Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3

This project was supported by Queen Mary Innovation Ltd Proof of Concept Fund (2012/13) and The William Harvey Research Foundation

Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders

Background Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Methods Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Results A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. Conclusions This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts

Kynance Cove; or the Cornish Smugglers. A tale of the last century.

Dialecto Literario. -- Dialecto de Cornwall. -- Pertenece a la colección LD-1800-1950 de The Salamanca Corpus. --William Bentinck Forfar, 1810-1895. -- Kynance Cove; or the Cornish Smugglers. A Tale of the Last Century. -- 1865.[ES] Novela que se desarrolla en Cornwall y que contiene dialecto de Cornwall. [EN] A novel that takes place in Cornwall and contains Cornish English

Probing the structure, dynamics, and bonding of coinage metal complexes of white phosphorus

A series of cationic white phosphorus complexes of the coinage metals Au and Cu have been synthesised and characterised both in the solid state and in solution. All complexes feature a P4 unit coordinated through an edge P-P vector (η(2)-like), although the degree of activation (as measured by the coordinated P-P bond length) is greater in the gold species. All of the cations are fluxional on the NMR timescale at room temperature, but in the case of the gold systems fluxionality is frozen out at -90 °C. Electronic structure calculations suggest that this fluxionality proceeds via an η(1)-coordinated M-P4 intermediate

A parameterized approach to modeling and forecasting mortality

A new method is proposed of constructing mortality forecasts. This parameterized approach utilizes Generalized Linear Models (GLMs), based on heteroscedastic Poisson (non-additive) error structures, and using an orthonormal polynomial design matrix. Principal Component (PC) analysis is then applied to the cross-sectional fitted parameters. The produced model can be viewed either as a one-factor parameterized model where the time series are the fitted parameters, or as a principal component model, namely a log-bilinear hierarchical statistical association model of Goodman [Goodman, L.A., 1991. Measures, models, and graphical displays in the analysis of cross-classified data. J. Amer. Statist. Assoc. 86(416), 1085–1111] or equivalently as a generalized Lee–Carter model with p interaction terms. Mortality forecasts are obtained by applying dynamic linear regression models to the PCs. Two applications are presented: Sweden (1751–2006) and Greece (1957–2006)

Severe transient left ventricular dysfunction induced by thyrotoxicosis

We report on a 44-year-old woman presenting with chest pain and dyspnoea without previous stress-related events. By means of echocardiography severe left ventricular dysfunction and wall motion abnormalities resembling stress-induced cardiomyopathy (Tako Tsubo) were seen. Laboratory investigation revealed thyrotoxicosis and elevated cardiac markers. Six days after starting medical treatment, complete restoration of the left ventricular function was observed. The transient left ventricular dysfunction was induced by thyrotoxicosis resembling stress-induced cardiomyopathy that resolved completely after medical treatment

Single Amino Acid Changes Impact the Ability of Drosophila melanogaster Cecropins to Inhibit Growth of Providencia Pathogens

As antibiotic-resistant bacteria spread worldwide, the need to develop novel antimicrobial agents is urgent. One rich source of potential antimicrobials is the insect immune system, as insects produce a wide range of antimicrobial peptides (AMPs) with diverse sequences and structures. Insects also encounter many bacterial pathogens, some of which are closely related to pathogens of clinical relevance. However, despite interest in AMPs as therapeutics, the relationships between the amino acid sequence, biophysical properties, antimicrobial activity, and specificity are still not generalizable. To improve our understanding of these relationships, we assessed how single amino acid changes in cecropin AMPs produced by the fruit fly, Drosophila melanogaster, impact both their structure and their ability to inhibit the growth of Providencia species isolated from wild-caught D. melanogaster. These pathogens are of particular interest as they have a range of virulence in fruit flies, and work in vivo suggests that differences in virulence could be partially attributable to differential susceptibility to AMPs. D. melanogaster cecropins are 40 amino acids long but vary at only 5 residues with largely conservative changes. We found that these changes could impact inhibitory concentrations by up to 8-fold against Providencia species. Our investigation focused on a single amino acid position due to the importance of a flexible “hinge” in cecropin function. We found that altering the identity of this amino acid alone greatly impacted antimicrobial activity, changing bacterial susceptibility up to 16-fold. Generally, Providencia species that are less virulent in vivo are more susceptible to cecropin AMPs in vitro. We also observed differences in the kinetics of permeabilization and bacterial killing between species, suggesting that peptide-membrane interactions were differently affected by single amino acid changes and that bacteria in this genus may vary in their membrane composition