PPCRKB: a risk factor knowledge base of postoperative pulmonary complications.

Postoperative pulmonary complications (PPCs) are highly heterogeneous disorders with diverse risk factors frequently occurring after surgical interventions, resulting in significant financial burdens, prolonged hospitalization and elevated mortality rates. Despite the existence of multiple studies on PPCs, a comprehensive knowledge base that can effectively integrate and visualize the diverse risk factors associated with PPCs is currently lacking. This study aims to develop an online knowledge platform on risk factors for PPCs (Postoperative Pulmonary Complications Risk Factor Knowledge Base, PPCRKB) that categorizes and presents the risk and protective factors associated with PPCs, as well as to facilitate the development of individualized prevention and management strategies for PPCs based on the needs of each investigator. The PPCRKB is a novel knowledge base that encompasses all investigated potential risk factors linked to PPCs, offering users a web-based platform to access these risk factors. The PPCRKB contains 2673 entries, 915 risk factors that have been categorized into 11 distinct groups. These categories include habit and behavior, surgical factors, anesthetic factors, auxiliary examination, environmental factors, clinical status, medicines and treatment, demographic characteristics, psychosocial factors, genetic factors and miscellaneous factors. The PPCRKB holds significant value for PPC research. The inclusion of both quantitative and qualitative data in the PPCRKB enhances the ability to uncover new insights and solutions related to PPCs. It could provide clinicians with a more comprehensive perspective on research related to PPCs in future. Database URL: http://sysbio.org.cn/PPCs.

Structure and Formation Mechanisms in Tantalum and Niobium Oxides in Superconducting Quantum Circuits.

Improving the qubit's lifetime (T1) is crucial for fault-tolerant quantum computing. Recent advancements have shown that replacing niobium (Nb) with tantalum (Ta) as the base metal significantly increases T1, likely due to a less lossy native surface oxide. However, understanding the formation mechanism and nature of both surface oxides is still limited. Using aberration-corrected transmission electron microscopy and electron energy loss spectroscopy, we found that Ta surface oxide has fewer suboxides than Nb oxide. We observed an abrupt oxidation state transition from Ta2O5 to Ta, as opposed to the gradual shift from Nb2O5, NbO2, and NbO to Nb, consistent with thermodynamic modeling. Additionally, amorphous Ta2O5 exhibits a closer-to-crystalline bonding nature than Nb2O5, potentially hindering H atomic diffusion toward the oxide/metal interface. Finally, we propose a loss mechanism arising from the transition between two states within the distorted octahedron in an amorphous structure, potentially causing two-level system loss. Our findings offer a deeper understanding of the differences between native amorphous Ta and Nb oxides, providing valuable insights for advancing superconducting qubits through surface oxide engineering.

Prophylactic dose of rivaroxaban versus warfarin for the treatment of isolated calf muscle vein thrombosis: a retrospective propensity score-matched analysis.

BACKGROUND: Prophylactic dose of rivaroxaban is often used in treatment of isolated calf muscle vein thrombosis (ICMVT), nevertheless, its effect is less reported. This study aims to evaluate short-term outcomes in patients with ICMVT who received prophylactic dose of rivaroxaban or warfarin therapy. METHODS: A retrospective analysis of 472 ICMVT patients who received two different treatment regimens was undertaken. Propensity score matching method was used to balance the confounding effect of baseline clinical data. Chi-squared test and logistic regression analysis were used to compare outcomes (venous thromboembolism events, bleeding events, complete clot resolution) according to the type of treatment regimens before and after propensity score matching. Univariate and multivariable analysis were used to investigate risk factors for incomplete clot resolution of ICMVT after propensity score matching. RESULTS: 242 ICMVT patients received prophylactic dose of rivaroxaban (rivaroxaban group, RG), and 230 received warfarin (warfarin group, WG). After propensity score matching, 156 patients were included in each group; Venous thromboembolism (VTE) events occurred in 14 (9.0%) patients in the RG and 10 (6.4%) in the WG (P = 0.395); No major bleeding events occurred in each group, and clinically relevant non-major bleeding events occurred in 5 (3.2%) patients in the RG and 10 (6.4%) in the WG (P = 0.186); Complete clot resolution at 3 months occurred in 80 (51.3%) patients in the RG and 100 (64.1%) in the WG (P = 0.022). Logistic regression analysis showed that there were no significant differences between RG and WG in VTE events (odds ratio 1.439, 95% confidence interval 0.619 to 3.347, P = 0.397) and clinically relevant non-major bleeding events (odds ratio 0.483, 95% confidence interval 0.161 to 1.449, P = 0.194); it revealed that complete clot resolution rate at 3 months was different in the two groups (odds ratio 0.589, 95% confidence interval 0.375 to 0.928, P = 0.022). Treatment regimens (prophylactic dose of rivaroxaban), thrombosis (maximum diameter >7 mm) and risk factors for VTE (non-surgery risk factors, mainly referring to active malignancy) were risk factors for incomplete clot resolution of ICMVT (P < 0.05). CONCLUSIONS: In this retrospective study with a short-term follow-up, ICMVT patients who received prophylactic dose of rivaroxaban had no significant differences in VTE and bleeding events compared to those who received warfarin therapy (the overall INR > 2.0 for >50% of the time); but it was not conducive to complete clot resolution.

Emerging chemotherapy-based treatments in anaplastic thyroid cancer: an updated analysis of prospective studies.

Background: For patients with anaplastic thyroid cancer (ATC) without mutational driver genes, chemotherapy is suggested to be the first-line treatment option. However, the benefits of chemotherapy in treating ATC are limited. In this analysis, we collected the prospective data reported since 2010 to analyze the emerging chemotherapy-based treatments in ATC comprehensively. Methods: For this updated analysis, we searched PubMed (MEDLINE), Web of Science, Embase, and Cochrane CENTRAL databases from 1 January 2010 to 7 February 2024 for prospective clinical studies that contained chemotherapy-based treatments. This analysis was done to pool overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), disease control rates (DCRs), and grade 3 or worse treatment-related adverse events (TRAEs). Results: Six prospective clinical trials with 232 patients were included. Chemotherapy was commonly combined with targeted therapy or radiotherapy. The pooled median OS was 6.0 months (95% CI 4.1-9.7), and the median PFS was 3.2 months (95% CI 1.9-6.0) in patients with ATC who received chemotherapy-based strategies. The integrated ORR and DCR were 21% (95% CI 15%-27%) and 64% (95% CI 55%-72%), respectively. Regarding the grade 3 or worse TRAE, the pooled incidence was 68% (95% CI 47%-86%). Conclusion: Although the emerging chemotherapy-based treatments showed antitumor activity in patients with ATC, these strategies failed to prolong the survival time substantially. More practical, safe, and novel therapeutic regimens for patients with ATC warrant further investigations.

Macrophage-derived exosomes promote telomere fragility and senescence in tubular epithelial cells by delivering miR-155.

BACKGROUND: Chronic kidney disease (CKD) is highly prevalent worldwide, and its global burden is substantial and growing. CKD displays a number of features of accelerated senescence. Tubular cell senescence is a common biological process that contributes to CKD progression. Tubulointerstitial inflammation is a driver of tubular cell senescence and a common characteristic of CKD. However, the mechanism by which the interstitial inflammation drives tubular cell senescence remains unclear. This paper aims to explore the role of exosomal miRNAs derived from macrophages in the development of tubular cell senescence. METHODS: Among the identified inflammation-related miRNAs, miR-155 is considered to be one of the most important miRNAs involved in the inflammatory response. Macrophages, the primary immune cells that mediate inflammatory processes, contain a high abundance of miR-155 in their released exosomes. We assessed the potential role of miR-155 in tubular cell senescence and renal fibrosis. We subjected miR-155-/- mice and wild-type controls, as well as tubular epithelial cells (TECs), to angiotensin II (AngII)-induced kidney injury. We assessed kidney function and injury using standard techniques. TECs were evaluated for cell senescence and telomere dysfunction in vivo and in vitro. Telomeres were measured by the fluorescence in situ hybridization. RESULTS: Compared with normal controls, miR-155 was up-regulated in proximal renal tubule cells in CKD patients and mouse models of CKD. Moreover, the expression of miR-155 was positively correlated with the extent of renal fibrosis, eGFR decline and p16INK4A expression. The overexpression of miR-155 exacerbated tubular senescence, evidenced by increased detection of p16INK4A/p21expression and senescence-associated ß-galactosidase activity. Notably, miR-155 knockout attenuates renal fibrosis and tubule cell senescence in vivo. Interestingly, once released, macrophages-derived exosomal miR-155 was internalized by TECs, leading to telomere shortening and dysfunction through targeting TRF1. A dual-luciferase reporter assay confirmed that TRF1 was the direct target of miR-155. Thus, our study clearly demonstrates that exosomal miR-155 may mediate communication between macrophages and TECs, subsequently inducing telomere dysfunction and senescence in TECs. CONCLUSIONS: Our work suggests a new mechanism by which macrophage exosomes are involved in the development of tubule senescence and renal fibrosis, in part by delivering miR-155 to target TRF1 to promote telomere dysfunction. Our study may provide novel strategies for the treatment of AngII-induced kidney injury.

Roxadustat on Renal Anemia with Macroinflammation: A Retrospective Cohort Study.

Introduction: Roxadustat, the first-in-class drug for the treatment of renal anemia, has demonstrated efficacy in renal anemia with microinflammation. Additional data are needed regarding the efficacy of roxadustat on renal anemia with systemic macroinflammation. Methods: Three cohorts of renal anemia based on the basic level of high-sensitivity CRP were included. Patients with hsCRP ≤2 mg/L were selected as non-inflammation (NI) group; 2< hsCRP ≤10 mg/L as microinflammation (MI) group; hsCRP≥10 mg/L as macroinflammation (MA) group. Patients received oral roxadustat three times per week for 52 weeks. The primary end point was the hemoglobin level over weeks 12-52. The second end point was the cumulative proportion of patients achieving hemoglobin response by the end of week 12. Results: A total of 107 patients with chronic kidney diseases (CKDs) were enrolled. Overall, the baseline hemoglobin level of patients was 79.99 ± 11.20 g/L. Roxadustat could significantly increase the hemoglobin level in all of the three groups and did not show any significant difference (p > 0.05, respectively). Meanwhile, compared with that of the NI group, there was no significant difference in hemoglobin response rate in the MA group both at week 12 (p = 0.06; 95% confidence interval [CI], 0.9531-13.75) and week 52 (p = 0.37; 95% CI, 0.5080-7.937). Moreover, the hemoglobin response was independent of baseline hsCRP level (p = 0.72, 95% CI, -0.1139 to 0.0794). More importantly, roxadustat significantly reduced ferritin and serum iron levels and increased total iron-binding capacity in the three groups, which showed no significant differences among the three groups (p > 0.05, respectively). Conclusion: Roxadustat significantly improves anemia in CKD patients with systemic macroinflammation.

Erratum: Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury: Erratum.

[This corrects the article DOI: 10.7150/thno.54550.].

CD8 T cells induce the peritubular capillary rarefaction during AKI to CKD transition.

Acute kidney injury (AKI) transformed to chronic kidney disease (CKD) is a critical clinical issue characterized by tubulointerstitial inflammation (TII) and fibrosis. However, the exact mechanism remains largely unclear. In this study, we used single-cell RNA sequencing (scRNA-seq) to obtain a high-resolution profile of T cells in AKI to CKD transition with a mice model of unilateral ischemia-reperfusion injury (uIRI). We found that T cells accumulated increasingly with the progression of AKI to CKD, which was categorized into 9 clusters. A notably increased proportion of CD8 T cells via self-proliferation occurred in the early stage of AKI was identified. Further study revealed that the CD8 T cells were recruited through CXCL16-CXCR6 pathway mediated by macrophages. Notably, CD8 T cells induced endothelial cell apoptosis via Fas ligand-Fas signaling. Consistently, increased CD8 T cell infiltration accompanied with peritubular capillaries (PTCs) rarefaction was observed in uIRI mice. More impressively, the loss of PTCs and renal fibrosis was remarkably ameliorated after the elimination of CD8 T cells. In summary, our study provides a novel insight into the role of CD8 T cells in the transition from AKI to CKD via induction of PTCs rarefaction, which could suggest a promising therapeutic target for AKI.

A Chinese Multi-Specialty Delphi Consensus to Optimize RAASi Usage and Hyperkalaemia Management in Patients with Chronic Kidney Disease and Heart Failure.

Objective Variations are present in common clinical practices regarding best practice in managing hyperkalaemia (HK), there is therefore a need to establish a multi-specialty approach to optimal renin-angiotension-aldosterone system inhibitors (RAASi) usage and HK management in patients with chronic kidney disease (CKD) & heart failure (HF).This study aimed to establish a multi-speciality approach to the optimal use of RAASi and the management of HK in patients with CKD and HF. Methods A steering expert group of cardiology and nephrology experts across China were convened to discuss challenges to HK management through a nominal group technique. The group then created a list of 41 statements for a consensus questionnaire, which was distributed for a further survey in extended panel group of cardiologists and nephrologists across China. Consensus was assessed using a modified Delphi technique, with agreement defined as "strong" (≥75% and <90%) and "very strong" (≥90%). The steering group, data collection, and analysis were aided by an independent facilitator. Results A total of 150 responses from 21 provinces across China were recruited in the survey. Respondents were comprised of an even split (n=75, 50%) between cardiologists and nephrologists. All 41 statements achieved the 75% consensus agreement threshold, of which 27 statements attained very strong consensus (≥90% agreement) and 14 attained strong consensus (agreement between 75% and 90%). Conclusion Based on the agreement levels from respondents, the steering group agreed a set of recommendations intended to improve patient outcomes in the use of RAASi therapy and HK management in China.

Identification of stable reference genes for relative quantification of long RNA expression in urinary extracellular vesicles.

Urinary extracellular vesicles (uEVs) are rich in valuable biomolecule information which are increasingly recognized as potential biomarkers for various diseases. uEV long RNAs are among the critical cargos capable of providing unique transcriptome information of the source cells. However, consensus regarding ideal reference genes for relative long RNAs quantification in uEVs is not available as of date. Here we explored stable reference genes through profiling the long RNA expression by RNA-seq following unsupervised analysis and validation studies. Candidate reference genes were identified using four algorithms: NormFinder, GeNorm, BestKeeper and the Delta Ct method, followed by validation. RNA profile showed uEVs contained abundant long RNAs information and the core transcriptome was related to cellular structures, especially ribosome which functions mainly as translation, protein and RNA binding molecules. Analysis of RNA-seq data identified RPL18A, RPL11, RPL27, RACK1, RPSA, RPL41, H1-2, RPL4, GAPDH, RPS27A as candidate reference genes. RT-qPCR validation revealed that RPL41, RPSA and RPL18A were reliable reference genes for long RNA quantification in uEVs from patients with diabetes mellitus (DM), diabetic nephropathy (DN), IgA nephropathy (IgAN) and prostate cancer (PCA). Interestingly, RPL41 also outperformed traditional reference genes in renal tissues of DN and IgAN, as well as in plasma EVs of several types of cancers. The stable reference genes identified in this study may facilitate development of uEVs as novel biomarkers and increase the accuracy and comparability of biomarker studies.

Podocyte-derived soluble RARRES1 drives kidney disease progression through direct podocyte and proximal tubular injury.

Retinoic acid receptor responder protein-1 (RARRES1) is a podocyte-enriched transmembrane protein whose increased expression correlates with human glomerular disease progression. RARRES1 promotes podocytopenia and glomerulosclerosis via p53-mediated podocyte apoptosis. Importantly, the cytopathic actions of RARRES1 are entirely dependent on its proteolytic cleavage into a soluble protein (sRARRES1) and subsequent podocyte uptake by endocytosis, as a cleavage mutant RARRES1 exerted no effects in vitro or in vivo. As RARRES1 expression is upregulated in human glomerular diseases, here we investigated the functional consequence of podocyte-specific overexpression of RARRES1 in mice in the experimental focal segmental glomerulosclerosis and diabetic kidney disease. We also examined the effects of long-term RARRES1 overexpression on slowly developing aging-induced kidney injury. As anticipated, the induction of podocyte overexpression of RARRES1 (Pod-RARRES1WT) significantly worsened glomerular injuries and worsened kidney function in all three models, while overexpression of RARRES1 cleavage mutant (Pod-RARRES1MT) did not. Remarkably, direct uptake of sRARRES1 was also seen in proximal tubules of injured Pod-RARRES1WT mice and associated with exacerbated tubular injuries, vacuolation, and lipid accumulation. Single-cell RNA sequence analysis of mouse kidneys demonstrated RARRES1 led to a marked deregulation of lipid metabolism in proximal tubule subsets. We further identified matrix metalloproteinase 23 (MMP23) as a highly podocyte-specific metalloproteinase and responsible for RARRES1 cleavage in disease settings, as adeno-associated virus 9-mediated knockdown of MMP23 abrogated sRARRES1 uptake in tubular cells in vivo. Thus, our study delineates a previously unrecognized mechanism by which a podocyte-derived protein directly facilitates podocyte and tubular injury in glomerular diseases and suggests that podocyte-specific functions of RARRES1 and MMP23 may be targeted to ameliorate glomerular disease progression in vivo.

Discovery of N-X anomeric amides as electrophilic halogenation reagents.

Electrophilic halogenation is a widely used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom into drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely on either the invention of new reagents or activating commercially available reagents with various additives such as Lewis or Brønsted acids, Lewis bases and hydrogen-bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Here we report the invention of a class of halogenating reagents based on anomeric amides, taking advantage of the energy stored in the pyramidalized nitrogen of N-X anomeric amides as a driving force. These robust halogenating methods are compatible with a variety of functional groups and heterocycles, as exemplified on over 50 compounds (including 13 gram-scale examples and 1 flow chemistry scale-up).

HIF-1α and adaptor protein LIM and senescent cell antigen-like domains protein 1 axis promotes tubulointerstitial fibrosis by interacting with vimentin in angiotensin II-induced hypertension.

BACKGROUND AND PURPOSE: Activation of the renin-angiotensin system, as a hallmark of hypertension and chronic kidney diseases (CKD) is the key pathophysiological factor contributing to the progression of tubulointerstitial fibrosis. LIM and senescent cell antigen-like domains protein 1 (LIMS1) plays an essential role in controlling of cell behaviour through the formation of complexes with other proteins. Here, the function and regulation of LIMS1 in angiotensin II (Ang II)-induced hypertension and tubulointerstitial fibrosis was investigated. EXPERIMENTAL APPROACH: C57BL/6 mice were treated with Ang II to induce tubulointerstitial fibrosis. Hypoxia-inducible factor-1α (HIF-1α) renal tubular-specific knockout mice or LIMS1 knockdown AAV was used to investigate their effects on Ang II-induced renal interstitial fibrosis. In vitro, HIF-1α or LIMS1 was knocked down or overexpressed in HK2 cells after exposure to Ang II. KEY RESULTS: Increased expression of tubular LIMS1 was observed in human kidney with hypertensive nephropathy and in murine kidney from Ang II-induced hypertension model. Tubular-specific knockdown of LIMS1 ameliorated Ang II-induced tubulointerstitial fibrosis in mice. Furthermore, we demonstrated that LIMS1 was transcriptionally regulated by HIF-1α in tubular cells and that tubular HIF-1α knockout ameliorates LIMS1-mediated tubulointerstitial fibrosis. In addition, LIMS1 promotes Ang II-induced tubulointerstitial fibrosis by interacting with vimentin. CONCLUSION AND IMPLICATIONS: We conclude that HIF-1α transcriptionally regulated LIMS1 plays a central role in Ang II-induced tubulointerstitial fibrosis through interacting with vimentin. Our finding represents a new insight into the mechanism of Ang II-induced tubulointerstitial fibrosis and provides a novel therapeutic target for progression of CKD.

Carbon quaternization of redox active esters and olefins by decarboxylative coupling.

The synthesis of quaternary carbons often requires numerous steps and complex conditions or harsh reagents that act on heavily engineered substrates. This is largely a consequence of conventional polar-bond retrosynthetic disconnections that in turn require multiple functional group interconversions, redox manipulations, and protecting group chemistry. Here, we report a simple catalyst and reductant combination that converts two types of feedstock chemicals, carboxylic acids and olefins, into tetrasubstituted carbons through quaternization of radical intermediates. An iron porphyrin catalyst activates each substrate by electron transfer or hydrogen atom transfer, and then combines the fragments using a bimolecular homolytic substitution (SH2) reaction. This cross-coupling reduces the synthetic burden to procure numerous quaternary carbon---containing products from simple chemical feedstocks.

A rice GT61 glycosyltransferase possesses dual activities mediating 2-O-xylosyl and 2-O-arabinosyl substitutions of xylan.

MAIN CONCLUSION: A member of the rice GT61 clade B is capable of transferring both 2-O-xylosyl and 2-O-arabinosyl residues onto xylan and another member specifically catalyses addition of 2-O-xylosyl residue onto xylan. Grass xylan is substituted predominantly with 3-O-arabinofuranose (Araf) as well as with some minor side chains, such as 2-O-Araf and 2-O-(methyl)glucuronic acid [(Me)GlcA]. 3-O-Arabinosylation of grass xylan has been shown to be catalysed by grass-expanded clade A members of the glycosyltransferase family 61. However, glycosyltransferases mediating 2-O-arabinosylation of grass xylan remain elusive. Here, we performed biochemical studies of two rice GT61 clade B members and found that one of them was capable of transferring both xylosyl (Xyl) and Araf residues from UDP-Xyl and UDP-Araf, respectively, onto xylooligomer acceptors, whereas the other specifically catalysed Xyl transfer onto xylooligomers, indicating that the former is a xylan xylosyl/arabinosyl transferase (named OsXXAT1 herein) and the latter is a xylan xylosyltransferase (named OsXYXT2). Structural analysis of the OsXXAT1- and OsXYXT2-catalysed reaction products revealed that the Xyl and Araf residues were transferred onto O-2 positions of xylooligomers. Furthermore, we demonstrated that OsXXAT1 and OsXYXT2 were able to substitute acetylated xylooligomers, but only OsXXAT1 could xylosylate GlcA-substituted xylooligomers. OsXXAT1 and OsXYXT2 were predicted to adopt a GT-B fold structure and molecular docking revealed candidate amino acid residues at the predicted active site involved in binding of the nucleotide sugar donor and the xylohexaose acceptor substrates. Together, our results establish that OsXXAT1 is a xylan 2-O-xylosyl/2-O-arabinosyl transferase and OsXYXT2 is a xylan 2-O-xylosyltransferase, which expands our knowledge of roles of the GT61 family in grass xylan synthesis.

Maximizing the Value of Real-World Data and Real-World Evidence to Accelerate Healthcare Transformation in China: Summary of External Advisory Committee Meetings.

Use of real-world data (RWD) is gaining wide attention. To bridge the gap between diverse healthcare stakeholders and to leverage the impact of Chinese real-world evidence (RWE) globally, a multi-stakeholder External Advisory Committee (EAC) and EAC meetings were initiated, aiming to elucidate the current and evolving RWD landscape in China, articulate the values of RWE in ensuring Chinese patients' equitable access to affordable medicines and solutions, and identify strategic opportunities and partnerships for expansion of RWE generation in China. Chinese and international experts who are clinicians and academic researchers were selected as EAC members based on their professional background and familiarity with RWD/RWE. Three EAC meetings were held quarterly in 2023. Various topics were presented and discussed for insights and suggestions. Nine experts from China, one from South Korea, and two from Europe were selected as EAC members and attended these meetings. Experts' presentations were summarized by theme, including the RWD landscape and RWE enablement in China, as well as global development of a patient-centric ecosystem. Experts' insights and suggestions on maximizing the RWD/RWE value to accelerate healthcare transformation in China were collected. We concluded that though data access, sharing, and quality are still challenging, RWD is developing to support evidence generation in the medicinal product lifecycle, inform clinical practice, and empower patient management in China. RWD/RWE creates value, accelerates healthcare transformation, and improves patient outcomes. Fostering a patient-centric ecosystem across healthcare stakeholders and maintaining global partnerships and collaboration are essential for unlocking the power of RWD/RWE.

Improvement of roughness in ultrasonic assisted magnetorheological finishing of small titanium alloy nuts by orthogonal test method.

Titanium alloy with high corrosion resistance, high strength-to-density ratio, and excellent biocompatibility has a wide range of applications in the field of biomedical implants. Polishing experiments of titanium alloy with a small size and complex shapes were investigated using an ultrasonic assisted magnetorheological finishing (UMRF) device excited by a three-pole magnetic field generator. The models of the normal force and the shear force were first proposed based on the Preston equation to analyze the mechanism of material removal in the UMRF process. Subsequently, the single-factor experiments using titanium alloy nuts (M3) and the MR polishing fluid with silicon carbide abrasives were carried out. Furthermore, to improve the surface roughness and the change rate of surface roughness of nuts, orthogonal tests with a standard L9(34) orthogonal array were designed and performed based on the optimized process parameters obtained from the single-factor experiment. The results indicated the effect on surface roughness and change rate of surface roughness as applied current > roller speed > ultrasonic amplitude > spindle speed and applied current > roller speed > spindle speed > ultrasonic amplitude, respectively. Moreover, the surface roughness was improved from an initial 1.247 µm to a final 0.104 µm after the polishing for 80 min under these optimal process parameters.

High-dose Vitamin C injection ameliorates against sepsis-induced myocardial injury by anti-apoptosis, anti-inflammatory and pro-autophagy through regulating MAPK, NF-κB and PI3K/AKT/mTOR signaling pathways in rats.

AIMS: This study aimed to evaluate the effects of VC on SIMI in rats. METHODS: In this study, the survival rate of high dose VC for SIMI was evaluated within 7 days. Rats were randomly assigned to three groups: Sham group, CLP group, and high dose VC (500 mg/kg i.v.) group. The animals in each group were treated with drugs for 1 day, 3 days or 5 days, respectively. Echocardiography, myocardial enzymes and HE were used to detect cardiac function. IL-1ß, IL-6, IL-10 and TNF-α) in serum were measured using ELISA kits. Western blot was used to detect proteins related to apoptosis, inflammation, autophagy, MAPK, NF-κB and PI3K/Akt/mTOR signaling pathways. RESULTS: High dose VC improved the survival rate of SIMI within 7 days. Echocardiography, HE staining and myocardial enzymes showed that high-dose VC relieved SIMI in rats in a time-dependent manner. And compared with CLP group, high-dose VC decreased the expressions of pro-apoptotic proteins, while increased the expression of anti-apoptotic protein. And compared with CLP group, high dose VC decreased phosphorylation levels of Erk1/2, P38, JNK, NF-κB and IKK α/ß in SIMI rats. High dose VC increased the expression of the protein Beclin-1 and LC3-II/LC3-I ratio, whereas decreased the expression of P62 in SIMI rats. Finally, high dose VC attenuated phosphorylation of PI3K, AKT and mTOR compared with the CLP group. SIGNIFICANCE: Our results showed that high dose VC has a good protective effect on SIMI after continuous treatment, which may be mediated by inhibiting apoptosis and inflammatory, and promoting autophagy through regulating MAPK, NF-κB and PI3K/AKT/mTOR pathway.

HIPK2 C-terminal domain inhibits NF-κB signaling and renal inflammation in kidney injury.

HIPK2 is a multifunctional kinase that acts as a key pathogenic mediator of chronic kidney disease and fibrosis. It acts as a central effector of multiple signaling pathways implicated in kidney injury, such as TGF-ß/Smad3-mediated extracellular matrix accumulation, NF-κB-mediated inflammation, and p53-mediated apoptosis. Thus, a better understanding of the specific HIPK2 regions necessary for distinct downstream pathway activation is critical for optimal drug development for CKD. Our study now shows that caspase-6-mediated removal of the C-terminal region of HIPK2 (HIPK2-CT) lead to hyperactive p65 NF-κB transcriptional response in kidney cells. In contrast, the expression of cleaved HIPK2-CT fragment could restrain the NF-κB transcriptional activity by cytoplasmic sequestration of p65 and the attenuation of IκBα degradation. Therefore, we examined whether HIPK2-CT expression can be exploited to restrain renal inflammation in vivo. The induction of HIPK2-CT overexpression in kidney tubular cells attenuated p65 nuclear translocation, expression of inflammatory cytokines, and macrophage infiltration in the kidneys of mice with unilateral ureteral obstruction and LPS-induced acute kidney injury. Collectively, our findings indicate that the HIPK2-CT is involved in the regulation of nuclear NF-κB transcriptional activity and that HIPK2-CT or its analogs could be further exploited as potential antiinflammatory agents to treat kidney disease.