Risk factors for acute kidney injury and kidney relapse in patients with lupus podocytopathy.

Background: Patients with lupus podocytopathy show a high incidence of acute kidney injury (AKI) and relapse, but the risk factors and mechanisms were unclear. This study analysed the clinicopathological features and risk factors for AKI and relapse in lupus podocytopathy patients. Methods: The cohort of lupus podocytopathy was generated by screening the biopsies of patients with lupus nephritis (LN) from 2002 to 2022 and was divided into the mild glomerular lesion (MGL) and focal segmental glomerulosclerosis (FSGS) groups based on glomerular morphological characteristics. The acute (ATI) and chronic (CTI) tubulointerstitial lesions were semi-quantitatively scored. Logistic and Cox regressions were employed to identify the risk factors for AKI and relapse, respectively. Results: Among 6052 LN cases, 98 (1.6%) were diagnosed as lupus podocytopathy, with 71 in the MGL group and 27 in the FSGS group. All patients presented with nephrotic syndrome and 33 (34.7%) of them had AKI. Seventy-seven (78.6%) patients achieved complete renal response (CRR) within 12 weeks of induction treatment, in which there was no difference in the CRR rate between glucocorticoid monotherapy and combination therapy with glucocorticoids plus immunosuppressants. Compared with the MGL group, patients in the FSGS group had significantly higher incidences of hypertension and haematuria; in addition, they had higher Systemic Lupus Erythematosus Disease Activity Index 2000, ATI and CTI scores but a significantly lower CRR rate. Urinary protein ≥7.0 g/24 h and serum C3 ≤0.750 g/l were independent risk factors for AKI. During a median follow-up of 78 months, 57 cases (60.0%) had relapse and none reached the kidney endpoint. Failure to achieve CRR within 12 weeks, maintenance with glucocorticoid monotherapy and AKI at onset were independent risk factors for kidney relapse. Conclusions: In this study, histological subtypes of lupus podocytopathy were found to be associated with clinical features and treatment response. In addition, several risk factors associated with AKI occurrence and kidney relapse were identified.

Optical Information Transmission and Multimode Fluorescence Anticounterfeiting of Ca2-xMgxGe7O16:Mn2.

Multimode emission of Mn2+ for multimode fluorescence anticounterfeiting is achieved by cation site and interstitial occupancy in Ca2-xMgxGe7O16. The rings in Ca2-xMgxGe7O16 have a significant distortion for Mn2+ ions to enter the ring interstitials with a luminescence center at 665 nm, which is supported by XRD refinement results and first-principles calculations. The interstitial Mn2+ ion has good thermal stability with an activation energy of 0.36 eV. Surprisingly, these two luminescence centers, the cation site Mn and the interstitial Mn, have an obvious afterglow, and the disappearing afterglow will reappear by heating or irradiating with the 980 nm laser. The afterglow is significantly enhanced, as MnO2 is used as the manganese source, which is explained in detail by the thermal luminescence spectrum. Finally, Ca2-xMgxGe7O16:Mn2+ fully demonstrates its excellent prospects in fluorescent anticounterfeiting, information encryption, and optical information storage.

Targeting myeloma metabolism: How abnormal metabolism contributes to multiple myeloma progression and resistance to proteasome inhibitors.

Multiple myeloma is a hematological malignancy that has evolved from antibody-secreting B lymphocytes. Like other types of cancers, myeloma cells have acquired functional capabilities which are referred to as "Hallmarks of Cancer", and one of their most important features is the metabolic disorders. Due to the high secretory load of the MM cells, the first-line medicine proteasome inhibitors have found their pronounced effects in MM cells for blocking the degradation of misfolded proteins, leading to their accumulation in the ER and overwhelming ER stress. Moreover, proteasome inhibitors have been reported to be effective in myeloma by targeting glucose, lipid, amino acid metabolism of MM cells. In this review, we have described the abnormal metabolism of the three major nutrients, such as glucose, lipid and amino acids, which participate in the cellular functions. We have described their roles in myeloma progression, how they could be exploited for therapeutic purposes, and current therapeutic strategies targeting these metabolites, hoping to uncover potential novel therapeutic targets and promote the development of future therapeutic approaches.

High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes.

Most of the single-nucleotide polymorphisms (SNPs) associated with insulin resistance (IR)-relevant phenotypes by genome-wide association studies (GWASs) are located in noncoding regions, complicating their functional interpretation. Here, we utilized an adapted STARR-seq to evaluate the regulatory activities of 5,987 noncoding SNPs associated with IR-relevant phenotypes. We identified 876 SNPs with biased allelic enhancer activity effects (baaSNPs) across 133 loci in three IR-relevant cell lines (HepG2, preadipocyte, and A673), which showed pervasive cell specificity and significant enrichment for cell-specific open chromatin regions or enhancer-indicative markers (H3K4me1, H3K27ac). Further functional characterization suggested several transcription factors (TFs) with preferential allelic binding to baaSNPs. We also incorporated multi-omics data to prioritize 102 candidate regulatory target genes for baaSNPs and revealed prevalent long-range regulatory effects and cell-specific IR-relevant biological functional enrichment on them. Specifically, we experimentally verified the distal regulatory mechanism at IRS1 locus, in which rs952227-A reinforces IRS1 expression by long-range chromatin interaction and preferential binding to the transcription factor HOXC6 to augment the enhancer activity. Finally, based on our STARR-seq screening data, we predicted the enhancer activity of 227,343 noncoding SNPs associated with IR-relevant phenotypes (fasting insulin adjusted for BMI, HDL cholesterol, and triglycerides) from the largest available GWAS summary statistics. We further provided an open resource (http://www.bigc.online/fnSNP-IR) for better understanding genetic regulatory mechanisms of IR-relevant phenotypes.

MADGAN:A microbe-disease association prediction model based on generative adversarial networks.

Researches have demonstrated that microorganisms are indispensable for the nutrition transportation, growth and development of human bodies, and disorder and imbalance of microbiota may lead to the occurrence of diseases. Therefore, it is crucial to study relationships between microbes and diseases. In this manuscript, we proposed a novel prediction model named MADGAN to infer potential microbe-disease associations by combining biological information of microbes and diseases with the generative adversarial networks. To our knowledge, it is the first attempt to use the generative adversarial network to complete this important task. In MADGAN, we firstly constructed different features for microbes and diseases based on multiple similarity metrics. And then, we further adopted graph convolution neural network (GCN) to derive different features for microbes and diseases automatically. Finally, we trained MADGAN to identify latent microbe-disease associations by games between the generation network and the decision network. Especially, in order to prevent over-smoothing during the model training process, we introduced the cross-level weight distribution structure to enhance the depth of the network based on the idea of residual network. Moreover, in order to validate the performance of MADGAN, we conducted comprehensive experiments and case studies based on databases of HMDAD and Disbiome respectively, and experimental results demonstrated that MADGAN not only achieved satisfactory prediction performances, but also outperformed existing state-of-the-art prediction models.

A real-time voice cloning system with multiple algorithms for speech quality improvement.

With the development of computer technology, speech synthesis techniques are becoming increasingly sophisticated. Speech cloning can be performed as a subtask of speech synthesis technology by using deep learning techniques to extract acoustic information from human voices and combine it with text to output a natural human voice. However, traditional speech cloning technology still has certain limitations; excessively large text inputs cannot be adequately processed, and the synthesized audio may include noise artifacts like breaks and unclear phrases. In this study, we add a text determination module to a synthesizer module to process words the model has not included. The original model uses fuzzy pronunciation for such words, which is not only meaningless but also affects the entire sentence. Thus, we improve the model by splitting the letters and pronouncing them separately. Finally, we also improved the preprocessing and waveform conversion modules of the synthesizer. We replace the pre-net module of the synthesizer and use an upgraded noise reduction algorithm combined with the SV2TTS framework to achieve a system with superior speech synthesis performance. Here, we focus on improving the performance of the synthesizer module to achieve higher-quality speech synthesis audio output.

Persistent inflammation-immunosuppression-catabolism syndrome in patients with systemic lupus erythematosus.

OBJECTIVE: To evaluate the clinical characteristics and prognosis of systemic lupus erythematosus (SLE) with persistent inflammation-immunosuppression-catabolism syndrome (PICS). METHODS: We retrospectively analyzed patients with SLE who were admitted to the renal intensive care unit (ICU) for over 14 days at Jinling Hospital from July 2010 to July 2018. According to the diagnostic criteria of PICS, we divided the SLE patients into a PICS group and a non-PICS group. We performed a multivariate Cox regression analysis on the risk factors for death in these two groups by comparing the clinical features and prognosis. RESULTS: A total of 96 SLE patients met the inclusion and exclusion criteria of this study, including 61 patients in the PICS group and 35 patients in the non-PICS group. The PICS group patients required a longer length of stay in ICU with higher inflammatory indicators (such as C-reactive protein, procalcitonin and interleukin-6) and lower immune levels (such as total, CD3 + , CD4 + , CD8 + and CD20 + lymphocytes) compared to the non-PICS group patients (P < 0.01). Hemoglobin, platelets, serum creatinine, serum blood urea nitrogen and SLE Disease Activity Index (SLE-DAI) score in the PICS group were lower than those in the non-PICS group (P < 0.05), suggesting severe hematological injury in the PICS group and relatively severe renal damage in the non-PICS group. The rates of PICS combined with sepsis, acute respiratory distress syndrome, mechanical ventilation, gram-positive bacteria, gram-negative bacteria, fungi and double infections were higher than those in the non-PICS group (P < 0.05). The 3-year survival rate was 50.82% in the PICS group and 85.71% in the non-PICS group. The 3-year renal survival rate was 32.79% in the PICS group and 51.43% in the non-PICS group. Multivariate Cox regression found that the total lymphocyte count during ICU admission was an independent risk factor for death in SLE patients with PICS. CONCLUSION: Patients with SLE complicated with PICS had longer ICU stays, a lower level of SLE activity, a higher risk of secondary infection and a significantly lower survival rate than non-PICS patients.

Long-term follow-up of autologous peripheral blood hematopoietic stem cell transplantation for refractory lupus nephritis-a series study of 20 patients.

BACKGROUND: Autologous hematopoietic cell transplantation (ASCT) improves immunologic homeostasis in autoimmune diseases. ASCT-treated refractory lupus nephritis (LN) has been reported. Nevertheless, the long-term outcome of patients with refractory LN after ASCT remains unknown. This study reports the outcomes of 20 refractory lupus patients with 10-year of follow-up after receiving ASCT. METHODS: Twenty-two patients with LN refractory to immunosuppressive therapy were enrolled. Twenty patients were examined closely and two cases died within 100 days after ASCT. Hematopoietic cell mobilization with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) was followed by collection of CD34+ positively selected cells. The conditioning regimen consisted of intravenous cyclophosphamide, rabbit antithymocyte globulin, methylprednisolone, and G-CSF. All immunosuppressive therapies were discontinued at the start of mobilization and corticosteroids were tapered rapidly after ASCT. RESULTS: Data was collected from 22 patients with refractory LN treated by ASCT. 59% were female, duration of lupus before ASCT was 46 (33-71) months, and median duration of follow-up after ASCT was 89.5 (56-108) months. 20 long-term followed up patients had an average follow-up time of 92 months (63.25-109.5). Eighteen patients achieved complete remission, one patient reached partial remission, one patient without remission started peritoneal dialysis at month 12, and one patient received short-term renal replacement therapy before ASCT started hemodialysis at 84 months after transplantation. Nine patients relapsed 10 times during the follow-up, and three patients received rituximab. Two patients relapsed during pregnancy after complete response and the Apgar scores of infants were 9 and 10, respectively. All nine patients received glucocorticoids and immunosuppressive medication after relapse and responded again. The 10-year overall survival, 10-year disease-free survival rate, and 10-year renal survival were 100%, 35%, and 90%, respectively. The rate of relapse was 45%. Complications included hypocytosis, infection, B-type insulin resistance syndrome, and monoclonal immunoglobulinemia. CONCLUSION: This study suggests ASCT is effective and safety in treating refractory LN and is beneficial to improve their long-term outcomes.

OsDOF11 Promotes Crown Root Formation via Cytokinin in Oryza Sativa.

BACKGROUND: Crown root is the main part of root system, which performs an important role in rice growth and development, especially in nutrition and water assimilation. Previously, we reported negative feedback regulation loop between Oryza sativa DNA BINDING WITH ONE FINGER 11 (OsDOF11) and cytokinin by Oryza sativa CYTOKININ OXIDASE/DEHYDROGENASE 4 (OsCKX4) in rice development. METHODS: Reverse transcription quantitative RT-PCR analyses was used to analyze the related gene transcript level. Nitrogen and hormone were measured by CHN-Nitrogen analyser and Liquid chromatography mass spectrometer, respectively. Exogenous application of cytokinin and [13C] sucrose labeled stable isotope uptake experiments help us to explain the relationship between OsDOF11 and cytokinin. RESULTS: We demonstrate the role of OsDOF11 in root development. We note that the loss function of OsDOF11 displays the reduced crown roots number, low activity of nitrogen assimilation and low content of cytokinin and auxin. The expression level of WUSCHEL-related homeobox (OsWOX11), A-type response regulator 2 (OsRR2), OsRR3, and OsCKX4 were decreased in osdof11-1, as well as in OsDOF11 RNA interference 9 mutants (RNAi-9 lines). Through Exogenous application of multiple concentrations of cytokinin as treatment to osdof11-1 mutant, RNAi-9 lines, and wild type (WT). We found that the crown roots number of osdof11-1 plants were rescued as the cytokinin concentration increased gradually from 1 µM to 10 µM, but the effect was weaker in RNAi-9 line. And cytokinin inhibited sucrose uptake activity from Murashige-Skoog medium with 3.0% sucrose (MS30) by OsDOF11 in rice root. CONCLUSIONS: OsDOF11 promotes crown root formation via cytokinin in oryza sativa. These results provide a physiological basis for further analysis of the OsDOF11 function of in rice root development.

Glomerular Exostosin as a Subtype and Activity Marker of Class 5 Lupus Nephritis.

BACKGROUND AND OBJECTIVES: There have been only several studies on the correlation between glomerular exostosin expression and membranous lupus nephritis. In this study, we validate the previous findings in Chinese patients with class 5 lupus nephritis. DESIGN, SETTING, PARTICIPANTS, & MEASURE: One hundred sixty-five patients with class 5 lupus nephritis and varying numbers of control patients were included. Exostosin1/exostosin2 staining was performed by immunohistochemistry, and the staining intensity was quantified using an imaging analysis system. Between-group comparisons were tested for statistical significance using the Pearson chi-squared test, the Fisher exact test, the unpaired t test, the Mann-Whitney U test, or one-way ANOVA. RESULTS: In total, 46% of patients with class 5 lupus nephritis, 9% of patients with class 5 + 3/4 lupus nephritis, and none of the other classes of lupus nephritis were exostosin positive. Only three patients were exostosin positive among the 61 patients with other secondary membranous nephropathy. The exostosin-positive rate in nephrotic patients was significantly higher than that in patients without nephrotic syndrome (P<0.001), and the exostosin staining intensities of the patients with exostosin-positive class 5 were positively correlated with proteinuria (r=0.53; P<0.001). Compared with the patients with exostosin-negative cases, the patients with exostosin-positive cases had higher proteinuria levels (3.9 [interquartile range, 2.0-6.3] g/d versus 2.3 [interquartile range, 1.0-3.6] g/d; P<0.001); lower scores of activity index (1 [interquartile range, 1-2] versus 2 [interquartile range, 1-3]; P=0.001), chronicity index (1 [interquartile range, 0-2] versus 2 [interquartile range, 1-2]; P=0.02), and tubular atrophy score (0 [interquartile range, 0-1] versus 1 [interquartile range, 0-1]; P=0.008); a higher proportion of extensive subepithelial deposition (62% versus 27%; P<0.001); a similar treatment response; and comparable time to kidney end point. Among the 47 patients with class 5 who underwent repeat biopsy, 97% of those with exostosin-negative cases remained negative, whereas 44% of those with exostosin-positive cases were still positive. The rate of histologic transition in the patients with exostosin-negative class 5 was significantly higher than that in the patients with exostosin-positive class 5 (59% versus 22%; P=0.03). CONCLUSIONS: Exostosin positivity occurred frequently in patients with class 5 lupus nephritis, and patients with exostosin-positive cases had more severe proteinuria and a lower rate of histologic transition than the exostosin-negative patients.

Chromosome 1 instability in multiple myeloma: Aberrant gene expression, pathogenesis, and potential therapeutic target.

Multiple myeloma (MM), the terminally differentiated B cells malignancy, is widely considered to be incurable since many patients have either developed drug resistance or experienced an eventual relapse. To develop precise and efficient therapeutic strategies, we must understand the pathogenesis of MM. Thus, unveiling the driver events of MM and its further clonal evolution will help us understand this complicated disease. Chromosome 1 instabilities are the most common genomic alterations that participate in MM pathogenesis, and these aberrations of chromosome 1 mainly include copy number variations and structural changes. The chromosome 1q gains/amplifications and 1p deletions are the most frequent structural changes of chromosomes in MM. In this review, we intend to focus on the genes that are affected by chromosome 1 instability: some tumor suppressors were lost or down regulated in 1p deletions, and others that contributed to tumorigenesis were upregulated in 1q gains/amplifications. We have summarized their biological function as well as their roles in the MM pathogenesis, hoping to uncover potential novel therapeutical targets and promote the development of future therapeutic approaches.

ExsgRNA: reduce off-target efficiency by on-target mismatched sgRNA.

Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing technology has been widely used to facilitate efficient genome editing. Current popular sgRNA design tools only consider the sgRNA perfectly matched to the target site and provide the results without any on-target mismatch. We suppose taking on-target gRNA-DNA mismatches into consideration might provide better sgRNA with similar binding activity and reduced off-target sites. Here, we trained a seq2seq-attention model with feedback-loop architecture, to automatically generate sgRNAs with on-target mismatches. Dual-luciferase reporter experiment showed that multiple sgRNAs with three mismatches could achieve the 80% of the relative activity of the perfect matched sgRNA. Meanwhile, it could reduce the number of off-target sites using sgRNAs with on-target mismatches. Finally, we provided a freely accessible web server sgRNA design tool named ExsgRNA. Users could submit their target sequence to this server and get optimal sgRNAs with less off-targets and similar on-target activity compared with the perfect-matched sgRNA.

Good pregnancy outcomes in lupus nephritis patients with complete renal remission.

BACKGROUND: The aim of this study was to investigate pregnancy outcomes and risk factors in patients with lupus nephritis (LN). METHODS: A total of 158 pregnancies in 155 women with LN were divided into a remission group and a control group according to whether they achieved complete renal remission (CRR) prior to pregnancy. The adverse pregnancy outcomes and risk factors were retrospectively analyzed. RESULTS: In the remission group, 130 LN patients with 133 pregnancies (two twin pregnancies) delivered 127 live births; 25 LN patients with 25 pregnancies delivered 19 live births in the control group. Compared with the control group, the remission group had significantly lower incidence of LN relapse, fetal loss and premature birth. For LN patients in the remission group, a CRR duration <18 months [odds ratio (OR) 11.24, 95% confidence interval (CI) 2.95-42.80, P < 0.001] and anti-C1q antibody positivity before pregnancy (OR 7.2, 95% CI 1.38-37.41, P = 0.019) were independent risk factors for LN relapse; anti-phospholipid antibody positivity (OR 9.32, 95% CI 1.27-68.27, P = 0.028) and prednisone dosage during pregnancy ≥12.5 mg/day (OR 3.88, 95% CI 1.37-10.99, P = 0.011) were independent risk factors for fetal loss and premature birth, respectively; and age >30 years was an independent risk factor for preeclampsia and premature birth. CONCLUSION: LN patients with a CRR duration greater than 18 months were associated with good pregnancy outcomes and lower LN relapse. Age, anti-C1q and anti-phospholipid antibodies, and prednisone dosage during pregnancy were risk factors for adverse pregnancy outcomes.

Long-term renal outcomes of mesangial proliferative lupus nephritis in Chinese patients.

OBJECTIVE: This study aimed to explore the long-term outcomes of mesangial proliferative lupus nephritis (LN class II) and the factors associated with its relapse and histological transformation in Chinese patients. METHODS: 104 SLE patients with biopsy-proven LN class II were included and divided into proteinuria group (proteinuria ≥ 0.4 g/24 h, with or without microscopic hematuria) and hematuria group (microscopic hematuria with proteinuria < 0.4 g/24 h).Patients were treated with glucocorticoid alone (GC monotherapy) or GC in combination with other immunosuppressant (combination therapy). The rates of remission, relapse, histological transformation, end-stage renal disease (ESRD), adverse events, and risk factors related to the outcomes were analyzed. RESULTS: During the median follow-up of 77.5 (IQR 58-116.5) months, all the 104 patients achieved remission. Relapse occurred in 69 cases (66.3%), of which 37 were of renal relapse (35.6%). Histological transformation was found in 14 of the 16 (87.5%) cases who received repeated renal biopsy after renal relapse. At the end of follow-up, 3 (2.9%) patients developed ESRD. There were no significant differences in the rates of relapse, histological transformation, adverse events and in the time from remission to relapse between the proteinuria group and the hematuria group. In contrast, the cumulative relapse rate in the GC monotherapy group was much higher than that in the combination group (P < 0.01). Adverse events occurred in 55 (57.3%) patients during follow-up. CONCLUSIONS: Patients with LN class II have high rates of relapse and renal histological transformation and need optimal maintenance therapy. KEY POINTS: • The rates of relapse and histological transformation are high in patients with LN class II. • Patients with LN class II are suggested to receive combination therapy and consider repeat renal biopsy after renal relapse.

MCC Regulator of WNT Signaling Pathway (MCC) Is a Podocyte Essential Gene.

Podocytes are an integral part of the glomerular filtration barrier. Many genes are already known to be essential for podocyte survival, structure and function, but there are more podocyte essential genes to be identified. By single-cell RNA-seq of mouse podocytes, we detected the expression of gene encoding MCC regulator of WNT signaling pathway (MCC) in majority of the podocytes and speculated that MCC is essential for podocytes. We confirmed MCC expression in mouse podocytes and further showed its expression in human podocytes. To experimentally prove the essentiality of MCC for podocytes, we knocked down MCC in cultured podocytes and found marked morphological change of cell shape, cytoskeletal F-actin stress fiber disruption, increased apoptosis, and downregulation of podocyte essential genes, CD2AP and WT1, demonstrating that MCC is essential for podocytes. Since MCC has been implicated in cell cycle and ß-catenin signaling, we examined the expression of cell cycle related genes and activity of ß-catenin in the MCC knockdown podocytes, but did not find significant changes. To further explore the mechanism underlying the role of MCC in podocytes, we performed RNA-sequencing and bioinformatics analysis of MCC knockdown podocytes and found a significant enrichment of the regulated genes in lamellipodia formation. Consistently, we found that MCC is present in lamellipodia and MCC knockdown resulted in loss of lamellipodia in the cells. Lastly, we found that MCC was downregulated in podocytes treated with puromycin aminonucleosides and in glomeruli of diabetic mice and FSGS patients, implicating MCC is involved in the development of podocytopathy and proteinuria. In conclusion, MCC is potentially essential for podocytes and its downregulation may be involved in podocytopathy.

A novel approach to identify the mechanism of miR-145-5p toxicity to podocytes based on the essential genes targeting analysis.

MicroRNAs (miRNAs) are emerging as effective therapeutic agents. When testing whether miR-145-5p could alleviate kidney injury, we unexpectedly found that extracellular vesicles loaded with miR-145-5p induced proteinuria and podocyte foot process effacement in normal control mice. To explore the mechanism of miR-145-5p's toxicity to podocytes, we hypothesized that miR-145-5p could enter podocytes and inhibit genes essential for podocytes. We demonstrated that systemically administered miRNA can enter podocytes. Next, we predicted 611 podocyte essential genes based on single-cell RNA sequencing (RNA-seq) and found that 32 of them are predicted to be targeted by miR-145-5p. Functional annotation of the 32 podocyte essential genes revealed small GTPase-mediated signal transduction as the top pathway. We experimentally validated that miR-145-5p targeted Arhgap24 and Srgap1, the essential regulators of the Rho family of small GTPases, increased the activity of Rac1 and Cdc42, and reduced RhoA activity, accompanied by cellular injury, in podocytes. These results explain how miR-145-5p has deleterious effect on podocytes. Most importantly, our study provides a novel approach to investigate how a miRNA affects a given cell type, allowing not only identification of the molecular mechanism underlying an observed side effect of a miRNA drug but also prediction of miRNA drug toxicity on various cell types.

OsDOF11 Affects Nitrogen Metabolism by Sucrose Transport Signaling in Rice (Oryza sativa L.).

Carbon and nitrogen antagonistically regulate multiple developmental processes. However, the molecular mechanism affecting nitrogen metabolism by sucrose transport remains poorly defined. Previously, we noted that Oryza sativa DNA BINDING WITH ONE FINGER 11 (OsDOF11) mediated sucrose transport by binding to the promoter regions of Sucrose Transporter 1 (SUT1), Oryza sativa Sugars Will Eventually be Exported Transporters 11 (OsSWEET11), and OsSWEET14. Here, we note that OsDOF11 promotes nitrogen uptake and then maintains the ratio of fresh weight to dry weight in seedling plants and the effective leaf blade at flowering stages. Mutants of the sucrose transporter gene OsSWEET14 displayed a phenotype similar to that of OsDOF11. By microarray analysis and qRT-PCR in OsDOF11 mutant plants, OsDOF11 affected the transcription level of amino acid metabolism-related genes. We further found that mainly amino acid contents were reduced in flag leaves but increased in seeds. Both sugar and organic nitrogen changes caused the ratio of fresh weight to dry weight to decrease in OsDOF11 mutant seedling plants and mature leaves, which might result in vigorous reduced metabolic activity and become less susceptible to stress. These results demonstrated that OsDOF11 affected nitrogen metabolism by sugar distribution in rice, which provided new insight that OsDOF11 coordinated with C and N balance to maintain plant growth activity.

DDRS: Detection of drug response SNPs specifically in patients receiving drug treatment.

Detecting SNPs associated with drug efficacy or toxicity is helpful to facilitate personalized medicine. Previous studies usually find SNPs associated with clinical outcome only in patients received a specific treatment. However, without information from patients without drug treatment, it is possible that the detected SNPs are associated with patients' clinical outcome even without drug treatment. Here we aimed to detect drug response SNPs based on data from patients with and without drug treatment through combing the cox proportional-hazards model and pairwise Kaplan-Meier survival analysis. A pipeline named Detection of Drug Response SNPs (DDRS) was built and applied to TCGA breast cancer data including 363 patients with doxorubicin treatment and 321 patients without any drug treatment. We identified 548 doxorubicin associated SNPs. Drug response score derived from these SNPs were associated with drug-resistant level (indicated by IC50) of breast cancer cell lines. Enrichment analyses showed that these SNPs were enriched in active epigenetic regulation markers (e.g., H3K27ac). Compared with random genes, the cis-eQTL genes of these SNPs had a shorter protein-protein interaction distance to doxorubicin associated genes. In addition, linear discriminant analysis showed that the eQTL gene expression levels could be used to predict clinical outcome for patients with doxorubicin treatment (AUC = 0.738). Specifically, we identified rs2817101 as a drug response SNP for doxorubicin treatment. Higher expression level of its cis-eQTL gene GSTA1 is associated with poorer survival. This approach can also be applied to identify new drug associated SNPs in other cancers.

Tackling Dialysis Burden around the World: A Global Challenge.

CKD is a global problem that causes significant burden to the healthcare system and the economy in addition to its impact on morbidity and mortality of patients. Around the world, in both developing and developed economies, the nephrologists and governments face the challenges of the need to provide a quality and cost-effective kidney replacement therapy for CKD patients when their kidneys fail. In December 2019, the 3rd International Congress of Chinese Nephrologists was held in Nanjing, China, and in the meeting, a symposium and roundtable discussion on how to deal with this CKD burden was held with opinion leaders from countries and regions around the world, including Australia, Canada, China, Hong Kong, Singapore, Taiwan, the UK, and the USA. The participants concluded that an integrated approach with early detection of CKD, prompt treatment to slow down progression, promotion of home-based dialysis therapy like peritoneal dialysis and home HD, together with promotion of kidney transplantation, are possible effective ways to combat this ongoing worldwide challenge.