A comparative study of two thienopyrimidine Schiff base probes for sequential monitoring of Ga3+ and Pd2.

Two Schiff base probes (S1 and S2) were prepared and synthesized by incorporating thienopyrimidine into salicylaldehyde or 3-ethoxysalicylaldehyde individually, with the aim of detecting Ga3+ and Pd2+ sequentially. Upon chelation with Ga3+, S1 and S2 exhibited fluorescence enhancement in DMSO/H2O buffer. Both S1-Ga3+ and S2-Ga3+ were quenched by Pd2+. The limit of detection for S1 in response to Ga3+ and Pd2+ was 2.86 × 10-7 and 4.4 × 10-9 M, respectively. For S2, the limit of detection for Ga3+ and Pd2+ was 4.15 × 10-8 and 3.0 × 10-9 M, respectively. Furthermore, the complexation ratios of both S1 and S2 with Ga3+ and Pd2+ were determined to be 1:2 through Job's plots, ESI-MS analysis, and theoretical calculations. Two molecular logic gates were constructed, leveraging the response behaviors of S1 and S2. Moreover, the potential utility of S1 and S2 for monitoring Ga3+ and Pd2+ in domestic water was verified.

The comparative study of two new Schiff bases derived from 5-(thiophene-2-yl)isoxazole as "Off-On-Off" fluorescence sensors for the sequential detection of Ga3+ and Fe3+ ions.

Two new Schiff bases, TIC ((E)-N'-(2-hydroxybenzylidene)-5-(thiophene-2-yl)isoxazole-3-carbohydrazide) and TIE ((E)-N'-(3-ethoxy-2-hydroxybenzylidene)-5-(thiophene-2-yl)isoxazole-3-carbohydrazide), have been designed and synthesized as chemosensors for distinct recognition of Ga3+ and Fe3+ ions. TIE demonstrated a prominent "turn on" response characterized by clear distinguished fluorescence when coordination with Ga3+ ions in the DMSO/H2O buffer solution. In comparison, TIC also showed "turn on" response of blue fluorescence which was more selective and sensitive than that of TIE due to the steric hindrance of ethoxy group of TIE. The newly formed complexes TIC-Ga3+ and TIE-Ga3+ may act as selective "turn-off" fluorescent probes towards Fe3+ ions. Limits of detection of TIC and TIE towards Ga3+ ions were 7.8809 × 10-9 M and 2.6277 × 10-8 M, respectively. Limits of detection of TIC-Ga3+ and TIE-Ga3+ towards Fe3+ ions were 8.6562 × 10-9 M and 3.3764 × 10-7 M, respectively. The molar ratio of the complex between the sensor and Ga3+ or Fe3+ ions were all 1:2 determined through Job's Plot, mass spectrometry, and theoretical calculations. Both sensors were utilized for the determination of target ions in environment water samples, and the portable paper sensors for detecting Ga3+ ions have been successfully developed.

Validation of Enhancer Regions in Primary Human Neural Progenitor Cells using Capture STARR-seq.

Genome-wide association studies (GWAS) and expression analyses implicate noncoding regulatory regions as harboring risk factors for psychiatric disease, but functional characterization of these regions remains limited. We performed capture STARR-sequencing of over 78,000 candidate regions to identify active enhancers in primary human neural progenitor cells (phNPCs). We selected candidate regions by integrating data from NPCs, prefrontal cortex, developmental timepoints, and GWAS. Over 8,000 regions demonstrated enhancer activity in the phNPCs, and we linked these regions to over 2,200 predicted target genes. These genes are involved in neuronal and psychiatric disease-associated pathways, including dopaminergic synapse, axon guidance, and schizophrenia. We functionally validated a subset of these enhancers using mutation STARR-sequencing and CRISPR deletions, demonstrating the effects of genetic variation on enhancer activity and enhancer deletion on gene expression. Overall, we identified thousands of highly active enhancers and functionally validated a subset of these enhancers, improving our understanding of regulatory networks underlying brain function and disease.

Thienopyrimidine-derived multifunctional fluorescence sensor for the detection of Cu2+, Fe3+, and PPi in different solvents.

Hydrazine substituted thienopyrimidine, a new fluorophore, was used to synthesize a novel Schiff base R1 as a chemosensor via the condensation with p-formyltriphenylamine, and the structure was confirmed using nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS) analysis. When treated with Cu2+ in dimethylsulfoxide (DMSO)/H2O buffer, R1 showed a phenomenon of fluorescence quenching, which was reversible with the action of ethylenediaminetetraacetic acid (EDTA). When treated with Fe3+ in dimethylformamide (DMF)/H2O buffer, R1 exhibited the same phenomenon, but fluorescence was recovered with inorganic pyrophosphate (PPi) quantitatively. The complexation ratios for R1-Cu2+ and R1-Fe3+ were both 1:2, which were manifested by MS titrations and corresponding Job's plots. The limits of detection of R1 for Cu2+ and Fe3+ were 3.11 × 10-8 and 1.24 × 10-7 M, respectively. The sensing mechanism of R1 toward Cu2+ and Fe3+ was confirmed using density functional theory calculations and electrostatic potential analysis. Test strips of R1 were fabricated successfully for on-site detection of Cu2+ and Fe3+. In addition, R1 was applied to recognize Cu2+ and Fe3+ in actual water samples with satisfactory recovery.

Fangji Huangqi decoction ameliorates membranous nephropathy through the upregulation of BNIP3-mediated mitophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Fangji Huangqi Decoction (FJHQ), a traditional Chinese medicinal formula outlined in Zhang Zhongjing's "Jin Gui Yao Lue" during the Han Dynasty, is often used to treat conditions characterized by symptoms like edema and dysuria, including membranous nephropathy (MN). Despite its proven clinical effectiveness, the exact mechanisms through which FJHQ acts on MN remain elusive. AIM OF THE STUDY: This study aimed to investigate whether FJHQ enhances BNIP3-mediated mitophagy in podocytes by promoting BNIP3 expression and whether this improvement leads to the amelioration of MN. MATERIALS AND METHODS: In this study, by establishing passive Heymann nephritis (PHN) rats, an experimental rat model of MN induced by sheep anti-rat Fx1A serum, we evaluated the effects of FJHQ in vivo. In vitro experiments were carried out by treating primary podocytes with experimental rat serum. Furthermore, the potential mechanism by which FJHQ acts through BNIP3 was further examined by transfecting primary podocytes with the siRNA of BNIP3 or the corresponding control vector. RESULTS: After 4 weeks, significant kidney damage was observed in the rats in the model group, comparatively, FJHQ markedly decreased urine volume, 24-h urinary protein, blood urea nitrogen (BUN), creatinine (Scr), and increased serum total albumin (ALB). Histology showed that FJHQ caused significant improvements in glomerular hyperplasia, and IgG immune complex deposition in MN rats. JC-1 fluorescence labelling and flow cytometry analysis showed that FJHQ could significantly increase mitochondrial membrane potential in vivo. In the mitochondria of MN model rats, FJHQ was able to down-regulate the expression of P62 and up-regulate the expression of BNIP3, LC3B, and LC3 II/LC3 I, according to Western blot and immunofluorescence studies. Furthermore, FJHQ has been shown to significantly up-regulate mitochondrial membrane potential, down-regulate P62 expression in mitochondria, and up-regulate the expression of BNIP3, LC3B, and LC3 II/LC3 I in mitochondria at the cellular level. After the administration of the autophagy inhibitor chloroquine, the serum of rats treated with FJHQ further increased the expression of LC3 II/LC3 I in primary podocytes, showing higher autophagy flow. After the interference of BNIP3 in podocytes, the effect of FJHQ on mitochondrial membrane potential and autophagy-related proteins almost disappeared. CONCLUSION: FJHQ enhanced mitophagy in podocytes by promoting the expression of BNIP3, thereby contributing to the amelioration of MN. This work reveals the possible underlying mechanism by which FJHQ improves MN and provides a new avenue for MN treatment.

An improved Bi-LSTM method based on heterogeneous features fusion and attention mechanism for ECG recognition.

Electrocardiogram (ECG) plays a critical role in early prevention and diagnosis of cardiovascular diseases. However, extracting powerful deep features from ECG signal for recognition is still a challenging problem today due to the variable abnormal rhythms and noise distribution. This work proposes a Bi-LSTM algorithm based on heterogeneous features fusion and attention mechanism (HFFAM + Bi-LSTM). Combining the empirical features and the features learned by the deep learning network, HFFAM + Bi-LSTM can comprehensively extract the temporal frequency information and spatial structure information of the ECG signal. Meanwhile, a novel attention mechanism based on improved DTW (AM-DTW) is designed to analyze and control the fusion process of features. The role of AM-DTW in HFFAM + Bi-LSTM is twofold, one is to measure the feature similarity between ECG signal sets with different labels using the improved DTW, and the other is to distinguish the features into isomorphic and heterogeneous features as well as adaptive weighting of the features. It is worth mentioning that overly similar isomorphic features are filtered out to further optimize the algorithm. Thus, HFFAM + Bi-LSTM has the advantage of strengthening the heterogeneous information in the feature subspace while accounting for the isomorphic features. The accuracy of HFFAM + Bi-LSTM reaches up to 98.1 % and 97.1 % on the simulated and real datasets, respectively. Compared to the all benchmark models, the classification accuracy of HFFAM + Bi-LSTM is 1.3 % higher than the best. The experiments also demonstrate that HFFAM + Bi-LSTM has better performance compared with existing methods, which provides a new scheme for automatic detection of ECG signal.

On-Demand Assembly of Nanocrystals into a Superstructure Library in Co(OH)2 Single-Walled Nanotubes.

The hierarchical self-assembly of colloidal particles facilitates the bottom-up manufacturing of metamaterials with synergistically integrated functionalities. Here, we define a modular assembly methodology that enables multinary co-assembly of nanoparticles in one-dimensional confined space. A series of isotropic and anisotropic nanocrystals such as plasmonic, metallic, visible, and near-infrared responsive nanoparticles as well as transition-metal phosphides can be selectively assembled within the single-walled Co(OH)2 nanotubes to achieve various increasingly sophisticated assembly systems, including unary, binary, ternary, and quaternary superstructures. Moreover, the selective assembly of distinct functional nanoparticles produces different integrated functional superstructures. This generalizable methodology provides predictable pathways to complex architectures with structural programming and customization that are otherwise inaccessible.

Cascading effects of hypobaric hypoxia on the testis: insights from a single-cell RNA sequencing analysis.

Most mammals tolerate exposure to hypobaric hypoxia poorly as it may affect multiple regulatory mechanisms and inhibit cell proliferation, promote apoptosis, limit tissue vascularization, and disrupt the acid-base equilibrium. Here, we quantified the functional state of germ cell development and demonstrated the interaction between the germ and somatic cells via single-cell RNA sequencing (scRNA-seq). The present study elucidated the regulatory effects of hypobaric hypoxia exposure on germ cell formation and sperm differentiation by applying enrichment analysis to genomic regions. Hypobaric hypoxia downregulates the genes controlling granule secretion and organic matter biosynthesis, upregulates tektin 1 (TEKT1) and kinesin family member 2C (KIF2C), and downregulates 60S ribosomal protein 11 (RPL11) and cilia- and flagella-associated protein 206 (CFAP206). Our research indicated that prosaposin-G protein-coupled receptor 37 (PSAP-GPR37) ligands mediate the damage to supporting cells caused by hypobaric hypoxic exposure. The present work revealed that hypoxia injures peritubular myoid (PTM) cells and spermatocytes in the S phase. It also showed that elongating spermatids promote maturation toward the G2 phase and increase their functional reserve for sperm-egg binding. The results of this study provide a theoretical basis for future investigations on prophylactic and therapeutic approaches toward protecting the reproductive system against the harmful effects of hypobaric hypoxic exposure.

Metabolic engineering of oleaginous yeast in the lipogenic phase enhances production of nervonic acid.

Insufficient biosynthesis efficiency during the lipogenic phase can be a major obstacle to engineering oleaginous yeasts to overproduce very long-chain fatty acids (VLCFAs). Taking nervonic acid (NA, C24:1) as an example, we overcame the bottleneck to overproduce NA in an engineered Rhodosporidium toruloides by improving the biosynthesis of VLCFAs during the lipogenic phase. First, evaluating the catalytic preferences of three plant-derived ketoacyl-CoA synthases (KCSs) rationally guided reconstructing an efficient NA biosynthetic pathway in R. toruloides. More importantly, a genome-wide transcriptional analysis endowed clues to strengthen the fatty acid elongation (FAE) module and identify/use lipogenic phase-activated promoter, collectively addressing the stagnation of NA accumulation during the lipogenic phase. The best-designed strain exhibited a high NA content (as the major component in total fatty acid [TFA], 46.3%) and produced a titer of 44.2 g/L in a 5 L bioreactor. The strategy developed here provides an engineering framework to establish the microbial process of producing valuable VLCFAs in oleaginous yeasts.

Single-cell RNA sequencing shows the immune cell landscape in the kidneys of patients with idiopathic membranous nephropathy.

Idiopathic membranous nephropathy (IMN) is a leading pathological type of the adult primary nephrotic syndrome. Some patients develop end-stage renal disease due to poor response to treatment with steroid and immunosuppressive agents. In order to explore the molecular mechanism of IMN, we collected renal tissue samples from IMN patients and healthy controls and performed analysis by single-cell RNA sequencing (scRNA-seq). A total of 11 kidney cell clusters were identified, including multiple myeloid cell clusters, NK/T cell clusters, and B cell clusters. Most kidney parenchymal and immune cells were enriched in the regulation of immune response, inflammation, fibrosis and endoplasmic reticulum stress. The macrophage population in the IMN group showed a highly activated profile with up-regulated genes related to chemotaxis, inflammation, phagocytosis and fibrosis. CD8+ T cells continued to be cytotoxic in IMN; however, a transition to "inflammageing" GZMK+ CD8+ T cells was observed. The proportion of activated B cells in renal tissues of IMN patients was much higher than that of normal controls, indicating that B cells in IMN might be activated by constant antigenic stimulation. Moreover, the cell-cell interaction analysis revealed the potential communication between renal glomerular cells and immune cells in IMN. Overall, scRNA-seq was applied to IMN to unravel the characteristics of immune cells and elucidate possible underlying mechanisms involved in the pathogenesis of IMN.

A systematic review of the applicability of emergency department assessment of chest pain score-accelerated diagnostic protocol for risk stratification of patients with chest pain.

The emergency department assessment of chest pain score-accelerated diagnostic protocol (EDACS-ADP) are commonly used for risk stratification in undifferentiated patients with acute chest pain. This systematic review aimed to investigate EDACS-ADP for risk stratification of emergency department (ED) patients with chest pain. The PubMed, Web of Science, Medline, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases were searched for related studies without restrictions on the publication year. The Quality Assessment of Diagnostic Accuracy Studies 2 tool was used to assess the risk of bias, and Stata 16.0 was used to determine the combined sensitivity, specificity, positive diagnostic likelihood ratio (DLR), and negative DLR. Twelve studies comprising 14 290 patients were identified. Of these, 7537 (52.74%) patients were considered low risk, and 67 (0.89%) had major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular death within 30 days of the patients' ED presentation. EDACS-ADP showed a combined sensitivity of 0.97 (95% confidence interval [CI]: 0.95-0.99); specificity, 0.58 (0.53-0.63); positive DLR, 2.34 (2.08-2.63); negative DLR, 0.04 (0.02-0.09); diagnostic odds ratio, 53.11 (26.45-106.63); and summary receiver operating characteristic area under the curve, 0.83 (0.79-0.86). Despite the large statistical heterogeneity of the results, EDACS-ADP identified a considerable number of low-risk patients for early discharge, with a specificity >50% and an incidence of MACE within 30-days of patients' ED presentation <1%. Thus, it is a useful tool with a potential for clinical application.

Ultrathin Carbon Nitride Nanosheets Exfoliated and In Situ Modified with a Nickel Bis(Chelate) Complex for Boosting Photocatalytic Performances.

Exfoliation and interfacial modification of two-dimensional (2D) polymeric carbon nitride (CN) are considerably vital for applications in photo/electrocatalysis fields. Here, a grinding-ultrasonic route was designed to construct nickel bis(chelate) complex (Ni(abt)2, abt = 2-aminobenzenethiolate)-modified CN ultrathin nanosheets. Under the assistance of the shear force derived from the grinding process, Ni(abt)2 was implanted into the interlamination of bulk CN, resulting in the formation of ultrathin CN (UCN) nanosheets. Simultaneously, Ni(abt)2 molecules were anchored on the surfaces of as-formed UCN nanosheets due to the π-π stacking interaction. Interestingly, compared with single Ni(abt)2 and UCN, the as-obtained Ni(abt)2/UCN nanosheets exhibited excellent photocatalytic hydrogen evolution capability. A molecule-semiconductor internal electron transmission mechanism was suggested for explaining the separation and transfer of electron-hole pairs. Density functional theory (DFT) calculations demonstrated that the interface-induced electron redistribution tuned the electron density and hydrogen adsorption of the active centers, thus enhancing the photocatalytic performance of the hybrid catalyst. In addition, the as-obtained Ni(abt)2/UCN nanosheets could also catalyze the reduction of nitroaromatics in the presence of NaBH4. It was found that under the simulated sunlight irradiation, the conversion efficiency of nitroaromatic compounds to amino aromatic ones was up to 97.3%, far higher than that under the condition without light irradiation (51.7%), suggesting that the photocatalytic-produced hydrogen took part in the reduction of nitroaromatic compounds.

Species-Level Characterization of the Microbiome in Breast Tissues with Different Malignancy and Hormone-Receptor Statuses Using Nanopore Sequencing.

Unambiguous evidence indicates that microbes are closely linked to various human diseases, including cancer. Most prior work investigating the microbiome of breast tissue describes an association between compositional differences of microbial species in benign and malignant tissues, but few studies have examined the relative abundance of microbial communities within human breast tissue at the species level. In this work, a total of 44 breast tissue samples including benign and malignant tissues with adjacent normal breast tissue pairs were collected, and Oxford Nanopore long-read sequencing was employed to assess breast tissue microbial signatures. Nearly 900 bacterial species were detected from the four dominant phyla: Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes. The bacteria with the highest abundance in all breast tissues was Ralstonia pickettii, and its relative abundance increased with decreasing malignancy. We further examined the breast-tissue microbiome composition with different hormone-receptor statuses, and the relative abundance of the genus Pseudomonas increased most significantly in breast tissues. Our study provides a rationale for exploring microbiomes associated with breast carcinogenesis and cancer development. Further large-cohort investigation of the breast microbiome is necessary to characterize a microbial risk signature and develop potential microbial-based prevention therapies.

Ginkgo biloba seed exocarp: A waste resource with abundant active substances and other components for potential applications.

Ginkgo biloba seed exocarp contains a variety of bioactive components, such as polysaccharides, flavonoids, terpenoid trilactones, and ginkgolic acids, which have a high value of utilization. However, Ginkgo biloba seed exocarp is always treated as waste of ginkgo seeds processing. To maximize the utilization of Ginkgo biloba seed exocarp, it is necessary to deliberate and arouse researchers' attention. This review demonstrated the extraction method, purification method, and determination method of bioactive components in Ginkgo biloba seed exocarp and summarized its composition and bioactivities. Moreover, the future study of Ginkgo biloba seed exocarp resource is prospected, hoping to provide a theoretical basis and direction for its further development and utilization.

Identification of UCP1 and UCP2 as Potential Prognostic Markers in Breast Cancer: A Study Based on Immunohistochemical Analysis and Bioinformatics.

Background: Uncoupling protein 1 (UCP1) and UCP2 are associated with tumor metabolism and immunity. However, the prognostic value and molecular mechanisms underlying their action in breast cancer (BC) remain unclear. Materials and methods: In TCGA-BRCA cohort, we investigated the expression characteristics of UCP mRNAs, analyzed their prognostic value by Kaplan-Meier survival analysis, their potential molecular functions by gene set enrichment analysis, and their relationship with immune infiltrating cell types using TIMER and CIBERSORT, along with the assessment of their association with mutational profiles. Kaplan-Meier survival analysis was performed for UCPs in our cohort and their association with BC thermogenesis was assessed by thermal tomography. Results: High expression of UCP1 and UCP2 were positive prognostic markers for BC. UCP1 was associated with the impaired glucose metabolism, while UCP2 with enhanced anti-tumor immunity. High expressions of UCP1 and UCP2 were associated with CDH1 mutations. High UCP1 expression was associated with a high rate of thermogenesis in BC. Conclusions: These results implied a key role of UCP1 and UCP2 in prognosis, metabolism, and immune infiltration in BC. Further investigation of the relevant molecular mechanisms may provide new strategies for BC treatment.

Assessing the Impact of Continuous Vaccination and Voluntary Isolation on the Dynamics of COVID-19: A Mathematical Optimal Control of SEIR Epidemic Model.

In order to study the impact of continuous vaccination and voluntary isolation for the COVID-19, a susceptible-exposed-infected-recovered-quarantine-vaccines (SEIR-QV) model is proposed. A basic regeneration number R 0 is defined to determine the extinction or persistence of the disease. We numerically analyze the impact of key parameters based on actual parameters of COVID-19, such as the vaccination rate, population importation rate, and natural (or causal) mortality transmission rate on the dynamics of disease transmission. Then we obtain sensitivity indices of some parameters on R 0 by sensitivity analysis. Finally, the stability of the system and the effectiveness of the optimal control strategy are verified by numerical simulation.

A Facile Method to Determine the Native Contents of 4'-O-Methylpyridoxine and 4'-O-Methylpyridoxine-5'-glucoside in Ginkgo biloba Seeds.

4'-O-Methylpyridoxine (MPN) and MPN-5'-glucoside (MPNG) are collectively known as ginkgotoxin, which are the main toxic ingredients of excessive consumption of Ginkgo biloba seeds. Water extraction is the generally adopted sample preparation method for high-performance liquid chromatography determination of ginkgotoxin. However, endogenous enzymes such as glycosidases in Ginkgo biloba seeds can hydrolyze MPNG to MPN in the process of water extraction, which will result in the measured contents of MPN and MPNG but not their natural contents in Ginkgo biloba seeds. In this work, inhibitors for the endogenous enzymes were first screened, and it was found that silver fluoride could effectively inhibit endogenous enzymes such as glucosidase and phosphatase. The optimized concentration of silver fluoride was 25 mmol/L, which could effectively inhibit the endogenous enzymes for more than 60 h. A new sample preparation method based on water extraction with 25 mmol/L silver fluoride addition was thus developed. This method was employed to determine the native contents of MPN and MPNG in the exotesta and kernel of five Ginkgo biloba seed cultivars. The result showed that the contents of MPNG in the exotesta and kernel of five cultivars were significantly higher than those of MPN. MPNG was present at high content in raw seeds, which was the main form of ginkgotoxin in seeds. The method established in this work is simple and effective and can be used to accurately quantify the native contents of MPN and MPNG.

A Validation Study Comparing Risk Prediction Models of IgA Nephropathy.

We aimed to validate three IgAN risk models proposed by an international collaborative study and another CKD risk model generated by an extended CKD cohort with our multicenter Chinese IgAN cohort. Biopsy-proven IgAN patients with an eGFR ≥15 ml/min/1.73 m2 at baseline and a minimum follow-up of 6 months were enrolled. The primary outcomes were a composite outcome (50% decline in eGFR or ESRD) and ESRD. The performance of those models was assessed using discrimination, calibration, and reclassification. A total of 2,300 eligible cases were enrolled. Of them, 288 (12.5%) patients reached composite outcome and 214 (9.3%) patients reached ESRD during a median follow-up period of 30 months. Using the composite outcome for analysis, the Clinical, Limited, Full, and CKD models had relatively good performance with similar C statistics (0.81, 0.81, 0.82, and 0.82, respectively). While using ESRD as the end point, the four prediction models had better performance (all C statistics > 0.9). Furthermore, subgroup analysis showed that the models containing clinical and pathological variables (Full model and Limited model) had better discriminatory abilities than the models including only clinical indicators (Clinical model and CKD model) in low-risk patients characterized by higher baseline eGFR (≥60 ml/min/1.73 m2). In conclusion, we validated recently reported IgAN and CKD risk models in our Chinese IgAN cohort. Compared to pure clinical models, adding pathological variables will increase performance in predicting ESRD in low-risk IgAN patients with baseline eGFR ≥60 ml/min/1.73 m2.

Increased Lifetime Risk of ESRD in Familial IgA Nephropathy.

INTRODUCTION: Familial IgA nephropathy (IgAN) has been widely reported. However, its clinicohistologic characteristics and long-term prognosis are not clear. METHODS: A total of 348 familial IgAN cases from 167 independent families were recruited and their clinicohistologic characteristics as well as lifetime risk of end-stage renal disease (ESRD) were compared to 1116 sporadic IgAN patients from the same geographic region. RESULTS: Of all familial IgAN patients, 60 (17%) came from 32 single-generation (SG; all affected individuals are siblings) families, whereas 286 (82%) came from 134 multiple-generation (MG; affected individuals were present in at least 2 consecutive generations) families. The lifetime ESRD risk was significantly higher in familial patients than sporadic ones after adjusting by gender (hazard ratio [HR]=1.40, 95% confidence interval [CI]: 1.12-1.74, P = 0.004), with 5 years younger in median ESRD age (60 years vs. 65 years in familial and sporadic cases separately). Interestingly, among familial patients, we found cases from SG families (vs. MG families: HR = 2.62, 95% CI: 1.59-4.31, P < 0.001) or with early onset (onset age <30 years) (vs. late onset: HR = 4.79, 95% CI: 3.16-7.26, P < 0.001) had higher lifetime ESRD risk. Furthermore, among sporadic patients, men had lower estimated glomerular filtration rate (eGFR), higher urine protein, higher Oxford T score, and higher risk for life span ESRD compared with women (male vs. female, 25% vs. 17%, P = 0.003) whereas these gender differences were not seen in familial patients. CONCLUSION: Familial IgAN cases had poorer renal outcomes and less gender differences compared with sporadic cases. These findings provide evidence that familial disease represent a distinct subtype of more progressive IgAN. Early diagnosis could improve the prognosis of cases with familial IgAN.

Ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple-negative breast cancer by upregulating Ras/ERK and PI3K/Akt pathways.

BACKGROUND: Clinical management of triple-negative breast cancer (TNBC) patients remain challenging because of the development of chemo-resistance. Identification of biomarkers for risk stratification of chemo-resistance and therapeutic decision-making to overcome such resistance is thus necessary. METHODS: Retrospective analysis was performed to identify potential stratification biomarkers. The levels of ceramide kinase (CERK) was determined in breast cancer patients. The roles of CERK and its downstream signaling pathways were analysed using cellular and biochemical assays. RESULTS: CERK upregulation was identified as a biomarker for chemotherapeutic response in TNBC. A > 2-fold change in CERK (from tumor)/CERK (from normal counterpart) was significantly associated with chemo-resistance (OR = 2.66, 95% CI 1.18-7.34), P = 0.04. CERK overexpression was sufficient to promote TNBC growth and migration, and confer chemo-resistance in TNBC cell lines, although this resistance could be overcome via CERK inhibition. Mechanistic studies suggest that CERK mediates intrinsic resistance and inferior response to chemotherapy in TNBC by regulating multiple oncogenic pathways such as Ras/ERK, PI3K/Akt/mTOR, and RhoA. CONCLUSIONS: Our work provides an explanation for the heterogeneity of chemo-response across TNBC patients and demonstrates that CERK inhibition offers a therapeutic strategy to overcome treatment resistance.