Towards designer organelles by subverting the peroxisomal import pathway

The development of ‘designer’ organelles could be a key strategy to enable foreign pathways to be efficiently controlled within eukaryotic biotechnology. A fundamental component of any such system will be the implementation of a bespoke protein import pathway that can selectively deliver constituent proteins to the new compartment in the presence of existing endogenous trafficking systems. Here we show that the protein–protein interactions that control the peroxisomal protein import pathway can be manipulated to create a pair of interacting partners that still support protein import in moss cells, but are orthogonal to the naturally occurring pathways. In addition to providing a valuable experimental tool to give new insights into peroxisomal protein import, the variant receptor-signal sequence pair forms the basis of a system in which normal peroxisomal function is downregulated and replaced with an alternative pathway, an essential first step in the creation of a designer organelle

Investigating changes in blood-cerebrospinal fluid barrier function in a rat model of chronic hypertension using non-invasive magnetic resonance imaging

Chronic hypertension is a major risk factor for the development of neurodegenerative disease, yet the etiology of hypertension-driven neurodegeneration remains poorly understood. Forming a unique interface between the systemic circulation and the brain, the blood-cerebrospinal fluid barrier (BCSFB) at the choroid plexus (CP) has been proposed as a key site of vulnerability to hypertension that may initiate downstream neurodegenerative processes. However, our ability to understand BCSFB’s role in pathological processes has, to date, been restricted by a lack of non-invasive functional measurement techniques. In this work, we apply a novel Blood-Cerebrospinal Fluid Barrier Arterial Spin Labeling (BCSFB-ASL) Magnetic resonance imaging (MRI) approach with the aim of detecting possible derangement of BCSFB function in the Spontaneous Hypertensive Rat (SHR) model using a non-invasive, translational technique. SHRs displayed a 36% reduction in BCSFB-mediated labeled arterial water delivery into ventricular cerebrospinal fluid (CSF), relative to normotensive controls, indicative of down-regulated choroid plexus function. This was concomitant with additional changes in brain fluid biomarkers, namely ventriculomegaly and changes in CSF composition, as measured by T1 lengthening. However, cortical cerebral blood flow (CBF) measurements, an imaging biomarker of cerebrovascular health, revealed no measurable change between the groups. Here, we provide the first demonstration of BCSFB-ASL in the rat brain, enabling non-invasive assessment of BCSFB function in healthy and hypertensive rats. Our data highlights the potential for BCSFB-ASL to serve as a sensitive early biomarker for hypertension-driven neurodegeneration, in addition to investigating the mechanisms relating hypertension to neurodegenerative outcomes

Plasticity of the human visual system after retinal gene therapy in patients with Leber's congenital amaurosis.

Much of our knowledge of the mechanisms underlying plasticity in the visual cortex in response to visual impairment, vision restoration, and environmental interactions comes from animal studies. We evaluated human brain plasticity in a group of patients with Leber's congenital amaurosis (LCA), who regained vision through gene therapy. Using non-invasive multimodal neuroimaging methods, we demonstrated that reversing blindness with gene therapy promoted long-term structural plasticity in the visual pathways emanating from the treated retina of LCA patients. The data revealed improvements and normalization along the visual fibers corresponding to the site of retinal injection of the gene therapy vector carrying the therapeutic gene in the treated eye compared to the visual pathway for the untreated eye of LCA patients. After gene therapy, the primary visual pathways (for example, geniculostriate fibers) in the treated retina were similar to those of sighted control subjects, whereas the primary visual pathways of the untreated retina continued to deteriorate. Our results suggest that visual experience, enhanced by gene therapy, may be responsible for the reorganization and maturation of synaptic connectivity in the visual pathways of the treated eye in LCA patients. The interactions between the eye and the brain enabled improved and sustained long-term visual function in patients with LCA after gene therapy

An international network to monitor the structure, composition and dynamics of Amazonian forests (RAINFOR)

The Amazon basin is likely to be increasingly affected by environmental changes: higher temperatures, changes in precipitation, CO2 fertilization and habitat fragmentation. To examine the important ecological and biogeochemical consequences of these changes, we are developing an international network, RAINFOR, which aims to monitor forest biomass and dynamics across Amazonia in a co-ordinated fashion in order to understand their relationship to soil and climate. The network will focus on sample plots established by independent researchers, some providing data extending back several decades. We will also conduct rapid transect studies of poorly monitored regions. Field expeditions analysed local soil and plant properties in the first phase (2001–2002). Initial results suggest that the network has the potential to reveal much information on the continental-scale relations between forest and environment. The network will also serve as a forum for discussion between researchers, with the aim of standardising sampling techniques and methodologies that will enable Amazonian forests to be monitored in a coherent manner in the coming decades

Corticosterone Potentiation of Cocaine-Induced Reinstatement of Conditioned Place Preference in Mice is Mediated by Blockade of the Organic Cation Transporter 3

The mechanisms by which stressful life events increase the risk of relapse in recovering cocaine addicts are not well understood. We previously reported that stress, via elevated corticosterone, potentiates cocaine-primed reinstatement of cocaine seeking following self-administration in rats and that this potentiation appears to involve corticosterone-induced blockade of dopamine clearance via the organic cation transporter 3 (OCT3). In the present study, we use a conditioned place preference/reinstatement paradigm in mice to directly test the hypothesis that corticosterone potentiates cocaine-primed reinstatement by blockade of OCT3. Consistent with our findings following self-administration in rats, pretreatment of male C57/BL6 mice with corticosterone (using a dose that reproduced stress-level plasma concentrations) potentiated cocaine-primed reinstatement of extinguished cocaine-induced conditioned place preference. Corticosterone failed to re-establish extinguished preference alone but produced a leftward shift in the dose–response curve for cocaine-primed reinstatement. A similar potentiating effect was observed upon pretreatment of mice with the non-glucocorticoid OCT3 blocker, normetanephrine. To determine the role of OCT3 blockade in these effects, we examined the abilities of corticosterone and normetanephrine to potentiate cocaine-primed reinstatement in OCT3-deficient and wild-type mice. Conditioned place preference, extinction and reinstatement of extinguished preference in response to low-dose cocaine administration did not differ between genotypes. However, corticosterone and normetanephrine failed to potentiate cocaine-primed reinstatement in OCT3-deficient mice. Together, these data provide the first direct evidence that the interaction of corticosterone with OCT3 mediates corticosterone effects on drug-seeking behavior and establish OCT3 function as an important determinant of susceptibility to cocaine use

Opposition as victimhood in newspaper debates about same-sex marriage

In this paper, we take a queer linguistics approach to the analysis of data from British newspaper articles which discuss the introduction of same-sex marriage. Drawing on methods from CDA and corpus linguistics, we focus on the construction of agency in relation to the government extending marriage to same-sex couples, and those resisting this. We show that opponents to same-sex marriage are represented and represent themselves as victims whose moral values, traditions, and civil liberties are being threatened by the state. Specifically, we argue that victimhood is invoked in a way that both enables and permits discourses of implicit homophobia

Small-scale magnetic buoyancy and magnetic pumping effects in a turbulent convection

We determine the nonlinear drift velocities of the mean magnetic field and nonlinear turbulent magnetic diffusion in a turbulent convection. We show that the nonlinear drift velocities are caused by the three kinds of the inhomogeneities, i.e., inhomogeneous turbulence; the nonuniform fluid density and the nonuniform turbulent heat flux. The inhomogeneous turbulence results in the well-known turbulent diamagnetic and paramagnetic velocities. The nonlinear drift velocities of the mean magnetic field cause the small-scale magnetic buoyancy and magnetic pumping effects in the turbulent convection. These phenomena are different from the large-scale magnetic buoyancy and magnetic pumping effects which are due to the effect of the mean magnetic field on the large-scale density stratified fluid flow. The small-scale magnetic buoyancy and magnetic pumping can be stronger than these large-scale effects when the mean magnetic field is smaller than the equipartition field. We discuss the small-scale magnetic buoyancy and magnetic pumping effects in the context of the solar and stellar turbulent convection. We demonstrate also that the nonlinear turbulent magnetic diffusion in the turbulent convection is anisotropic even for a weak mean magnetic field. In particular, it is enhanced in the radial direction. The magnetic fluctuations due to the small-scale dynamo increase the turbulent magnetic diffusion of the toroidal component of the mean magnetic field, while they do not affect the turbulent magnetic diffusion of the poloidal field.Comment: 13 pages, 4 figure, REVTEX4, Geophysical and Astrophysical Fluid Dynamics, in pres

Neonatal retroauricular cellulitis as an indicator of group B streptococcal bacteremia: a case report

<p>Abstract</p> <p>Introduction</p> <p>The relation between cellulitis and Group B streptococcus infection in newborns and small infants was first reported during the early 1980s and named cellulitis-adenitis syndrome. We report a case of a neonate with cellulitis-adenitis syndrome in an unusual location (retroauricular).</p> <p>Case presentation</p> <p>A 21-day-old Caucasian female infant was brought to the emergency department with fever, irritability and a decreased appetite. Physical examination revealed erythema and painful, mild swelling in the right retroauricular region. The blood count and C-reactive protein level were normal. She was treated with ceftriaxone. The fever and irritability were resolved after 24 hours, and the cellulitis was clearly reduced after two days of hospitalization. Blood culture yielded Group B streptococcus.</p> <p>Conclusion</p> <p>A thorough evaluation must be done, and lumbar punctures for infants with cellulitis must be considered. We emphasize the lack of data about acute phase reactants to predict bacteremia and meningitis and to adjust the duration of parenteral antibiotic therapy to address this syndrome.</p

Shigella sonnei genome sequencing and phylogenetic analysis indicate recent global dissemination from Europe

Shigella are human-adapted Escherichia coli that have gained the ability to invade the human gut mucosa and cause dysentery1,2, spreading efficiently via low-dose fecal-oral transmission3,4. Historically, S. sonnei has been predominantly responsible for dysentery in developed countries, but is now emerging as a problem in the developing world, apparently replacing the more diverse S. flexneri in areas undergoing economic development and improvements in water quality4-6. Classical approaches have shown S. sonnei is genetically conserved and clonal7. We report here whole-genome sequencing of 132 globally-distributed isolates. Our phylogenetic analysis shows that the current S. sonnei population descends from a common ancestor that existed less than 500 years ago and has diversified into several distinct lineages with unique characteristics. Our analysis suggests the majority of this diversification occurred in Europe, followed by more recent establishment of local pathogen populations in other continents predominantly due to the pandemic spread of a single, rapidly-evolving, multidrug resistant lineage