Astragaloside IV relieves passive heymann nephritis and podocyte injury by suppressing the TRAF6/NF-κb axis.

The pathogenesis of membranous nephropathy (MN) involves podocyte injury that is attributed to inflammatory responses induced by local immune deposits. Astragaloside IV (AS-IV) is known for its robust anti-inflammatory properties. Here, we investigated the effects of AS-IV on passive Heymann nephritis (PHN) rats and TNF-α-induced podocytes to determine the underlying molecular mechanisms of MN. Serum biochemical parameters, 24-h urine protein excretion and renal histopathology were evaluated in PHN and control rats. The expression of tumor necrosis factor receptor associated factor 6 (TRAF6), the phosphorylation of nuclear factor kappa B (p-NF-κB), the expression of associated proinflammatory cytokines (TNF-α, IL-6 and IL-1ß) and the ubiquitination of TRAF6 were measured in PHN rats and TNF-α-induced podocytes. We detected a marked increase in mRNA expression of TNF-α, IL-6 and IL-1ß and in the protein abundance of p-NF-κB and TRAF6 within the renal tissues of PHN rats and TNF-α-induced podocytes. Conversely, there was a reduction in the K48-linked ubiquitination of TRAF6. Additionally, AS-IV was effective in ameliorating serum creatinine, proteinuria, and renal histopathology in PHN rats. This effect was concomitant with the suppression of NF-κB pathway activation and decreased expression of TNF-α, IL-6, IL-1ß and TRAF6. AS-IV decreased TRAF6 levels by promoting K48-linked ubiquitin conjugation to TRAF6, which triggered ubiquitin-mediated degradation. In summary, AS-IV averted renal impairment in PHN rats and TNF-α-induced podocytes, likely by modulating the inflammatory response through the TRAF6/NF-κB axis. Targeting TRAF6 holds therapeutic promise for managing MN.

The potential of integrating stereotactic ablative radiotherapy techniques with hyperfractionation for lung cancer.

BACKGROUND: Limited literature exists on the feasibility and effectiveness of integrating stereotactic ablative radiotherapy (SABR) techniques with hyperfractionated regimens for patients with lung cancer. This study aims to assess whether the SABR technique with hyperfractionation can potentially reduce lung toxicity. METHODS: We utilized the linear-quadratic model to find the optimal fraction to maximize the tumor biological equivalent dose (BED) to normal-tissue BED ratio. Validation was performed by comparing the SABR plans with 50 Gy/5 fractions and hyperfractionationed plans with 88.8 Gy/74 fractions with the same tumor BED and planning criteria for 10 patients with early-stage lung cancer. Mean lung BED, Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP), critical volume (CV) criteria (volume below BED of 22.92 and 25.65 Gy, and mean BED for lowest 1000 and 1500 cc) and the percentage of the lung receiving 20Gy or more (V20) were compared using the Wilcoxon signed-rank test. RESULTS: The transition point occurs when the tumor-to-normal tissue ratio (TNR) of the physical dose equals the TNR of α/ß in the BED dose-volume histogram of the lung. Compared with the hypofractionated regimen, the hyperfractionated regimen is superior in the dose range above but inferior below the transition point. The hyperfractionated regimen showed a lower mean lung BED (6.40 Gy vs. 7.73 Gy) and NTCP (3.50% vs. 4.21%), with inferior results concerning CV criteria and higher V20 (7.37% vs. 7.03%) in comparison with the hypofractionated regimen (p < 0.01 for all). CONCLUSIONS: The hyperfractionated regimen has an advantage in the high-dose region of the lung but a disadvantage in the low-dose region. Further research is needed to determine the superiority between hypo- and hyperfractionation.

The impact of surgical volume on outcomes in newly diagnosed colorectal cancer patients receiving definitive surgeries.

Colorectal cancer (CRC) patients who receive cancer surgeries from higher-volume providers may have better outcomes. However, the definitions of surgical volume may affect the results. We aim to analyze the effects of different definitions of surgical volume on patient outcomes. We conducted a nationwide population-based study in Taiwan that enrolled all patients who underwent definitive surgery for newly diagnosed CRC. We used three common definitions of surgical volume: total volume means the total surgical number conducted by the same provider during the study period; cumulative volume was calculated as the number of operations the surgeon performed before the index procedure; annual volume was calculated as the number of times the surgeon had been responsible for surgery during the index year. In this study, we included 100,009 newly diagnosed CRC patients, including 55.8% males, of median age 66 years at diagnosis (range 20-105 years). After adjustment for the patient and provider characteristics, we found that CRC patients receiving definitive surgery by higher-volume providers had better outcomes, especially where surgeon volume may play a more important role than hospital volume. The cumulative volume could predict the 5-year mortality of the study cohort better than the total and annual volume.

Direct observation of a magnetic-field-induced Wigner crystal.

Wigner predicted that when the Coulomb interactions between electrons become much stronger than their kinetic energy, electrons crystallize into a closely packed lattice1. A variety of two-dimensional systems have shown evidence for Wigner crystals2-11 (WCs). However, a spontaneously formed classical or quantum WC has never been directly visualized. Neither the identification of the WC symmetry nor direct investigation of its melting has been accomplished. Here we use high-resolution scanning tunnelling microscopy measurements to directly image a magnetic-field-induced electron WC in Bernal-stacked bilayer graphene and examine its structural properties as a function of electron density, magnetic field and temperature. At high fields and the lowest temperature, we observe a triangular lattice electron WC in the lowest Landau level. The WC possesses the expected lattice constant and is robust between filling factor ν ≈ 0.13 and ν ≈ 0.38 except near fillings where it competes with fractional quantum Hall states. Increasing the density or temperature results in the melting of the WC into a liquid phase that is isotropic but has a modulated structure characterized by the Bragg wavevector of the WC. At low magnetic fields, the WC unexpectedly transitions into an anisotropic stripe phase, which has been commonly anticipated to form in higher Landau levels. Analysis of individual lattice sites shows signatures that may be related to the quantum zero-point motion of electrons in the WC lattice.

Feasibility estimation of injected hydrodissection before definitive radiotherapy of pancreatic adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma is often not diagnosed until an advanced stage, and so most patients are not eligible for resection. For patients who are inoperable, definitive radiotherapy is crucial for local disease control. However, the pancreas is located close to other vulnerable gastrointestinal organs, making it challenging to deliver an adequate radiation dose. The surgical insertion of spacers or injection of fluids such as hydrogel before radiotherapy has been proposed, however, no study has discussed which patients are suitable for the procedure. METHODS: In this study, we reviewed 50 consecutive patients who received definitive radiotherapy at our institute to determine how many could have benefitted from hydrodissection to separate the pancreatic tumor from the adjacent gastrointestinal tract. By hypothetically injecting a substance using either computed tomography (CT)-guided or endoscopic methods, we aimed to increase the distance between the pancreatic tumor and surrounding hollow organs, as this would reduce the radiation dose delivered to the organs at risk. RESULTS: An interventional radiologist considered that hydrodissection was feasible in 23 (46%) patients with a CT-guided injection, while a gastroenterologist considered that hydrodissection was feasible in 31 (62%) patients with an endoscopic injection. Overall, we found 14 (28%) discrepancies among the 50 patients reviewed. Except for 1 patient who had no available trajectory with a CT-guided approach but in whom hydrodissection was considered feasible with an endoscopic injection, the other 13 patients had different interpretations of whether direct invasion was present in the CT images. CONCLUSION: Our results suggested that about half of the patients could have benefited from hydrodissection before radiotherapy. This finding could allow for a higher radiation dose and potentially better disease control.

Severity of Complications and Duration of Type 2 Diabetes and the Risk of Cancer: A Population-Based Study.

BACKGROUND: The literature on the association between diabetes severity and cancer risk is limited and inconclusive. The study aimed to evaluate the association between the adapted Diabetes Complications Severity Index (aDCSI) and the duration of type 2 diabetes and cancer risk. METHODS: Patients ages 20 years or older with newly diagnosed type 2 diabetes between January 1, 2007, and December 31, 2011, were identified from Taiwan National Health Insurance claims data. Standardized incidence ratios (SIR) were calculated to compare cancer incidence in people with diabetes with that in the general population. Poisson regression was used to examine whether SIRs differed by age, sex, aDSCI, and duration of diabetes. RESULTS: A total of 756,547 patients were included, with a median follow-up of 8.8 years. Excluding the first year after diagnosis, the SIR for overall cancer was 1.18 [95% confidence interval (CI) 1.17-1.19]. Higher aDCSI was associated with increased SIRs for overall [SIR ratio 1.03 (1.02-1.03) per point increase], head and neck (1.03; 1.01-1.04), liver (1.04; 1.03-1.05), pancreas (1.03; 1.00-1.05), kidney (1.13; 1.10-1.15), and leukemia (1.09; 1.06-1.13). There was no association between aDCSI and colorectal, extrahepatic biliary tract, uterus and thyroid cancer, and a negative association with breast cancer (0.97; 0.95-0.98). Type 2 diabetes duration was associated with increased SIRs for overall [1.01 (1.00-1.02) per year increase], head and neck (1.03; 1.01-1.05), and liver cancer (1.04; 1.02-1.05). CONCLUSIONS: The heterogeneity in the association between diabetes severity and diabetes-related cancers suggests diverse underlying connections. IMPACT: Adopting distinct approaches in further research and prevention strategies for different kinds of diabetes-related cancers is important.

Bi-cation incorporated Ni3N nanosheets boost water dissociation kinetics for enhanced alkaline hydrogen evolution activity.

Nickel nitride (Ni3N) is a promising electrocatalyst for the hydrogen evolution reaction (HER) owing to its excellent metallic features and has been demonstrated to exhibit considerable activity for water oxidation. However, its undesirable characteristics as an HER electrocatalyst due to its poor unfavourable d-band energy level significantly limit its water dissociation kinetics. Herein, the HER electrocatalytic activity of Ni3N was prominently enhanced via the simultaneous incorporation of bi-cations (vanadium (V) and iron (Fe), denoted as V-Fe-Ni3N). The optimized V-Fe-Ni3N displays impressive performance with an overpotential of 69 mV at 10 mA cm-2 and good stability in 1.0 M KOH, which is remarkably better than pristine Ni3N, V-doped Ni3N, and Fe-doped Ni3N and considerably closer to a commercial Pt/C catalyst. Based on density functional theory (DFT) studies, V and Fe atoms not only serve as active sites for promoting water dissociation kinetics but also tune the electronic structure of Ni3N to achieve optimized hydrogen adsorption capabilities. This work presents an inclusive understanding of the rational designing of high-performance transition metal nitride-based electrocatalysts for hydrogen production. Its electrocatalytic performance can be significantly enhanced by doping transition metal cations.

Unlatching the Additional Zinc Storage Ability of Vanadium Nitride Nanocrystallites.

Vanadium-based materials, due to their diverse valence states and open-framework lattice, are promising cathodes for aqueous zinc ion batteries (AZIBs), but encounters the major challenges of in situ electrochemical activation process, potent polarity of the aqueous electrolyte and periodic expansion/contraction for efficient Zn2+ storage. Herein, architecting vanadium nitride (VN) nanosheets over titanium-based hollow nanoarrays skeletal host (denoted VNTONC) can simultaneously modulate address those challenges by creating multiple interfaces and maintaining the (1 1 1) phase of VN, which optimizes the Zn2+ storage and the stability of VN. Benefiting from the modulated crystalline thermodynamics during the electrochemical activation of VN, two outcomes are achieved; I) the cathode transforms into a nanocrystalline structure with increased active sites and higher conductivity and; II) a significant portion of the (1 1 1) crystal facets is retained in the process leading to the additional Zn2+ storage capacity. As a result, the as-prepared VNTONC electrode demonstrates remarkable discharge capacities of 802.5 and 331.8 mAh g-1 @ 0.5 and 6.0 A g-1, respectively, due to the enhanced kinetics as validated by theoretical calculations. The assembled VNTONC||Zn flexible ZIB demonstrates excellent Zn storage properties up to 405.6 mAh g-1, and remarkable robustness against extreme operating conditions.

A universal method to fabricate high-valence transition metal-based HER electrocatalysts and direct Raman spectroscopic evidence for interfacial water regulation.

Valence modulation of transition metal oxides represents a highly effective approach in designing high-performance catalysts, particularly for pivotal applications such as the hydrogen evolution reaction (HER) in solar/electric water splitting and the hydrogen economy. Recently, there has been a growing interest in high-valence transition metal-based electrocatalysts (HVTMs) due to their demonstrated superiority in HER performance, attributed to the fundamental dynamics of charge transfer and the evolution of intermediates. Nevertheless, the synthesis of HVTMs encounters considerable thermodynamic barriers, which presents challenges in their preparation. Moreover, the underlying mechanism responsible for the enhancement in HVTMs still needs to be discovered. Hence, the universal synthesis strategies of the HVTMs are discussed, and direct Raman spectroscopic evidence for intermediates regulation is revealed to guide the further design of the HVTM electrocatalysts. This work offers new insights for facile designing of HVTMs electrocatalysts for energy conversion and storage through adjusting the reaction pathway.

Uncovering impaired mitochondrial and lysosomal function in adipose-derived stem cells from obese individuals with altered biological activity.

BACKGROUND: Adipose-derived stem cells (ADSCs) have been extensively used in preclinical and clinical trials for treating various diseases. However, the differences between ADSCs from lean individuals (L-ADSCs) and those from obese individuals (O-ADSCs) have not been thoroughly investigated, particularly regarding their mitochondrial and lysosomal functions. Therefore, this study aims to evaluate the differences between L-ADSCs and O-ADSCs in terms of cell biological activity, mitochondria, and lysosomes. METHODS: We first isolated and cultured L-ADSCs and O-ADSCs. We then compared the differences between the two groups in terms of biological activity, including cell proliferation, differentiation potential, and their effect on the polarization of macrophages. Additionally, we observed the mitochondrial and lysosomal morphology of ADSCs using an electronic microscope, MitoTracker Red, and lysotracker Red dyes. We assessed mitochondrial function by examining mitochondrial membrane potential and membrane fluidity, antioxidative ability, and cell energy metabolism. Lysosomal function was evaluated by measuring autophagy and phagocytosis. Finally, we performed transcriptome analysis of the ADSCs using RNA sequencing. RESULTS: The biological activities of O-ADSCs were decreased, including cell immunophenotypic profiles, cell proliferation, and differentiation potential. Furthermore, compared to L-ADSCs, O-ADSCs promoted M1-type macrophage polarization and inhibited M2-type macrophage polarization. Additionally, the mitochondrial morphology of O-ADSCs was altered, with the size of the cells becoming smaller and mitochondrial fragments increasing. O-ADSCs also exhibited decreased mitochondrial membrane potential and membrane fluidity, antioxidative ability, and energy metabolism. With respect to lysosomes, O-ADSCs contained ungraded materials in their lysosomes, enhanced lysosomal permeability, and reduced autophagy and phagocytosis ability. RNA sequence analysis indicated that the signalling pathways related to cell senescence, cancer, and inflammation were upregulated, whereas the signalling pathways associated with stemness, cell differentiation, metabolism, and response to stress and stimuli were downregulated. CONCLUSIONS: This study indicates that ADSCs from individuals (BMI > 30 kg/m2) exhibit impaired mitochondrial and lysosomal function with decreased biological activity.

Tunable-pH Environment Induced by Local Anchor Effect of High Lewis Basicity Conductive Polymers toward Glycerol Upgrading Assisted Hydrogen Evolution.

Hybrid organic/inorganic composites with the organic phase tailored to modulate the local chemical environment at the transition metal-based catalyst surface arise as an enchanting category of catalysts for electrocatalysis. A fundamental understanding of how the conductive polymers of different Lewis basicities affect the reaction path is, however, still lacking to guide rational catalyst design. Herein, polyaniline (PANI), poly(3,4-ethylenedioxythiophene) (PEDOT), and poly(vinyl alcohol) (PVA) manifesting different Lewis basicities are compared for their regulatory roles on the hydrogen evolution reaction (HER) and glycerol electrooxidation (GOR) pathways regarding local proton coverage. Concerted efforts from in situ Raman and DFT theoretical calculations unveil that conductive polymer/V2O5 surface with tunable local pH regulated by Lewis acidity/basicity. As a result of the tailored chemical environment, the restructured V2O5/PANI/NF composite demonstrates a low overall potential of 1.55 V at the partial current density of 50 mA cm-2 for formate. The glycerol upgrading assisted hydrogen evolution device composed of V2O5/PANI/NF exhibits excellent electrochemical performance at a maximal Faraday efficiency of 82%, ranking among state of the art.