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BACKGROUND: With double pressures of endemic and imported emerging infectious diseases (EIDs), China's ability to detect, prevent and control the unknown virus is of regional and global interest. This study aimed to establish an R&D Blueprint for EIDs in China by identifying the list of prioritized diseases and medical countermeasures (MCMs) that need proactive actions for the next pandemic. METHODS: The process mainly referred to the World Health Organization's prioritization methodology, supplemented by pipeline landscape, rapid risk assessment and multi-dimensional analysis. The study included five steps: 1) identifying potential pathogens, 2) screening into the long list, 3) prioritizing the long list, 4) identifying the final list and 5) generating an R&D Blueprint. RESULTS: China's R&D Blueprint identified 14 viral pathogens and two virus groups (i.e., Influenza HxNy and Coronavirus X) for proactive and representative MCM development. At least one diagnostic candidate in preclinical study, and one therapeutic and one vaccine candidate in Phase I/II clinical trials for each prioritized pathogen were suggested to be developed as strategic national stockpiles. Various generalized and innovative platform technologies were also highlighted for enhancing overall capacities of EID preparedness and response, covering basic research, experiment, detection, prevention and control, surveillance and information sharing. CONCLUSIONS: This is the first study in developing countries that established an R&D Blueprint of prioritized diseases, countermeasures and technologies. Our findings could help to drive pre-emptive scientific and technological actions toward emerging pathogens that may cause the next epidemic and could provide evidence-based strategies for developing countries to establish their national health research agenda tailored to health and research context under resource-limited settings.

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An efficient, diversity-oriented synthesis of indole-1,2-fused 1,4-benzodiazepines, tetrahydro-ß-carbolines, and 2,2'-bis(indolyl)methanes was established starting from tosyl-protected tryptamine. These diverse privileged skeletons were controllably constructed by adjusting different hydride donors and Brønsted acids. A variety of indole-1,2-fused 1,4-benzodiazepines were facilely accessed using benzaldehydes bearing cyclic amines as hydride donors via a cascade N-alkylation/dehydration/[1,5]-hydride transfer/Friedel-Crafts alkylation sequence. The reaction site could be switched when benzaldehydes bearing an alkoxy moiety as hydride donors were used for the generation of tetrahydro-ß-carbolines. On the other hand, the switchable synthesis of 2,2'-bis(indolyl)methanes could be achieved as well by applying p-TsOH·H2O as a catalyst. The reactions feature mild conditions, simple and practical operation, excellent efficiency and the use of EtOH as a green solvent. Using the concept of diversity-oriented, reagent-based synthesis, the inexpensive feedstock tryptamine was efficiently converted to three different types of privileged scaffolds, which facilitates rapid compound library synthesis for accelerating drug discovery.

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Background: Familial renal glucosuria (FRG) is a hereditary disorder caused by variants in SLC5A2 encoding sodium-glucose cotransporter 2 (SGLT2). In this study, we aimed to characterize proximal tubule solute transport, glucagon secretion and the genotype-phenotype relationship in FRG patients. Methods: We sequenced SLC5A2 and PDZK1IP1 in 21 FRG patients and measured the renal threshold of glucose (RTG) in 15 patients. We built an open-source online calculator of RTG, evaluated the proximal tubule transport of amino acid, uric acid and phosphate, and explored glucagon secretion after glucose ingestion in FRG patients. Results: We identified 12 novel SLC5A2 variants (G484D, R564W, A212S, c.574+1G>C, W649*, S592Cfs*6, Q579*, Y339*, V39F, G491E, A464E and G360D) in our cohort and yielded 111 SLC5A2 variants from literature review. RTG in our cohort ranged from 1.0 to 9.2 mmol/L. Patients with two SLC5A2 variants had lower RTG (3.9 vs 6.2 mmol/L) and higher 24-h urinary glucose excretion (24hUG) than single-variant carriers (291.0 vs 40.0 mmol/1.73 m2). Patients with homozygous missense or in-frame indels had mean 24hUG of 457.2 mmol/1.73 m2, comparable to those with homozygous truncating variants (445.0 mmol/1.73 m2) and significantly more than those with homozygous splicing variants (196.6 mmol/1.73 m2). Patients with homozygous missense variants involving conservative residues (582.0 mmol/1.73 m2) had more 24hUG than those with variants at non-conservative residues (257.6 mmol/1.73 m2). Four out of 14 tested patients had mild aminoaciduria. The RTG of FRG patients had no significant correlation to phosphate reabsorption but a potential negative correlation to the fractional excretion of uric acid. Postprandial suppression of glucagon secretion was absent in most FRG patients. Conclusions: We built a comprehensive map showing the impact of SLC5A2 variant type and variant location on glucosuria severity. Our results highlighted the role of key residues in maintaining the transport function of SGLT2 and the functional link between glucosuria and reabsorption of amino acid and uric acid in FRG patients.

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Although bacterial laccase (BLac) has many advantages including short fermentation period and adaptable activity to wide temperature and pH ranges, it is of challenge and significance to apply BLac to the biosensors, due to the intracellular secretion and poor electron transfer efficiency of BLac. Here, cell surface-displayed BLac (CSDBLac) was successfully constructed as whole-cell biocatalyst through microbial surface display technology, eliminating the mass transfer restriction and laborious purification steps. Meanwhile, MXenes/polyetherimide-multiwalled carbon nanotubes (MXenes/PEI-MWCNTs) nanohybrids were designed to immobilize CSDBLac and improve their electrochemical activity. Then, an electrochemical biosensor was successfully constructed to detect common phenolic pollutants (catechol and hydroquinone) by the co-immobilization of CSDBLac and MXenes/PEI-MWCNTs nanohybrids onto a glassy carbon electrode. Subsequently, it was successfully applied to the water samples assay with good reliability and repeatability. This work innovatively used BLac and nanohybrid as the core elements of biosensor, which not only effectively solved the application bottleneck of BLac on biosensors, but also dramatically promote the electro transfer efficiency between whole-cell biocatalyst and electrode. This method is of profound meanings for significantly improving the performance of phenolic biosensors and other biosensors from the origin.

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Purposes: This study was conducted to identify the frequent mutations from reported Chinese Gitelman syndrome (GS) patients, to predict the three-dimensional structure change of human Na-Cl co-transporter (hNCC), and to test the activity of these mutations and some novel mutations in vitro and in vivo. Methods: SLC12A3 gene mutations in Chinese GS patients previously reported in the PubMed, China National Knowledge Infrastructure, and Wanfang database were summarized. Predicted configurations of wild type (WT) and mutant proteins were achieved using the I-TASSER workplace. Six missense mutations (T60M, L215F, D486N, N534K, Q617R, and R928C) were generated by site-directed mutagenesis. 22Na+ uptake experiment was carried out in the Xenopus laevisoocyte expression system. In the study, 35 GS patients and 20 healthy volunteers underwent the thiazide test. Results: T60M, T163M, D486N, R913Q, R928C, and R959frameshift were frequent SLC12A3 gene mutations (mutated frequency >3%) in 310 Chinese GS families. The protein's three-dimensional structure was predicted to be altered in all mutations. Compared with WT hNCC, the thiazide-sensitive 22Na+ uptake was significantly diminished for all six mutations: T60M 22 ± 9.2%, R928C 29 ± 12%, L215F 38 ± 14%, N534K 41 ± 15.5%, Q617R 63 ± 22.1%, and D486N 77 ± 20.4%. In thiazide test, the net increase in chloride fractional excretion in 20 healthy controls was significantly higher than GS patients with or without T60M or D486N mutations. Conclusions: Frequent mutations (T60M, D486N, and R928C) and novel mutations (L215F, N534K, and Q617R) lead to protein structure alternation and protein dysfunction verified by 22Na+ uptake experiment in vitro and thiazide test on the patients.

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BACKGROUND: Urinary uromodulin (uUMOD) is one of the novel biomarkers for predicting AKI. However, currently available publications showed inconsistent results. We designed this meta-analysis to evaluate the potential association between uUMOD and AKI. METHODS: We searched research articles with no language restriction in Medline, Web of Science, Cochrane Library, Embase, and 3 Chinese datasets from inception to February 2021. We used random-effects models to estimate the standardized mean difference (SMD) between patients with AKI or not, while the leave-one-out method and random-effects meta-regression to evaluate the sensitivity and the impact of potential confounders such as age and surgery. RESULTS: The meta-analysis comprising 3148 subjects from 11 studies showed that the uUMOD of the AKI group is significantly lower than the non-AKI group (SMD: - 0.71; 95% confidence interval (CI), - 1.00, - 0.42, P < 0. 001, I2 = 78.8%). Subgroup analysis revealed the difference is also significant in a different age, surgery condition, and assay time but not acute rejection (AR) group, especially in children (SMD: - 1.21, 95% CI: - 1.80, - 0.61; P < 0.001) and patients undergoing surgery (SMD: - 1.03, 95% CI: - 1.75, - 0.30; P < 0.001). Lower uromodulin is associated with higher odds for AKI incidence (odds ratio = 2.47, 95% CI: 1.12, 5.47; P < 0.001, I2 = 89%). Meta-reggression found that age was associated with the SMD of uUMOD. The study outcome was reliably confirmed by the sensitivity analysis. CONCLUSION: The present study suggested a negative association between uUMOD and AKI especially in children and surgical patients.

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BACKGROUND: We previously observed that adenosine A1 receptor (A1AR) had a protective role in proximal tubular megalin loss associated with albuminuria in diabetic nephropathy (DN). In this study, we aimed to explore the role of A1AR in the fibrosis progression of DN. METHODS: We collected DN patients' samples and established a streptozotocin-induced diabetes model in wild-type (WT) and A1AR-deficient (A1AR-/-) mice. The location and expression of CD34, PDGFRß, and A1AR were detected in kidney tissue samples from DN patients by immunofluorescent and immunohistochemical staining. We also analyzed the expression of TGFß, collagen (I, III, and IV), α-SMA, and PDGFRß using immunohistochemistry in WT and A1AR-/- mice. CD34 and podoplanin expression were analyzed by Western blotting and immunohistochemical staining in mice, respectively. Human renal proximal tubular epithelial cells (HK2) were cultured in medium containing high glucose and A1AR agonist as well as antagonist. RESULTS: In DN patients, the expression of PDGFRß was higher with the loss of CD34. The location of PDGFRß and TGFß was near to each other. The A1AR, which was colocalized with CD34 partly, was also upregulated in DN patients. In WT-DN mice, obvious albuminuria and renal pathological leisure were observed. In A1AR-/- DN mice, more severe renal tubular interstitial fibrosis and more extracellular matrix deposition were observed, with lower CD34 expression and pronounced increase of PDGFRß. In HK2 cells, high glucose stimulated the epithelial-mesenchymal transition (EMT) process, which was inhibited by A1AR agonist. CONCLUSION: A1AR played a critical role in protecting the tubulointerstitial fibrosis process in DN by regulation of the peritubular microenvironment.

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Background: The association of uromodulin and hypertension has been observed in clinical studies, but not proven by a causal relationship. We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between uromodulin and blood pressure. Methods: We selected single nucleotide polymorphisms (SNPs) related to urinary uromodulin (uUMOD) and serum uromodulin (sUMOD) from a large Genome-Wide Association Studies (GWAS) meta-analysis study and research in PubMed. Six datasets based on the UK Biobank and the International Consortium for Blood Pressure (ICBP) served as outcomes with a large sample of hypertension (n = 46,188), systolic blood pressure (SBP, n = 1,194,020), and diastolic blood pressure (DBP, n = 1,194,020). The inverse variance weighted (IVW) method was performed in uUMOD MR analysis, while methods of IVW, MR-Egger, Weighted median, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were utilized on sUMOD MR analysis. Results: MR analysis of IVM showed the odds ratio (OR) of the uUMOD to hypertension ("ukb-b-14057" and "ukb-b-14177") is 1.04 (95% Confidence Interval (CI), 1.03-1.04, P < 0.001); the effect sizes of the uUMOD to SBP are 1.10 (Standard error (SE) = 0.25, P = 8.92E-06) and 0.03 (SE = 0.01, P = 2.70E-04) in "ieu-b-38" and "ukb-b-20175", respectively. The ß coefficient of the uUMOD to DBP is 0.88 (SE = 0.19, P = 4.38E-06) in "ieu-b-39" and 0.05 (SE = 0.01, P = 2.13E-10) in "ukb-b-7992". As for the sUMOD, the OR of hypertension ("ukb-b-14057" and "ukb-b-14177") is 1.01 (95% CI 1.01-1.02, all P < 0.001). The ß coefficient of the SBP is 0.37 (SE = 0.07, P = 1.26E-07) in "ieu-b-38" and 0.01 (SE = 0.003, P = 1.04E-04) in "ukb-b-20175". The sUMOD is causally associated with elevated DBP ("ieu-b-39": ß = 0.313, SE = 0.050, P = 3.43E-10; "ukb-b-7992": ß = 0.018, SE = 0.003, P = 8.41E-09). Conclusion: Our results indicated that high urinary and serum uromodulin levels are potentially detrimental in elevating blood pressure, and serve as a causal risk factor for hypertension.

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The switchable synthesis of 3-non, 3-mono, 3,3'-disubstituted 3,4-dihydroquinolin-2(1H)-ones was developed through a redox-neutral hydride-transfer/N-dealkylation/N-acylation strategy from o-aminobenzaldehyde with 4-hydroxycoumarin, and Meldrum's acid, respectively. The unprecedented strategy for the synthesis of 3,3'-highly functionalized 3,4-dihydroquinolin-2(1H)-one has been realized with the in situ utilization of the released HCHO via the o-QM involved Michael addition. In addition, the synthetic utility of this protocol has been well illustrated via concise synthesis of CYP11B2 inhibitor.

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The hydrogen-bonding-assisted construction of tetrahydroquinolines decorated with structurally diverse 3,3'-difunctional groups has been realized via a hydride transfer-involved three-step cascade reaction in the presence of morpholine. This protocol solves the limitation of acyclic 1,3-dicarbonyl compounds by one-pot synthesis of tetrahydroquinolines, featuring operational simplicity, broadly applicable substrates, and metal- and acid-free conditions with EtOH as a hydrogen-bonding donor.

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Structurally diverse amino acids and their ester derivatives were conveniently N,N'-dialkylated via a TFE-promoted cascade condensation/[1,5]-hydride transfer/cyclization for straightforward construction of pharmeutically significant tetrahydroquinazolines incorporating various amino acids, which featured broad substrate scope, the use of TFE as a sole solvent, additive-free and mild conditions.

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PURPOSE: In our previous study, exacerbation of albuminuria was observed in A1 adenosine receptor knockout (A1AR-/-) mice with diabetic nephropathy (DN), but the mechanism was unclear. Here, we investigated the relationship of megalin loss and albuminuria, to identify the protective effect of A1AR in megalin loss associated albuminuria by inhibiting pyroptosis-related caspase-1/IL-18 signaling of DN. METHODS: We successfully collected DN patients' samples and built diabetes mice models induced by streptozotocin. Megalin, cubilin, and A1AR expression were detected in kidney tissue samples from DN patients and mice through immunohistochemical and immunofluorescent staining. A1AR, caspase-1, interleukin-18 (IL-18) expression were analyzed using Western blotting in wild-type and A1AR -/- mice. Human renal proximal tubular epithelial cells (PTC) were cultured with high glucose to observe the effect of A1AR agonist and antagonist on caspase-1/IL-18 and megalin injury. RESULTS: The loss of megalin, co-localized with A1AR at PTC, was associated with the level of albuminuria in diabetic patients and mice. The injury of megalin-cubilin was accompanied with the A1AR upregulation (1.30±0.1 vs 0.98±0.2, P=0.042), the caspase-1 (1.33±0.1 vs 1.0±0.2, P=0.036), and IL-18 (1.26±0.2 vs 0.96±0.2, P=0.026) signaling activation in mice with DN. More severe pathological injury, 24 hrs urine albumin excretion (170.8±4.1 µg/d vs 132.0±2.9 µg/d vs 17.9±2.8 µg/d, P<0.001) and megalin-cubilin loss were observed in A1AR -/- DN mice with more pronounced caspase-1 (1.52±0.03 vs 1.20±0.01, P=0.017) and IL-18 (1.42±0.02 vs 1.21±0.02, P=0.018) secretion. High glucose could stimulate the secretion of caspase-1 (1.72 times, P≤0.01) and IL-18 (1.64 times, P≤0.01), which was abolished by A1AR agonist and aggravated by A1AR antagonist. CONCLUSION: A1AR played a protective role in proximal tubular megalin loss associated albuminuria by inhibiting the pyroptosis-related caspase-1/IL-18 signaling in DN.

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The pharmaceutically intriguing spiroindolenines incorporating tetrahydroquinoline were constructed via a hexafluoroisopropanol-promoted redox-neutral cascade cyclization from readily available starting materials. The benzazepinoindole skeletons could also be facilely accessed via one-pot sequential operation. Distinctive features of these transformations include their controllable access of the two privileged skeletons, high efficiency, simple operation, and mild reaction conditions.

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The inert benzylic C-H bond of π-electron-rich heteroaromatic 2,5-dialkylfuran derivatives was conveniently functionalized with ferrocenyl alcohols as alkylation reagents under catalytic acidic conditions at room temperature, which features chemo- and regiospecificity, mild and metallic catalyst-free conditions, and environmental benignity.

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An environmentally benign cascade redox-neutral process was developed for the efficient construction of pharmaceutically significant spirocyclic tetrahydro-quinolines via a 3-step cascade Knoevenagel condensation/[1,5]-hydride transfer/cyclization, which features green and additive-free conditions, wide substrate scope, and high step- and atom-economy.

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The aim of this study was to describe the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid (SUA) in patients with type 2 diabetes mellitus (T2DM). PubMed, CENTRAL, EMBASE and ClinicalTrials.gov were searched for randomized controlled trials of SGLT2 inhibitors in patients with T2DM up to May 20, 2017. A total of 62 studies, comprising 34 941 patients, were included. Any of the SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, tofogliflozin, luseogliflozin or ipragliflozin) significantly decreased SUA levels compared with control (total weighted mean difference [WMD] -37.73 µmol/L, 95% CI [-40.51, -34.95]). Treatment with empagliflozin resulted in a superior reduction in SUA (WMD -45.83 µmol/L, 95% CI [-53.03, -38.63]). The effect persisted during long-term treatment. Dapagliflozin decreased SUA in a dose-dependent manner (from 5 to 50 mg, P = .014). In subgroup analyses, greater reductions could be observed during the course of early diabetes and the SUA-lowering effect was abolished in patients with chronic kidney disease (estimated glomerular filtration rate <60 mL/min per 1.73 m2 ). The effect of SGLT2 inhibitors on SUA reduction suggests that this class of drugs might be beneficial for diabetic patients with hyperuricaemia.

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A simple and sensitive electroanalysis method has been developed for the direct determination of lead ions of nanomolar levels in real samples of drinking water and milk by employing magnetic mesoporous thiourea-formaldehyde resin (TUF@Fe3O4) nanocomposites as the capturing absorbents. Here, the prepared TUF@Fe3O4 with the large-surface-area mesoporous structure and strong Pb2+-binding ligands could facilitate the selective and large-scale adsorption of Pb2+ ions from the complex sample matrices to be further magnetically separated onto the magnetic electrodes. Moreover, the Pb2+ ions magnetically accumulated were electrochemically measured alternatively by the solid state-based anodic stripping of PbCl2. The detection limit was found to be 0.0070nmolL-1. The as-developed Pb2+ electroanalysis method with the magnetic electrodes and TUF@Fe3O4 nanocomposites could avoid the complicated sample preparation and electrode modification, thus holding the great potential of applications for the Pb2+ detection in different real samples.

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The organocatalytic alkylation of 2-methyl-N-heteroaromatics with alcohols has been achieved via SN1-type C(sp3)-H functionalization, providing a green and efficient synthesis of indole and ferrocene-functionalized N-heteroaromatics in high yields.

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AIM: To evaluate the effects of sodium-glucose co-transporter 2 (SGLT2) inhibition on renal function and albuminuria in patients with type 2 diabetes. METHODS: We conducted systematic searches of PubMed, Embase and Cochrane Central Register of Controlled Trials up to June 2016 and included randomized controlled trials of SGLT2 inhibitors in adult type 2 diabetic patients reporting estimated glomerular filtration rate (eGFR) and/or urine albumin/creatinine ratio (ACR) changes. Data were synthesized using the random-effects model. RESULTS: Forty-seven studies with 22,843 participants were included. SGLT2 inhibition was not associated with a significant change in eGFR in general (weighted mean difference (WMD), -0.33 ml/min per 1.73 m2, 95% CI [-0.90 to 0.23]) or in patients with chronic kidney disease (CKD) (WMD -0.78 ml/min per 1.73 m2, 95% CI [-2.52 to 0.97]). SGLT2 inhibition was associated with eGFR reduction in short-term trials (WMD -0.98 ml/min per 1.73 m2, 95% CI [-1.42 to -0.54]), and with eGFR preservation in long-term trials (WMD 2.01 ml/min per 1.73 m2, 95% CI [0.86 to 3.16]). Urine ACR reduction after SGLT2 inhibition was not statistically significant in type 2 diabetic patients in general (WMD -7.24 mg/g, 95% CI [-15.54 to 1.06]), but was significant in patients with CKD (WMD -107.35 mg/g, 95% CI [-192.53 to -22.18]). CONCLUSIONS: SGLT2 inhibition was not associated with significant changes in eGFR in patients with type 2 diabetes, likely resulting from a mixture of an initial reduction of eGFR and long-term renal function preservation. SGLT2 inhibition was associated with statistically significant albuminuria reduction in type 2 diabetic patients with CKD.