Background Unlike the case with creatinine, the conditions affecting the non−glomerular filtration rate (GFR) determinants of low molecular weight serum proteins, β-trace protein (BTP), β2-microglobulin (B2M) and cystatin C, are not well characterized. Study Design Pooled cross-sectional analysis of three studies. Setting & Participants 3156 persons with chronic kidney disease (CKD) from the MDRD (Modification of Diet in Renal Disease) Study, AASK (African American Study of Kidney Disease and Hypertension) and the CRIC (Chronic Renal Insufficiency Cohort) Study. Predictors Demographic and clinical factors hypothesized to be associated with non-GFR determinants of the filtration markers, selected from literature review and physiological and clinical considerations. Outcomes Serum levels of creatinine, BTP, B2M and cystatin C. Results In multivariable-adjusted errors-in-variables regression models that included adjustment for measured GFR (mGFR) and mGFR measurement error, creatinine had stronger associations with male sex, black race and higher urine creatinine than the other filtration markers. BTP was associated less strongly with age, similar in direction with sex, and opposite in direction with race than creatinine. Like cystatin C, B2M was associated less strongly with age, sex and race than creatinine. BTP, B2M and cystatin C were associated more strongly than creatinine with other factors, including urine protein and weight for BTP, smoking and urine protein for B2M and smoking for cystatin C. Limitations Findings may not be generalizable to populations without CKD, and residual confounding with GFR due to incomplete adjustment for GFR measurement error. Conclusions Like creatinine, serum levels of low molecular weight proteins are affected by conditions other than GFR. Knowledge of these conditions can aid the interpretation of GFR estimates and risk using these markers and guide the use of these filtration markers in developing GFR estimating equations.

BackgroundA non-dipper blood pressure (BP) pattern is very common in chronic kidney disease (CKD) patients and affects the progression and development of cardiovascular disease. However, data on the reversed dipper BP pattern on target-organ damage in Chinese CKD patients are lacking.MethodsA total of 540 CKD patients were enrolled. Ambulatory blood pressure monitoring (ABPM), clinical BP, ultrasonographic assessment and other clinical data were collected. Univariate and multivariate analyses were used to ascertain the relationship between ABPM results and clinical parameters.ResultsA total of 21.9% CKD patients had a reversed dipper BP pattern, 42% of patients had a non-dipper BP pattern and 36.1% of patients had a dipper BP pattern. Patients with reversed dipper BP pattern had the worst renal function and most severe cardiovascular damages among these CKD patients (p<0.05). The estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI) correlated significantly with the rate of decline of nocturnal BP. A reversed dipper BP pattern was an independent factor affecting kidney damage and left ventricular hypertrophy. Age, lower hemoglobin level, higher 24-h systolic BP from ABPM, and higher serum phosphate levels were independent associated with a reversed dipper BP pattern after multivariate logistic regression analyses.ConclusionThe reversed dipper BP pattern is closely related to severe renal damage and cardiovascular injuries in CKD patients, and special attention should be given to these CKD patients.

Spatiotemporal image fusion is considered as a promising way to provide Earth observations with both high spatial resolution and frequent coverage, and recently, learning-based solutions have been receiving broad attention. However, these algorithms treating spatiotemporal fusion as a single image super-resolution problem, generally suffers from the significant spatial information loss in coarse images, due to the large upscaling factors in real applications. To address this issue, in this paper, we exploit temporal information in fine image sequences and solve the spatiotemporal fusion problem with a two-stream convolutional neural network called StfNet. The novelty of this paper is twofold. First, considering the temporal dependence among image sequences, we incorporate the fine image acquired at the neighboring date to super-resolve the coarse image at the prediction date. In this way, our network predicts a fine image not only from the structural similarity between coarse and fine image pairs but also by exploiting abundant texture information in the available neighboring fine images. Second, instead of estimating each output fine image independently, we consider the temporal relations among time-series images and formulate a temporal constraint. This temporal constraint aiming to guarantee the uniqueness of the fusion result and encourages temporal consistent predictions in learning and thus leads to more realistic final results. We evaluate the performance of the StfNet using two actual data sets of Landsat-Moderate Resolution Imaging Spectroradiometer (MODIS) acquisitions, and both visual and quantitative evaluations demonstrate that our algorithm achieves state-of-the-art performance.

BackgroundCell-free microRNAs stably and abundantly exist in body fluids and emerging evidence suggests cell-free microRNAs as novel and non-invasive disease biomarker. Deregulation of miR-29 is involved in the pathogenesis of diabetic nephropathy and insulin resistance thus may be implicated in diabetic vascular complication. Therefore, we investigated the possibility of urinary miR-29 as biomarker for diabetic nephropathy and atherosclerosis in patients with type 2 diabetes.Methods83 patients with type 2 diabetes were enrolled in this study, miR-29a, miR-29b and miR-29c levels in urine supernatant was determined by TaqMan qRT-PCR, and a synthetic cel-miR-39 was added to the urine as a spike-in control before miRNAs extraction. Urinary albumin excretion rate and urine albumin/creatinine ratio, funduscopy and carotid ultrasound were used for evaluation of diabetic vascular complication. The laboratory parameters indicating blood glucose level, renal function and serum lipids were also collected.ResultsPatients with albuminuria (n = 42, age 60.62±12.00yrs) showed significantly higher comorbidity of diabetic retinopathy (p = 0.015) and higher levels of urinary miR-29a (p = 0.035) compared with those with normoalbuminuria (n = 41, age 58.54±14.40yrs). There was no significant difference in urinary miR-29b (p = 0.148) or miR-29c level (p = 0.321) between groups. Urinary albumin excretion rate significantly correlated with urinary miR-29a level (r = 0.286, p = 0.016), while urinary miR-29b significantly correlated with carotid intima-media thickness (cIMT) (r = 0.286, p = 0.046).ConclusionUrinary miR-29a correlated with albuminuria while urinary miR-29b correlated with carotid intima-media thickness (cIMT) in patients with type 2 diabetes. Therefore, they may have the potential to serve as alternative biomarker for diabetic nephropathy and atherosclerosis in type 2 diabetes.

Mesenchymal stem cells (MSCs) exhibit a potent immunomodulatory capacity and have been applied to treat diseases such as graft versus host disease and severe autoimmune diseases. However, the mechanism underlying their immunosuppressive effect is not yet completely understood. Here, we investigated the role of the CD73/adenosine pathway in immune modulation by MSCs using a mouse model of experimental autoimmune uveitis (EAU). Moreover, we examined the in vitro modulatory effect of MSCs mediated through the CD73/adenosine pathway in human and mouse T cells. We found that the severity of EAU was significantly attenuated by MSCs; however, most therapeutic effects of MSCs were lost by pretreatment with a CD73 inhibitor. The inhibitory mechanism of MSCs might be contributed by CD73 on MSCs that cooperated with CD39 and CD73 on activated T cells to produce adenosine, resulting in inhibition of T-cell proliferation. Furthermore, MSCs increased the expression of CD73 on CD4(+) T cells, and transforming growth factor-β1 (TGF-β1) was the only tested cytokine that contributed to upregulation of CD73. Hence, our study demonstrates that the CD73/adenosine pathway involves the immunomodulatory function of MSCs in autoimmune responses.

BackgroundEndothelial dysfunction is an early sign of diabetic cardiovascular disease and may contribute to progressive diabetic nephropathy (DN). There is increasing evidence that dysfunction of the endothelial tight junction is a crucial step in the development of endothelial hyperpermeability, but it is unknown whether this occurs in glomerular endothelial cells (GEnCs) during the progression of DN. We examined tight junction dysfunction of GEnCs during early-stage DN and the potential underlying mechanisms. We also examined the effect of simvastatin (3-Hydroxy-3-methylglutaryl CoA reductase inhibitor) on dysfunction of the tight junctions of cultured GEnCs and in db/db mice with early-stage DN.MethodsWe assessed the expression of occludin and ZO-1, two major components of the tight junction complex, in cultured rat GEnCs treated with high glucose and in 12 week-old db/db mice with early-stage DN. We also investigated activation of RhoA/ROCK1 signaling, GEnC permeability, and renal function of the mice.ResultsHigh glucose suppresses occludin expression and disrupts occludin/ZO-1 translocation in GEnCs. These changes were associated with increased permeability to albumin and activation of RhoA/ROCK1 signaling. Occludin and ZO-1 dysregulation also occurred in the glomeruli of mice with early-stage DN, and these abnormalities were accompanied by albuminuria and activation of RhoA/ROCK1 in isolated glomeruli. Simvastatin prevented high glucose or hyperglycemia-induced dysregulation of occludin and ZO-1 by inhibition of RhoA/ROCK1 signaling in cultured GEnCs and in db/db mice with early-stage DN.ConclusionOur results indicate that activation of RhoA/ROCK1 by high glucose disrupts the expression and translocation of occludin/ZO-1 and that simvastatin alleviates occludin/ZO-1 dysregulation and albuminuria by suppressing RhoA/ROCK1 signaling during early-stage DN. These results suggest a potential therapeutic strategy for preventing the onset of albuminuria in early-stage DN.

Protein sequence profile prediction aims to generate multiple sequences from structural information to advance the protein design. Protein sequence profile can be computationally predicted by energy-based method or fragment-based methods. By integrating these methods with neural networks, our previous method, SPIN2 has achieved a sequence recovery rate of 34%. However, SPIN2 employed only one dimensional (1D) structural properties that are not sufficient to represent 3D structures. In this study, we represented 3D structures by 2D maps of pairwise residue distances. and developed a new method (SPROF) to predict protein sequence profile based on an image captioning learning frame. To our best knowledge, this is the first method to employ 2D distance map for predicting protein properties. SPROF achieved 39.8% in sequence recovery of residues on the independent test set, representing a 5.2% improvement over SPIN2. We also found the sequence recovery increased with the number of their neighbored residues in 3D structural space, indicating that our method can effectively learn long range information from the 2D distance map. Thus, such network architecture using 2D distance map is expected to be useful for other 3D structure-based applications, such as binding site prediction, protein function prediction, and protein interaction prediction.

Nondipping blood pressure (BP) pattern is a potential independent risk factor for chronic kidney disease (CKD). Bedtime administration of valsartan is considered to normalize circadian rhythm and protect the kidneys and heart in CKD patients. However, more clinical trials are needed to confirm this benefit. Sixty patients with nondipping BP pattern and thirty patients with dipping BP pattern were enrolled in this study, and the patients with nondipping BP pattern were randomly divided into two groups and treated with bedtime or awakening doses of valsartan (80–320 mg). Nondipping BP patients treated with bedtime doses of valsartan showed a greater reduction in 24‐hour proteinuria and bedtime proteinuria, a greater delayed decline in estimated glomerular filtration rate, and more protection against myocardial hypertrophy (P<.05) compared with patients with the nondipping BP pattern treated with the awakening dose (P<.05). This was similar to patients with dipping BP. No severe clinical complications were recorded in these patients. Valsartan with bedtime dosing in CKD patients with the nondipping BP pattern have better renal and cardiovascular protection. Antihypertensive “chronotherapy” may be useful in clinical practice for CKD patients.