Extracellular Matrix Injury of Kidney Allografts in Antibody-Mediated Rejection: A Proteomics Study.

BACKGROUND: Antibody-mediated rejection (AMR) accounts for >50% of kidney allograft loss. Donor-specific antibodies (DSA) against HLA and non-HLA antigens in the glomeruli and the tubulointerstitium cause AMR while inflammatory cytokines such as TNFα trigger graft injury. The mechanisms governing cell-specific injury in AMR remain unclear. METHODS: Unbiased proteomic analysis of laser-captured and microdissected glomeruli and tubulointerstitium was performed on 30 for-cause kidney biopsy specimens with early AMR, acute cellular rejection (ACR), or acute tubular necrosis (ATN). RESULTS: A total of 107 of 2026 glomerular and 112 of 2399 tubulointerstitial proteins was significantly differentially expressed in AMR versus ACR; 112 of 2026 glomerular and 181 of 2399 tubulointerstitial proteins were significantly dysregulated in AMR versus ATN (P<0.05). Basement membrane and extracellular matrix (ECM) proteins were significantly decreased in both AMR compartments. Glomerular and tubulointerstitial laminin subunit γ-1 (LAMC1) expression decreased in AMR, as did glomerular nephrin (NPHS1) and receptor-type tyrosine-phosphatase O (PTPRO). The proteomic analysis revealed upregulated galectin-1, which is an immunomodulatory protein linked to the ECM, in AMR glomeruli. Anti-HLA class I antibodies significantly increased cathepsin-V (CTSV) expression and galectin-1 expression and secretion in human glomerular endothelial cells. CTSV had been predicted to cleave ECM proteins in the AMR glomeruli. Glutathione S-transferase ω-1, an ECM-modifying enzyme, was significantly increased in the AMR tubulointerstitium and in TNFα-treated proximal tubular epithelial cells. CONCLUSIONS: Basement membranes are often remodeled in chronic AMR. Proteomic analysis performed on laser-captured and microdissected glomeruli and tubulointerstitium identified early ECM remodeling, which may represent a new therapeutic opportunity.

Centroid of Age Neighborhoods: A New Approach to Estimate Biological Age.

Estimation of human biological age is an important and difficult challenge. Different biomarkers and numerous approaches have been studied for biological age prediction, each with its advantages and limitations. In this paper, we propose a new biological age estimation method, and investigate the performance of the new method. We introduce a centroid based approach, using the notion of age neighborhoods. Specifically, we develop a model, based on which we compute biological age using blood biomarkers, by considering the centroid or mediod of specially selected age neighborhoods. Experiments were performed on the National Health and Human Nutrition Examination Survey dataset with biomarkers (21 451 individuals). Compared with current popular methods for biological age prediction, our experiments show that the proposed age neighborhood model results in an improved performance in human biological age estimation.

Deep Learning using Convolutional LSTM estimates Biological Age from Physical Activity.

Human age estimation is an important and difficult challenge. Different biomarkers and numerous approaches have been studied for biological age estimation, each with its advantages and limitations. In this work, we investigate whether physical activity can be exploited for biological age estimation for adult humans. We introduce an approach based on deep convolutional long short term memory (ConvLSTM) to predict biological age, using human physical activity as recorded by a wearable device. We also demonstrate five deep biological age estimation models including the proposed approach and compare their performance on the NHANES physical activity dataset. Results on mortality hazard analysis using both the Cox proportional hazard model and Kaplan-Meier curves each show that the proposed method for estimating biological age outperforms other state-of-the-art approaches. This work has significant implications in combining wearable sensors and deep learning techniques for improved health monitoring, for instance, in a mobile health environment. Mobile health (mHealth) applications provide patients, caregivers, and administrators continuous information about a patient, even outside the hospital.

Surface-Based Body Shape Index and Its Relationship with All-Cause Mortality.

BACKGROUND: Obesity is a global public health challenge. In the US, for instance, obesity prevalence remains high at more than one-third of the adult population, while over two-thirds are obese or overweight. Obesity is associated with various health problems, such as diabetes, cardiovascular diseases (CVDs), depression, some forms of cancer, sleep apnea, osteoarthritis, among others. The body mass index (BMI) is one of the best known measures of obesity. The BMI, however, has serious limitations, for instance, its inability to capture the distribution of lean mass and adipose tissue, which is a better predictor of diabetes and CVDs, and its curved ("U-shaped") relationship with mortality hazard. Other anthropometric measures and their relation to obesity have been studied, each with its advantages and limitations. In this work, we introduce a new anthropometric measure (called Surface-based Body Shape Index, SBSI) that accounts for both body shape and body size, and evaluate its performance as a predictor of all-cause mortality. METHODS AND FINDINGS: We analyzed data on 11,808 subjects (ages 18-85), from the National Health and Human Nutrition Examination Survey (NHANES) 1999-2004, with 8-year mortality follow up. Based on the analysis, we introduce a new body shape index constructed from four important anthropometric determinants of body shape and body size: body surface area (BSA), vertical trunk circumference (VTC), height (H) and waist circumference (WC). The surface-based body shape index (SBSI) is defined as follows: SBSI = ((H(7/4))(WC(5/6)))/(BSA VTC) (1) SBSI has negative correlation with BMI and weight respectively, no correlation with WC, and shows a generally linear relationship with age. Results on mortality hazard prediction using both the Cox proportionality model, and Kaplan-Meier curves each show that SBSI outperforms currently popular body shape indices (e.g., BMI, WC, waist-to-height ratio (WHtR), waist-to-hip ratio (WHR), A Body Shape Index (ABSI)) in predicting all-cause mortality. CONCLUSIONS: We combine measures of both body shape and body size to construct a novel anthropometric measure, the surface-based body shape index (SBSI). SBSI is generally linear with age, and increases with increasing mortality, when compared with other popular anthropometric indices of body shape.