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Zhihong Liu - Top 30 Publications

Identification of selection signals by large-scale whole-genome resequencing of cashmere goats.

Inner Mongolia and Liaoning cashmere goats are two outstanding Chinese multipurpose breeds that adapt well to the semi-arid temperate grassland. These two breeds are characterized by their soft cashmere fibers, thus making them great models to identify genomic regions that are associated with cashmere fiber traits. Whole-genome sequencing of 70 cashmere goats produced more than 5.52 million single-nucleotide polymorphisms and 710,600 short insertions and deletions. Further analysis of these genetic variants showed some population-specific molecular markers for the two cashmere goat breeds that are otherwise phenotypically similar. By analyzing F ST and θπ outlier values, we identified 135 genomic regions that were associated with cashmere fiber traits within the cashmere goat populations. These selected genomic regions contained genes, which are potential involved in the production of cashmere fiber, such as FGF5, SGK3, IGFBP7, OXTR, and ROCK1. Gene ontology enrichment analysis of identified short insertions and deletions also showed enrichment in keratinocyte differentiation and epidermal cell differentiation. These findings demonstrate that this genomic resource will facilitate the breeding of cashmere goat and other Capra species in future.

MicroRNA‑20a promotes inflammation via the nuclear factor‑κB signaling pathway in pediatric pneumonia.

Pneumonia is a common respiratory disease worldwide, which is preventable and treatable; however, it is recognized as a leading cause of mortality in children. The present study aimed to investigate the role and mechanism of microRNA (miR)‑20a in inflammation in pediatric pneumonia. Clinical serum samples were collected from children with pneumonia and healthy children. Initially, the serum expression levels of miR‑20a were detected by reverse transcription‑quantitative polymerase chain reaction. Subsequently, A549 cells were randomly divided into four groups: Control group; lipopolysaccharide (LPS; 1 µg/ml) group; LPS + miR‑20a group; and LPS + miR‑20a + pyrrolidine dithiocarbamate (PDTC; 100 mmol/l) group. The concentrations of interleukin‑6 (IL‑6), tumor necrosis factor (TNF)‑α and C‑reactive protein (CRP) in clinical serum samples and A549 cells were determined by ELISA. In addition, the protein expression levels of inhibitor of nuclear factor (NF)‑κB α (IκBα) and phosphorylated (p)‑NF‑κB were measured by western blotting. The results demonstrated that miR‑20a was upregulated in children with pneumonia and in lung cells with LPS‑induced inflammatory injury (P<0.01). In addition, compared with the LPS group, cells in the LPS + miR‑20a group exhibited increased expression levels of IL‑6, TNF‑α and CRP (P<0.05). Overexpression of miR‑20a also resulted in upregulation of the expression levels of IκBα and p‑NF‑κB compared with in the LPS group (P<0.05). Furthermore, treatment with the NF‑κB inhibitor PDTC inhibited the expression of inflammatory factors compared with in the LPS + miR‑20a group (P<0.05). In conclusion, the present study indicated that miR‑20a is upregulated in pediatric pneumonia, and overexpression of miR‑20a may promote inflammation through activation of the NF‑κB signaling pathway.

Two Players Make a Formidable Combination: In Situ Generated Poly(acrylic anhydride-2-methyl-acrylic acid-2-oxirane-ethyl ester-methyl methacrylate) Cross-Linking Gel Polymer Electrolyte toward 5 V High-Voltage Batteries.

Electrochemical performance of high-voltage lithium batteries with high energy density is limited because of the electrolyte instability and the electrode/electrolyte interfacial reactivity. Hence, a cross-linking polymer network of poly(acrylic anhydride-2-methyl-acrylic acid-2-oxirane-ethyl ester-methyl methacrylate) (PAMM)-based electrolyte was introduced via in situ polymerization inspired by "shuangjian hebi", which is a statement in a traditional Chinese Kungfu story similar to the synergetic effect of 1 + 1 > 2. A poly(acrylic anhydride) and poly(methyl methacrylate)-based system is very promising as electrolyte materials for lithium-ion batteries, in which the anhydride and acrylate groups can provide high voltage resistance and fast ionic conductivity, respectively. As a result, the cross-linking PAMM-based electrolyte possesses a significant comprehensive enhancement, including electrochemical stability window exceeding 5 V vs Li(+)/Li, an ionic conductivity of 6.79 × 10(-4) S cm(-1) at room temperature, high mechanical strength (27.5 MPa), good flame resistance, and excellent interface compatibility with Li metal. It is also demonstrated that this gel polymer electrolyte suppresses the negative effect resulting from dissolution of Mn(2+) ions at 25 and 55 °C. Thus, the LiNi0.5Mn1.5O4/Li and LiNi0.5Mn1.5O4/Li4Ti5O12 cells using the optimized in situ polymerized cross-linking PAMM-based gel polymer electrolyte deliver stable charging/discharging profiles and excellent rate performance at room temperature and even at 55 °C. These findings suggest that the cross-linking PAMM is an intriguing candidate for 5 V class high-voltage gel polymer electrolyte toward high-energy lithium-on batteries.

Transcriptomic analysis uncovers novel synergistic mechanisms in combination therapy for lupus nephritis.

A recent clinical study showed that combination therapy consisting of mycophenolate mofetil, tacrolimus and steroids was shown to be more effective in achieving complete remission in patients with severe forms of lupus nephritis than conventional therapy consisting of intravenous cyclophosphamide and steroids. To explore the underlying molecular and cellular mechanisms of increased efficacy of the combination therapy regimen, we employed a mouse model of lupus nephritis, MRL/lpr mice, and treated them with monotherapies of prednisone, mycophenolate mofetil, or tacrolimus, or with their combination. Consistent with previous clinical findings, combination therapy markedly improved renal outcome compared to the monotherapies in mice with lupus nephritis. Transcriptomic analysis of their kidneys revealed distinct molecular pathways that were differentially regulated in combination therapy versus monotherapies. Combination therapy not only provided additive immunosuppressive effects, but also induced gene expression and molecular pathways to confer enhanced renoprotection. Specifically, combination therapy inhibited TLR7 expression in the kidneys of mice with lupus nephritis; combination of tacrolimus and mycophenolate mofetil led to better stabilization of the podocyte actin cytoskeleton through the reciprocal regulation of RhoA and Rac1 activities. Combination therapy strongly suppressed the IL-6/Stat3 pathway. These findings were further validated in renal biopsy samples from patients with lupus nephritis before and after treatments with mycophenolate mofetil, tacrolimus or combination therapy. Thus, our study further supports the earlier clinical finding and further provides insights into the molecular basis for increased efficacy of combination therapy.

Significance of MRI/Transrectal Ultrasound Fusion Three-Dimensional Model-Guided, Targeted Biopsy Based on Transrectal Ultrasound-Guided Systematic Biopsy in Prostate Cancer Detection: A Systematic Review and Meta-Analysis.

To assess MRI/Transrectal Ultrasound (TRUS) fusion three-dimensional model-guided targeted biopsy (3D-Tb) versus TRUS-guided systematic biopsy (Sb) in detecting overall and high-Gleason-score (≥7) prostate cancer (PCa).

Membrane binding of the insertion sequence of Proteus vulgaris L-amino acid deaminase stabilizes protein structure and increases catalytic activity.

Proteus vulgaris L-amino acid deaminase (pvLAAD) belongs to a class of bacterial membrane-bound LAADs mainly express in genus Proteus, Providencia and Morganella. These LAADs employ a non-cleavable N-terminal twin-arginine translocation (Tat) peptide to transport across membrane and bind to bacterial surface. Recent studies revealed that a hydrophobic insertion sequence (INS) in these LAADs also interacts with bacterial membrane. However, the functional significance of INS-membrane interaction is not clear. In this study, we made site-directed mutagenesis on the surface-exposed hydrophobic residues of pvLAAD INS, and we found that these mutations impaired the INS-membrane interaction but did not affect pvLAAD activity in the solution. We further found that when cell membrane is present, the catalytic activity can be increased by 8~10 folds for wild-type but not INS-mutated pvLAAD, indicating that the INS-membrane interaction is necessary for increasing activity of pvLAAD. Molecular dynamic (MD) simulations suggested that INS is flexible in the solution, and its conformational dynamics could lead to substrate channel distortion. Circular dichroism (CD) spectroscopy experiments indicated that bacterial membrane was able to maintain the conformation of INS. Our study suggests the function of the membrane binding of INS is to stabilize pvLAAD structure and increase its catalytic activity.

Clinicopathologic characteristics of light chain proximal tubulopathy with light chain inclusions involving multiple renal cell types
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Light chain proximal tubulopathy (LCPT) associated with plasma cell dyscrasias is a rare abnormality, especially cases involving multiple cell types. The aim of this study is to explore the characteristics and outcomes of these diseases. We comprehensively evaluated the clinical-pathological data, treatment, and outcomes of 6 LCPT patients with involvement of multiple cell types. In 3 cases, we found that the inclusions largely existed in tubular cells, while in 2 cases they coexisted in podocytes and tubular cells, and in 1 case they coexisted in histiocytes and tubular cells. The stain features and appearances of inclusions were specific and varied. Five patients displayed κ-light chains with crystal formation, while 1 patient displayed a λ subtype with increased lysosomes instead of crystals. Six patients presented with proteinuria, 4 with renal insufficiency, and 4 with complete or partial Fanconi syndrome. Our findings indicate that tubular cells are the most common location of cytoplasmic inclusions. Cases with κ-light chain storage are more common than λ, and the formation of crystals may be associated with the subtype of light chains. Immunoelectron microscopy could be used to increase sensitivity for the detection and location of monoclonal light chains. Therefore, these patients have some common clinical features with varied pathologic characteristics and prognoses but the same subtype of light chains.
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Toxicity of ammonia, cadmium, and nitrobenzene to four local fishes in the Liao River, China and the derivation of site-specific water quality criteria.

Water quality criteria (WQC) are considered to be an effective management tool for protecting aquatic environments. To derive site-specific WQC for an area, local data based on local species are essential to improve the applicability of WQC derived. Due to the paucity of local fish data available for the development of site-specific WQC for the Liao River, China, four local and widespread fishes (Pseudorasbora parva, Abbottina liaoningensis, Ctenogobius giurinus, and Misgurnus anguillicaudatus) were chosen to test their sensitivities to ammonia, cadmium and nitrobenzene. These compounds are common and regularly-measured pollutants in Chinese rivers. In addition to the published data for species resident in the Liao River, site-specific WQC for the three chemicals were derived using both a log-logistic species sensitivity distribution (SSD) and the method recommended by the USEPA, in line with current best practice, which were then compared with Chinese national WQC. It was found that A. liaoningensis was the most sensitive, followed, in order, by P. parva, C. giurinus and M. anguillicaudatus was the least sensitive, and this trend was the same to all three chemicals tested. When comparing the SSD derived solely from previously-published data with that including our data on local fish, there were significant differences identified among parameters describing the SSD curves for ammonia and nitrobenzene and significant differences were detected for site-specific WQC derived for all of the three chemicals. Based on the dataset with local fish data taxa, site-specific WQC of Liao River for ammonia, cadmium, and nitrobenzene were derived to be 20.53mg/L (at a pH of 7.0 and temperature of 20°C), 3.76μg/L (at a hardness of 100mg/L CaCO3), and 0.49mg/L, respectively. Using the same deriving method for each chemical, the national Chinese WQC were higher than site-specific WQC derived in this study for ammonia (national WQC of 25.16mg/L) and nitrobenzene (national WQC of 0.57mg/L), while the national WQC for cadmium was lower (national WQC of 1.81μg/L). These results indicated that published data can be helpful for use when deriving site-specific WQC but that there were differences between site-specific and national WQC which may lead to either over- or under-protection depending on the pollutant if national WQC were used as the basis for the water management of specific river systems, like the Liao River.

Identification of Nucleobindin-2 as a Potential Biomarker for Breast Cancer Metastasis Using iTRAQ-based Quantitative Proteomic Analysis.

Metastasis is a lethal step in the progression of breast cancer. None of the metastasis-associated biomarkers identified up to now has a definite prognostic value in breast cancer patients. This study was designed to identify biomarkers for breast cancer metastasis and predictors of the prognosis of breast cancer patients. The differentially expressed proteins between 23 paired primary breast tumor and metastatic lymph nodes were identified by quantitative iTRAQ proteomic analysis. Immunohistochemistry was applied to locate and assess the expression of NUCB2 in paired primary breast tumor and metastatic lymph node tissues (n = 106). The relationship between NUCB2 expression and the clinicopathological characteristics of breast cancer patients (n = 189) were analyzed by χ(2) test. Kaplan-Meier analysis and Cox hazard regression analysis were utilized to investigate the relationship between its expression and prognosis of breast cancer patients. The iTRAQ proteomic results showed that 4,837 confidential proteins were identified, 643 of which were differentially expressed in the primary breast cancer tissues and the paired metastatic lymph nodes. NUCB2 protein was found decreased in paired metastatic lymph nodes (P = 0.000), with the positive expression rate being 82% in primary breast cancer tissues and 47% in paired metastatic lymph nodes, respectively. According to Kaplan-Meier analysis, the overall survival time of patients with positive expression of NUCB2 protein were shorter than those with negative NUCB2 expression (P = 0.004). Cox regression model suggested that NUCB2 was a risk factor of breast cancer patients (P = 0.045, RR = 1.854). We conclude that NUCB2 can be used as a potential biomarker for breast cancer metastasis and a prognostic predictor of breast cancer patients.

Utility of abdominal skin plus subcutaneous fat and rectal mucosal biopsy in the diagnosis of AL amyloidosis with renal involvement.

Skin fat biopsy of the abdominal wall is a simple and safe method for detecting amyloidosis, and rectal mucosal biopsy is also frequently used for screening for the disease; however, the sensitivity of these approaches has not been fully studied. The aim of this study was to evaluate the efficacy of skin fat biopsy combined with rectal mucosal biopsy as a screening procedure for the diagnosis of systemic immunoglobulin light-chain (AL) amyloidosis.

Dual-Activator Codoped Upconversion Nanoprobe with Core-Multishell Structure for in Vitro and in Vivo Detection of Hydroxyl Radical.

Monitoring the fluctuation of hydroxyl radical (·OH) in the body can serve as an effective tool for the prediction of relative diseases; however, it is highly challenging due to the radical's short lifetime, high reactivity, and extremely low concentration. Sandwich structured lanthanide-doped upconversion nanoparticles (UCNPs) exhibit unique luminescence properties and great prospects in bioimaging. Nonetheless, their rather low luminescence efficiency and intensity are serious limitations for their application. Herein, we report on dual-activator codoped UCNPs with a core-multishell structure that greatly improve the luminescence intensity and lifetime by 46-fold and 2.6-fold, respectively, compared to those of the monoactivator doped sandwich structured UCNPs. Moreover, emitting ions in the designed core-multishell (CMS)-UCNPs were confined in a homogeneous and thin shell layer (∼2 nm); thus, the luminescence resonance energy transfer (LRET)-based [email protected] dye nanoprobe exhibited a largely shortened energy transfer distance and a pronounced luminescence quenching yield (97%), affording the nearly zero background signal and achieving an ultrahigh sensitivity for the detection of ·OH (with limit of quantitation (LOQ) of 0.10 fM). With good biocompatibility, low biotoxicity, and enhanced luminescence intensity and lifetime, the developed nanoprobe was competent in monitoring the subtle fluctuation of ·OH concentration both in vitro and in vivo.

Urinary Fibrinogen as a Predictor of Progression of CKD.

Fibrinogen has been reported to be involved in kidney tubulointerstitial fibrosis and podocyte injury in mouse models. However, the relationship between urinary fibrinogen and kidney outcomes has not been clarified in patients with CKD.

A de novo substructure generation algorithm for identifying the privileged chemical fragments of liver X receptorβ agonists.

Liver X receptorβ (LXRβ) is a promising therapeutic target for lipid disorders, atherosclerosis, chronic inflammation, autoimmunity, cancer and neurodegenerative diseases. Druggable LXRβ agonists have been explored over the past decades. However, the pocket of LXRβ ligand-binding domain (LBD) is too large to predict LXRβ agonists with novel scaffolds based on either receptor or agonist structures. In this paper, we report a de novo algorithm which drives privileged LXRβ agonist fragments by starting with individual chemical bonds (de novo) from every molecule in a LXRβ agonist library, growing the bonds into substructures based on the agonist structures with isomorphic and homomorphic restrictions, and electing the privileged fragments from the substructures with a popularity threshold and background chemical and biological knowledge. Using these privileged fragments as queries, we were able to figure out the rules to reconstruct LXRβ agonist molecules from the fragments. The privileged fragments were validated by building regularized logistic regression (RLR) and supporting vector machine (SVM) models as descriptors to predict a LXRβ agonist activities.

Bevacizumab significantly increases the risks of hypertension and proteinuria in cancer patients: A systematic review and comprehensive meta-analysis.

Published data regarding the overall risks and incidence of hypertension and proteinuria associated with bevacizumab were still unclear. To quantify the precise risks and incidence, we performed this comprehensive meta-analysis of 72 published clinical trials including 21902 cases and 20608 controls. The overall incidence, risk ratios (RRs), and 95% confidence intervals (95% CIs) were calculated using a fixed or random-effect model based on the heterogeneity. The incidence of all-grade and high-grade hypertension were 25.3% (95% CI: 21.5%-29.5%) and 8.2% (95% CI: 7%-9.8%) for patients treated with bevacizumab. And the incidence of all-grade and high-grade proteinuria were 18% (95% CI: 11.7%-26.6%) and 2.4% (95% CI: 1.8%-3.2%), respectively. Compared with controls, bevacizumab significantly increased the risks of all-grade (RR: 3.595, 95% CI: 2.952-4.378) and high-grade hypertension (RR: 5.173, 95% CI: 4.188-6.390). Obviously increased risks of all-grade (RR: 3.369, 95% CI: 2.492-4.556) and high-grade proteinuria (RR: 5.494, 95% CI: 3.991-7.564) were also observed. In the subgroup analysis, the risks of hypertension and proteinuria may significantly vary with bevacizumab dosage, cancer types and concomitant drugs. Whereas, no obvious difference were discovered when stratified based on phase of trials, age of patients, treatment line and duration. So, close monitor and effective management were highly recommended for the safe use of bevacizumab.

Synergic Anti-Pruritus Mechanisms of Action for the Radix Sophorae Flavescentis and Fructus Cnidii Herbal Pair.

Radix Sophorae Flavescentis (RSF) and Fructus Cnidii (FC) compose a typical herbal synergic pair in traditional Chinese medicine (TCM) for pruritus symptom treatments. The mechanisms of action for the synergy are not understood. This paper aims at predicting the anti-pruritus targets and the main active ingredients for the RSF and FC herbal pair. We demonstrate that the RSF-FC herbal pair can be elucidated by mining the chemical structures of compounds derived from RSF and FC. Based on chemical structure data, the putative targets for RSF and FC were predicted. Additional putative targets that interact with the anti-pruritus targets were derived by mapping the putative targets onto a PPI network. By examining the annotations of these proteins, we conclude that (1) RSF's active compounds are mainly alkaloids and flavonoids. The representative putative targets of the alkaloids are inflammation-related proteins (MAPK14, PTGS2, PTGS2, and F2) and pruritus-related proteins (HRH1, TRPA1, HTR3A, and HTR6). The representative putative targets of the flavonoids are inflammation-related proteins (TNF, NF-κB, F2, PTGS2, and PTGS2) and pruritus-related proteins (NR3C1 and IL2). (2) FC's active compounds are mainly coumarins. Their representative putative targets are CNS-related proteins (AChE and OPRK1) and inflammation-related proteins (PDE4D, TLR9, and NF-κB). (3) Both RSF and FC display anti-inflammatory effects, though they exhibit their anti-pruritus effects in different ways. Their synergy shows that RSF regulates inflammation-related pruritus and FC regulates CNS-related pruritus.

Therapeutic Mechanism of Glucocorticoids on Cellular Crescent Formation in Patients With Antiglomerular Basement Membrane Disease.

This study aimed to explore the therapeutic mechanism of glucocorticoids (GCs) in antiglomerular basement membrane disease.

Proteomic profile‑based screening of potential protein biomarkers in the urine of patients with nephrotic syndrome.

Nephrotic syndrome is not a single disease; rather, it is a term for numerous diseases and pathological types. Renal biopsy is of use in determining the diagnosis and prognosis, and for guiding treatment; however, the use of this intervention is limited due to its invasive nature. Abnormal kidney‑derived proteins in the urine of patients provide useful information regarding numerous pathological processes that occur in the kidneys, and may be considered a potential non‑invasive biomarker for kidney disease. Proteomic analysis exhibits the advantage of being high‑throughput and has previously been used to identify biomarkers of disease. The present study aimed to identify abnormal kidney‑derived proteins in the urine of patients with nephrotic syndrome using a novel proteomic strategy. Urine samples from 5 patients with nephrotic syndrome were subjected to acetone precipitation and albumin/immunoglobulin G depletion prior to analysis by two‑dimensional liquid chromatography tandem mass spectrometry. The resulting data were compared to a publicly available proteomic database of normal human plasma/urine and normal human kidney in PeptideAtlas, and of normal human kidney in the Human Protein Atlas. Candidate biomarkers were validated using ELISA analysis in 60 patients with nephrotic syndrome: 30 with focal segmental glomerulosclerosis (FSGS) and 30 with minimal change disease (MCD), as well as in 30 healthy controls. The initial screening identified 809 proteins in the urine of patients with nephrotic syndrome. A total of 13/809 proteins were additionally present in the kidney proteome of PeptideAtlas and the Human Protein Atlas, although not in normal human urine and normal human plasma according to PeptideAtlas; these were referred to as 'kidney‑derived disease‑associated proteins'. One of the kidney‑derived disease‑associated proteins, ubiquitin‑60S ribosomal protein L40 (UBA52) was observed to be increased in the urine of patients compared with normal controls [Creatinine, 637 ng/mg (216‑1,851) vs. 1.89 ng/mg (1.37‑3.33), P<0.001; and 18.58 ng/mg (11.11‑46.25) vs. 1.89 ng/mg (1.37‑3.33), P<0.001)], and the urinary UBA52 levels were significantly increased in patients with FSGS compared with in patients with MCD (P<0.001). In conclusion, the present study identified potential novel urinary protein biomarkers for nephrotic syndrome, in addition to an extensive urinary proteomic profile of patients with nephrotic syndrome.

Development of a Silicon-Rhodamine Based Near-Infrared Emissive Two-Photon Fluorescent Probe for Nitric Oxide.

Two-photon (TP) fluorescent probes are potential candidates for near-infrared (NIR) imaging which holds great promise in biological research. However, currently, most TP probes emit at wavelength <600 nm, which impedes their practical applications. In this work, we explored the TP properties of a silicon-rhodamine (SiR) derivative and hence developed the first SiR scaffold based "NIR-to-NIR" TP probe (SiRNO) for nitric oxide (NO). SiRNO exhibited high sensitivity and specificity, as well as fast response for NO detection. It was able to track the subtle variation of intracellular NO content in live cells. Owing to the NIR excitation and emission, SiRNO enabled the detection of NO in situ in the xenograft tumor mouse model, revealing the NO generation during the tumor progression. This work indicates that SiR can be an ideal platform for the development of NIR emissive TP probe and may thus promote the advancement of NIR imaging.

Genome-wide Target Enrichment-aided Chip Design: a 66 K SNP Chip for Cashmere Goat.

Compared with the commercially available single nucleotide polymorphism (SNP) chip based on the Bead Chip technology, the solution hybrid selection (SHS)-based target enrichment SNP chip is not only design-flexible, but also cost-effective for genotype sequencing. In this study, we propose to design an animal SNP chip using the SHS-based target enrichment strategy for the first time. As an update to the international collaboration on goat research, a 66 K SNP chip for cashmere goat was created from the whole-genome sequencing data of 73 individuals. Verification of this 66 K SNP chip with the whole-genome sequencing data of 436 cashmere goats showed that the SNP call rates was between 95.3% and 99.8%. The average sequencing depth for target SNPs were 40X. The capture regions were shown to be 200 bp that flank target SNPs. This chip was further tested in a genome-wide association analysis of cashmere fineness (fiber diameter). Several top hit loci were found marginally associated with signaling pathways involved in hair growth. These results demonstrate that the 66 K SNP chip is a useful tool in the genomic analyses of cashmere goats. The successful chip design shows that the SHS-based target enrichment strategy could be applied to SNP chip design in other species.

Multitarget Therapy for Maintenance Treatment of Lupus Nephritis.

Our previous studies showed that multitarget therapy is superior in efficacy to intravenous cyclophosphamide as an induction treatment for lupus nephritis in Asian populations. We conducted an open label, multicenter study for 18 months as an extension of the prior induction therapy trial in 19 renal centers in China to assess the efficacy and safety of multitarget maintenance therapy in patients who had responded at 24 weeks during the induction phase. Patients who had undergone multitarget induction therapy continued to receive multitarget therapy (tacrolimus, 2-3 mg/d; mycophenolate mofetil, 0.50-0.75 g/d; prednisone, 10 mg/d), and patients who had received intravenous cyclophosphamide induction treatment received azathioprine (2 mg/kg per day) plus prednisone (10 mg/d). We assessed the renal relapse rate during maintenance therapy as the primary outcome. We recruited 116 patients in the multitarget group and 90 patients in the azathioprine group. The multitarget and azathioprine groups had similar cumulative renal relapse rates (5.47% versus 7.62%, respectively; adjusted hazard ratio, 0.82; 95% confidence interval, 0.25 to 2.67; P=0.74), and serum creatinine levels and eGFR remained stable in both groups. The azathioprine group had more adverse events (44.4% versus 16.4% for multitarget therapy; P<0.01), and the multitarget group had a lower withdrawal rate due to adverse events (1.7% versus 8.9% for azathioprine; P=0.02). In conclusion, multitarget therapy as a maintenance treatment for lupus nephritis resulted in a low renal relapse rate and fewer adverse events, suggesting that multitarget therapy is an effective and safe maintenance treatment for patients with lupus nephritis.

A haplotype in CFH family genes confers high risk of rare glomerular nephropathies.

Despite distinct renal lesions, a series of rare glomerular nephropathies are reportedly mediated by complement overactivation. Genetic variations in complement genes contribute to disease risk, but the relationship of genotype to phenotype has not been straightforward. Here, we screened 11 complement genes from 91 patients with atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G) and membranoproliferative glomerulonephritis type I (MPGN I), and identified the concomitant presence of three missense variations located within the human complement Factor H (CFH) gene cluster. The three variations, rs55807605, rs61737525 and rs57960694, have strong linkage disequilibrium; subsequent haplotype analysis indicated that ATA increased the susceptibility of these renal diseases. In silico analysis, the CFHR3 rs61737525-T risk allele altered the physical and structural properties and generated a reduction in binding affinity of the CFHR3/C3b complex. Surface plasmon resonance (SPR) binding analysis further demonstrated the substitution induced a decrease of two orders of magnitude in C3b-binding properties, with a declined cofactor activity in fluid phase. These data suggest that the haplotype carrying the causative allele behaves as a partial C3 convertase deficiency, predisposing individuals to diverse pathologic lesions underlying complement overactivation. Such genotype-phenotype discrepancies allow better understanding about these nephropathies mediated by genetic complement disorders.

Expression of Fox-related genes in the skin follicles of Inner Mongolia Cashmere Goat.

The aim of this study was to investigate the expression of genes in cashmere goats at different periods of their fetal development.

Genome-wide identification of genes essential for podocyte cytoskeletons based on single-cell RNA sequencing.

Gene expression differs substantially among individual cells of the same type. We speculate that genes that are expressed in all but a portion of cells of a given cell type would be likely essential and required for either the cell survival (housekeeping) or for the cell type's unique structure and function, enabling the organism to survive. Here, we performed RNA-seq of 20 mouse podocytes using the Fluidigm C1 system and identified 335 genes that were expressed in all of them. Among them, 239 genes were also expressed in mesangial and endothelial cells and were involved in energy metabolism, protein synthesis, etc., as housekeeping genes. In contrast, 92 genes were preferentially expressed in podocytes (over five-fold versus expression in mesangial and endothelial cells) and are, therefore, the essential candidate genes specific for podocytes. Assessments by bioinformatics, conserved expression in human podocytes, and association with injury/disease all support the essentiality of these genes for podocytes. Factually, 27 of the 92 genes are already known to be essential for podocyte structure and function. Thirty-seven novel genes were functionally analyzed by siRNA silencing, and we found that a deficiency of 30 genes led to either cytoskeletal injury (FGFR1, AOX1, AIF1L, HAUS8, RAB3B, LPIN2, GOLIM4, CERS6, ARHGEF18, ARPC1A, SRGAP1, ITGB5, ILDR2, MPP5, TSC22D1, DNAJC11, SEPT10, MOCS2, FNBP1L, and TMOD3) or significant downregulation of CD2AP and synaptopodin (IFT80, MYOM2, ANXA4, CYB5R4, GPC1, ZNF277, NSF, ITGAV, CRYAB, and MTSS1). Thus, the list of genes essential for podocyte cytoskeletons is expanded by single-cell RNA sequencing. It appears that podocyte-specific essential genes are mainly associated with podocyte cytoskeletons.

Curative effect of 1.88-mg and 3.75-mg gonadotrophin-releasing hormone agonist on stage III-IV endometriosis: Randomized controlled study.

To compare the therapeutic effect of 1.88-mg and 3.75-mg gonadotrophin-releasing hormone agonist (GnRHa) in the treatment of stage III-IV endometriosis after laparoscopic surgery.

Effect of CYP3A4 and CYP3A5 Genetic Polymorphisms on the Pharmacokinetics of Sirolimus in Healthy Chinese Volunteers.

Sirolimus is a promising immunosuppressive drug for preventing the rejection of organ transplants. However, inter-individual variability in sirolimus pharmacokinetics causes adverse drug reactions, compromising therapeutic efficacy. Sirolimus is primarily metabolized by cytochrome CYP3A4 and CYP3A5. This study aimed to clarify the effect of CYP3A genetic polymorphisms, including the CYP3A4*1G and CYP3A5*3 polymorphisms, on the pharmacokinetics of sirolimus.

Oxygen Uptake Efficiency Slope Predicts Poor Outcome in Patients With Idiopathic Pulmonary Arterial Hypertension.

Few published studies have evaluated the power of the oxygen uptake efficiency slope (OUES) to predict outcomes in patients with idiopathic pulmonary arterial hypertension (IPAH), who typically die of right-sided heart failure. Our study sought to evaluate the power of OUES to predict clinical worsening and mortality in patients with IPAH.

An N-nitrosation reactivity-based two-photon fluorescent probe for the specific in situ detection of nitric oxide.

In situ fluorescence imaging of nitric oxide (NO) is a powerful tool for studying the critical roles of NO in biological events. However, the selective imaging of NO is still a challenge because most currently available fluorescent probes rely on the o-phenylenediamine (OPD) recognition site, which reacts with both NO and some abundant reactive carbonyl species (RCS) (such as dehydroascorbic acid and methylglyoxal) and some reactive oxygen/nitrogen species (ROS/RNS). To address this problem, a new fluorescent probe, NCNO, based on the N-nitrosation of aromatic secondary amine was designed to bypass the RCS, ROS, and RNS interference. As was expected, the probe NCNO could recognize NO with pronounced selectivity and sensitivity among ROS, RNS, and RCS. The probe was validated by detecting NO in live cells and deep tissues owing to its two-photon excitation and red-light emission. It was, hence, applied to monitor NO in ischemia reperfusion injury (IRI) in mice kidneys by two-photon microscopy for the first time, and the results vividly revealed the profile of NO generation in situ during the renal IRI process.

Digital pathology imaging as a novel platform for standardization and globalization of quantitative nephropathology.

The introduction of digital pathology to nephrology provides a platform for the development of new methodologies and protocols for visual, morphometric and computer-aided assessment of renal biopsies. Application of digital imaging to pathology made substantial progress over the past decade; it is now in use for education, clinical trials and translational research. Digital pathology evolved as a valuable tool to generate comprehensive structural information in digital form, a key prerequisite for achieving precision pathology for computational biology. The application of this new technology on an international scale is driving novel methods for collaborations, providing unique opportunities but also challenges. Standardization of methods needs to be rigorously evaluated and applied at each step, from specimen processing to scanning, uploading into digital repositories, morphologic, morphometric and computer-aided assessment, data collection and analysis. In this review, we discuss the status and opportunities created by the application of digital imaging to precision nephropathology, and present a vision for the near future.

SENP2 suppresses epithelial-mesenchymal transition of bladder cancer cells through deSUMOylation of TGF-βRI.

SUMO-specific protease 2 (SENP2) is a deSUMOylation protease that plays an important role in the regulation of transforming growth factor-β (TGF-β) signaling. Aberrant TGF-β signaling is common in human cancers and contributes to tumor metastasis by inducing an epithelial-mesenchymal transition (EMT). In previous studies, we demonstrated that SENP2 suppresses bladder cancer cell migration and invasion. However, little is known about whether SENP2 inhibits EMT by regulating TGF-β signaling in bladder cancer progression. Here, we investigated the role of SENP2 in regulating TGF-β signaling and bladder cancer metastasis in vitro and in vivo. We found that SENP2 is frequently downregulated in bladder cancer, especially in metastatic bladder cancer. SENP2 downregulation is associated with more aggressive phenotypes and poor patient outcomes. SENP2 knockdown results in a decrease of E-cadherin and an increase of N-cadherin and fibronectin at both transcript and protein levels, indicating that SENP2 negatively regulates EMT. On the contrary, SENP2 overexpression suppresses TGF-β signaling and TGF-β-induced EMT. We further demonstrated that SENP2 regulates TGF-β signaling partly through deSUMOylation of TGFβ receptor I (TGF-βRI). Functionally, SENP2 suppresses bladder cancer cell invasion in vitro and tumor metastasis in vivo, acts as a tumor suppressor gene in bladder cancer. Our results establish a function of SENP2 in metastatic progression and suggest its candidacy as a new prognostic biomarker and target for clinical management of bladder cancer.

Biomass-involved synthesis of N-substituted benzofuro2,3-dpyrimidine-4-amines and biological evaluation as novel EGFR tyrosine kinase inhibitors.

Shikimic acid (1) is a renewable biomass which could be obtained sustainably through natural product isolation or metabolic engineering. Owing to its great potential in chemical conversion, the value-added utilization of this non-grain biomass has received much attention in recent years. Based on the established transformation route from shikimic acid (1) to methyl 3-dehydroshikimate (3-MDHS, 2) and to the multi-functionalized methyl 2-amino-3-cyanobenzofuran-5-carboxylate (3), we disclose a facile and transition metal-free method to access a series of N-substituted benzofuro[2,3-d]pyrimidine-4-amines in 63%-90% yields. The identification of these compounds as EGFR tyrosine kinase inhibitors has also been described. Among them, compound 5h exhibited the most potent inhibitory effect against EGFR tyrosine kinase with an IC50 of 1.7 nM and excellent antiproliferative activity against A431 and A549 cell lines with a GI50 of 5.1 and 12.3 μM, respectively.