Engineering a pharmacologically superior form of leptin for the treatment of obesity

Leptin plays a central role in the homeostasis of body weight through its regulatory effects on appetite and energy expenditure, yet in trials as a therapeutic agent for the treatment of obesity in humans it has been disappointing. The poor clinical efficacy of leptin results from its short circulating half-life, low potency and poor solubility, necessitating large and frequent doses to obtain even modest clinical benefit. Engineered Fc-leptin immunofusins, consisting of the Fc fragment of an immunoglobulin gamma chain followed by leptin, exhibit improved pharmacological properties with very consistent and potent biological activities. Furthermore, in extending the circulating half-life of the protein in vivo from a few minutes for leptin to many hours for Fc-leptin, these proteins have the potential to reduce drastically the dosage and frequency of administration required to obtain clinical benefit. The results of this study show that the engineered leptin immunofusins described here have significantly enhanced pharmacological properties in comparison with the recombinant leptin that was used in clinical trials. As such, they could represent an important step towards a therapeutically superior form of leptin if the disappointing performance of leptin in early clinical trials was due to its poor pharmacological properties rather than any conceptual weakness in the strategy of using leptin for the treatment of obesity and its related disorders.     

An evaluation of the development of IT in a college of nursing and midwifery

This paper presents the findings of a case study of the development of IT in a College of Nursing and Midwifery. Data were collected by means of postal questionnaires, interviews, focus groups, direct observations and documentary evidence. The findings suggest that the majority of staff used some form of IT on a regular basis, but only 50% of students used college-based IT facilities. The main use of IT was for administrative and productive purposes and there was little evidence of IT in teaching/learning methods. Training offered to staff was poorly attended and training offered to students did not meet what they perceived as their needs. Although most staff used IT there was still evidence of resistance and stress related to IT use. The use of IT in the study college was driven by tactical considerations rather than as a part of an explicit strategy.     

WISC-III and CAS: Which Correlates Higher with Achievement for a Clinical Sample?

The relationships between Wechsler Intelligence Scale for Children-Third Edition (WISC-III) and the Cognitive Assessment System (CAS) with the Woodcock-Johnson Tests of Achievement (WJ-III) were examined for a sample of 119 children (87 males and 32 females) ages 6 to 16. The sample was comprised of children who were referred to a specialty clinic for evaluation. Participants were administered the WISC-III, the CAS, and the WJ-III, in that order. Results indicated that CAS/WJ-III correlations were consistently significantly higher than those found for the WISC-III/WJ-III. The four separate CAS scales added more variance above and beyond the four separate WISC-III scales than the WISC-III added above and beyond the CAS. In addition, the CAS Full Scale accounted for more unique variance and was a stronger predictor of WJ-III Academic Skills Cluster than the WISC-III Full Scale IQ. These results support the validity of the Planning, Attention, Simultaneous, and Successive theory as measured by the CAS in relation to the general intelligence model measured using the WISC-III for explaining variance in achievement for this clinical sample. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Optical add-drop multiplexers with low crosstalk

We propose and demonstrate three new optical add-drop multiplexer (OADM) architectures with simple and compact configuration and excellent crosstalk performance. The OADMs use a single multiport optical circulator and either one or two narrow-band fiber Bragg gratings, depending on the crosstalk requirement     

The structure of the keratan sulphate chains attached to fibromodulin from human articular cartilage

We have previously demonstrated that fibroblasts and invasive human breast carcinoma (HBC) cells specifically activate matrix metalloproteinase-2 (MMP-2) when cultured on 3-dimensional gels of type I collagen but not a range of other substrates. We show here the constitutive expression of membrane-type 1 (MT1)-MMP in both fibroblasts, and invasive HBC cell lines, that have fibroblastic attributes presumably acquired through an epithelial-to-mesenchymal transition (EMT). Treatment with collagen type I increased the steady-state MT1-MMP mRNA levels in these cells but did not induce either MT1-MMP expression or MMP-2 activation in noninvasive breast carcinoma cell lines, which retain epithelial features. Basal MT3-MMP mRNA expression had a pattern similar to that of MT1-MMP but was not up-regulated by collagen. MT4-MMP mRNA was seen in both invasive and noninvasive HBC cell lines and was also not collagen-regulated, and MT2-MMP mRNA was not detected in any of the HBC cell lines tested. These data support a role for MT1-MMP in the collagen-induced MMP-2-activation seen in these cells. In situ hybridization analysis of archival breast cancer specimens revealed a close parallel in expression of both collagen type I and MT1-MMP mRNA in peritumoral fibroblasts, which was correlated with aggressiveness of the lesion. Relatively high levels of expression of both mRNA species were seen in fibroblasts close to invasive tumor nests and, although only focally, in certain areas close to preinvasive tumors. These foci may represent hot spots for local degradation and invasive progression. Collectively, these results implicate MT1-MMP in collagen-stimulated MMP-2 activation and suggest that this mechanism may be employed in vivo by both tumor-associated fibroblasts and EMT-derived carcinoma cells to facilitate increased invasion and/or metastasis.     

Normal chaos: A new research paradigm for understanding practice

Our key point is this: if practitioners always have to work in imperfect ways with imperfect tools, with imperfect understanding using imperfect information and within imperfect systems where the degree of control available is limited, how do they cope, managerially (i.e., “deal effectively” with the issues before them)? As researchers, we believe the answer to that question is not known and, accordingly, we recommend a new research paradigm for understanding practice more generally. We call that paradigm normal chaos.     

Hydrodynamics of prey capture in sharks: effects of substrate

In suction feeding, a volume of water is drawn into the mouth of a predator. Previous studies of suction feeding in fishes have shown that significant fluid velocities are confined to a region within one mouth width from the mouth. Therefore, the predator must be relatively close to the prey to ensure capture success. Here, theoretical modelling is combined with empirical data to unravel the mechanism behind feeding on a substrate. First, we approached the problem theoretically by combining the stream functions of two sinks. Computational fluid dynamics modelling is then applied to make quantitative predictions regarding the effects of substrate proximity on the feeding hydrodynamics of a benthic shark. An oblique circular cylinder and a shark head model were used. To test the models, we used digital particle image velocimetry to record fluid flow around the mouth of white-spotted bamboo sharks, Chiloscyllium plagiosum, during suction feeding on the substrate and in the water column. Empirical results confirmed the modelling predictions: the length of the flow field can be doubled due to passive substrate effects during prey capture. Feeding near a substrate extends the distance over which suction is effective and a predator strike can be effective further from the prey.     

Neuromuscular patterns and the origin of trophic specialization in fishes

The pattern of muscle electrical activity in the pharyngeal muscles of the mollusc-eating sunfish Lepomis microlophus is highly specialized in comparison with the pattern displayed by most other members of the sunfish family and does not change when different prey are eaten. The closest genealogical relative of this species has the specialized muscle activity pattern for crushing prey when it feeds on snails but uses the primitive sequence of muscle activity during swallowing of other prey. The ability of species that crush snails to use molluscan prey effectively is due primarily to the evolutionary transformation of the neuromuscular program controlling the trophic apparatus.