Updated soil to fruit concentration ratios for radiocaesium compiled under the IAEA MODARIA II Programme.

Under the International Atomic Energy Agency (IAEA) Modelling and Data for Radiological Impact Assessments (MODARIA II) Programme, Working Group 4 activities included collating radionuclide transfer data from Japan following the Fukushima Daiichi Nuclear Power Plant accident and separately collating concentration ratio (CR) data for root uptake of radionuclides by crops grown in tropical and arid climates. In this paper, the newly compiled radiocaesium CR data for fruit from Japan, tropical and arid climates have been combined with the data originally compiled for the IAEA Technical Reports Series No. 472 (TRS 472) and additional data identified from the literature to produce an enhanced MODARIA II dataset of fruit radiocaesium CR values. Statistical analysis of the MODARIA II dataset by climate class (based on the Köppen-Geiger climate classification) indicated that the CR values for tropical climates were significantly higher (p< 0.05) than those for arid, temperate and cold climates. Statistical analysis of the MODARIA II dataset by soil group (based on soil texture) indicated that the CR values for coral sand soil (tropical climates only) and organic soil (temperate climates only) were significantly higher (p< 0.05) than those for the clay, loam and sand soil groups. Statistical analysis of the MODARIA II dataset by plant group (based on plant morphology) indicated that the CR values for non-woody trees (tropical climate bias) were significantly higher (p< 0.05) than those for herbaceous plants, shrubs and woody trees. Comparison of the MODARIA II dataset with original TRS 472 values showed only small changes in the fruit radiocaesium CR values for herbaceous plants and shrubs in temperate climates. There was a decrease in the CR values for woody trees in temperate climate across all soil groups. There was also a decrease in the CR values for tropical climates for all comparable soil groups.

Ensuring robust radiological risk assessment for wildlife: insights from the International Atomic Energy Agency EMRAS and MODARIA programmes.

In response to changing international recommendations and national requirements, a number of assessment approaches, and associated tools and models, have been developed over the last circa 20 years to assess radiological risk to wildlife. In this paper, we summarise international intercomparison exercises and scenario applications of available radiological assessment models for wildlife to aid future model users and those such as regulators who interpret assessments. Through our studies, we have assessed the fitness for purpose of various models and tools, identified the major sources of uncertainty and made recommendations on how the models and tools can best be applied to suit the purposes of an assessment. We conclude that the commonly used tiered or graded assessment tools are generally fit for purpose for conducting screening-level assessments of radiological impacts to wildlife. Radiological protection of the environment (or wildlife) is still a relatively new development within the overall system of radiation protection and environmental assessment approaches are continuing to develop. Given that some new/developing approaches differ considerably from the more established models/tools and there is an increasing international interest in developing approaches that support the effective regulation of multiple stressors (including radiation), we recommend the continuation of coordinated international programmes for model development, intercomparison and scenario testing.

Distribution of label spacings for genome mapping in nanochannels.

In genome mapping experiments, long DNA molecules are stretched by confining them to very narrow channels, so that the locations of sequence-specific fluorescent labels along the channel axis provide large-scale genomic information. It is difficult, however, to make the channels narrow enough so that the DNA molecule is fully stretched. In practice, its conformations may form hairpins that change the spacings between internal segments of the DNA molecule, and thus the label locations along the channel axis. Here, we describe a theory for the distribution of label spacings that explains the heavy tails observed in distributions of label spacings in genome mapping experiments.

State of the art: gene therapy of haemophilia.

Clinical gene therapy has been practiced for more than a quarter century and the first products are finally gaining regulatory/marketing approval. As of 2016, there have been 11 haemophilia gene therapy clinical trials of which six are currently open. Each of the ongoing phase 1/2 trials is testing a variation of a liver-directed adeno-associated viral (AAV) vector encoding either factor VIII (FVIII) or factor IX (FIX) . As summarized herein, the clinical results to date have been mixed with some perceived success and a clear recognition of the immune response to AAV as an obstacle to therapeutic success. We also attempt to highlight promising late-stage preclinical activities for AAV-FVIII where, due to inherent challenges with manufacture, delivery and transgene product biosynthesis, more technological development has been necessary to achieve results comparable to what has been observed previously for AAV-FIX. Finally, we describe the development of a stem cell-based lentiviral vector gene therapy product that has the potential to provide lifelong production of FVIII and provide a functional 'cure' for haemophilia A. Integral to this program has been the incorporation of a blood cell-specific gene expression element driving the production of a bioengineered FVIII designed for optimal efficiency. As clearly outlined herein, haemophilia remains at the forefront of the rapidly advancing clinical gene therapy field where there exists a shared expectation that transformational advances are on the horizon.

Predicting exposure of wildlife in radionuclide contaminated wetland ecosystems.

Many wetlands support high biodiversity and are protected sites, but some are contaminated with radionuclides from routine or accidental releases from nuclear facilities. This radiation exposure needs to be assessed to demonstrate radiological protection of the environment. Existing biota dose models cover generic terrestrial, freshwater, and marine ecosystems, not wetlands specifically. This paper, which was produced under IAEA's Environmental Modelling for Radiation Safety (EMRAS) II programme, describes an evaluation of how models can be applied to radionuclide contaminated wetlands. Participants used combinations of aquatic and terrestrial model parameters to assess exposure. Results show the importance of occupancy factor and food source (aquatic or terrestrial) included. The influence of soil saturation conditions on external dose rates is also apparent. In general, terrestrial parameters provided acceptable predictions for wetland organisms. However, occasionally predictions varied by three orders of magnitude between assessors. Possible further developments for biota dose models and research needs are identified.

Expanding the ortholog approach for hemophilia treatment complicated by factor VIII inhibitors.

BACKGROUND: The formation of neutralizing antibodies (inhibitors) directed against human coagulation factor VIII (hFVIII) is a life-threatening pathogenic response that occurs in 20-30% of severe congenital hemophilia A patients and 0.00015% of the remaining population (i.e. acquired hemophilia A). Interspecies amino acid sequence disparity among FVIII orthologs represents a promising strategy to mask FVIII from existing inhibitors while retaining procoagulant function. Evidence for the effectiveness of this approach exists in clinical data obtained for porcine FVIII (pFVIII) products, which have demonstrated efficacy in the setting of congenital and acquired hemophilia. OBJECTIVES: In the current study, recombinant (r) ovine FVIII (oFVIII) was evaluated for antigenicity and procoagulant activity in the context of human patient-derived and murine model-generated FVIII inhibitors. METHODS: The antigenicity of roFVIII was assessed using (i) inhibitor patient plasma samples, (ii) murine anti-FVIII MAbs, (iii) immunized murine hemophilia A plasmas and (iv) an in vivo model of acquired hemophilia A. RESULTS: Overall, roFVIII demonstrated reduced reactivity to, and inhibition by, anti-hFVIII immunoglobulin in patient plasmas. Additionally, several hFVIII epitopes were predicted and empirically shown not to exist within roFVIII. In a murine hemophilia A model designed to mimic clinical inhibitor formation, it was demonstrated that inhibitor titers to roFVIII were significantly reduced when compared with the orthologous immunogens, rhFVIII or rpFVIII. Furthermore, in a murine model of acquired hemophilia A, roFVIII administration conferred protection from bleeding following tail transection. CONCLUSION: These data support the investigation of FVIII orthologs as treatment modalities in both the congenital and acquired FVIII inhibitor settings.

High-throughput screening identifies compounds that enhance lentiviral transduction.

A difficulty in the field of gene therapy is the need to increase the susceptibility of hematopoietic stem cells (HSCs) to ex vivo genetic manipulation. To overcome this obstacle a high-throughput screen was performed to identify compounds that could enhance the transduction of target cells by lentiviral vectors. Of the 1280 compounds initially screened using the myeloid-erythroid-leukemic K562 cell line, 30 were identified as possible enhancers of viral transduction. Among the positive hits were known enhancers of transduction (camptothecin, etoposide and taxol), as well as the previously unidentified phorbol 12-myristate 13-acetate (PMA). The percentage of green fluorescent protein (GFP)-positive-expressing K562 cells was increased more than fourfold in the presence of PMA. In addition, the transduction of K562 cells with a lentiviral vector encoding fVIII was four times greater in the presence of PMA as determined by an increase in the levels of provirus in genetically modified cells. PMA did not enhance viral transduction of all cell types (for example, sca-1(+) mouse hematopoietic cells) but did enhance viral transduction of human bone marrow-derived CD34(+) cells. Notably, the percentage of GFP-positive CD34(+) cells was increased from 7% in the absence of PMA to greater than 22% in the presence of 1 nM PMA. PMA did not affect colony formation of CD34(+) cells or the expression of the hematopoietic markers CD34 and CD45. These data demonstrate that high-throughput screening can be used to identify compounds that increase the transduction efficiency of lentiviral vectors, identifying PMA as a potential enhancer of lentiviral HSC transduction.

Plutonium in wildlife and soils at the Maralinga legacy site: persistence over decadal time scales.

The mobility of plutonium (Pu) in soils, and its uptake into a range of wildlife, were examined using recent and ∼25 year old data from the Taranaki area of the former Maralinga weapons test site, Australia. Since its initial deposition in the early 1960s, the dispersed Pu has been incorporated into the soil profile and food chain through natural processes, allowing for the study of Pu sequestration and dynamics in relatively undisturbed semi-arid conditions. The data indicate downward mobility of Pu in soil at rates of ∼0.2-0.3 cm per year for the most mobile fraction. As a result, while all of the Pu was initially deposited on the ground surface, approximately 93% and 62% remained in the top 0-2 cm depth after 25- and 50-years respectively. No large-scale lateral spreading of the Taranaki plume was observed. Pu activity concentrations in 0-1 cm soils with biotic crusts were not elevated when compared with nearby bare soils, although a small number of individual data suggest retention of Pu-containing particles may be occurring in some biotic crusts. Soil-to-animal transfer, as measured by concentration ratios (CRwo-soil), was 4.1E-04 (Geometric Mean (GM)) in mammals, which aligns well with those from similar species and conditions (such as the Nevada Test Site, US), but are lower than the GM of the international mammal data reported in the Wildlife Transfer Database (WTD). These lower values are likely due to the presence of a low-soluble, particulate form of the Pu in Maralinga soils. Arthropod concentration ratios (3.1E-03 GM), were similar to those from Rocky Flats, US, while values for reptiles (2.0E-02 GM) were higher than the WTD GM value which was dominated by data from Chernobyl. Comparison of uptake data spanning approximately 30 years indicates no decrease over time for mammals, and a potential increase for reptiles. The results confirm the persistence of bioavailable Pu after more than 50 years since deposition, and also the presence of larger-sized particles which currently affect CRwo-soil calculations, and which may serve as an ongoing source of bioavailable Pu as they are subjected to weathering into the future.

Generation of an optimized lentiviral vector encoding a high-expression factor VIII transgene for gene therapy of hemophilia A.

We previously compared the expression of several human factor VIII (fVIII) transgene variants and demonstrated the superior expression properties of B domain-deleted porcine fVIII. Subsequently, a hybrid human/porcine fVIII molecule (HP-fVIII) comprising 91% human amino-acid sequence was engineered to maintain the high-expression characteristics of porcine fVIII. The bioengineered construct then was used effectively to treat knockout mice with hemophilia A. In the current study, we focused on optimizing self-inactivating (SIN) lentiviral vector systems by analyzing the efficacy of various lentiviral components in terms of virus production, transduction efficiency and transgene expression. Specifically, three parameters were evaluated: (1) the woodchuck hepatitis post-transcriptional regulatory element (WPRE), (2) HIV versus SIV viral vector systems and (3) various internal promoters. The inclusion of a WPRE sequence had negligible effects on viral production and HP-fVIII expression. HIV and SIV vectors were compared and found to be similar with respect to transduction efficiency in both K562s and HEK-293T cells. However, there was an enhanced expression of HP-fVIII by the SIV system, which was evident in both K562 and BHK-M cell lines. To further compare expression of HP-fVIII from an SIV-based lentiviral system, we constructed expression vectors containing the high expression transgene and a human elongation factor-1 alpha, cytomegalovirus (CMV) or phosphoglycerate kinase promoter. Expression was significantly greater from the CMV promoter, which also yielded therapeutic levels of HP-fVIII in hemophilia A mice. Based on these studies, an optimized vector contains the HP-fVIII transgene driven by a CMV internal promoter within a SIV-based lentiviral backbone lacking a WPRE.

The IAEA handbook on radionuclide transfer to wildlife.

An IAEA handbook presenting transfer parameter values for wildlife has recently been produced. Concentration ratios (CRwo-media) between the whole organism (fresh weight) and either soil (dry weight) or water were collated for a range of wildlife groups (classified taxonomically and by feeding strategy) in terrestrial, freshwater, marine and brackish generic ecosystems. The data have been compiled in an on line database, which will continue to be updated in the future providing the basis for subsequent revision of the Wildlife TRS values. An overview of the compilation and analysis, and discussion of the extent and limitations of the data is presented. Example comparisons of the CRwo-media values are given for polonium across all wildlife groups and ecosystems and for molluscs for all radionuclides. The CRwo-media values have also been compared with those currently used in the ERICA Tool which represented the most complete published database for wildlife transfer values prior to this work. The use of CRwo-media values is a pragmatic approach to predicting radionuclide activity concentrations in wildlife and is similar to that used for screening assessments for the human food chain. The CRwo-media values are most suitable for a screening application where there are several conservative assumptions built into the models which will, to varying extents, compensate for the variable data quality and quantity, and associated uncertainty.

Bone marrow transplantation improves the outcome of Atm-deficient mice through the migration of ATM-competent cells.

Ataxia telangiectasia (A-T) is a highly pleiotropic disorder. Patients suffer from progressive neurodegeneration, severe bronchial complications, immunodeficiency, hypersensitivity to radiotherapy and elevated risk of malignancies. Leukemia and lymphoma, along with lung failure, are the main causes of morbidity and mortality in A-T patients. At present, no effective therapy for A-T exists. One promising therapeutic approach is bone marrow transplantation (BMT) that is already used as a curative therapy for other genomic instability syndromes. We used an established clinically relevant non-myeloablative host-conditioning regimen and transplanted green fluorescent protein (GFP)-expressing ataxia telangiectasia mutated (ATM)-competent bone marrow-derived cells (BMDCs) into Atm-deficient mice. GFP expression allowed tracking of the potential migration of the cells into the tissues of recipient animals. Donor BMDCs migrated into the bone marrow, blood, thymus, spleen and lung tissue of Atm-deficient mice showing an ATM-competent phenotype. BMT inhibited thymic lymphomas, normalized T-lymphocyte populations, improved weight gain and rearing activity of Atm-deficient mice. In contrast, no GFP(+) cells were found in the cerebellum or cerebrum, and we detected decreased size index in MRI imaging of the cerebellum in 8-month-old transplanted Atm-deficient mice in comparison to wild-type mice. The repopulation with ATM-competent BMDCs is associated with a prolonged lifespan and significantly improved the phenotype of Atm-deficient mice.

Formation and photocatalytic decomposition of a pellicle on anatase surfaces.

The acquired dental pellicle plays a critical role in the adhesion and detachment of dental plaque bacteria. It has been reported that titanium dioxide biomaterials decompose single-protein films by photocatalysis. However, it is not known whether this can also be achieved with complex structured pellicle films. This in vitro study investigated in real-time the formation and photocatalytic decomposition of human pellicle at anatase-saliva interfaces. Nanostructured polycrystalline anatase layers were deposited on titanium-coated quartz crystals by magnetron-sputtering, serving as a model for titanium implant surfaces. The quartz crystals were used as acoustic sensors in a quartz-crystal microbalance (QCM) system with dissipation. In situ UV irradiation of pellicle-covered anatase caused a statistically significant decrease of the adsorbed salivary mass. In contrast, photocatalytic decomposition of pellicle could not be observed on reference titanium surfaces. Wettability characterization revealed superhydrophilicity of anatase upon UV irradiation, whereas titanium was unaffected. XPS measurements provide further information concerning the decomposition of the salivary films. The results suggest that the photocatalytic activity of polycrystalline anatase-modified biomaterial surfaces is able to decompose complex structured macromolecular pellicle films. Therefore, this study opens the way to surface modifications supporting therapeutic approaches of biofilm removal.

Multifunctional nature of UV-irradiated nanocrystalline anatase thin films for biomedical applications.

Anatase is known to decompose organic material by photocatalysis and to enhance surface wettability once irradiated by ultraviolet (UV) light. In this study, pulse magnetron-sputtered anatase thin films were investigated for their suitability with respect to specific biomedical applications, namely superhydrophilic and biofilm degrading implant surfaces. UV-induced hydrophilicity was quantified by static and dynamic contact angle analysis. Photocatalytic protein decomposition was analyzed by quartz crystal microbalance with dissipation. The surfaces were characterized by X-ray diffraction, atomic force microscopy, scanning electron microscopy and X-ray photoelectron spectroscopy. The radical formation on anatase, responsible for photocatalytic effects, was analyzed by electron spin resonance spectroscopy. Results have shown that the nanocrystalline anatase films, in contrast to reference titanium surfaces, were sensitive to UV irradiation and showed rapid switching towards superhydrophilicity. The observed decrease in carbon adsorbents and the increase in the fraction of surface hydroxyl groups upon UV irradiation might contribute to this hydrophilic behavior. UV irradiation of anatase pre-conditioned with albumin protein layers induces the photocatalytic decomposition of these model biofilms. The observed degradation is mainly caused by hydroxyl radicals. It is concluded that nanocrystalline anatase films offer different functions at implant interfaces, e.g. bedside hydrophilization of anatase-coated implants for improved osseointegration or the in situ decomposition of conditioning films forming the basal layer of biofilms in the oral cavity.

Congenital stationary night blindness in mice - a tale of two Cacna1f mutants.

BACKGROUND: Mutations in CACNA1F, which encodes the Ca(v)1.4 subunit of a voltage-gated L-type calcium channel, cause X-linked incomplete congenital stationary night blindness (CSNB2), a condition of defective retinal neurotransmission which results in night blindness, reduced visual acuity, and diminished ERG b-wave. We have characterized two putative murine CSNB2 models: an engineered null-mutant, with a stop codon (G305X); and a spontaneous mutant with an ETn insertion in intron 2 of Cacna1f (nob2). METHODS: Cacna1f ( G305X ): Adults were characterized by visual function (photopic optokinetic response, OKR); gene expression (microarray) and by cell death (TUNEL) and synaptic development (TEM). Cacna1f ( nob2 ): Adults were characterized by properties of Cacna1f mRNA (cloning and sequencing) and expressed protein (immunoblotting, electrophysiology, filamin [cytoskeletal protein] binding), and OKR. RESULTS: The null mutation in Cacna1f ( G305X ) mice caused loss of cone cell ribbons, failure of OPL synaptogenesis, ERG b-wave and absence of OKR. In Cacna1f ( nob2 ) mice alternative ETn splicing produced ~90% Cacna1f mRNA having a stop codon, but ~10% mRNA encoding a complete polypeptide. Cacna1f ( nob2 ) mice had normal OKR, and alternatively-spliced complete protein had WT channel properties, but alternative ETn splicing abolished N-terminal protein binding to filamin. CONCLUSIONS: Ca(v)1.4 plays a key role in photoreceptor synaptogenesis and synaptic function in mouse retina. Cacna1f ( G305X ) is a true knockout model for human CSNB2, with prominent defects in cone and rod function. Cacna1f ( nob2 ) is an incomplete knockout model for CSNB2, because alternative splicing in an ETn element leads to some full-length Ca(v)1.4 protein, and some cones surviving to drive photopic visual responses.

Temperature dependence of Cav1.4 calcium channel gating.

The CACNA1F gene encodes the pore-forming subunit of the L-type Cav1.4 voltage-gated calcium channel (VGCC) and plays a central role in tonic vesicular release at photoreceptor ribbon synapses. The main objective of this study was to examine the effects of temperature on human Cav1.4 cDNA clone VGCCs. With 20 mM Ba2+ as charge carrier, increasing the temperature from 23 degrees C to 37 degrees C increases whole-cell conductance, shifts the voltage-dependence of activation to more hyperpolarized voltages, and accelerates the degree of recovery from inactivation over a given time, but does not significantly alter the half-inactivation potential (Vh). The window current for Cav1.4 was also shifted to more hyperpolarized voltages, observable from approximately -35 mV to +20 mV at 37 degrees C in 20 mM Ba2+. Several comparable results were observed when characterizing Cav1.2 at temperatures ranging from 23 degrees C to 37 degrees C. However, one difference between Cav1.4 and Cav1.2 was the temperature dependence of voltage-dependent inactivation kinetics. Increasing temperature from 23 degrees C to 37 degrees C accelerates Cav1.4 inactivation kinetics approximately 50-fold, whereas Cav1.2 only accelerates approximately 10-fold over the same temperature range. The time constant of inactivation (tauh) temperature coefficient (Q10) was 18.8 for Cav1.4 over a temperature range of 23 degrees to 33 degrees C (corresponding to an activation energy Ea=221 kJ/mol), compared with Cav1.2 with a Q10 of 3 (Ea=90 kJ/mol) recorded under identical conditions. In addition, Cav1.4 was also tested using 2 mM Ca2+ as a charge carrier and similar changes in current-voltage Boltzmann parameters and gating kinetics were observed. Hence, despite the accelerated inactivation kinetics of Cav1.4 channels observed at near physiological temperatures the window current is preserved and could allow for tonic glutamate release from photoreceptors in the retina during dark adapted conditions.

Functional analysis of congenital stationary night blindness type-2 CACNA1F mutations F742C, G1007R, and R1049W.

Congenital stationary night blindess-2 (incomplete congenital stationary night blindness (iCSNB) or CSNB-2) is a nonprogressive, X-linked retinal disease which can lead to clinical symptoms such as myopia, hyperopia, nystagmus, strabismus, decreased visual acuity, and impaired scotopic vision. These clinical manifestations are linked to mutations found in the CACNA1F gene which encodes for the Ca(v)1.4 voltage-gated calcium channel. To better understand the physiological effects of these mutations, three missense mutants, F742C, G1007R and R1049W, previously shown to be mutated in patients with CSNB-2, were transiently expressed in human embryonic kidney (HEK) tsA-201 cells and characterized using whole-cell patch clamp. The G1007R mutation is located in transmembrane segment 5 (S5) of domain III and R1049W is located in the extracellular linker between S5 and the P-loop of domain III. Both mutants produced full length proteins that targeted to the membrane but did not support ionic currents. In 20 mM Ba(2+), F742C (S6 domain II) produced a approximately 21 mV hyperpolarizing shift in half activation potential (V(a[1/2])) and a approximately 23 mV hyperpolarizing shift in half inactivation potential (V(h[1/2])). Additionally, F742C displayed slower inactivation kinetics and a smaller whole cell conductance (G(max)). In physiological 2 mM Ca(2+), F742C produced a approximately 19 mV hyperpolarizing shift in V(a[1/2]). These findings suggest that the pathology of CSNB-2 in patients with these missense mutations in the Ca(v)1.4 calcium channel is the result in either a gain of function (F742C) or a loss of function (G1007R, R1049W).

Effects of extracellular pH on neuronal calcium channel activation.

Previous studies have shown that extracellular pH (pHo) alters gating and permeation properties of cardiac L- and T-type channels. However, a comprehensive study investigating the effects of pHo on all other voltage-gated calcium channels is lacking. Here, we report the effects of pHo on activation parameters slope factor (S), half-activation potential (Va), reversal potential (Erev), and maximum slope conductance (Gmax) of the nine known neuronal voltage-gated calcium channels transiently expressed in tsA-201 cells. In all cases, acidification of the extracellular bathing solution results in a depolarizing shift in the activation curve and reduction in peak current amplitudes. Relative to a physiological pHo of 7.25, statistically significant depolarizing shifts in Va were observed for all channels at pHo 7.00 except Cav1.3 and 3.2, which showed significant shifts at pHo 6.75 and below. All channels displayed significant reductions in Gmax relative to pHo 7.25 at pHo 7.00 except Cav1.2, 2.1, and 3.1 which required acidification to pHo 6.75. Upon acidification Cav3 channels displayed the largest changes in Vas and exhibited the largest reduction in Gmax compared with other channel subtypes. Taken together, these results suggest that significant modulation of calcium channel currents can occur with changes in pHo. Acidification of the external solution did not produce significant shifts in observed Erevs or blockade of outward currents for any of the nine channel subtypes. Finally, we tested a simple Woodhull-type model of current block by assuming blockade of the pore by a single proton. In all cases, the amount of blockade observed could not be explained in these simple terms, suggesting that proton modulation is more complicated, involving more than one site or gating modification as has been previously described for cardiac L- and T-type channels.

N-type calcium channel blockers: novel therapeutics for the treatment of pain.

Highly selective Ca(v)2.2 voltage-gated calcium channel (VGCC) inhibitors have emerged as a new class of therapeutics for the treatment of chronic and neuropathic pain. Cone snail venoms provided the first drug in class with FDA approval granted in 2005 to Prialt (omega-conotoxin MVIIA, Elan) for the treatment of neuropathic pain. Since this pioneering work, major efforts underway to develop alternative small molecule inhibitors of Ca(v)2.2 calcium channel have met with varied success. This review focuses on the properties of the Ca(v)2.2 calcium channel in different pain states, the action of omega-conotoxins GVIA, MVIIA and CVID, describing their structure-activity relationships and potential as leads for the design of improved Ca(v)2.2 calcium channel therapeutics, and finally the development of small molecules for the treatment of chronic pain.

Exponentially growing solutions in homogeneous Rayleigh-Bénard convection.

It is shown that homogeneous Rayleigh-Bénard flow, i.e., Rayleigh-Bénard turbulence with periodic boundary conditions in all directions and a volume forcing of the temperature field by a mean gradient, has a family of exact, exponentially growing, separable solutions of the full nonlinear system of equations. These solutions are clearly manifest in numerical simulations above a computable critical value of the Rayleigh number. In our numerical simulations they are subject to secondary numerical noise and resolution dependent instabilities that limit their growth to produce statistically steady turbulent transport.