superb paradigm for the directed assembly of thermally conductive and flexible GFs to achieve scalable and high-performance TIMs, overcoming the long-standing bottleneck of mechanical-thermal mismatch in TIM design.

Saikosaponin D Inhibits Lung Metastasis of Colorectal Cancer Cells by Inducing Autophagy and Apoptosis.

Saikosaponin D (SSD), derived from Bupleurum falcatum L., has various pharmacological properties, including immunoregulatory, anti-inflammatory, and anti-allergic effects. Several studies have investigated the anti-tumor effects of SSD on cancer in multiple organs. However, its role in colorectal cancer (CRC) remains unclear. Therefore, this study aimed to elucidate the suppressive effects of SSD on CRC cell survival and metastasis. SSD reduced the survival and colony formation ability of CRC cells. SSD-induced autophagy and apoptosis in CRC cells were measured using flow cytometry. SSD treatment increased LC3B and p62 autophagic factor levels in CRC cells. Moreover, SSD-induced apoptosis occurred through the cleavage of caspase-9, caspase-3, and PARP, along with the downregulation of the Bcl-2 family. In the in vivo experiment, a reduction in the number of metastatic tumor nodules in the lungs was observed after the oral administration of SSD. Based on these results, SSD inhibits the metastasis of CRC cells to the lungs by inducing autophagy and apoptosis. In conclusion, SSD suppressed the proliferation and metastasis of CRC cells, suggesting its potential as a novel substance for the metastatic CRC treatment.