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AIMS: Targeting vascular inflammation represents a novel therapeutic approach to reduce complications of atherosclerosis. Neutralizing the pro-inflammatory cytokine interleukin-1β (IL-1β) using canakinumab, a monoclonal antibody, reduces the incidence of cardiovascular events in patients after myocardial infarction (MI). The biological basis for these beneficial effects remains incompletely understood. We sought to explore the mechanisms of IL-1β-targeted therapies.METHODS AND RESULTS: In mice with early atherosclerosis (ApoE-/- mice on a high-cholesterol diet for six weeks), we found that three weeks of NLRP3-inflammasome inhibition or anti-IL-1β treatment (using either MCC950, an NLRP3 inflammasome inhibitor which blocks production and release of active IL-1β; or a murine analog of canakinumab) dampened accumulation of leukocytes in atherosclerotic aortas, which consequently resulted in slower progression of atherosclerosis. Causally, we found that endothelial cells from atherosclerotic aortas lowered expression of leukocyte chemoattractants and adhesion molecules upon NLRP3-inflammasome inhibition, indicating that NLRP3-inflammasome- and IL-1β-targeted therapies reduced blood leukocyte recruitment to atherosclerotic aortas. In accord, adoptive transfer experiments revealed that anti-IL-1β treatment mitigated blood myeloid cell uptake to atherosclerotic aortas. We further report that anti-IL-1β treatment and NLRP3-inflammasome inhibition reduced inflammatory leukocyte supply by decreasing proliferation of bone marrow hematopoietic stem and progenitor cells, demonstrating that suppression of IL-1β and the NLRP3-inflammasome lowered production of disease-propagating leukocytes. Using bone marrow reconstitution experiments, we observed that hematopoietic cell-specific NLRP3-inflammasome activity contributed to both enhanced recruitment and increased supply of blood inflammatory leukocytes. Further experiments that queried whether anti-IL-1β treatment reduced vascular inflammation also in post-MI accelerated atherosclerosis documented the operation of convergent mechanisms (reduced supply and uptake of inflammatory leukocytes). In line with our pre-clinical findings, post-MI patients on canakinumab treatment showed reduced blood monocyte numbers.CONCLUSIONS: Our murine and human data reveal that anti-IL-1β treatment and NLRP3-inflammasome inhibition dampened vascular inflammation and progression of atherosclerosis through reduced blood inflammatory leukocyte 1) supply and 2) uptake into atherosclerotic aortas providing additional mechanistic insights into links between hematopoiesis and atherogenesis, and into the beneficial effects of NLRP3-inflammasome- and IL-1β-targeted therapies.TRANSLATIONAL PERSPECTIVE: Therapeutic targeting of vascular inflammation represents a promising avenue to reduce complications of atherosclerosis. Neutralizing the pro-inflammatory cytokine interleukin-1β (IL-1β) reduces the incidence of cardiovascular events in patients with prior myocardial infarction. However, the mechanisms underlying these beneficial effects remain incompletely understood. This study explored how IL-1β and NLRP3-inflammasome suppression mitigated plaque progression. Our murine and human data reveal that pharmacological anti-IL-1β treatment and NLRP3-inflammasome inhibition dampened inflammatory leukocyte accumulation in atherosclerotic aortas through 1) decreased blood inflammatory leukocyte supply and 2) reduced blood inflammatory leukocyte uptake into in atherosclerotic aortas. These data provide additional mechanistic insights into links between hematopoiesis and atherogenesis, and inform future anti-inflammatory interventions in patients with atherosclerosis.

Sodium‐glucose co-transporter 2 (SGLT2) inhibitors have recently emerged as an effective means to protect kidney function in people with type 2 diabetes and chronic kidney disease (CKD). In this review, we explore the role of SGLT2 inhibition in these individuals. SGLT2 inhibitors specifically act to inhibit sodium and glucose reabsorption in the early proximal tubule of the renal nephron. Although originally developed as glucose-lowering agents through their ability to induce glycosuria, it became apparent in cardiovascular outcome trials that the trajectory of kidney function decline was significantly slowed and the incidence of serious falls in kidney function was reduced in participants receiving an SGLT2 inhibitor. These observations have recently led to specific outcome trials in participants with CKD, including DAPA-CKD, CREDENCE and EMPA-KIDNEY, and real-world studies, like CVD-REAL-3, that have confirmed the observation of kidney benefits in this setting. In response, recent KDIGO Guidelines have recommended the use of SGLT2 inhibitors as first line therapy in patients with CKD, alongside statins, renin–angiotensin–aldosterone system inhibitors and multifactorial risk factor management as indicated. However, SGLT2 inhibitors remain significantly underutilized in the setting of CKD. Indeed, an inertia paradox exists, with patients with more severe disease less likely to receive an SGLT2 inhibitor. Concerns regarding safety appear unfounded, as acute kidney injury, hyperkalaemia, major acute cardiovascular events and cardiac death in patients with CKD appear to be lower following SGLT2 inhibition. The first-in-class indication of dapagliflozin for CKD may begin a new approach to managing kidney disease in type 2 diabetes.

Background: Low high-density lipoprotein cholesterol (HDL-C) and type II diabetes are associated with an increased risk for cancer. Patients with type II diabetes typically have low HDL-C; however, the association between HDL-C and cancer has not been examined in this population.Methods: A total of 11,140 patients with type II diabetes were followed for a median of 5 years. Cox proportional hazard models were used to assess the association between baseline HDL-C and risk of cancer incidence and cancer death, with adjustments made for potential confounders. To explore the possibility of reverse causation, analyses were repeated for the cancers occurring in the first and second halves of follow-up.Results: Six hundred and ninety-nine patients developed cancer, with 48% occurring within the first half of follow-up. For every 0.4 mmol/L lower baseline HDL-C, there was a 16% higher risk of cancer [HR 1.16; 95% confidence interval (CI), 1.06–1.28; P = 0.0008] and cancer death (HR 1.16; 95% CI, 1.01–1.32; P = 0.03). After adjustment for confounding, the higher risk remained significant for cancer (adjusted HR 1.10; 95% CI, 1.00–1.22; P = 0.05) but not for cancer death (adjusted HR 1.08; 95% CI, 0.93–1.25; P = 0.31). The association was driven by cancers occurring within the first half of follow-up (adjusted HR 1.22; 95% CI, 1.05–1.41; P = 0.008) as no significant association was found between HDL-C and cancer in the second half of follow-up.Conclusions: Low HDL-C is associated with cancer risk in patients with type II diabetes. However, this association may be explained by confounding and reverse causation.Impact: HDL-C is not a risk factor for cancer in type II diabetes. Cancer Epidemiol Biomarkers Prev; 22(9); 1628–33. ©2013 AACR.

PDF file - 85K, Baseline characteristics stratified by subsequent cancer cases versus non-cases.

Glucose-responsive insulin-delivery platforms that are sensitive to dynamic glucose concentration fluctuations and provide both rapid and prolonged insulin release have great potential to control hyperglycemia and avoid hypoglycemia diabetes. Here, biodegradable and charge-switchable phytoglycogen nanoparticles capable of glucose-stimulated insulin release are engineered. The nanoparticles are “nanosugars” bearing glucose-sensitive phenylboronic acid groups and amine moieties that allow effective complexation with insulin (≈95% loading capacity) to form nanocomplexes. A single subcutaneous injection of nanocomplexes shows a rapid and efficient response to a glucose challenge in two distinct diabetic mouse models, resulting in optimal blood glucose levels (below 200 mg dL–1) for up to 13 h. The morphology of the nanocomplexes is found to be key to controlling rapid and extended glucoseregulated insulin delivery in vivo. These studies reveal that the injected nanocomplexes enabled efficient insulin release in the mouse, with optimal bioavailability, pharmacokinetics, and safety profiles. These results highlight a promising strategy for the development of a glucose-responsive insulin delivery system based on a natural and biodegradable nanosugar.

Aims/hypothesis The study aims to quantify the global trend of the disease burden of type 2 diabetes caused by various risks factors by country income tiers. Methods Data on type 2 diabetes, including mortality and disability-adjusted life years (DALYs) during 1990–2019, were obtained from the Global Burden of Disease Study 2019. We analysed mortality and DALY rates and the population attributable fraction (PAF) in various risk factors of type 2 diabetes by country income tiers. Results Globally, the age-standardised death rate (ASDR) attributable to type 2 diabetes increased from 16.7 (15.7, 17.5)/100,000 person-years in 1990 to 18.5 (17.2, 19.7)/100,000 person-years in 2019. Similarly, age-standardised DALY rates increased from 628.3 (537.2, 730.9)/100,000 person-years to 801.5 (670.6, 954.4)/100,000 person-years during 1990–2019. Lower-middle-income countries reported the largest increase in the average annual growth of ASDR (1.3%) and an age-standardised DALY rate (1.6%) of type 2 diabetes. The key PAF attributing to type 2 diabetes deaths/DALYs was high BMI in countries of all income tiers. With the exception of BMI, while in low- and lower-middle-income countries, risk factors attributable to type 2 diabetes-related deaths and DALYs are mostly environment-related, the risk factors in high-income countries are mostly lifestyle-related. Conclusions/interpretation Type 2 diabetes disease burden increased globally, but low- and middle-income countries showed the highest growth rate. A high BMI level remained the key contributing factor in all income tiers, but environmental and lifestyle-related factors contributed differently across income tiers. Data availability To download the data used in these analyses, please visit the Global Health Data Exchange at http://ghdx.healthdata.org/gbd-2019. Graphical abstract

Diabetic kidney disease (DKD) remains a major cause of morbidity and mortality in diabetes and is a key cause of end-stage kidney disease (ESKD) worldwide. Major clinical advances have been confirmed in large trials demonstrating renoprotection, adding to the benefits of existing intensive glucose and blood pressure control therapies. Furthermore, there are exciting new treatments predominantly at an experimental and early clinical phase which appear promising.The authors review DKD in the context of existing and emerging therapies affording cardiorenal benefits including SGLT2 inhibitors and GLP-1 receptor agonists. They explore novel therapies demonstrating potential including a newly developed mineralocorticoid receptor antagonist and endothelin receptor blockade, while evaluating the utility of DPP4 inhibitors in current clinical practice. They also consider the recent evidence of emerging therapies targeting metabolic pathways with enzyme inhibitors, anti-fibrotic agents, and agents modulating transcription factors.Significant improvements have been made in the management of DKD with SGLT2i and GLP-1 agonists providing impressive renoprotection, with novel progress in renin-angiotensin-aldosterone system (RAAS) blockade with finerenone. There is also great potential for several new experimental therapies. These advances provide us with optimism that the outlook of this devastating condition will continue to improve.

To investigate the prognostic value of metabolic syndrome (MetS) and its relationship with renal structure changes in patients with type 2 diabetes and associated diabetic nephropathy (DN).411 Chinese patients with type 2 diabetes and biopsy-confirmed DN were enrolled in this retrospective study. MetS was defined according to the modified criteria of the 2005 International Diabetes Federation. Baseline demographics and clinical information at the time of renal biopsy were extracted from the hospital's electronic medical records system. Renal pathological findings were assessed according to Renal Pathology Society system. Univariate and multivariate logistic regression analyses were performed to define the pathological covariates associated with MetS. A competing risk model, with death as the competing risk, was used to estimate the sub-distribution hazard ratio (SHR) of MetS for end-stage kidney disease (ESKD).224 (55%) patients had MetS. Patients with MetS had poor renal function and more severe interstitial fibrosis tubular atrophy scores (IFTA) than those without MetS. Multivariate logistic regression analysis revealed that IFTA was significantly associated with MetS (odds ratio per score increase 1.45, 95% confidence interval [CI] 1.02-2.05). Of the patients with DN at risk, 40% of patients progressed to ESKD. After adjusting for renal function and pathological parameters, the presence of MetS was an independent predictor for progression to ESKD (SHR 1.93, 95% CI 1.34-2.79). The SHRs for progression to ESKD also increased as the number of MetS components increased. Additionally, adding the IFTA scores improved the prognostic power of a model that only contained MetS and clinical covariates for predicting future ESKD.MetS is an independent prognostic predictor of ESKD in patients with T2D and DN, while adding the IFTA scores increased the prognostic value of MetS for renal outcome.

Activation of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome has been reported in diabetic complications including diabetic kidney disease (DKD). However, it remains unknown if NLRP3 inhibition is renoprotective in a clinically relevant interventional approach with established DKD. We therefore examined the effect of the NLRP3-specific inhibitor MCC950 in streptozotocin-induced diabetic mice to measure the impact of NLRP3 inhibition on renal inflammation and associated pathology in DKD. We identified an adverse effect of MCC950 on renal pathology in diabetic animals. Indeed, MCC950-treated diabetic animals showed increased renal inflammation and macrophage infiltration in association with enhanced oxidative stress as well as increased mesangial expansion and glomerulosclerosis when compared with vehicle-treated diabetic animals. Inhibition of the inflammasome by MCC950 in diabetic mice led to renal up-regulation of markers of inflammation (Il1β, Il18 and Mcp1), fibrosis (Col1, Col4, Fn1, α-SMA, Ctgf and Tgfβ1) and oxidative stress (Nox2, Nox4 and nitrotyrosine). In addition, enhanced glomerular accumulation of pro-inflammatory CD68 positive cells and pro-oxidant factor nitrotyrosine was identified in the MCC950-treated diabetic compared with vehicle-treated diabetic animals. Collectively, in this interventional model of established DKD, NLRP3 inhibition with MCC950 did not show renoprotective effects in diabetic mice. On the contrary, diabetic mice treated with MCC950 exhibited adverse renal effects particularly enhanced renal inflammation and injury including mesangial expansion and glomerulosclerosis.

Aims: To investigate whether renal pathology is an independent predictor for end-stage renal disease (ESRD) in diabetic kidney diseases (DKD) with nephrotic range proteinuria. Methods: A total of 199 DKD patients with nephrotic range proteinuria underwent renal biopsy and were divided into an ESRD group and a non-ESRD group. A Kaplan–Meier analysis was used to compare renal survival rate, and univariate and multivariate Cox proportional hazard analyses were used to determine the predictors of the ESRD. Results: The mean age of included patients was 51.49 ± 9.12 years and 113 patients (56.8%) progressed to ESRD. The median follow-up period was 16 (12–28) months. The glomerular pathology class III is the most common type (54.3%). In the Kaplan–Meier analysis, compared with patients without ESRD, patients with ESRD had a longer duration of diabetes (≥6 years), lower eGFR (

Plant physiology can offer invaluable insights to accelerate genetic gain. However, translating physiological understanding into breeding decisions has been an ongoing and complex endeavor. Here we demonstrate an approach to leverage physiology and genomics to hasten crop improvement. A half-diallel maize (Zea mays) experiment resulting from crossing 9 elite inbreds was conducted at 17 locations in the USA corn belt and 6 locations at managed stress environments between 2017 and 2019 covering a range of water environments from 377 to 760 mm of evapotranspiration and family mean yields from 542 to 1,874 g m−2. Results from analyses of 35 families and 2,367 hybrids using crop growth models linked to whole-genome prediction (CGM–WGP) demonstrated that CGM–WGP offered a predictive accuracy advantage compared to BayesA for untested genotypes evaluated in untested environments (r = 0.43 versus r = 0.27). In contrast to WGP, CGMs can deal effectively with time-dependent interactions between a physiological process and the environment. To facilitate the selection/identification of traits for modeling yield, an algorithmic approach was introduced. The method was able to identify 4 out of 12 candidate traits known to explain yield variation in maize. The estimation of allelic and physiological values for each genotype using the CGM created in silico phenotypes (e.g. root elongation) and physiological hypotheses that could be tested within the breeding program in an iterative manner. Overall, the approach and results suggest a promising future to fully harness digital technologies, gap analysis, and physiological knowledge to hasten genetic gain by improving predictive skill and definition of breeding goals.

Objective To investigate the relationship between serum uric acid (SUA) level and renal outcome in patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN). Methods A total of 393 Chinese patients with T2DM and biopsy-proven DN and followed at least 1 year were enrolled in this study. Patients were stratified by the quartiles of baseline level of SUA: Q1 group: 286.02 ± 46.66 μmol/L (n = 98); Q2 group: 358.23 ± 14.03 μmol/L (n = 99); Q3 group: 405.50 ± 14.59 μmol/L (n = 98) and Q4 group: 499.14 ± 56.97μmol/L (n = 98). Renal outcome was defined by progression to end-stage renal disease (ESRD). Kaplan–Meier survival analysis and Cox proportional hazards model were used to analyze the association between SUA quartiles and the renal outcomes. Results During the median 3-year follow-up period, there were 173 ESRD outcome events (44.02%). No significant difference between SUA level and the risk of progression of DN (P = 0.747) was shown in the Kaplan–Meier survival analysis. In multivariable-adjusted model, hazard ratios for developing ESRD were 1.364 (0.621–2.992; P = 0.439), 1.518 (0.768–3.002; P = 0.230) and 1.411 (0.706–2.821; P = 0.330) for the Q2, Q3 and Q4, respectively, in comparison with the Q1 (P = 0.652). Conclusions No significant association between SUA level and renal outcome of ESRD in Chinese patients with T2DM and DN was found in our study. Besides, the role of uric acid-lowering therapy in delaying DN progression and improving ESRD outcome had not yet been proven. Further study was needed to clarify the renal benefit of the uric acid-lowering therapy in the treatment of DN.

Chunmei Qin,1– 3 Yiting Wang,1,2 Lijun Zhao,1,2 Junlin Zhang,1,2 Honghong Ren,1,2 Yutong Zou,1,2 Yucheng Wu,1,2 Tingli Wang,1,2 Yuancheng Zhao,1,2 Rui Zhang,1,2 Huan Xu,4 Jie Zhang,5 Mark E Cooper,6 Fang Liu1,2 1Division of Nephrology, West China Hospital of Sichuan University, Chengdu, People’s Republic of China; 2Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, People’s Republic of China; 3Department of Nephrology, Luzhou People’s Hospital, Luzhou, People’s Republic of China; 4Division of Pathology, West China Hospital of Sichuan University, Chengdu, People’s Republic of China; 5Key Laboratory of Transplant Engineering and Immunology, Chengdu, People’s Republic of China; 6Department of Diabetes, Central Clinical School, Monash University, Melbourne, AustraliaCorrespondence: Fang Liu, Division of Nephrology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86-28-18980601214, Fax +86-28-85422335, Email liufangfh@163.comObjective: The rate of kidney function decline in patients with diabetic kidney disease (DKD) is known to differ. This study analyzed the clinicopathologic features and related risk factors affecting long-term renal survival in Chinese type 2 diabetic patients with rapid estimated glomerular filtration rate (eGFR) decline.Methods: In this retrospective descriptive study, 191 DKD patients were first classified as rapid eGFR decliners and slow eGFR decliners on the basis of the median eGFR slope value (− 8.0 mL/min/1.73 m2/year). In total, 96 patients with rapid eGFR decline were included in the analyses and subsequently allocated to end-stage renal disease (ESRD) and non-ESRD groups. Baseline clinicopathological data of rapid eGFR decliners were collected. Cox proportional hazard analysis was performed to calculate the hazard ratios (HRs) for progression to ESRD.Results: During a median follow-up of 25 months, 52 (54.2%) rapid eGFR decliners progressed to ESRD. These 52 rapid eGFR decliners had poorer renal function, lower hemoglobin and albumin concentrations, higher total cholesterol and baseline proteinuria levels, and more severe interstitial inflammation than those who did not progress to ESRD. After adjustment for age, gender, baseline eGFR, proteinuria, hemoglobin level, serum albumin concentration, and histopathologic parameters, multivariate Cox proportional hazard analysis revealed that eGFR (HR 0.973, 95% CI 0.956– 0.989) and proteinuria (HR 1.125, 95% CI 1.030– 1.228) were associated with the increased risk of progression to ESRD.Conclusion: Higher proteinuria and lower eGFR were independent risk factors for renal progression in Chinese patients with type 2 diabetes and rapid eGFR decline.Keywords: diabetic kidney disease, rapid eGFR decline, clinical, pathological, type 2 diabetes

Key Message: Convolutional Neural Networks (CNNs) can perform similarly or better than standard genomic prediction methods when sufficient genetic, environmental, and management data are provided. Abstract: Predicting phenotypes from genetic (G), environmental (E), and management (M) conditions is a long-standing challenge with implications to agriculture, medicine, and conservation. Most methods reduce the factors in a dataset (feature engineering) in a subjective and potentially oversimplified manner. Deep neural networks such as Multilayer Perceptrons (MPL) and Convolutional Neural Networks (CNN) can overcome this by allowing the data itself to determine which factors are most important. CNN models were developed for predicting agronomic yield from a combination of replicated trials and historical yield survey data. The results were more accurate than standard methods when tested on held-out G, E, and M data (r = 0.50 vs. r = 0.43), and performed slightly worse than standard methods when only G was held out (r = 0.74 vs. r = 0.80). Pre-training on historical data increased accuracy compared to trial data alone. Saliency map analysis indicated the CNN has “learned” to prioritize many factors of known agricultural importance.

Obesity, diabetes mellitus, hypertension and cardiovascular disease are risk factors for chronic kidney disease (CKD) and kidney failure. Chronic, low-grade inflammation is recognized as a major pathogenic mechanism that underlies the association between CKD and obesity, impaired glucose tolerance, insulin resistance and diabetes, through interaction between resident and/or circulating immune cells with parenchymal cells. Thus, considerable interest exists in approaches that target inflammation as a strategy to manage CKD. The initial phase of the inflammatory response to injury or metabolic dysfunction reflects the release of pro-inflammatory mediators including peptides, lipids and cytokines, and the recruitment of leukocytes. In self-limiting inflammation, the evolving inflammatory response is coupled to distinct processes that promote the resolution of inflammation and restore homeostasis. The discovery of endogenously generated lipid mediators — specialized pro-resolving lipid mediators and branched fatty acid esters of hydroxy fatty acids — which promote the resolution of inflammation and attenuate the microvascular and macrovascular complications of obesity and diabetes mellitus highlights novel opportunities for potential therapeutic intervention through the targeting of pro-resolution, rather than anti-inflammatory pathways., Inflammation is a known driver of diabetes and obesity-associated kidney disease. This Review describes the role of endogenous lipid mediators — specialized pro-resolving lipid mediators and branched fatty acid esters of hydroxy fatty acids — in the resolution of inflammation and explores how insights into their function could identify new targets for therapeutic intervention., Key points The role of inflammation in the pathogenesis of diabetes and obesity-associated kidney disease is increasingly appreciated; cytokines and pro-inflammatory lipids have important roles as drivers of inflammation and in the pathogenesis of impaired glucose tolerance, insulin resistance and diabetes. The initiation and resolution of inflammation occurs via a coordinated host response, involving pro-inflammatory and anti-inflammatory or pro-resolving mediators, which are produced at the site of organ injury in a temporally controlled manner. The discovery of endogenously generated lipid mediators that promote the resolution of inflammation and attenuate microvascular and macrovascular complications of diabetes and obesity highlights potential opportunities for therapeutic intervention. ‘Resolution pharmacology’ is a novel therapeutic paradigm that seeks to make targeted use of endogenous pro-resolving mediators to treat chronic inflammation, such as occurs in diabetic kidney disease.

Most of the chemical compound collection (currently about 200 000), assembled at the N. D. Zelinsky Institute of Organic Chemistry over the past 30 years, has been screened for antimicrobial activity against five ESKAPE pathogens and two fungi at the University of Queensland on a charitable basis. A total of 2517 active molecules (MIC ≤ 32 μg ml–1) were found, of which about 10% are active at very low concentrations (MIC ≤ 1 μg ml–1). Structures of 142 012 compounds and experimental data on their antimicrobial activity are publicly available through the demo version of the CheD software and the public database of the Community for Open Antimicrobial Drug Discovery.

Failure to resolve inflammation underlies many prevalent pathologies. Recent insights have identified lipid mediators, typified by lipoxins (LXs), as drivers of inflammation resolution, suggesting potential therapeutic benefit. We report the asymmetric preparation of novel quinoxaline-containing synthetic-LXA4-mimetics (QNX-sLXms). Eight novel compounds were screened for their impact on inflammatory responses. Structure–activity relationship (SAR) studies showed that (R)-6 (also referred to as AT-02-CT) was the most efficacious and potent anti-inflammatory compound of those tested. (R)-6 significantly attenuated lipopolysaccharide (LPS)- and tumor-necrosis-factor-α (TNF-α)-induced NF-κB activity in monocytes and vascular smooth muscle cells. The molecular target of (R)-6 was investigated. (R)-6 activated the endogenous LX receptor formyl peptide receptor 2 (ALX/FPR2). The anti-inflammatory properties of (R)-6 were further investigated in vivo in murine models of acute inflammation. Consistent with in vitro observations, (R)-6 attenuated inflammatory responses. These results support the therapeutic potential of the lead QNX-sLXm (R)-6 in the context of novel inflammatory regulators.

Activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome drives release of the proinflammatory cytokines interleukin (IL)-1β and IL-18 and induces pyroptosis (lytic cell death). These events drive chronic inflammation, and as such, NLRP3 has been implicated in a large number of human diseases. These range from autoimmune conditions, the simplest of which is NLRP3 gain-of-function mutations leading to an orphan disease, cryopyrin-associated period syndrome, to large disease burden indications, such as atherosclerosis, heart failure, stroke, neurodegeneration, asthma, ulcerative colitis, and arthritis. The potential clinical utility of NLRP3 inhibitors is substantiated by an expanding list of indications in which NLRP3 activation has been shown to play a detrimental role. Studies of pharmacological inhibition of NLRP3 in nonclinical models of disease using MCC950 in combination with human genetics, epigenetics, and analyses of the efficacy of biologic inhibitors of IL-1β, such as anakinra and canakinumab, can help to prioritize clinical trials of NLRP3-directed therapeutics. Although MCC950 shows excellent (nanomolar) potency and high target selectivity, its pharmacokinetic and toxicokinetic properties limited its therapeutic development in the clinic. Several improved, next-generation inhibitors are now in clinical trials. Hence the body of research in a plethora of conditions reviewed herein may inform analysis of the potential translational value of NLRP3 inhibition in diseases with significant unmet medical need. SIGNIFICANCE STATEMENT: The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is one of the most widely studied and best validated biological targets in innate immunity. Activation of NLRP3 can be inhibited with MCC950, resulting in efficacy in more than 100 nonclinical models of inflammatory diseases. As several next-generation NLRP3 inhibitors are entering proof-of-concept clinical trials in 2020, a review of the pharmacology of MCC950 is timely and significant.

Special Issue: Feeding the World: The Future of Plant Breeding Asymmetry of investment in crop research leads to knowledge gaps and lostopportunities to accelerate genetic gain through identifying new sources andcombinations of traits and alleles. On the basis of consultation with scientistsfrom most major seed companies, we identified several research areas withthree common features: (i) relatively underrepresented in the literature; (ii) highprobability of boosting productivity in a wide range of crops and environments;and (iii) could be researched in‘precompetitive’space, leveraging previousknowledge, and thereby improving models that guide crop breeding and man-agement decisions. Areas identified included research into hormones, recombi-nation, respiration, roots, and source–sink, which, along with new opportunitiesin phenomics, genomics, and bioinformatics, make it more feasible to explorecrop genetic resources and improve breeding strategies. The authors acknowledge the following scientists for helping to achieve a consensus on research bottlenecks with significant implications for crop improvement: Yann Manes (Syngenta), Jeremy Derory (Limagrain), Bruno Marty (BASF), and Hans Braun (recent director of the Global Wheat Program, CIMMYT). We acknowledge Renee Lafitte (Bill and Melinda Gates Foundation) for helpful feedback on the manuscript and Fatima Escalante for valuable assistance in coordinating edits to the manuscript and its formatting. M.R. acknowledges the International Wheat Yield Partnership (https://iwyp.org/) for establishing a precedent of integrating different research strands in wheat for targeted prebreeding and the Foundation for Food and Agricultural Research (https://foundationfar.org/) for supporting a translational research and prebreeding pipeline at CIMMYT to identify and stack climate resilience traits in wheat.

Diabetes is a noncommunicable disease and arguably represents the greatest pandemic in human history. Diabetic kidney disease (DKD) is seen in both type 1 and type 2 diabetes and can be detected in up to 30–50% of diabetic subjects. DKD is a progressive chronic kidney disease (CKD) and is a leading cause of mortality and morbidity in patients with diabetes. Renal fibrosis and inflammation are the major pathological features of DKD. There are a large number of independent and overlapping profibrotic and pro-inflammatory pathways involved in the pathogenesis and progression of DKD. Among these pathways, the transforming growth factor-β (TGF-β) pathway plays a key pathological role by promoting fibrosis. Sirtuin-1 (SIRT1) is a protein deacetylase that has been shown to be renoprotective with an anti-inflammatory effect. It is postulated that a reduction in renal SIRT1 levels could play a key role in the pathogenesis of DKD and that restoration of SIRT1 will attenuate DKD. Cell division autoantigen 1 (CDA1) synergistically enhances the profibrotic effect of TGF-β in DKD by regulating the expression of the TGF-β type I receptor (TβRI). CDA1 has also been found to be an inhibitor of SIRT1 in the DNA damage response. Indeed, targeting CDA1 in experimental DKD not only attenuates diabetes-associated renal fibrosis but also attenuates the expression of key pro-inflammatory genes such as tumor necrosis factor-α (TNF-α) and Monocyte Che moattractant Protein-1 (MCP-1). In conclusion, there is a large body of experimental data to support the view that targeting CDA1 is a superior approach to directly targeting TGF-β in DKD since it is not only safe but also efficacious in retarding both fibrosis and inflammation.

Background: Human NADPH oxidase 5 (NOX5) is expressed and functionally active in peripheral blood mononuclear cells (PBMCs) . In those with diabetes, there is increased NOX5 expression in atherosclerotic plaques with associated coronary artery disease (CAD) and within the glomeruli in kidney biopsies. We hypothesise that NOX5 expression in circulating PBMCs is increased in patients with diabetes, particularly in those with comorbid unstable CAD and chronic kidney disease (CKD) . Methods: 55 males aged 33-83 years underwent elective or emergency coronary angiography/angioplasty at the Alfred Hospital Catheter Laboratory. PBMCs from whole blood were processed for flow-cytometry to measure NOX5 protein. In parallel, NOX5 expression was measured in PBMCs by qPCR. In vitro, human macrophages (THP-1) were incubated in normal (5 mM) and high glucose (25 mM) . NOX5 expression and inflammatory markers were measured by qPCR. Results: NOX5 protein expression in PBMCs was primarily driven by expression in monocytes (CD 45+/CD14+ cells) and was increased in diabetic and non-diabetic patients with CKD (28.7±4.2 vs. 17.3±1.7 AU; p=0.0038) and in diabetic patients with CKD versus without CKD (27.5±4.1 vs. 14.6±2.3 AU; p=0.012) . CAD with acute presentation was associated with increased NOX5 expression versus elective presentation (25.9±2.9 vs. 16.8±1.9 AU; p=0.0085) , particularly in diabetic patients presenting acutely versus electively (29.1±4.2 vs. 13.9±2.4 AU; p=0.0025) . A 4-fold upregulation of NOX5 gene was observed in patients with CKD versus without CKD irrespective of diabetes or CAD (p=0.018) . In vitro, there was a 2-fold increase in NOX5, TNF-α and IL-6 expression in THP-1 cells exposed to high glucose. Conclusion: CKD and unstable CAD appear to be key factors for increased NOX5 expression in circulating PBMCs. Measurement of NOX5 in PBMCs may serve as a valuable prognostic biomarker and attractive therapeutic target in patients with clustering diabetic complications. Disclosure T.J.Block: None. K.Sourris: None. W.Khan: None. P.Kantharidis: None. J.C.Jha: None. M.E.Cooper: Advisory Panel; Bayer AG, Merck Sharp & Dohme Corp., Consultant; Boehringer Ingelheim International GmbH, Research Support; Novo Nordisk, Speaker's Bureau; AstraZeneca, Servier Laboratories. J.Shaw: None. K.Jandeleit-dahm: None.

Purpose To investigate the association between urinary complement proteins and renal outcome in biopsy-proven diabetic nephropathy (DN). Methods Untargeted proteomic and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses and targeted proteomic analysis using parallel reaction-monitoring (PRM)-mass spectrometry was performed to determine the abundance of urinary complement proteins in healthy controls, type 2 diabetes mellitus (T2DM) patients, and patients with T2DM and biopsy-proven DN. The abundance of each urinary complement protein was individually included in Cox proportional hazards models for predicting progression to end-stage renal disease (ESRD). Results Untargeted proteomic and functional analysis using the KEGG showed that differentially expressed urinary proteins were primarily associated with the complement and coagulation cascades. Subsequent urinary complement proteins quantification using PRM showed that urinary abundances of C3, C9, and complement factor H (CFAH) correlated negatively with annual estimated glomerular filtration rate (eGFR) decline, while urinary abundances of C5, decay-accelerating factor (DAF), and CD59 correlated positively with annual rate of eGFR decline. Furthermore, higher urinary abundance of CFAH and lower urinary abundance of DAF were independently associated with greater risk of progression to ESRD. Urinary abundance of CFAH and DAF had a larger area under the curve (AUC) than that of eGFR, proteinuria, or any pathological parameter. Moreover, the model that included CFAH or DAF had a larger AUC than that with only clinical or pathological parameters. Conclusion Urinary abundance of complement proteins was significantly associated with ESRD in patients with T2DM and biopsy-proven DN, indicating that therapeutically targeting the complement pathway may alleviate progression of DN.

Because plants capture water and nutrients through roots, it was proposed that changes in root systems architecture (RSA) might underpin the 3-fold increase in maize (Zea mays L.) grain yield over the last century. Here we show that both RSA and yield have changed with decades of maize breeding, but not the crop water uptake. Results from X-ray phenotyping in controlled environments showed that single cross (SX) hybrids have smaller root systems than double cross (DX) hybrids for root diameters between 2465 µm and 181µm (P, Emerging opportunity to continue long-term genetic gain in maize yield in the US corn belt by improving the balance between canopy, root, and reproductive growth and development.

OBJECTIVE To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. RESEARCH DESIGN AND METHODS Cox proportional hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI >0.21) status. The primary outcomes were macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness. RESULTS There were 11,140 participants (mean age, 65.8 years; 42.5% women, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90–1.19) in the frail versus 0.84 (95% CI 0.74–0.94) in the nonfrail (P = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15–10.63) vs. 4.80 (3.84–5.76) in nonfrail (P < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups. CONCLUSIONS It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose-lowering and BP-lowering treatments.