p21 is decreased in polycystic kidney disease and leads to increased epithelial cell cycle progression: roscovitine augments p21 levels.

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease with few treatment options other than renal replacement therapy. p21, a cyclin kinase inhibitor which has pleiotropic effects on the cell cycle, in many cases acts to suppress cell cycle progression and to prevent apoptosis. Because defects in cell cycle arrest and apoptosis of renal tubular epithelial cells occur in PKD, and in light of earlier reports that polycystin-1 upregulates p21 and that the cyclin-dependent kinase inhibitor roscovitine arrests progression in a mouse model, we asked whether (1) p21 deficiency might underlie ADPKD and (2) the mechanism of the salutary roscovitine effect on PKD involves p21.Methodsp21 levels in human and animal tissue samples as well as cell lines were examined by immunoblotting and/or immunohistochemisty. Apoptosis was assessed by PARP cleavage. p21 expression was attenuated in a renal tubular epithelial cell line by antisense methods, and proliferation in response to p21 attenuation and to roscovitine was assessed by the MTT assay.ResultsWe show that p21 is decreased in human as well as a non-transgenic rat model of ADPKD. In addition, hepatocyte growth factor, which induces transition from a cystic to a tubular phenotype, increases p21 levels. Furthermore, attenuation of p21 results in augmentation of cell cycle transit in vitro. Thus, levels of p21 are inversely correlated with renal tubular epithelial cell proliferation. Roscovitine, which has been shown to arrest progression in a murine model of PKD, increases p21 levels and decreases renal tubular epithelial cell proliferation, with no affect on apoptosis.ConclusionThe novelty of our study is the demonstration in vivo in humans and rat models of a decrement of p21 in cystic kidneys as compared to non-cystic kidneys. Validation of a potential pathogenetic model of increased cyst formation due to enhanced epithelial proliferation and apoptosis mediated by p21 suggests a mechanism for the salutary effect of roscovitine in ADPKD and supports further investigation of p21 as a target for future therapy

Genetic Determinism and the Innate-Acquired Distinction in Medicine

This article illustrates in which sense genetic determinism is still part of the contemporary interactionist consensus in medicine. Three dimensions of this consensus are discussed: kinds of causes, a continuum of traits ranging from monogenetic diseases to car accidents, and different kinds of determination due to different norms of reaction. On this basis, this article explicates in which sense the interactionist consensus presupposes the innate–acquired distinction. After a descriptive Part 1, Part 2 reviews why the innate–acquired distinction is under attack in contemporary philosophy of biology. Three arguments are then presented to provide a limited and pragmatic defense of the distinction: an epistemic, a conceptual, and a historical argument. If interpreted in a certain manner, and if the pragmatic goals of prevention and treatment (ideally specifying what medicine and health care is all about) are taken into account, then the innate–acquired distinction can be a useful epistemic tool. It can help, first, to understand that genetic determination does not mean fatalism, and, second, to maintain a system of checks and balances in the continuing nature–nurture debates

Buwchitin:A Ruminal Peptide with Antimicrobial Potential against <i>Enterococcus faecalis</i>

Antimicrobial peptides (AMPs) are gaining popularity as alternatives for treatment of bacterial infections and recent advances in omics technologies provide new platforms for AMP discovery. We sought to determine the antibacterial activity of a novel antimicrobial peptide, buwchitin, against Enterococcus faecalis. Buwchitin was identified from a rumen bacterial metagenome library, cloned, expressed and purified. The antimicrobial activity of the recombinant peptide was assessed using a broth microdilution susceptibility assay to determine the peptide's killing kinetics against selected bacterial strains. The killing mechanism of buwchitin was investigated further by monitoring its ability to cause membrane depolarization (diSC3(5) method) and morphological changes in E. faecalis cells. Transmission electron micrographs of buwchitin treated E. faecalis cells showed intact outer membranes with blebbing, but no major damaging effects and cell morphology changes. Buwchitin had negligible cytotoxicity against defibrinated sheep erythrocytes. Although no significant membrane leakage and depolarization was observed, buwchitin at minimum inhibitory concentration (MIC) was bacteriostatic against E. faecalis cells and inhibited growth in vitro by 70% when compared to untreated cells. These findings suggest that buwchitin, a rumen derived peptide, has potential for antimicrobial activity against E. faecalispublishersversionPeer reviewe

Atherosclerotic Biomarkers and Aortic Atherosclerosis by Cardiovascular Magnetic Resonance Imaging in the Framingham Heart Study

Background: The relations between subclinical atherosclerosis and inflammatory biomarkers have generated intense interest but their significance remains unclear. We sought to determine the association between a panel of biomarkers and subclinical aortic atherosclerosis in a community‐based cohort. Methods and Results: We evaluated 1547 participants of the Framingham Heart Study Offspring cohort who attended the 7th examination cycle and underwent both cardiovascular magnetic resonance imaging (CMR) and assays for 10 biomarkers associated with atherosclerosis: high‐sensitivity C‐reactive protein, fibrinogen, intercellular adhesion molecule‐1, interleukin‐6, interleukin‐18, lipoprotein‐associated phospholipase‐A2 activity and mass, monocyte chemoattractant protein‐1, P‐selectin, and tumor necrosis factor receptor‐2. In logistic regression analysis, we found no significant association between the biomarker panel and the presence of aortic plaque (global P=0.53). Using Tobit regression with aortic plaque as a continuous variable, we noted a modest association between biomarker panel and aortic plaque volume in age‐ and sex‐adjusted analyses (P=0.003). However, this association was attenuated after further adjustment for clinical covariates (P=0.09). Conclusions: In our community‐based cohort, we found no significant association between our multibiomarker panel and aortic plaque. Our results underscore the strengths and limitations of the use of biomarkers for the identification of subclinical atherosclerosis and the importance of traditional risk factors

The rumen microbiome:An underexplored resource for novel antimicrobial discovery

Antimicrobial peptides (AMPs) are promising drug candidates to target multi-drug resistant bacteria. The rumen microbiome presents an underexplored resource for the discovery of novel microbial enzymes and metabolites, including AMPs. Using functional screening and computational approaches, we identified 181 potentially novel AMPs from a rumen bacterial metagenome. Here, we show that three of the selected AMPs (Lynronne-1, Lynronne-2 and Lynronne-3) were effective against numerous bacterial pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). No decrease in MRSA susceptibility was observed after 25 days of sub-lethal exposure to these AMPs. The AMPs bound preferentially to bacterial membrane lipids and induced membrane permeability leading to cytoplasmic leakage. Topical administration of Lynronne-1 (10% w/v) to a mouse model of MRSA wound infection elicited a significant reduction in bacterial counts, which was comparable to treatment with 2% mupirocin ointment. Our findings indicate that the rumen microbiome may provide viable alternative antimicrobials for future therapeutic applicationpublishersversionPeer reviewe

Review Article : Feudalism or Absolute Monarchism?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68809/2/10.1177_009770049001600304.pd

Connective Tissue Activation. I. The Nature, Specificity, Measurement and Distribution of Connective Tissue Activating Peptide

A polypeptide which induces hypermetabolism in normal synovial fibroblasts in tissue culture is described. The metabolic changes induced included a marked increase in hyaluronate formation, lactate formation and glucose uptake; formation of soluble and fibrous collagen was depressed. An assay method is presented which permits quantitative comparisons of samples for connective tissue activating peptide (CTAP) activity. The CTAP appeared to be widely distributed in human tissues, the amount of activity being a function of cell density. A role for CTAP in rheumatoid inflammation is proposed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/37716/1/1780140107_ftp.pd

Penser l'évolution : l'intégration du contexte dans l'étude de la phylogenèse, de l'ontogenèse et de la cognition

Thinking About Evolution : Integrating the Context in Ontogeny, Phytogeny and Cognition. This article comments on Piaget's treatment of internal and external causation in his writings on development, evolution and cognition. Piaget criticized internalist and programming models for their a priorism and implicit preformationism ; he also rejected externalism for its naive empiricism. He consistently tried, in fact, to construct a third way between them. However, because he adopted the habitual conceptual system in which chance and malleability are associated with external forces, while fixity and necessity are associated with internal ones, Piaget consistently overemphasized internal necessity and underemphasized the constitutive role of context. I argue that a fuller application of the interactionist approach, making no distinction between exogenous and endogenous development, obviates the need to privilege internal factors in order to explain regularity of outcome. Thus, species-typicality in development does not require genetic programs, any more than mathematics does. Such a rethinking of programmed development casts doubt on Piaget's account of evolution : had he taken his own descriptions of the mutualistic, interactive nature of variation and natural selection more seriously, he might not have felt the need to insist on phenocopy. Finally, objectivity, usually seen as involving a separation of knowledge from context, can be reconceptualized in a way that includes the social context in its very definition.Dans ses écrits concernant les rôles respectifs de facteurs internes et externes dans le développement, l'évolution et la cognition, Piaget critiqua l'internalisme, lui reprochant son préformationisme implicite et son recours à Va priori ; il rejeta également l'externalisme, à cause de son empirisme naïf. Tout son oeuvre constitue, en effet, la recherche d'une troisième voie au-delà de cette opposition. Toutefois, il n'a jamais vraiment réussi à remettre en cause le système conceptuel habituel, selon lequel le hasard et la malléabilité sont associés avec des forces externes, alors que la nécessité et la fixité sont associés avec des forces internes. Par conséquent, son intérêt pour les régularités du développement intellectuel l'a systématiquement conduit à surestimer la nécessité interne, et à sousestimer le rôle constitutif du contexte. En fait, une application plus conséquente de l'approche interactionniste, évitant toute distinction entre développement interne et développement externe, permet d'expliquer les régularités des processus évolutifs sans privilégier les facteurs internes. Ainsi, pas plus que les mathématiques, l'ontogenèse typique de l'espèce ne requiert aucun recours au concept de programme génétique. En ce qui concerne l'évolution, Piaget a bien noté que la variation d'une part et la sélection naturelle de l'autre se définissent mutuellement, par interaction ; toutefois, s'il avait tiré toutes les conclusions de cette optique, il aurait pu éviter sa malencontreuse insistance sur la phénocopie. L'objectivité enfin, loin de requérir une séparation entre connaissance et contexte, résulte de la prise en compte du rôle du contexte social dans la constitution même des connaissances scientifiques.Oyama Susan, Havelange Véronique, Stewart John Robert. Penser l'évolution : l'intégration du contexte dans l'étude de la phylogenèse, de l'ontogenèse et de la cognition. In: Intellectica. Revue de l'Association pour la Recherche Cognitive, n°16, 1993/1. Biologie et cognition. pp. 133-150