A Protein‐Based Pentavalent Inhibitor of the Cholera Toxin B‐Subunit

Protein toxins produced by bacteria are the cause of many life-threatening diarrheal diseases. Many of these toxins, including cholera toxin (CT), enter the cell by first binding to glycolipids in the cell membrane. Inhibiting these multivalent protein/carbohydrate interactions would prevent the toxin from entering cells and causing diarrhea. Here we demonstrate that the site-specific modification of a protein scaffold, which is perfectly matched in both size and valency to the target toxin, provides a convenient route to an effective multivalent inhibitor. The resulting pentavalent neoglycoprotein displays an inhibition potency (IC50) of 104 pM for the CT B-subunit (CTB), which is the most potent pentavalent inhibitor for this target reported thus far. Complexation of the inhibitor and CTB resulted in a protein heterodimer. This inhibition strategy can potentially be applied to many multivalent receptors and also opens up new possibilities for protein assembly strategies

Coprocessing of pharmaceutical cocrystals for high quality and enhanced physicochemical stability

Solid state synthesis of high-quality indomethacin–saccharin cocrystals was achieved using hot melt extrusion. The physical and chemical stability of the formed cocrystals was enhanced through coprocessing with inert excipients at the final kneading zone. For the purposes of the study, the synthesized cocrystals were coprocessed with a crystalline hydrophilic polymer (PEG 6000), an amorphous hydrophilic polymer (hydroxypropylmethyl cellulose, HPMC), and an aluminometasilicate inorganic (Neusilin) excipient. Physiochemical characterization of the suspended cocrystals in the Neusilin and HPMC carriers revealed superior stability and the absence of any interactions between the excipients and the parent cocrystals. In contrast extruded cocrystals that were not suspended in any excipient or coprocessed with PEG 6000 underwent disassociation under accelerated conditions. Surface dissolution analysis demonstrated that Neusilin and PEG 6000 have no effect on the cocrystal dissolution rates (>90%), while HPMC led to in situ gelling effect and hence in slower rates (∼4%). In conclusion, cocrystals with high crystallinity and improved physicochemical stability can be synthesized by coprocessing with excipients that are inert and nonmiscible and have good thermal stability and low viscosity

Associations between neuropsychiatric and health status outcomes in individuals with probable mTBI

Mild traumatic brain injury (mTBI) is a common occurrence, and may impact distal outcomes in a subgroup of individuals. Improved characterization of health outcomes and identification of factors associated with poor outcomes is needed to better understand the impact of mTBI, particularly in those with co-occurring posttraumatic stress disorder (PTSD). Participants in a data repository of the Injury and Traumatic Stress (INTRuST) Clinical Consortium (n = 625) completed functional disability [FD] and health-related quality of life [HRQOL] questionnaires, and a subset completed a neuropsychological assessment. FD and HRQOL were compared among participants with probable mTBI (mTBI), probable mTBI with PTSD (mTBI/PTSD), and health comparison participants (HC). Associations between symptoms, neuropsychological performance, and health outcomes were examined in those with probable mTBI with and without PTSD (n = 316). Individuals in the mTBI/PTSD group endorsed poorer health outcomes than those in the mTBI group, who endorsed poorer outcomes than those in the HC group. Individuals in either mTBI group performed worse than those in the HC on verbal learning and memory and psychomotor speed. Health outcomes were correlated with mental health and postconcussive symptoms, as well as neuropsychological variables. mTBI may adversely impact self-reported health, with the greatest effect observed in individuals with co-occurring mTBI/PTSD

Maternal neurofascin-specific autoantibodies bind to structures of the fetal nervous system during pregnancy, but have no long term effect on development in the rat

Neurofascin was recently reported as a target for axopathic autoantibodies in patients with multiple sclerosis (MS), a response that will exacerbate axonal pathology and disease severity in an animal model of multiple sclerosis. As transplacental transfer of maternal autoantibodies can permanently damage the developing nervous system we investigated whether intrauterine exposure to this neurofascin-specific response had any detrimental effect on white matter tract development. To address this question we intravenously injected pregnant rats with either a pathogenic anti-neurofascin monoclonal antibody or an appropriate isotype control on days 15 and 18 of pregnancy, respectively, to mimic the physiological concentration of maternal antibodies in the circulation of the fetus towards the end of pregnancy. Pups were monitored daily with respect to litter size, birth weight, growth and motor development. Histological studies were performed on E20 embryos and pups sacrificed on days 2, 10, 21, 32 and 45 days post partum. Results: Immunohistochemistry for light and confocal microscopy confirmed passively transferred anti-neurofascin antibody had crossed the placenta to bind to distinct structures in the developing cortex and cerebellum. However, this did not result in any significant differences in litter size, birth weight, or general physical development between litters from control mothers or those treated with the neurofascin-specific antibody. Histological analysis also failed to identify any neuronal or white matter tract abnormalities induced by the neurofascin-specific antibody. Conclusions: We show that transplacental transfer of circulating anti-neurofascin antibodies can occur and targets specific structures in the CNS of the developing fetus. However, this did not result in any pre- or post-natal abnormalities in the offspring of the treated mothers. These results assure that even if anti-neurofascin responses are detected in pregnant women with multiple sclerosis these are unlikely to have a negative effect on their children

Informing investment to reduce inequalities: a modelling approach

Background: Reducing health inequalities is an important policy objective but there is limited quantitative information about the impact of specific interventions. Objectives: To provide estimates of the impact of a range of interventions on health and health inequalities. Materials and methods: Literature reviews were conducted to identify the best evidence linking interventions to mortality and hospital admissions. We examined interventions across the determinants of health: a ‘living wage’; changes to benefits, taxation and employment; active travel; tobacco taxation; smoking cessation, alcohol brief interventions, and weight management services. A model was developed to estimate mortality and years of life lost (YLL) in intervention and comparison populations over a 20-year time period following interventions delivered only in the first year. We estimated changes in inequalities using the relative index of inequality (RII). Results: Introduction of a ‘living wage’ generated the largest beneficial health impact, with modest reductions in health inequalities. Benefits increases had modest positive impacts on health and health inequalities. Income tax increases had negative impacts on population health but reduced inequalities, while council tax increases worsened both health and health inequalities. Active travel increases had minimally positive effects on population health but widened health inequalities. Increases in employment reduced inequalities only when targeted to the most deprived groups. Tobacco taxation had modestly positive impacts on health but little impact on health inequalities. Alcohol brief interventions had modestly positive impacts on health and health inequalities only when strongly socially targeted, while smoking cessation and weight-reduction programmes had minimal impacts on health and health inequalities even when socially targeted. Conclusions: Interventions have markedly different effects on mortality, hospitalisations and inequalities. The most effective (and likely cost-effective) interventions for reducing inequalities were regulatory and tax options. Interventions focused on individual agency were much less likely to impact on inequalities, even when targeted at the most deprived communities

Lectures on Cosmic Inflation and its Potential Stringy Realizations

These notes present a brief introduction to Hot Big Bang cosmology and Cosmic Inflation, together with a selection of some recent attempts to embed inflation into string theory. They provide a partial description of lectures presented in courses at Dubrovnik in August 2006, at CERN in January 2007 and at Cargese in August 2007. They are aimed at graduate students with a working knowledge of quantum field theory, but who are unfamiliar with the details of cosmology or of string theory.Comment: 68 pages, lectures given at Dubrovnik, Aug 2006; CERN, January 2007; and Cargese, Aug 200

Lessons for sustainability from the world's most sustainable culture

Sustainable development is one of the key challenges faced by societies today. Yet it is not a new challenge; throughout history, societies have faced the need to live within environmental constraints. Some have done so well, and some poorly. One society which did well for tens of thousands of years is that of Aboriginal Australia. This paper explores some lessons from Aboriginal Australia which have resonance in the modern world and shows that countries which have learned those lessons are in fact more sustainable than those which have not. It thus suggests that there is much that the pantheon of human experience can teach the modern world as it endeavours to create a sustainable future