Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications

Endothelial dysfunction is a central pathomechanism in diabetes-associated complications. We hypothesized a pathogenic role in this dysfunction of cathepsin S (Cat-S), a cysteine protease that degrades elastic fibers and activates the protease-activated receptor-2 (PAR2) on endothelial cells. We found that injection of mice with recombinant Cat-S induced albuminuria and glomerular endothelial cell injury in a PAR2-dependent manner. In vivo microscopy confirmed a role for intrinsic Cat-S/PAR2 in ischemia-induced microvascular permeability. In vitro transcriptome analysis and experiments using siRNA or specific Cat-S and PAR2 antagonists revealed that Cat-S specifically impaired the integrity and barrier function of glomerular endothelial cells selectively through PAR2. In human and mouse type 2 diabetic nephropathy, only CD68(+) intrarenal monocytes expressed Cat-S mRNA, whereas Cat-S protein was present along endothelial cells and inside proximal tubular epithelial cells also. In contrast, the cysteine protease inhibitor cystatin C was expressed only in tubules. Delayed treatment of type 2 diabetic db/db mice with Cat-S or PAR2 inhibitors attenuated albuminuria and glomerulosclerosis (indicators of diabetic nephropathy) and attenuated albumin leakage into the retina and other structural markers of diabetic retinopathy. These data identify Cat-S as a monocyte/macrophage-derived circulating PAR2 agonist and mediator of endothelial dysfunction-related microvascular diabetes complications. Thus, Cat-S or PAR2 inhibition might be a novel strategy to prevent microvascular disease in diabetes and other diseases.

The Dark Side of Nudging: The Ethics, Political Economy, and Law of Libertarian Paternalism

Libertarian paternalism, as advanced by Cass Sunstein, is seriously flawed, but not primarily for the reasons that most commentators suggest. Libertarian paternalism and its attendant regulatory implications are too libertarian, not too paternalistic, and as a result are in considerable tension with ‘thick’ conceptions of human dignity. We make four arguments. The first is that there is no justification for a presumption in favor of nudging as a default regulatory strategy, as Sunstein asserts. It is ordinarily less effective than mandates; such mandates rarely offend personal autonomy; and the central reliance on cognitive failures in the nudging program is more likely to offend human dignity than the mandates it seeks to replace. Secondly, we argue that nudging as a regulatory strategy fits both overtly and covertly, often insidiously, into a more general libertarian program of political economy. Thirdly, while we are on the whole more concerned to reject the libertarian than the paternalistic elements of this philosophy, Sunstein’s work, both in Why Nudge?, and earlier, fails to appreciate how nudging may be manipulative if not designed with more care than he acknowledges. Lastly, because of these characteristics, nudging might even be subject to legal challenges that would give us the worst of all possible regulatory worlds: a weak regulatory intervention that is liable to be challenged in the courts by well-resourced interest groups. In such a scenario, and contrary to the ‘common sense’ ethos contended for in Why Nudge?, nudges might not even clear the excessively low bar of doing something rather than nothing. Those seeking to pursue progressive politics, under law, should reject nudging in favor of regulation that is more congruent with principles of legality, more transparent, more effective, more democratic, and allows us more fully to act as moral agents. Such a system may have a place for (some) nudging, but not one that departs significantly from how labeling, warnings and the like already function, and nothing that compares with Sunstein’s apparent ambitions for his new movement.

Reduced risk of pancreatic cancer associated with asthma and nasal allergies

OBJECTIVE: Studies indicate an inverse association between ductal adenocarcinoma of the pancreas (PDAC) and nasal allergies. However, controversial findings are reported for the association with asthma. Understanding PDAC risk factors will help us to implement appropriate strategies to prevent, treat and diagnose this cancer. This study assessed and characterised the association between PDAC and asthma and corroborated existing reports regarding the association between allergies and PDAC risk.

DESIGN: Information about asthma and allergies was collated from 1297 PDAC cases and 1024 controls included in the PanGenEU case-control study. Associations between PDAC and atopic diseases were studied using multilevel logistic regression analysis. Meta-analyses of association studies on these diseases and PDAC risk were performed applying random-effects model.

RESULTS: Asthma was associated with lower risk of PDAC (OR 0.64, 95% CI 0.47 to 0.88), particularly long-standing asthma (>=17 years, OR 0.39, 95% CI 0.24 to 0.65). Meta-analysis of 10 case-control studies sustained our results (metaOR 0.73, 95% CI 0.59 to 0.89). Nasal allergies and related symptoms were associated with lower risk of PDAC (OR 0.66, 95% CI 0.52 to 0.83 and OR 0.59, 95% CI 0.46 to 0.77, respectively). These results were supported by a meta-analysis of nasal allergy studies (metaOR 0.6, 95% CI 0.5 to 0.72). Skin allergies were not associated with PDAC risk.

CONCLUSIONS: This study shows a consistent inverse association between PDAC and asthma and nasal allergies, supporting the notion that atopic diseases are associated with reduced cancer risk. These results point to the involvement of immune and/or inflammatory factors that may either foster or restrain pancreas carcinogenesis warranting further research to understand the molecular mechanisms driving this association.

Molecular mechanisms mediating the beneficial metabolic effects of [Arg4]tigerinin-1R in mice with diet-induced obesity and insulin resistance

The frog skin host-defense peptide tigerinin-1R stimulates insulin release in vitro and improves glucose tolerance and insulin sensitivity in animal models of type 2 diabetes. This study extends these observation by investigating the molecular mechanisms of action underlying the beneficial metabolic effects of the analogue [Arg4]tigerinin-1R in mice with diet induced obesity, glucose intolerance and insulin resistance. The study also investigates the electrophysiological effects of the peptide on KATP and L-type Ca2+ channels in BRINBD11 clonal β cells. Non-fasting plasma glucose and glucagon concentrations were significantly (P<0.05) decreased and plasma insulin increased by twice daily treatment with [Arg4]tigerinin-1R (75 nmol.kg-1 body weight) for 28 days. Oral and intraperitoneal glucose tolerance were significantly (P < 0.05) improved accompanied by enhanced secretion and action of insulin. The peptide blocked KATP channels and, consistent with this, improved beta cell responses of isolated islets to a range of secretagogues. Peptide administration resulted in up-regulation of key functional genes in islets involved insulin secretion (Abcc8, Kcnj11, Cacna1c and Slc2a2) and in skeletal muscle involved with insulin action (Insr, Irs1, Pdk1, Pik3ca, and Slc2a4). These observations encourage further development of tigerinin-1R analogues for the treatment of patients with type 2 diabetes.

A study of Aldred's multiple glosses to the Lindisfarne Gospels

Aldred, the glossator of the Lindisfarne Gospels, presents himself as carefully rendering the Latin lemmata in front of him, in terms of both their internal structure and meaning. His work includes a very high number of multiple glosses, which often attempt to clarify the polysemous character of a lemma or to provide additional information. This paper explores the multiple glosses including different lexemes which Aldred added to lexical lemmata in Mark’s Gospel in an attempt to establish whether there is any correlation between Aldred’s ordering practices and the frequency with which he used the interpretamenta to render those lemmata. The results of the study show some preference for placing the interpretamentum which most commonly renders the Latin lemma in first position, although Aldred’s practice is not fully consistent.

From syntagmatic to paradigmatic spatial zeroes: the loss of the preposition se in inner Asia Minor Greek

We trace the diachronic development of the preposition se in inner Asia Minor Greek from its use to mark a range of spatial functions to its ultimate loss and replacement by zero. We propose that, before spreading to all syntactic and semantic contexts, zero marking was contextually-dependent on the presence/absence of a prenominal genitive modifying the head noun of Ground-encoding NPs and on the presence/absence of Region-encoding postpositions. We attribute these developments to an informational load relief strategy aimed at producing more economical utterances as well as to language contact with Turkish, which favoured structural convergence on the adpositional level between the two languages.

An efficient method for optimal location and sizing of fixed and switched shunt capacitors in large distribution systems

This paper proposes a computationally efficient methodology for the optimal location and sizing of static and switched shunt capacitors in large distribution systems. The problem is formulated as the maximization of the savings produced by the reduction in energy losses and the avoided costs due to investment deferral in the expansion of the network. The proposed method selects the nodes to be compensated, as well as the optimal capacitor ratings and their operational characteristics, i.e. fixed or switched. After an appropriate linearization, the optimization problem was formulated as a large-scale mixed-integer linear problem, suitable for being solved by means of a widespread commercial package. Results of the proposed optimizing method are compared with another recent methodology reported in the literature using two test cases: a 15-bus and a 33-bus distribution network. For the both cases tested, the proposed methodology delivers better solutions indicated by higher loss savings, which are achieved with lower amounts of capacitive compensation. The proposed method has also been applied for compensating to an actual large distribution network served by AES-Venezuela in the metropolitan area of Caracas. A convergence time of about 4 seconds after 22298 iterations demonstrates the ability of the proposed methodology for efficiently handling large-scale compensation problems.

A multi-objective approach for the motion planning of redundant manipulators

Kinematic redundancy occurs when a manipulator possesses more degrees of freedom than those required to execute a given task. Several kinematic techniques for redundant manipulators control the gripper through the pseudo-inverse of the Jacobian, but lead to a kind of chaotic inner motion with unpredictable arm configurations. Such algorithms are not easy to adapt to optimization schemes and, moreover, often there are multiple optimization objectives that can conflict between them. Unlike single optimization, where one attempts to find the best solution, in multi-objective optimization there is no single solution that is optimum with respect to all indices. Therefore, trajectory planning of redundant robots remains an important area of research and more efficient optimization algorithms are needed. This paper presents a new technique to solve the inverse kinematics of redundant manipulators, using a multi-objective genetic algorithm. This scheme combines the closed-loop pseudo-inverse method with a multi-objective genetic algorithm to control the joint positions. Simulations for manipulators with three or four rotational joints, considering the optimization of two objectives in a workspace without and with obstacles are developed. The results reveal that it is possible to choose several solutions from the Pareto optimal front according to the importance of each individual objective.

Strength improvement of adhesively-bonded joints using a reverse-bent geometry

Adhesive bonding of components has become more efficient in recent years due to the developments in adhesive technology, which has resulted in higher peel and shear strengths, and also in allowable ductility up to failure. As a result, fastening and riveting methods are being progressively replaced by adhesive bonding, allowing a big step towards stronger and lighter unions. However, single-lap bonded joints still generate substantial peel and shear stress concentrations at the overlap edges that can be harmful to the structure, especially when using brittle adhesives that do not allow plasticization in these regions. In this work, a numerical and experimental study is performed to evaluate the feasibility of bending the adherends at the ends of the overlap for the strength improvement of single-lap aluminium joints bonded with a brittle and a ductile adhesive. Different combinations of joint eccentricity were tested, including absence of eccentricity, allowing the optimization of the joint. A Finite Element stress and failure analysis in ABAQUS® was also carried out to provide a better understanding of the bent configuration. Results showed a major advantage of using the proposed modification for the brittle adhesive, but the joints with the ductile adhesive were not much affected by the bending technique.

Historic and recent occurrences of pinnipeds in the Archipelago of the Azores

The Archipelago of the Azores (Portugal) is located between 378 and 418N and 258 and 318W and crosses the Mid-Atlantic Ridge. It is the most isolated archipelago in the Atlantic, situated 1600 km west of mainland Portugal and 3500 km from the eastern coast of the United States of America. At present, the only population of seals occurring in the Portuguese territory is found on Desertas Islands, Archipelago of Madeira, where a colony of 24 Mediterranean monk seals, Monachus monachus (Hermann, 1779), still persists (Pires and Neves 2001). Nonetheless, historical accounts reported by Frutuoso (1983) dating from the early to late 1500s mention sightings of ‘‘sea wolves’’ (the old Portuguese folk term for the Mediterranean monk seal) at several sites along the Azorean Island of Santa Maria. Little is known about the occurrence of monk seals in this area over the past five centuries, but the species certainly did not escape deliberate killing by the first settlers. While the early monk seal reports by Frutuoso (1983) are the only reports referring to the presence of colonies of seals in the Azores, more recently several sightings and strandings of vagrant seals of other species have been noted.

Identification of three Sorex species with microsatellite markers

Three sibling species of shrews, the common shrew (Sorex araneus), the Valais shrew (S. antinorii) and the Jersey shrew (S. coronatus) are morphologically similar. Different techniques based on karyorypes, morphology, biochemistry and genetic markers have been developed to identify individuals from these taxa. In this paper, we have used multiple microsatellite markers (L13, L14 and L99) to identify 55 dead animals coming from the Tarentaise Valley in France. As some individuals showed an unclear pattern with loci previously thought to be diagnostic (Lugon-Moulin et al. 2000), we have used morphologic measurements (Hausser et al. 1991) to confirm the status of these animals. This analysis clearly showed the limitations of the use of genetic diagnostic markers that have been designed in local populations and then applied to a wider scale. Even if these markers have great advantages over other techniques (i.e. simple to use and do not require samples from living animals), they should always be used with caution. There is always a risk of a locus not being diagnostic in the sampling region or in finding individuals with hybrid genotypes. Additional genetic markers should then be used, simultaneously with other identification techniques, to be sure of the status of the individuals.

The examination of predictors of success in two programmes requiring self-direction /

The new Physiotherapy and Occupational Therapy programmes, based in the Faculty of Health Sciences, McMaster University (Hamilton, Ontario) are unique. The teaching and learning philosophies utilized are based on learner-centred and selfdirected learning theories. The 1991 admissions process of these programmes attempted to select individuals who would make highly qualified professionals and who would have the necessary skills to complete such unique programmes. In order to: 1 . learn more about the concept of self-directed learning and its related characteristics in health care professionals; 2. examine the relationship between various student characteristics - personal, learner and those assessed during the admissions process - and final course grades, and 3. determine which, if any, smdent characteristics could be considered predictors for success in learner-centred programmes requiring self-directed learning skills, a correlational research design was developed and carried out. Thirty Occupational Therapy and thirty Physiotherapy smdents were asked to complete 2 instruments - a questionnaire developed by the author and the Oddi Continuing Learning Inventory (Oddi, 1986). Course grades and ratings of students during the admissions process were also obtained. Both questionnaires were examined for reliability, and factor analyses were conducted to determine construct validity. Data obtained from the questionnaires, course grades and student ratings (from the admissions process) were analyzed and compared using the Contingency Co-efficient, the Pearson's product-moment correlation co-efficient, and the multiple regression analysis model. The research findings demonstrated a positive relationship (as identified by Contingency Coefficient or Pearson r values) between various course grades and the following personal and learner characteristics: field of smdy of highest level of education achieved, level of education achieved, sex, marital stams, motivation for completing the programmes, reasons for eru-oling in the programmes, decision to enrol in the programmes, employment history, preferred learning style, strong selfconcept and the identification of various components of the concept of self-directed learning. In most cases, the relationships were significant to the 0.01 or 0.(X)1 levels. Results of the multiple regression analyses demonstrated that several learner and admissions characteristic variables had R^ values that accounted for the largest proportion of the variance in several dependent variables. Thus, these variables could be considered predictors for success. The learner characteristics included: level of education and strong self-concept. The admissions characteristics included: ability to evaluate strengths, ability to give feedback, curiosity and creativity, and communication skills. It is recommended that research continue to be conducted to substantiate the relationships found between course grades and characteristic variables in more diverse populations. "Success in self-directed programmes" from the learner's perspective should also be investigated. The Oddi Continuing Learning Inventory should continue to be researched. Further research may lead to refinement or further development of the instrument, and may provide further insight into self-directed learner attributes. The concept of self-directed learning continues to be incorporated into educational programmes, and thus should continue to be explored.