Molecular Phylogeny, Classification and Evolution of Conopeptides

Conopeptides are toxins expressed in the venom duct of cone snails (Conoidea, Conus). These are mostly well-structured peptides and mini-proteins with high potency and selectivity for a broad range of cellular targets. In view of these properties, they are widely used as pharmacological tools and many are candidates for innovative drugs. The conopeptides are primarily classified into superfamilies according to their peptide signal sequence, a classification that is thought to reflect the evolution of the multigenic system. However, this hypothesis has never been thoroughly tested. Here we present a phylogenetic analysis of 1,364 conopeptide signal sequences extracted from GenBank. The results validate the current conopeptide superfamily classification, but also reveal several important new features. The so-called "cysteine-poor” conopeptides are revealed to be closely related to "cysteine-rich” conopeptides; with some of them sharing very similar signal sequences, suggesting that a distinction based on cysteine content and configuration is not phylogenetically relevant and does not reflect the evolutionary history of conopeptides. A given cysteine pattern or pharmacological activity can be found across different superfamilies. Furthermore, a few conopeptides from GenBank do not cluster in any of the known superfamilies, and could represent yet-undefined superfamilies. A clear phylogenetically based classification should help to disentangle the diversity of conopeptides, and could also serve as a rationale to understand the evolution of the toxins in the numerous other species of conoideans and venomous animals at larg

Zincalstibite-9R: the first nine-layer polytype with the layered double hydroxide structure-type

Zincalstibite-9R, a new polytype in the hydrotalcite supergroup is reported from the Monte Avanza mine, Italy. It occurs as pale blue curved disc-like tablets flattened on {001} intergrown to form rosettes typically less than 50 μm in diameter, with cyanophyllite and linarite in cavities in baryte. Zincalstibite-9R is uniaxial (−), with refractive indices ω = 1.647(2) and ε = 1.626(2) measured in white light. The empirical formula (based on 12 OH groups) is (Zn^(2+)_(1.09)Cu^(2+)_(0.87)Al_(0.04))_(Σ2.00)Al_(1.01) (Sb^(5+)_(0.97)Si_(0.02))Σ_(0.99)(OH)_(12), and the ideal formula is (Zn,Cu)_2Al(OH)_6[Sb(OH)_6]. Zincalstibite-9R crystallizes in space group R3İ, with ɑ = 5.340(2), c = 88.01(2) Å, V = 2173.70(15) Å^3 and Z = 9. The crystal structure was refined to R_1 = 0.0931 for 370 unique reflections [F_o > 4σ(F)] and R_1 = 0.0944 for all 381 unique reflections. It has the longest periodic layer stacking sequence for a layered double hydroxide compound reported to date

mTOR independent alteration in ULK1 Ser758 phosphorylation following chronic LRRK2 kinase inhibition

Unc-51 Like Kinase 1 (ULK1) is a critical regulator of the biogenesis of autophagosomes, the central component of the catabolic macroautophagy pathway. Regulation of ULK1 activity is dependent upon several phosphorylation events acting to repress or activate the enzymatic function of this protein. Phosphorylation of Ser758 ULK1 has been linked to repression of autophagosome biogenesis and was thought to be exclusively dependent upon mTOR complex 1 kinase activity. In this study, a novel regulation of Ser758 ULK1 phosphorylation is reported following prolonged inhibition of the Parkinson's disease linked protein Leucine Rich Repeat Kinase 2 (LRRK2). Here, modulation of Ser758 ULK1 phosphorylation following LRRK2 inhibition is decoupled from the repression of autophagosome biogenesis and independent of mTOR complex 1 activity

The non-specific lethal complex regulates genes and pathways genetically linked to Parkinson’s disease

Genetic variants conferring risk for Parkinson's disease have been highlighted through genome-wide association studies, yet exploration of their specific disease mechanisms is lacking. Two Parkinson's disease candidate genes, KAT8 and KANSL1, identified through genome-wide studies and a PINK1-mitophagy screen, encode part of the histone acetylating non-specific lethal complex. This complex localises to the nucleus, where it has a role in transcriptional activation, and to mitochondria, where it has been suggested to have a role in mitochondrial transcription. In this study, we sought to identify whether the non-specific lethal complex has potential regulatory relationships with other genes associated with Parkinson's disease in human brain. Correlation in the expression of non-specific lethal genes and Parkinson's disease-associated genes was investigated in primary gene co-expression networks utilising publicly available transcriptomic data from multiple brain regions (provided by the Genotype-Tissue Expression Consortium and UK Brain Expression Consortium), whilst secondary networks were used to examine cell-type specificity. Reverse engineering of gene regulatory networks generated regulons of the complex, which were tested for heritability using stratified linkage disequilibrium score regression. Prioritised gene targets were then validated in vitro using a QuantiGene multiplex assay and publicly available chromatin immunoprecipitation-sequencing data. Significant clustering of non-specific lethal genes was revealed alongside Parkinson's disease-associated genes in frontal cortex primary co-expression modules, amongst other brain regions. Both primary and secondary co-expression modules containing these genes were enriched for mainly neuronal cell types. Regulons of the complex contained Parkinson's disease-associated genes and were enriched for biological pathways genetically linked to disease. When examined in a neuroblastoma cell line, 41% of prioritised gene targets showed significant changes in mRNA expression following KANSL1 or KAT8 perturbation. KANSL1 and H4K8 chromatin immunoprecipitation-sequencing data demonstrated NSL complex activity at many of these genes. In conclusion, genes encoding the non-specific lethal complex are highly correlated with and regulate genes associated with Parkinson's disease. Overall, these findings reveal a potentially wider role for this protein complex in regulating genes and pathways implicated in Parkinson's disease

Contribution of Large Pig for Renal Ischemia-Reperfusion and Transplantation Studies: The Preclinical Model

Animal experimentation is necessary to characterize human diseases and design adequate therapeutic interventions. In renal transplantation research, the limited number of in vitro models involves a crucial role for in vivo models and particularly for the porcine model. Pig and human kidneys are anatomically similar (characterized by multilobular structure in contrast to rodent and dog kidneys unilobular). The human proximity of porcine physiology and immune systems provides a basic knowledge of graft recovery and inflammatory physiopathology through in vivo studies. In addition, pig large body size allows surgical procedures similar to humans, repeated collections of peripheral blood or renal biopsies making pigs ideal for medical training and for the assessment of preclinical technologies. However, its size is also its main drawback implying expensive housing. Nevertheless, pig models are relevant alternatives to primate models, offering promising perspectives with developments of transgenic modulation and marginal donor models facilitating data extrapolation to human conditions

Flux quanta driven by high-density currents in low-impurity V3Si and LuNi2B2C: free flux flow and flux-core size effect

High density direct currents (DC) are used to drive flux quanta via the Lorentz force towards a highly ordered "free flux flow" (FFF) dynamic state, made possible by the weak-pinning environment of high-quality, single-crystal samples of two low-Tc superconducting compounds, V3Si and LuNi2B2C. We report the effect of the magnetic field-dependent fluxon core size on flux flow resistivity rho_f. Much progress has been made in minimizing the technical challenges associated with the use of high currents. Attainment of a FFF phase is indicated by the saturation at highest currents of flux-flow dissipation levels that are well below the normal state resistance and have field-dependent values. The field dependence of the corresponding rho_f is shown to be consistent with a prediction based on a model for the decrease of flux core size at higher fields in weak-coupling BCS s-wave materials.Comment: More empirical treatment of the magnetoresistive correction of V3Si data by additional measurement and analysis (involving two new coauthors, Favreau and Henderson). End result is the same, making for a stronger manuscrip

11th Applied isotope geochemistery conference AIG-11

36Cl measurements in groundwaters of the deep confined aquifer of the Lake Chad Basin (LCB) were performed in order to constrain groundwater geochemical ages and residence times. Twenty-seven wells were sampled in Nigeria, Niger and Chad in the southern parts of the large (700 000 km2) multilayered aquifer of the LCB. 36Cl/Cl values range between 11±1.10-15 to 148±8.10-15 at/at. The highest ratios are observed near the recharge zone of the Nigerian part of the Continental Terminal aquifer, while the lowest ones are found in wells located near the southern fringe of the present-day lake Chad. Chloride concentrations are low (below 100 mg/l) and not correlated to the 36Cl/Cl values, indicating negligible dissolution of evaporites in most samples. Reliable 36Cl ages can be calculated along the different flow paths investigated, suggesting residence times of the deep groundwaters larger than 300 000 years. These results are consistent with new AMS-14C data below the detection limit but are in contradiction with previous 14C data obtained in the area

Omsite, (Ni,Cu)_2Fe^(3+)(OH)_6[Sb(OH)_6], a new member of the cualstibite group from Oms, France

Omsite (IMA 2012-025) is a new mineral from the Correc d'en Llinassos, Oms, Pyrénées-Orientales Department, France. It occurs as bright yellow to amber yellow discoidal tablets, flattened on {001}, which form rosettes typically 50–100 μm in diameter. Omsite generally crystallizes on siderite without associated supergene minerals; it occurs less commonly with glaukosphaerite. Crystals have a vitreous to resinous lustre, and are transparent to translucent. Omsite is not fluorescent in either short-wave or long-wave ultraviolet light. It has an estimated hardness of 3 on the Mohs' scale, is brittle with an irregular fracture, and has one poor cleavage on {001}. The calculated density is 3.378 g cm^(−3). Crystals are uniaxial (−), with indices of refraction of ω = 1.728(3) and ε = 1.66(1), measured in white light. Pleochroism is ω = orange-yellow, ε = pale orange-yellow; ω > ε. The empirical formula [based on 12 (OH + Cl) p.f.u.] is (Ni^(2+)_(1.099)Cu^(2+)_(0.665)Mg_(0.107)Fe^(3+)_(0.045) _(Σ1.916)Fe^(3+)_(1.000)(Sb^(5+)_(0.947)As_(0.072)Na_(0.029)_(Σ1.048)OH_(11.967)Cl_(0.033). Omsite crystallizes in space group P3İ, with unit-cell parameters ɑ = 5.3506(8), c = 19.5802(15) Å, V = 485.46(10) Å3 and Z = 2 determined by single crystal X-ray diffraction. The five strongest lines in the X-ray powder diffraction pattern [d in Å, (I_(rel)), (hkl)] are as follows: 4.901, (100), (004); 4.575, (83), (011); 2.3539, (81), (114İ); 1.8079, (48), (118İ); 3.781, (34), (103). The crystal structure was solved to R_1 = 0.0896 for 356 observed reflections [F_o>4σF_o] and 0.1018 for all the 469 unique reflections. Omsite is a layered double hydroxide (LDH) mineral, with a topology consistent with members of the hydrotalcite supergroup and cualstibite group