Phage display selected magnetite interacting Adhirons for shape controlled nanoparticle synthesis

Adhirons are robust, well expressing, peptide display scaffold proteins, developed as an effective alternative to traditional antibody binding proteins for highly specific molecular recognition applications. This paper reports for the first time the use of these versatile proteins for material binding, and as tools for controlling material synthesis on the nanoscale. A phage library of Adhirons, each displaying two variable binding loops, was screened to identify specific proteins able to interact with [100] faces of cubic magnetite nanoparticles. The selected variable regions display a strong preference for basic residues such as lysine. Molecular dynamics simulations of amino acid adsorption onto a [100] magnetite surface provides a rationale for these interactions, with the lowest adsorption energy observed with lysine. These proteins direct the shape of the forming nanoparticles towards a cubic morphology in room temperature magnetite precipitation reactions, in stark contrast to the high temperature, harsh reaction conditions currently used to produce cubic nanoparticles. These effects demonstrate the utility of the selected Adhirons as novel magnetite mineralization control agents using ambient aqueous conditions. The approach we outline with artificial protein scaffolds has the potential to develop into a toolkit of novel additives for wider nanomaterial fabrication

The role of miniaturization in the evolution of the mammalian jaw and middle ear

The evolution of the mammalian jaw is one of the most important innovations in vertebrate history, and underpins the exceptional radiation and diversification of mammals over the last 220 million years. In particular, the transformation of the mandible into a single tooth-bearing bone and the emergence of a novel jaw joint—while incorporating some of the ancestral jaw bones into the mammalian middle ear—is often cited as a classic example of the repurposing of morphological structures. Although it is remarkably well-documented in the fossil record, the evolution of the mammalian jaw still poses the paradox of how the bones of the ancestral jaw joint could function both as a joint hinge for powerful load-bearing mastication and as a mandibular middle ear that was delicate enough for hearing. Here we use digital reconstructions, computational modelling and biomechanical analyses to demonstrate that the miniaturization of the early mammalian jaw was the primary driver for the transformation of the jaw joint. We show that there is no evidence for a concurrent reduction in jaw-joint stress and increase in bite force in key non-mammaliaform taxa in the cynodont–mammaliaform transition, as previously thought. Although a shift in the recruitment of the jaw musculature occurred during the evolution of modern mammals, the optimization of mandibular function to increase bite force while reducing joint loads did not occur until after the emergence of the neomorphic mammalian jaw joint. This suggests that miniaturization provided a selective regime for the evolution of the mammalian jaw joint, followed by the integration of the postdentary bones into the mammalian middle ear

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy

Anthropometric data from three groups of adolescent girls - preoperative adolescent idiopathic scoliosis (AIS), screened for scoliosis and normals were analysed by comparing skeletal data between higher and lower body mass index subsets. Unexpected findings for each of skeletal maturation, asymmetries and overgrowth are not explained by prevailing theories of AIS pathogenesis. A speculative pathogenetic theory for girls is formulated after surveying evidence including: (1) the thoracospinal concept for right thoracic AIS in girls; (2) the new neuroskeletal biology relating the sympathetic nervous system to bone formation/resorption and bone growth; (3) white adipose tissue storing triglycerides and the adiposity hormone leptin which functions as satiety hormone and sentinel of energy balance to the hypothalamus for long-term adiposity; and (4) central leptin resistance in obesity and possibly in healthy females. The new theory states that AIS in girls results from developmental disharmony expressed in spine and trunk between autonomic and somatic nervous systems. The autonomic component of this double neuro-osseous theory for AIS pathogenesis in girls involves selectively increased sensitivity of the hypothalamus to circulating leptin (genetically-determined up-regulation possibly involving inhibitory or sensitizing intracellular molecules, such as SOC3, PTP-1B and SH2B1 respectively), with asymmetry as an adverse response (hormesis); this asymmetry is routed bilaterally via the sympathetic nervous system to the growing axial skeleton where it may initiate the scoliosis deformity (leptin-hypothalamic-sympathetic nervous system concept = LHS concept). In some younger preoperative AIS girls, the hypothalamic up-regulation to circulating leptin also involves the somatotropic (growth hormone/IGF) axis which exaggerates the sympathetically-induced asymmetric skeletal effects and contributes to curve progression, a concept with therapeutic implications. In the somatic nervous system, dysfunction of a postural mechanism involving the CNS body schema fails to control, or may induce, the spinal deformity of AIS in girls (escalator concept). Biomechanical factors affecting ribs and/or vertebrae and spinal cord during growth may localize AIS to the thoracic spine and contribute to sagittal spinal shape alterations. The developmental disharmony in spine and trunk is compounded by any osteopenia, biomechanical spinal growth modulation, disc degeneration and platelet calmodulin dysfunction. Methods for testing the theory are outlined. Implications are discussed for neuroendocrine dysfunctions, osteopontin, sympathoactivation, medical therapy, Rett and Prader-Willi syndromes, infantile idiopathic scoliosis, and human evolution. AIS pathogenesis in girls is predicated on two putative normal mechanisms involved in trunk growth, each acquired in evolution and unique to humans

Spectral evidence for irradiated halite on Mars

Abstract The proposed chloride salt-bearing deposits on Mars have an enigmatic composition due to the absence of distinct spectral absorptions for the unique mineral at all wavelengths investigated. We report on analyses of remote visible-wavelength spectroscopic observations that exhibit properties indicative of the mineral halite (NaCl) when irradiated. Visible spectra of halite are generally featureless, but when irradiated by high-energy particles they develop readily-identifiable spectral alterations in the form of color centers. Consistent spectral characteristics observed in the reflectance data of the chloride salt-bearing deposits support the presence of radiation-formed color centers of halite on the surface of Mars. We observe a seasonal cycle of color center formation with higher irradiated halite values during winter months, with the colder temperatures interpreted as increasing the formation efficiency and stability. Irradiated halite identified on the surface of Mars suggests that the visible surface is being irradiated to the degree that defects are forming in alkali halide crystal structures

Dynamic light scattering study of inhibition of nucleation and growth of hydroxyapatite crystals by osteopontin.

We study the effect of isoforms of osteopontin (OPN) on the nucleation and growth of crystals from a supersaturated solution of calcium and phosphate ions. Dynamic light scattering is used to monitor the size of the precipitating particles and to provide information about their concentration. At the ion concentrations studied, immediate precipitation was observed in control experiments with no osteopontin in the solution, and the size of the precipitating particles increased steadily with time. The precipitate was identified as hydroxyapatite by X-ray diffraction. Addition of native osteopontin (nOPN) extracted from rat bone caused a delay in the onset of precipitation and reduced the number of particles that formed, but the few particles that did form grew to a larger size than in the absence of the protein. Recombinant osteopontin (rOPN), which lacks phosphorylation, caused no delay in initial calcium phosphate precipitation but severely slowed crystal growth, suggesting that rOPN inhibits growth but not nucleation. rOPN treated with protein kinase CK2 to phosphorylate the molecule (p-rOPN) produced an effect similar to that of nOPN, but at higher protein concentrations and to a lesser extent. These results suggest that phosphorylations are critical to OPN's ability to inhibit nucleation, whereas the growth of the hydroxyapatite crystals is effectively controlled by the highly acidic OPN polypeptide. This work also demonstrates that dynamic light scattering can be a powerful tool for delineating the mechanism of protein modulation of mineral formation

A typical intensity autocorrelation function, , obtained from a control experiment with no protein.

<p>The heavy dashed curve is a fit to the cumulant expansion given in Eq. (3), performed on data with s and to minimize the influence of noise at short and long lag times. The dotted curve is an extrapolation of the fit over the rest of the measured <i>τ</i> range.</p

Delay time for the onset of crystal growth as a function of protein concentration.

<p>Data are plotted for both nOPN and p-rOPN. Concentrations lower than those plotted had no measurable delay. The dotted lines are linear fits to the data for each protein.</p

Growth rate of the precipitating partcles at = 200 nm plotted as a function of protein concentration.

<p>Growth rate of the precipitating partcles at  = 200 nm plotted as a function of protein concentration.</p