Delayed blockade of the kinin B1 receptor reduces renal inflammation and fibrosis in obstructive nephropathy

Renal fibrosis is the common histological feature of advanced glomerular and tubulointerstitial disease leading to end-stage renal disease (ESRD). However, specific antifibrotic therapies to slow down the evolution to ESRD are still absent. Because persistent inflammation is a key event in the development of fibrosis, we hypothesized that the proinflammatory kinin B1 receptor (B1R) could be such a new target. Here we show that, in the unilateral ureteral obstruction model of renal fibrosis, the B1R is overexpressed and that delayed treatment with an orally active nonpeptide B1R antagonist blocks macrophage infiltration, leading to a reversal of the level of renal fibrosis. In vivo bone marrow transplantation studies as well as in vitro studies on renal cells show that part of this antifibrotic mechanism of B1R blockade involves a direct effect on resident renal cells by inhibiting chemokine CCL2 and CCL7 expression. These findings suggest that blocking the B1R is a promising antifibrotic therapy.     

The cellular prion protein and its role in Alzheimer disease

The cellular prion protein (PrP^C) is a membrane-bound glycoprotein especially abundant in the central nervous system (CNS). The scrapie prion protein (PrP^Sc, also termed prions) is responsible of transmissible spongiform encephalopathies (TSE), a group of neurodegenerative diseases which affect humans and other mammal species, although the presence of PrP^C is needed for the establishment and further evolution of prions.The present work compares the expression and localization of PrP^C between healthy human brains and those suffering from Alzheimer disease (AD).In both situations we have observed a rostrocaudal decrease in the amount of PrP^C within the CNS, both by immunoblotting and immunohistochemistry techniques. PrP^C is higher expressed in our control brains than in AD cases. There was a neuronal loss and astogliosis in our AD cases. There was a tendency of a lesser expression of PrP^C in AD cases than in healthy ones. And in AD cases, the intensity of the expression of the unglycosylated band is higher than the di- and monoglycosylated bands.With regards to amyloid plaques, those present in AD cases were positively labeled for PrP^C, a result which is further supported by the presence of PrP^C in the amyloid plaques of a transgenic line of mice mimicking AD.The work was done according to Helsinki Declaration of 1975, and approved by the Ethics Committee of the Faculty of Medicine of the University of Navarre.Key words: cellular prion protein, Alzheimer disease, transgenic mice     

Towards modelling the flexible timing of shoot development: simulation of maize organogenesis based on coordination within and between phytomers

Background and Aims

Experimental evidence challenges the approximation, central in crop models, that developmental events follow a fixed thermal time schedule, and indicates that leaf emergence events play a role in the timing of development. The objective of this study was to build a structural development model of maize (Zea mays) based on a set of coordination rules at organ level that regulate duration of elongation, and to show how the distribution of leaf sizes emerges from this.

Methods

A model of maize development was constructed based on three coordination rules between leaf emergence events and the dynamics of organ extension. The model was parameterized with data from maize grown at a low plant population density and tested using data from maize grown at high population density.

Key Results

The model gave a good account of the timing and duration of organ extension. By using initial conditions associated with high population density, the model reproduced well the increase in blade elongation duration and the delay in sheath extension in high-density populations compared with low-density populations. Predictions of the sizes of sheaths at high density were accurate, whereas predictions of the dynamics of blade length were accurate up to rank 9; moderate overestimation of blade length occurred at higher ranks.

Conclusions

A set of simple rules for coordinated growth of organs is sufficient to simulate the development of maize plant structure without taking into account any regulation by assimilates. In this model, whole-plant architecture is shaped through initial conditions that feed a cascade of coordination events.     

A Self-Reported Screening Tool for Detecting Community-Dwelling Older Persons with Frailty Syndrome in the Absence of Mobility Disability: The FiND Questionnaire

Background

The “frailty syndrome” (a geriatric multidimensional condition characterized by decreased reserve and diminished resistance to stressors) represents a promising target of preventive interventions against disability in elders. Available screening tools for the identification of frailty in the absence of disability present major limitations. In particular, they have to be administered by a trained assessor, require special equipment, and/or do not discriminate between frail and disabled individuals. Aim of this study is to verify the agreement of a novel self-reported questionnaire (the “Frail Non-Disabled” [FiND] instrument) designed for detecting non-mobility disabled frail older persons with results from reference tools.

Methodology/Principal Findings

Data are from 45 community-dwelling individuals aged ≥60 years. Participants were asked to complete the FiND questionnaire separately exploring the frailty and disability domains. Then, a blinded assessor objectively measured the frailty status (using the phenotype proposed by Fried and colleagues) and mobility disability (using the 400-meter walk test). Cohen''s kappa coefficients were calculated to determine the agreement between the FiND questionnaire with the reference instruments. Mean age of participants (women 62.2%) was 72.5 (standard deviation 8.2) years. Seven (15.6%) participants presented mobility disability as being unable to complete the 400-meter walk test. According to the frailty phenotype criteria, 25 (55.6%) participants were pre-frail or frail, and 13 (28.9%) were robust. Overall, a substantial agreement of the instrument with the reference tools (kappa = 0.748, quadratic weighted kappa = 0.836, both p values<0.001) was reported with only 7 (15.6%) participants incorrectly categorized. The agreement between results of the FiND disability domain and the 400-meter walk test was excellent (kappa = 0.920, p<0.001).

Conclusions/Significance

The FiND questionnaire presents a very good capacity to correctly identify frail older persons without mobility disability living in the community. This screening tool may represent an opportunity for diffusing awareness about frailty and disability and supporting specific preventive campaigns.     

Model-Assisted Analysis of Sugar Metabolism throughout Tomato Fruit Development Reveals Enzyme and Carrier Properties in Relation to Vacuole Expansion

A kinetic model combining enzyme activity measurements and subcellular compartmentation was parameterized to fit the sucrose, hexose, and glucose-6-P contents of pericarp throughout tomato (Solanum lycopersicum) fruit development. The model was further validated using independent data obtained from domesticated and wild tomato species and on transgenic lines. A hierarchical clustering analysis of the calculated fluxes and enzyme capacities together revealed stage-dependent features. Cell division was characterized by a high sucrolytic activity of the vacuole, whereas sucrose cleavage during expansion was sustained by both sucrose synthase and neutral invertase, associated with minimal futile cycling. Most importantly, a tight correlation between flux rate and enzyme capacity was found for fructokinase and PPi-dependent phosphofructokinase during cell division and for sucrose synthase, UDP-glucopyrophosphorylase, and phosphoglucomutase during expansion, thus suggesting an adaptation of enzyme abundance to metabolic needs. In contrast, for most enzymes, flux rates varied irrespectively of enzyme capacities, and most enzymes functioned at <5% of their maximal catalytic capacity. One of the major findings with the model was the high accumulation of soluble sugars within the vacuole together with organic acids, thus enabling the osmotic-driven vacuole expansion that was found during cell division.     

Cytokeratin analysis of breast and leukemia tumor cell lines by flow cytometry

Using four human tumor cell lines, MCF-7 and T47-D from breast tumors, MOLT-4 and K-562 from leukemia, flow cytometric DNA analysis of pure and mixed cell population was performed using monoclonal antibodies to cytokeratin to distinguish cytokeratin-containing carcinoma cells from leukemia cells which do not contain cytokeratins. Surprisingly, on pure or mixed K-562 cells, we found positive labeling with KL1, CK8, and CK18 antibodies (results confirmed by immunocytology). This preliminary study has allowed a DNA analysis on epithelial cells of human breast tumors.     

Confidence intervals of evolutionary distances between sequences and comparison with usual approaches including the bootstrap method

Two methods are commonly employed for evaluating the extent of the uncertainty of evolutionary distances between sequences: either some estimator of the variance of the distance estimator, or the bootstrap method. However, both approaches can be misleading, particularly when the evolutionary distance is small. We propose using another statistical method which does not have the same defect: interval estimation. We show how confidence intervals may be constructed for the Jukes and Cantor (1969) and Kimura two-parameter (1980) estimators. We compare the exact confidence intervals thus obtained with the approximate intervals derived by the two previous methods, using artificial and biological data. The results show that the usual methods clearly underestimate the variability when the substitution rate is low and when sequences are short. Moreover, our analysis suggests that similar results may be expected for other evolutionary distance estimators.