Highly transparent Ce:Nd:YAG ceramic with good light conversion capacity for solar-pumped solid-state lasers.

Developing a high quality ceramic laser gain medium for solar directly pumped solid state lasers is essential, and yet the light conversion efficiency of the gain media for solar pumping remains a challenge. In this study, Ce and Nd ions, co-doped YAG transparent ceramics with theoretical transmittance and stable Ce3+ valent state were developed, and revealed that the absorbed visible light and light conversion efficiency in Ce,Nd:YAG ceramics were 3.98 times and 1.34 times higher than those in widely reported Cr,Nd:YAG ceramics, respectively. A concentration matching principle between Ce3+ and Nd3+ ions in YAG was established, and a higher Nd3+ ion doping concentration with a relatively low Ce3+ concentration was favorable to improve both the light conversion efficiency and emission intensity at 1064 nm of Ce,Nd:YAG ceramics. Energy transfer efficiency from Ce3+ to Nd3+ of the 0.3 at.%Ce,1.5at.%Nd:YAG ceramic reached as high as 61.71% at room temperature. Surprisingly, it was further promoted to 64.31% at a higher temperature of 473 K. More excited electrons at the upper energy level of Ce3+ ion under the high temperature accounted for this novel phenomenon. This study proposes a new design strategy of gain materials for solar directly pumped solid state lasers.

Functionalized extracellular nanovesicles as advanced CRISPR delivery systems.

The clustered regularly interspaced short palindromic repeat (CRISPR) system, an emerging tool for genome editing, has garnered significant public interest for its potential in treating genetic diseases. Despite the rapid advancements in CRISPR technology, the progress in developing effective delivery strategies lags, impeding its clinical application. Extracellular nanovesicles (EVs), either in their endogenous forms or with engineered modifications, have emerged as a promising solution for CRISPR delivery. These EVs offer several advantages, including high biocompatibility, biological permeability, negligible immunogenicity, and straightforward production. Herein, we first summarize various types of functional EVs for CRISPR delivery, such as unmodified, modified, engineered virus-like particles (VLPs), and exosome-liposome hybrid vesicles, and examine their distinct intracellular pathways. Then, we outline the cutting-edge techniques for functionalizing extracellular vesicles, involving producer cell engineering, vesicle engineering, and virus-like particle engineering, emphasizing the diverse CRISPR delivery capabilities of these nanovesicles. Lastly, we address the current challenges and propose rational design strategies for their clinical translation, offering future perspectives on the development of functionalized EVs.

Combined Effects of the Serum IgA/C3 Ratio and Glomerular C3 Staining on the Renal Outcome in Adult Immunoglobulin A Nephropathy.

INTRODUCTION: The aim of this study was to evaluate the predictive value of the serum IgA/C3 ratio and glomerular C3 deposits in kidney biopsy in adult IgA nephropathy. METHODS: The study included 718 adult IgAN patients diagnosed based on kidney biopsy. Patients without corticosteroids or immunosuppressive drugs >1 month were regularly followed up for at least 1 year or until the study endpoint. The optimum serum IgA/C3 ratio was calculated by the AUROC-based cutoff ratio. Proteinuria, creatinine, eGFR, serum IgA, and serum C3 were evaluated at baseline. Kidney biopsy was categorized using the Oxford classification, with a calculation of the MEST-C score. The degree of glomerular C3 staining was semiquantitatively determined (grade 0, no or trace; grade 1, mild; grade 2, moderate; grade 3, marked) by immunofluorescence microscopy. The patients were divided into four groups by the serum IgA/C3 ratio and glomerular C3 staining. RESULTS: The baseline data suggested that when the serum IgA/C3 ratio was at the same level, patients with a high glomerular C3 staining score (≥2) always had mesangial proliferation, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis (group 1 vs. group 2; group 3 vs. group 4). When glomerular C3 staining was at the same level, proteinuria was significantly higher in patients with serum IgA/C3<2.806 (group 1 vs. group 3; group 2 vs. group 4), which was contrary to previous studies that have suggested that the serum level of IgA/C3 was associated with disease severity. Hence, this study set out to investigate the combined effects of the serum IgA/C3 ratio and glomerular C3 staining on the renal outcome in adult IgA nephropathy. Renal survival analysis indicated that serum IgA/C3 ≥2.806 and glomerular C3 staining ≥2 (group 1) may be correlated with a poorer prognosis, especially in different clinicopathological characteristics of IgAN patients based on the subgroup analysis. Multivariate Cox analysis demonstrated that hypertension, serum creatinine, CKD stage, T1/2 and C3 staining were independent predictive factors of renal survival. CONCLUSIONS: The combination of serum IgA/C3 and C3 staining may contribute to improved optimization of the prognostic model in IgAN patients, especially patients with different sexes and degrees of disease. However, further study is required for validation in the future.

Asymmetric Synthesis of Trisubstituted Vicinal Diols through Copper(I)-Catalyzed Diastereoselective and Enantioselective Allylation of Ketones with Siloxypropadienes.

Chiral trisubstituted vicinal diols are a type of important organic compounds, serving as both common structure units in bioactive natural products and chiral auxiliaries in asymmetric synthesis. Herein, by using siloxypropadienes as the precursors of allyl copper(I) species, a copper(I)-catalyzed diastereoselective and enantioselective reductive allylation of ketones was achieved, providing both syn-diols and anti-diols in good to excellent enantioselectivity. DFT calculations show that cis-γ-siloxy-allyl copper species are generated favorably with either 1-TBSO-propadiene or 1-TIPSO-propadiene. Moreover, the steric difference of TBS group and TIPS group distinguishes the face selectivity of acetophenone, leading to syn-selectivity for 1-TBSO-propadiene and anti-selectivity for 1-TIPSO-propadiene. Easy transformations of the products were performed, demonstrating the synthetic utility of the present method. Moreover, one chiral diol prepared in the above transformations was used as a suitable organocatalyst for the catalytic asymmetric reductive self-coupling of aldimines generated in situ with B2(neo)2.

Risk Factors for Post-Operative Multi-Drug-Resistant Organism Bacterial Infection in Patients With Stanford Acute Type A Aortic Dissection.

Background: To explore the risk factors for multi-drug-resistant organism (MDRO) infection in patients with Stanford acute type A aortic dissection (ATAAD). We conducted a retrospective cohort study using the data of post-operative patients with ATAAD in our hospital. Patients and Methods: This study included 82 post-operative patients with ATAAD in the past decade. They were divided into a MDRO group (n = 31) and a non-MDRO group (n = 51) according to whether they had acquired multi-drug-resistant (MDR) bacterial infection. Multivariable logistic regression was used to analyze the risk factors for MDR infections in patients with ATAAD. Results: The incidence of multi-drug-resistant bacterial infection was 37.80%. Seventeen factors, including hospital stay (p = 0.007), utilization of third-generation cephalosporins (p = 0.0068), antibiotic species of exposure (p = 0.0002), leukocyte-depleted red blood cell suspension dosage (p < 0.0001), fresh frozen plasma dosage (p < 0.0001), application of blood purification (p = 0.0493), and the total antibiotic days of exposure (p = 0.0001) diverged between the two groups (all p < 0.05). The logistic regression analysis revealed that the utilization of third-generation cephalosporins (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.01-5.33; p = 0.0478), antibiotic species of exposure (OR, 5.76; 95% CI, 1.45-22.83; p = 0.0128), leukocyte-depleted red blood cell suspension dosage (OR, 12.43; 95% CI, 2.71-57.07; p = 0.0012), and fresh frozen plasma dosage (OR, 5.05; 95% CI, 1.18-21.56; p = 0.0286) were independent variables for MDRO infections. Among the 23 drug-resistant bacteria detected, Acinetobacter baumannii was the main pathogen. Conclusions: Our study shows that the utilization of third-generation cephalosporins, antibiotic species of exposure, leukocyte-depleted red blood cell suspension dosage, and fresh frozen plasma dosage were independent risk factors for post-operative multi-drug-resistant infection in patients with ATAAD. Acinetobacter baumannii occupied the largest share of resistant bacteria that induce infection in post-operative patients with ATAAD.

Uric acid-based ratios for predicting renal failure in Chinese IgA nephropathy patients.

Objective: The uric acid/albumin ratio (UAR), a novel, simple, and compositive laboratory biomarker, has recently attracted attention for predicting disease prediction and disease prognosis. However, whether uric acid-related biomarkers (especially UAR) could serve as prognostic indicator for IgAN is unclear. Methods: In this retrospective cohort study, biopsy-confirmed IgAN patients from 2009 to 2017 from West China Hospital were evaluated. The optimal cutoff value of UAR for renal outcome was defined using the Youden index by the area under receiver operating characteristic curve (AUC). The patients were then categorized into the high UAR group and the low UAR group. Renal endpoints were defined as progression to ESRD, eGFR decreased ≥50% of the baseline level, or initiation of renal replacement treatment. Kaplan‒Meier survival analysis and Cox regression analysis were used to identify factors influencing IgAN outcomes. Results: A total of 1143 patients with a median age of 33.0 (26.0-42.0) (44.2% men) were included in the study. The best cut-off UAR concerned with renal survival was determined to be 9.94 with a specificity of 77.5% and a sensitivity of 61.5% (J, 0.390; AUC, 0.750). Then, the patients were divided into two groups labelled as low and high UAR ratios (≥ 9.94 and <9.94, respectively). More severe clinical manifestations and pathological lesions were observed in the high UAR group. Multivariate Cox regression analysis after adjusted for important clinicopathological parameters manifested that a high UAR was an independent prognostic biomarker for IgAN. (p = 0.036, HR =2.56, 95% CI: 1.07-6.16). Conclusion: UAR might be a novel predictor for renal progression and contribute to targeted management.

Interleukin-10 increases macrophage-mediated chemotherapy resistance via FABP5 signaling in multiple myeloma.

Macrophages (MΦs) protect multiple myeloma (MM) cells from chemotherapy-induced apoptosis, and interleukin-10 (IL-10) is frequently elevated in the MM microenvironment. However, the role of IL-10 in MΦ-induced tumor chemotherapy resistance has not yet been clarified. In the present study, bone marrow-derived MΦs were treated with IL-10 (IL10-MΦs), and IL10-MΦ-induced MM chemotherapy resistance was evaluated. IL-10 promoted MΦ-mediated resistance to MM chemotherapy. In addition, IL-10 treatment increased lipid accumulation and fatty acid ß-oxidation in MΦs. Mechanistically, IL-10 increased fatty acid binding protein 5 (FABP5) expression in MΦs, and targeting FABP5 decreased MM chemotherapy resistance induced by IL10-MΦs in vitro and enhanced chemotherapeutic efficacy in vivo. Inhibition of FABP5 decreased the expression of Carnitine Palmitoyltransferase 1A (CPT1A) in IL10-MΦs. In addition, inhibition of CPT1A in IL10-MΦs decreased IL10-MΦ-mediated MM chemotherapy resistance. Peroxisome proliferator-activated receptor γ (PPARγ) is upstream of FABP5 signaling. Inhibition of PPARγ in IL10-MΦs decreased IL10-MΦ-mediated MM chemotherapy resistance in vitro. Collectively, our work indicates that IL-10 enhances MΦ-mediated MM chemotherapy resistance via FABP5 signaling and targeting FABP5 has potentially important clinical implications.

Motor Imagery Brain-Computer Interface in Rehabilitation of Upper Limb Motor Dysfunction After Stroke.

The rehabilitation effect of patients with moderate or severe upper limb motor dysfunction after stroke is poor, which has been the focus of research owing to the difficulties encountered. Brain-computer interface (BCI) represents a hot frontier technology in brain neuroscience research. It refers to the direct conversion of the sensory perception, imagery, cognition, and thinking of users or subjects into actions, without reliance on peripheral nerves or muscles, to establish direct communication and control channels between the brain and external devices. Motor imagery brain-computer interface (MI-BCI) is the most common clinical application of rehabilitation as a non-invasive means of rehabilitation. Previous clinical studies have confirmed that MI-BCI positively improves motor dysfunction in patients after stroke. However, there is a lack of clinical operation demonstration. To that end, this study describes in detail the treatment of MI-BCI for patients with moderate and severe upper limb dysfunction after stroke and shows the intervention effect of MI-BCI through clinical function evaluation and brain function evaluation results, thereby providing ideas and references for clinical rehabilitation application and mechanism research.

IL-24 is the key effector of Th9 cell-mediated tumor immunotherapy.

Th9 cells are powerful effector T cells for cancer immunotherapy. However, the underlying antitumor mechanism of Th9 cells still needs to be further elucidated. Here, we show that Th9 cells express high levels of not only IL-9, but also IL-24. We found that knockout of Il24 gene in Th9 cells promotes Th9 cell proliferation in vitro, but decreases Th9 cell survival in vitro and in vivo. Interestingly, knockout of Il24 gene in Th9 cells decreases the tumor-specific cytotoxicity of Th9 cells in vitro. In addition, immunotherapy with Il24 knockout Th9 cells exhibit less tumor inhibition than regular Th9 cells in mouse tumor models. We found that inhibition of Foxo1 by a specific inhibitor downregulates IL-24 expression in Th9 cells and decreases Th9 cell antitumor efficacy in vivo. Our results identify IL-24 as a powerful antitumor effector of Th9 cells and provide a target in Th9 cell-mediated tumor therapy.

Roles of mesangial C3 and C1q deposition in the clinical manifestations and prognosis of IgAN.

BACKGROUND AND AIM: Immunoglobulin A nephropathy (IgAN) is regarded as the most common type of glomerulonephritis around the world and has the potential to result in renal failure. Complement activation has been addressed by a great body of evidence in the pathogenesis of IgAN. We aimed to evaluate the predictive value of C3 and C1q deposition for disease progression in IgAN patients in this retrospective study. METHODS: We recruited 1191 biopsy-diagnosed IgAN patients, and they were divided into different groups according to their glomerular immunofluorescence examination of renal biopsy tissues: 1) C3 deposits ≥ 2 + group (N = 518) and C3 deposits < 2 + group (N = 673). 2) C1q deposit-positive group (N = 109) and C1q deposit-negative group (N = 1082). The renal outcomes were end-stage renal disease (ESRD) and/or an estimated glomerular filtration rate (eGFR) decrease greater than 50% from the baseline value. Kaplan-Meier analyses were performed to evaluate renal survival. Univariate and multivariate Cox proportional hazard regression models were used to evaluate the effect of C3 and C1q deposition on renal outcome in IgAN patients. In addition, we compared the predictive value of mesangial C3 and C1q deposition in IgAN patients. RESULTS: The median follow-up period was 53 months (interquartile range 36-75 months). During follow-up, 7% (84) of patients progressed to ESRD, and 9% (111) of patients had an eGFR decline ≥ 50%. IgAN patients complicated with C3 deposits ≥ 2 + were associated with more severe renal dysfunction and pathologic lesions at the time of renal biopsy. The crude incidence rates for the endpoint were 12.5% (84 out of 673) and 17.2% (89 out of 518) in the C3 < 2 + and C3 ≥ 2 + groups, respectively (P = 0.022). Of C1q deposit-positive and C1q deposit-negative patients, 22.9% (25 out of 109) and 13.7% (148 out of 1082) reached the composite endpoint, respectively (P = 0.009). Adding C3 deposition to clinical and pathologic models had better predictability of renal disease progression than C1q. CONCLUSION: Glomerular C3 and C1q deposits affected the clinicopathologic features of IgAN patients and emerged as independent predictors and risk factors for renal outcomes. In particular, the predictive ability of C3 was slightly better than that of C1q.

A Novel Quantitative Electrocardiography Strategy Reveals the Electroinhibitory Effect of Tamoxifen on the Mouse Heart.

Tamoxifen, a selective estrogen receptor modulator, was initially used to treat cancer in women and more recently to induce conditional gene editing in rodent hearts. However, little is known about the baseline biological effects of tamoxifen on the myocardium. In order to clarify the short-term effects of tamoxifen on cardiac electrophysiology of myocardium, we applied a single-chest-lead quantitative method and analyzed the short-term electrocardiographic phenotypes induced by tamoxifen in the heart of adult female mice. We found that tamoxifen prolonged the PP interval and caused a decreased heartbeat, and further induced atrioventricular block by gradually prolonging the PR interval. Further correlation analysis suggested that tamoxifen had a synergistic and dose-independent inhibition on the time course of the PP interval and PR interval. This prolongation of the critical time course may represent a tamoxifen-specific ECG excitatory-inhibitory mechanism, leading to a reduction in the number of supraventricular action potentials and thus bradycardia. Segmental reconstructions showed that tamoxifen induced a decrease in the conduction velocity of action potentials throughout the atria and parts of the ventricles, resulting in a flattening of the P wave and R wave. In addition, we detected the previously reported prolongation of the QT interval, which may be due to a prolonged duration of the ventricular repolarizing T wave rather than the depolarizing QRS complex. Our study highlights that tamoxifen can produce patterning alternations in the cardiac conduction system, including the formation of inhibitory electrical signals with reduced conduction velocity, implying its involvement in the regulation of myocardial ion transport and the mediation of arrhythmias. A Novel Quantitative Electrocardiography Strategy Reveals the Electroinhibitory Effect of Tamoxifen on the Mouse Heart（Figure 9）. A working model of tamoxifen producing acute electrical disturbances in the myocardium. SN, sinus node; AVN, atrioventricular node; RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle.

Association of obesity with the development of end stage renal disease in IgA nephropathy patients.

Background and aim: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. We aimed to evaluate whether obesity is a risk factor for IgAN patients. Methods: A total of 1054 biopsy-proven IgAN patients were analyzed in this retrospective study. Patients were divided into four groups according to their body weight index (BMI) at the period of renal biopsy: underweight group (BMI< 18.5, N=75), normal weight group (18.5≤BMI<24, N=587), overweight group (24≤BMI<28, N=291) and obesity group (28≤BMI, N=101). The endpoint of our study was end stage renal disease (ESRD: eGFR <15 mL/min/1.73 m2 or having renal replacement treatment). Kaplan-Meier analyses and Cox proportional hazard models were performed to evaluate renal survival. Propensity-score matching (PSM) was performed to get the matched cohort to evaluate the role of obesity in IgAN patients. Besides, the effect modification of obesity and hypertension in IgAN patients was clarified by the synergy index. Results: IgAN patients complicated with obesity had more severe renal dysfunction at the time of renal biopsy than those with optimal body weight. In addition, patients with obesity tended to have higher risk of metabolic disorders, such as hyperuricemia (64.4% vs 37%, p<0.001), hypertriglyceridemia (71.3% vs 32.5%, p<0.001) and hypercholesterolemia (46.5% vs 35.6%, p=0.036). It was observed that obesity patients had higher rate of unhealthy behaviors, such as smoking (27.7% vs 16.4%, p=0.006) and alcohol drinking (29.7% vs 19.9%, p=0.027). Although obesity was not confirmed as an independent risk factor for IgAN patients, we found that IgAN patients with obesity presented with higher incidence of hypertension, as well as lower event-free renal survival rate (log-rank p < 0.001), especially in patients with 24-h urine protein ≥ 1g (log-rank p =0.002). In addition, the synergy index showed that there was positive interaction between obesity and hypertension in IgAN. Conclusion: Obesity is an important risk factor for IgAN patients when combined with hypertension. Hypertension appears to be common in obese IgAN patients.

Essential role of MESP1-RING1A complex in cardiac differentiation.

Heart development is controlled by a complex transcriptional network composed of transcription factors and epigenetic regulators. Mutations in key developmental transcription factor MESP1 and chromatin factors, such as PRC1 and cohesin components, have been found in human congenital heart diseases (CHDs), although their functional mechanism during heart development remains elusive. Here, we find that MESP1 interacts with RING1A/RING1, the core component of PRC1. RING1A depletion impairs human cardiomyocyte differentiation, and cardiac abnormalities similar to those in patients with MESP1 mutations were observed in Ring1A knockout mice. Mechanistically, MESP1 associates with RING1A to activate cardiogenic genes through promoter-enhancer interactions regulated by cohesin and CTCF and histone acetylation mediated by p300. Importantly, CHD mutations of MESP1 significantly affect such mechanisms and impair target gene activation. Together, our results demonstrate the importance of MESP1-RING1A complex in heart development and provide insights into the pathogenic mechanisms of CHDs caused by mutations in MESP1, PRC1, and cohesin components.

Prognostic value of the albumin-to-fibrinogen ratio (AFR) in IgA nephropathy patients.

BACKGROUND: The albumin-to-fibrinogen ratio (AFR), a novel inflammatory marker, has been studied in various diseases. However, whether AFR could act as a prognostic factor for IgAN patients remains unclear. We aimed to investigate the prognostic value of AFR in IgAN. METHODS: A total of 1289 biopsy-confirmed primary IgAN patients from 2008 to 2018 in West China Hospital, Sichuan University, were studied retrospectively. Receiver operating characteristic curve analysis was generated to assess and compare the ability of indicators to predict survival. Based on the cut-off value of AFR, IgAN patients were classified into the low AFR group and the high AFR group. The demographic and clinical-histopathological data were collected. Renal endpoints included eGFR decreased ≥50 % of the baseline level, ESRD, renal transplantation and/or death. Patients were followed up until a composite endpoint. Kaplan-Meier survival curves and Cox proportional hazards models were used to determine independent predictors. RESULTS: The area under the curve (AUC) of AFR was 0.677, with an optimal cut-off value of 12.44. IgAN patients were classified into two groups (low AFR group: AFR < 12.44, n = 541; high AFR group: AFR ≥ 12.44, n = 748) with a median follow-up of 55.3 (36.4-78.6) months. A higher composition of hypertension, worse renal function, higher proteinuria, and more severe pathological lesions were significantly shown in the low AFR group. Further multivariable Cox regression analyses showed that a low AFR was an independent risk factor for renal survival (HR 1.90, 95 % CI 1.29-2.81, p = 0.001). Kaplan-Meier curves showed that the cumulative incidences of both ESRD and composite end point were significantly higher in patients with AFR < 12.44 (both p < 0.001). CONCLUSIONS: Our study demonstrated that a low AFR (<12.44) is an independent prognostic factor of poor renal prognosis in Chinese IgAN patients.

Triglyceride-Glucose Index May Predict Renal Survival in Patients with IgA Nephropathy.

Background: The triglyceride−glucose (TyG) index is a simple, novel and reliable surrogate marker of insulin resistance. However, evidence for the prognostic impact of an elevated TyG index on IgA nephropathy (IgAN) is limited. Therefore, we evaluated the relationship between the TyG index and the risk of renal progression in IgAN. Method: This cohort study involved biopsy-proven IgAN between January 2009 and December 2018 in West China Hospital, in which patients were assigned to two groups based on the cut-off value of TyG using receiver operating characteristic (ROC) curves. A 1:1 matched-pair analysis was established to optimize the bias in IgAN by propensity score matching (PSM). The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. The composite endpoint was defined by eGFR decreased ≥50% of the baseline level, end-stage kidney disease (ESKD), renal transplantation and/or death. Univariable and multivariable Cox proportional hazard models were applied to confirm the predictive value of the optimal marker. Results: Before PSM, a total of 1210 participants were ultimately included. During a median follow-up period of 55.8 months (range 37.20−79.09 months), 129 participants progressed to the composite endpoint (10.7%). After PSM, 366 patients were enrolled in the matched cohort, of whom 34 (9.3%) patients reached the endpoints. Based on the cut-off value of the TyG index, patients were divided into the low TyG index group (TyG ≤ 8.72, n = 690) and the high TyG index group (TyG > 8.72, n = 520). Further analysis demonstrated that a higher TyG index was significantly associated with a higher risk of reaching composite endpoints in IgAN patients in both the unmatched and matched cohorts (before PSM: HR 2.509, 95% CI 1.396−4.511, p = 0.002; after PSM: HR 2.654, 95% CI 1.299−5.423, p = 0.007). Conclusion: A high TyG index is associated with a higher risk of renal progression.

Prognostic Value of Triglyceride to High-Density Lipoprotein Cholesterol Ratio (TG/HDL-C) in IgA Nephropathy Patients.

Background: The triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio is an easy-to-use atherogenic and prognostic marker which has attracted increasing attention these days. However, whether TG/HDL-C correlate with outcomes in IgA nephropathy (IgAN) patients remains unknown. To clarify these issues, we conducted this study. Methods: A total of 1146 patients from West China Hospital of Sichuan University were retrospectively analysed between 2008 and 2018.The demographic, clinical and pathological data of all patients at the time of biopsy were collected. Then, patients were divided into the high TG/HDL group (TG/HDL ≥ 1.495, N=382) and the low TG/HDL group (TG/HDL-C < 1.495, N=764) based on the optimal cut-off value of the TG/HDL-C using receive operating curve. Cox proportional hazard models and Kaplan-Meier curves were used to evaluate the renal outcomes of IgAN. Results: The median age of the patients was 33 (26-42) years, and 44.5% were men. By correlation analysis, we found that the TG/HDL-C ratio was negatively correlated with the eGFR (r = 0.250, P < 0.001) but positively correlated with proteinuria (r = 0.230, P< 0.001), BMI (r=0.380, P<0.001) and serum uric (r =0.308, P< 0.001). Patients with a higher TG/HDL-C ratio tended to have hypertension [odds ratio (OR), 1.987; 95% CI, 1.527-2.587; P<0.001] and more severe pathologic lesions with tubular atrophy/interstitial fibrosis (OR, 1.610; 95% CI, 1.203-2.154; P=0.001). During a median follow-up period of 54.1 (35.6-73.2) months, a high TG/HDL ratio was strongly associated with worse renal survival in IgAN patients (log-rank: P <0.001). Multivariate Cox analysis demonstrated that a high TG/HDL-C ratio (HR 1.775, 95% CI 1.056-2.798; P=0.029) was an independent predictive marker to ESRD. Conclusion: In this study, we addressed the importance of TG/HDL-C ratio as a predictive marker for IgAN progression.

Study on Bulk Texture and Mechanical Properties of As-Extruded Wide Mg-Al-Zn Alloy Sheets with Different Al Addition.

The wide Mg alloy sheets produced by hot extrusion usually can easily form an inhomogeneous texture, resulting in anisotropic mechanical properties and poor formability. However, few studies have been carried out on the bulk texture investigation at different areas of as-extruded Mg alloy sheets, especially the Mg alloys with different alloying elements. In this work, the effect of Al on the bulk texture and mechanical properties at different areas for three wide Mg-Al-Zn alloy sheets with different Al contents (Mg-3Al-0.5Zn, Mg-8Al-0.5Zn and Mg-9Al-0.5Zn) are mainly investigated by neutron diffraction. The results showed that a strong and uneven basal texture was formed in the Mg-3Al-0.5Zn sheet. Meanwhile, the intensity of the basal texture was significantly weakened due to the numerous fine precipitates of Mg17Al12 particles, with the Al content increasing, which hinder the grain growth during extrusion, while fine recrystallized grains have a more random orientation. The enhanced tensile properties in Mg-8Al-0.5Zn and Mg-9Al-0.5Zn alloy sheets are ascribed to the cooperation effect of a refined microstructure, precipitates and weakened basal texture. Among the three Mg alloy sheets, the Mg-8Al-0.5Zn alloy sheet has a yield strength of about 270 MPa, an ultimate tensile strength of about 330 MPa and ultimate elongation of about 16% in the extrusion direction, which possesses the most excellent comprehensive mechanical properties.

Platelet-to-Albumin Ratio: A Novel IgA Nephropathy Prognosis Predictor.

Background: Chronic inflammation is related to the development of IgA nephropathy (IgAN). Emerging studies have reported that platelet-related parameters including platelet (PLT), platelet-to-albumin ratio (PAR), and platelet-to-lymphocyte ratio (PLR) are proved to be novel prognostic indicators for several inflammatory diseases. Whether platelet-related parameters could serve as predictors for IgAN remains unknown. Methods: A total of 966 IgAN patients were enrolled in this retrospective study and were divided into several groups based on the optimal cut-off value of the platelet-related parameters. End-stage renal disease was used as the renal endpoint. A 1:2 propensity score (PS) match was then carried out to eliminate significant differences at baseline. The area under the receiver operating characteristic curve (AUROC), Kaplan-Meier (K-M) curve, and Cox proportional hazards analyses were performed to evaluate their predictive effect. Results: Without considering the effect of covariates, the K-M curve showed that PLT, PLR, and PAR were strongly correlated with the renal outcomes of IgAN. However, the AUROC revealed that the PAR and PLR had better predictive power than the PLT. Multivariate Cox regression adjusting for demographic data, pathological findings, treatment, and laboratory results indicated that compared with PLR, albumin and PLT, PAR seemed to be a better marker of adverse renal outcome, implying that PAR was the only platelet-related parameter that could be used as an independent risk factor. Notably, high PAR patients seemed to have more severe clinical manifestations and pathological lesions. However, after eliminating the influence of different baselines on outcome variables, the PAR could still predict the poor prognosis of IgAN. To more accurately evaluate the predictive power of the PAR, we analyzed the predictive effect of the PAR on patients with different clinicopathological characteristics through subgroup analysis. It was indicated that the PAR might better predict the prognosis and outcome of patients whose disease was already very severe. Conclusion: PAR might be used as an independent risk factor for IgAN progression.

Cryptococcus neoformans capsule regrowth experiments reveal dynamics of enlargement and architecture.

The polysaccharide capsule of fungal pathogen Cryptococcus neoformans is a critical virulence factor that has historically evaded complete characterization. Cryptococcal polysaccharides are known to either remain attached to the cell as capsular polysaccharides (CPSs) or to be shed into the extracellular space as exopolysaccharides (EPSs). While many studies have examined the properties of EPS, far less is known about CPS. In this work, we detail the development of new physical and enzymatic methods for the isolation of CPS which can be used to explore the architecture of the capsule and isolated capsular material. We show that sonication or Glucanex enzyme cocktail digestion yields soluble CPS preparations, while use of a French pressure cell press or Glucanex digestion followed by cell disruption removed the capsule and produced cell wall-associated polysaccharide aggregates that we call "capsule ghosts", implying an inherent organization that allows the CPS to exist independent of the cell wall surface. Since sonication and Glucanex digestion were noncytotoxic, it was also possible to observe the cryptococcal cells rebuilding their capsule, revealing the presence of reducing end glycans throughout the capsule. Finally, analysis of dimethyl sulfoxide-extracted and sonicated CPS preparations revealed the conservation of previously identified glucuronoxylomannan motifs only in the sonicated CPS. Together, these observations provide new insights into capsule architecture and synthesis, consistent with a model in which the capsule is assembled from the cell wall outward using smaller polymers, which are then compiled into larger ones.

Tetrahydrobiopterin induces proteasome inhibitor resistance and tumor progression in multiple myeloma.

Multiple myeloma (MM) still remains an incurable disease due to widespread drug resistance and high frequency of relapse. In this study, we found that tetrahydrobiopterin (BH4) promotes MM cell proliferation and tumor growth in vivo. BH4 also increases MM bortezomib (Bor) resistance in vitro and in vivo. We show that BH4 increases the expressions of USP7 and USP46 in MM cells, which are responsible for MM Bor resistance primed by BH4. BH4 promotes the degradation of P53 and the activation of NF-κB signaling through the up-regulation of USP7 and USP46. Furthermore, the inhibition of USPs increases the therapeutic effects of Bor in MM tumor bearing mice. Our results demonstrate the important role of BH4 in MM Bor resistance and tumor progression in vivo. These findings could potentially have clinical implications.