GM1 Ganglioside role in the interaction of Alpha-synuclein with lipid membranes: Morphology and structure.

Alpha-Synuclein (AS) is the protein playing the major role in Parkinson's disease (PD), a neurological disorder characterized by the degeneration of dopaminergic neurons and the accumulation of AS into amyloid plaques. The aggregation of AS into intermediate aggregates, called oligomers, and their pathological relation with biological membranes are considered key steps in the development and progression of the disease. Here we propose a multi-technique approach to study the effects of AS in its monomeric and oligomeric forms on artificial lipid membranes containing GM1 ganglioside. GM1 is a component of functional membrane micro-domains, called lipid rafts, and has been demonstrated to bind AS in neurons. With the aim to understand the relation between gangliosides and AS, here we exploit the complementarity of microscopy (Atomic Force Microscopy) and neutron scattering (Small Angle Neutron Scattering and Neutron Reflectometry) techniques to analyze the structural changes of two different membranes (Phosphatidylcholine and Phosphatidylcholine/GM1) upon binding with AS. We observe the monomer- and oligomer-interactions are both limited to the external membrane leaflet and that the presence of ganglioside leads to a stronger interaction of the membranes and AS in its monomeric and oligomeric forms with a stronger aggressiveness in the latter. These results support the hypothesis of the critical role of lipid rafts not only in the biofunctioning of the protein, but even in the development and the progression of the Parkinson's disease.

Asymmetric alloy formation at the Fe-on-Ti and Ti-on-Fe interfaces.

The Fe-on-Ti and Ti-on-Fe interfaces were studied experimentally by Mössbauer spectroscopy (MS), transmission electron microscopy (TEM) and x-ray reflectometry (XRR) on Ti/Fe/Ti trilayers grown on Si(1 1 1) substrates by vacuum evaporation. The nanoscale structure and composition were explored in cross sections using TEM, the layer structure and the interface widths by specular x-ray reflectometry. MS was applied to identify the interface alloy phases and to determine the pure and alloyed Fe layer fractions. The experimental results were compared with molecular dynamics (MD) simulations of layer growth on Fe or Ti underlayers of different orientations. The concentration distributions provided by MD simulations show an asymmetry at the interfaces in the layer growth direction. The transition is atomically sharp at the Ti-on-Fe interface for the (0 0 1) and (1 1 0) crystallographic orientations of the Fe underlayer, while it spreads over a few atomic layers for Fe(1 1 1) underlayer and for all studied Ti underlayer orientations at the Fe-on-Ti interface. MS and XRR data on Ti/Fe/Ti trilayers confirm the asymmetry between the bottom and top Fe interface, but the inferred interface widths considerable exceed those deduced from the MD simulations.

Note: 4-bounce neutron polarizer for reflectometry applications.

A neutron polarizer using four successive reflections on m = 2.5 supermirrors was built and installed at the GINA neutron reflectometer at the Budapest Neutron Centre. This simple setup exhibits 99.6% polarizing efficiency with 80% transmitted intensity of the selected polarization state. Due to the geometry, the higher harmonics in the incident beam are filtered out, while the optical axis of the beam remains intact for easy mounting and dismounting the device in an existing experimental setup.

Erratum: Lattice Dynamics of EuO: Evidence for Giant Spin-Phonon Coupling [Phys. Rev. Lett. 116, 185501 (2016)].

This corrects the article DOI: 10.1103/PhysRevLett.116.185501.

Lattice Dynamics of EuO: Evidence for Giant Spin-Phonon Coupling.

Comprehensive studies of lattice dynamics in the ferromagnetic semiconductor EuO have been performed by a combination of inelastic x-ray scattering, nuclear inelastic scattering, and ab initio calculations. A remarkably large broadening of the transverse acoustic phonons was discovered at temperatures above and below the Curie temperature T_{C}=69 K. This result indicates a surprisingly strong momentum-dependent spin-phonon coupling induced by the spin dynamics in EuO.

Anomalous Lattice Dynamics of EuSi_{2} Nanoislands: Role of Interfaces Unveiled.

We report a systematic lattice dynamics study of EuSi_{2} films and nanoislands by in situ nuclear inelastic scattering on ^{151}Eu and ab initio theory. The Eu-partial phonon density of states of the nanoislands exhibits anomalous excess of phonon states at low and high energies, not present in the bulk and at the EuSi_{2}(001) surface. We demonstrate that atomic vibrations along the island-substrate interface give rise to phonon states both at low and high energies, while atomic vibrations across the island-island interface result in localized high-energy phonon modes.

Evolution of magnetism on a curved nano-surface.

To design custom magnetic nanostructures, it is indispensable to acquire precise knowledge about the systems in the nanoscale range where the magnetism forms. In this paper we present the effect of a curved surface on the evolution of magnetism in ultrathin iron films. Nominally 70 Å thick iron films were deposited in 9 steps on 3 different types of templates: (a) a monolayer of silica spheres with 25 nm diameter, (b) a monolayer of silica spheres with 400 nm diameter and (c) for comparison a flat silicon substrate. In situ iron evaporation took place in an ultrahigh vacuum chamber using the molecular beam epitaxy technique. After the evaporation steps, time differential nuclear forward scattering spectra, grazing incidence small angle X-ray scattering images and X-ray reflectivity curves were recorded. In order to reconstruct and visualize the magnetic moment configuration in the iron cap formed on top of the silica spheres, micromagnetic simulations were performed for all iron thicknesses. We found a great influence of the template topography on the onset of magnetism and on the developed magnetic nanostructure. We observed an individual magnetic behaviour for the 400 nm spheres which was modelled by vortex formation and a collective magnetic structure for the 25 nm spheres where magnetic domains spread over several particles. Depth selective nuclear forward scattering measurements showed that the formation of magnetism begins at the top region of the 400 nm spheres in contrast to the 25 nm particles where the magnetism first appears in the region where the spheres are in contact with each other.

Nuclear forward scattering of synchrotron radiation by 99Ru.

We measured nuclear forward scattering spectra utilizing the (99)Ru transition, 89.571(3) keV, with a notably mixed E2/M1 multipolarity. The extension of the standard evaluation routines to include mixed multipolarity allows us to extract electric and magnetic hyperfine interactions from (99)Ru-containing compounds. This paves the way for several other high-energy Mössbauer transitions, E ∼ 90 keV. The high energy of such transitions allows for operando nuclear forward scattering studies in real devices.

GINA--a polarized neutron reflectometer at the Budapest Neutron Centre.

The setup, capabilities, and operation parameters of the neutron reflectometer GINA, the recently installed "Grazing Incidence Neutron Apparatus" at the Budapest Neutron Centre, are introduced. GINA, a dance-floor-type, constant-energy, angle-dispersive reflectometer is equipped with a 2D position-sensitive detector to study specular and off-specular scattering. Wavelength options between 3.2 and 5.7 Å are available for unpolarized and polarized neutrons. Spin polarization and analysis are achieved by magnetized transmission supermirrors and radio-frequency adiabatic spin flippers. As a result of vertical focusing by a five-element pyrolytic graphite monochromator, the reflected intensity from a 20 × 20 mm(2) sample has been doubled. GINA is dedicated to studies of magnetic films and heterostructures, but unpolarized options for non-magnetic films, membranes, and other surfaces are also provided. Shortly after its startup, reflectivity values as low as 3 × 10(-5) have been measured by the instrument. The instrument capabilities are demonstrated by a non-polarized and a polarized reflectivity experiment on a Si wafer and on a magnetic film of [(62)Ni/(nat)Ni](5) isotope-periodic layer composition. The facility is now open for the international user community. Its further development is underway establishing new sample environment options and spin analysis of off-specularly scattered radiation as well as further decreasing the background.

A risk-based approach to optimize autologous hematopoietic stem cell (HSC) collection with the use of plerixafor.

Autologous hematopoietic stem cell (HSC) transplant is an effective treatment for patients with hematological malignancies. Unfortunately, 15-30% of patients fail to mobilize a sufficient number of HSCs for the transplant. Plerixafor is now used as a salvage mobilization regimen, with good success. We describe here a risk-based approach for the use of plerixafor, based on the circulating CD34(+) cell count and the CD34(+) cell dose collected after 4 days of G-CSF, that identifies potential poor HSC mobilizers upfront. A total of 159 patients underwent HSC collections using this approach. Of these, 55 (35%) were identified as high risk owing to low CD34(+) cell number or low yield on day 1 of collection, and received plerixafor on the subsequent days of collection. Of the 159 patients, 151 (95%) were able to provide adequate collections with the first mobilization attempt in a median of 1.7 days using this approach. Of the eight who failed initial mobilization, 5 successfully underwent re-mobilization with plerixafor and G-CSF and 3 (1.9%) were mobilization failures. This approach helped to control the overall cost of HSC collections for our BMT program by decreasing the need for remobilization, reducing the number of collection days and avoiding the use of plerixafor in all patients.

Non-invasive stimulation of the vibrissal pad improves recovery of whisking function after simultaneous lesion of the facial and infraorbital nerves in rats.

We have recently shown that manual stimulation of target muscles promotes functional recovery after transection and surgical repair to pure motor nerves (facial: whisking and blink reflex; hypoglossal: tongue position). However, following facial nerve repair, manual stimulation is detrimental if sensory afferent input is eliminated by, e.g., infraorbital nerve extirpation. To further understand the interplay between sensory input and motor recovery, we performed simultaneous cut-and-suture lesions on both the facial and the infraorbital nerves and examined whether stimulation of the sensory afferents from the vibrissae by a forced use would improve motor recovery. The efficacy of 3 treatment paradigms was assessed: removal of the contralateral vibrissae to ensure a maximal use of the ipsilateral ones (vibrissal stimulation; Group 2), manual stimulation of the ipsilateral vibrissal muscles (Group 3), and vibrissal stimulation followed by manual stimulation (Group 4). Data were compared to controls which underwent surgery but did not receive any treatment (Group 1). Four months after surgery, all three treatments significantly improved the amplitude of vibrissal whisking to 30° versus 11° in the controls of Group 1. The three treatments also reduced the degree of polyneuronal innervation of target muscle fibers to 37% versus 58% in Group 1. These findings indicate that forced vibrissal use and manual stimulation, either alone or sequentially, reduce target muscle polyinnervation and improve recovery of whisking function when both the sensory and the motor components of the trigemino-facial system regenerate.

Electron proportional gas counter for linear and elliptical Mössbauer polarimetry.

Design, characterization, and selected applications of a novel electron detector dedicated to conventional perpendicular- and low-angle-incidence conversion electron Mössbauer spectroscopy are presented. The setup is suitable for varying the incident angle and external magnetic fields on Mössbauer source and absorber. Test experiments were performed on alpha-(57)Fe films using a conventional single-line (57)Co(Rh) and magnetically split, (57)Co(alpha-Fe) Mössbauer sources. The integral "blackness effect" in conversion-electron Mössbauer spectra of (57)Fe isotope-enriched absorbers is demonstrated and shown to be pronounced at shallow angles of incidence. In order to determine the alignment and sign of the hyperfine field in an isotope-enriched absorber, the blackness effect is accounted for in a semiempirical way by using single-line source/absorber experimental relative intensities determined independently. This method works with high accuracy for linear polarimetry; however it is only a rough approximation in the case of nearly circular polarimetry.

Perioperative steroid administration inhibits angiogenic host tissue response to porous polyethylene (Medpor) implants.

Porous polyethylene (Medpor) is an alloplastic biomaterial, which is commonly used in plastic and reconstructive surgery. In the present study, we analyzed the effect of perioperative steroid administration on the inflammatory and angiogenic host tissue response to implanted Medpor. For this purpose, Medpor was implanted into the dorsal skinfold chamber of prednisolone-treated and vehicle-treated (control) balb/c mice and analyzed by means of intravital fluorescence microscopy over a 14-day period. Incorporation of the implants was evaluated by histology. An aortic ring assay and Western blot analyses were performed to determine in vitro the effect of prednisolone on angiogenesis. Implantation of Medpor did not induce a leukocytic inflammatory host tissue response. However, in prednisolone-treated and control animals giant cells could be detected at the interface between the implants and the surrounding granulation tissue as a typical indicator for a chronic foreign body reaction. Interestingly, perioperative prednisolone administration inhibited vascularisation of the implants, as indicated by a significantly decreased functional density of newly developing capillary blood vessels. Accordingly, prednisolone suppressed in vitro endothelial sprouting and tube formation in the aortic ring assay and reduced proliferating cell nuclear antigen (PCNA), Tie2, vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 expression of murine endothelioma cells. In conclusion, prednisolone treatment inhibits the early vascularisation of Medpor implants due to direct inhibition of distinct angiogenic mechanisms. Therefore, perioperative steroid therapy should be avoided in case of Medpor implantation to achieve a rapid incorporation of the biomaterial at the implantation site.

Aromatase inhibitor-induced arthralgia: clinical experience and treatment recommendations.

It is well documented that the aromatase inhibitors (AIs) are superior to tamoxifen as adjuvant endocrine therapy in postmenopausal women with hormone receptor-positive breast cancer. However, compared with tamoxifen, an elevated incidence of arthralgia has been observed during AI treatment. Concerns have been raised that AI-induced arthralgia may dissuade patients from completing their full AI treatment course, and may also deter physicians from prescribing an AI if they feel that patients may be at risk of permanent joint damage. Patient education about the possibility of experiencing arthralgia, and effective management of symptoms if they appear, are important in helping patients adhere to AI treatment, and consequently improving breast cancer outcomes. In this paper, we discuss the potential mechanisms behind AI-induced arthralgia, review the frequency with which arthralgia occurs, and propose for the first time an algorithm specifically for the treatment of AI-induced arthralgia. As with joint pain in non-breast cancer patients, a sequential approach to disease management is recommended, involving modifying the patient's lifestyle in addition to taking a stratified approach to pharmacological intervention with analgesia and anti-inflammatory medication. Knowing that joint symptoms can be managed in most patients may encourage patient-physician communication and treatment compliance.

Transforming growth factor-beta1-antisense modulates the expression of hepatocyte growth factor/scatter factor in keloid fibroblast cell culture.

Abnormal wound healing processes can result in hypertrophic scars and keloids. Transforming growth factor-beta1 (TGF-beta1) and hepatocyte growth factor/scatter factor (HGF/SF) are biphasic growth factor cytokines in physiologic and pathophysiologic conditions. Findings have shown TGF-beta1 to be pivotal in the formation of keloid tissue. Therefore, neutralizing antibodies may allow wound healing without keloid formation. As reported, TGF-beta1 is antagonized by HGF/SF. Some authors have reported that exogenous administration of HGF/SF prevented scar formation. Hence, this study targeted TGF-beta1 and determined the levels of HGF/SF in fibroblast cell culture. Keloid tissue was taken from seven patients. Another seven patients with mature nonhypertrophic scar served as controls. All tissues were cultured, and fibroblast cultures were used for further experiments. The TGF-beta1 antisense was administered at 3 and 6 micromol/ml, and HGF/SF levels were determined after 16, 24, and 48 h of incubation. The levels of HGF/SF showed significant differences after incubation with antisense oligonucleotides. The increasing antisense levels resulted in increased HGF/SF levels (up to 87.66 pg/ml after 48 h of incubation). In conclusion, targeting TGF-beta1 resulted in significantly increased levels of HGF/SF. The clinical relevance could include the use of locally administered HGF/SF in protein or gene form to minimize formation of keloids. Nevertheless, wound healing is the result of many interacting cytokines, so neutralizing or targeting one protein could result in no significant effect.

Toxicologic evaluation of modified gum acacia: mutagenicity, acute and subchronic toxicity.

Modified gum acacia, produced from acacia gum by a process analogous to the production of modified food starch, was tested for mutagenicity in the microbial reverse mutation assay. The assay employed a wide range of dose levels, both with and without metabolic activation. Test results gave no indication that modified gum acacia possessed any mutagenic potential. The acute oral toxicity of modified gum acacia was determined in two studies employing Sprague-Dawley rats, and the LD50 values were found to be >2000 mg/kg. The primary dermal irritation potential of modified gum acacia was evaluated in rabbits by the Draize method. Test results indicated that modified gum acacia was slightly irritating by the Environmental Protection Agency (EPA) classification but not a primary irritant by Consumer Product Safety Commission (CPSC) guidelines. The subchronic toxicity of modified gum acacia was examined in Sprague-Dawley rats fed diets containing 0%, 1%, 2.5%, and 5% modified gum acacia for 13 weeks. No dose-related effects on survival, growth, hematology, blood chemistry, organ weights, or pathologic lesions were observed. Results of these studies indicate that modified gum acacia does not possess mutagenic potential and that animals are not adversely affected by acute or subchronic exposure to modified gum acacia.

Twenty eight-day dietary toxicity study of Luo Han fruit concentrate in Hsd:SD rats.

A 28-day dietary study was conducted in Hsd:SD rats to evaluate the safety of PureLo, a non-caloric powdered concentrate of the Chinese fruit Luo Han Guo, which derives its sweetening properties from triterpene glycosides called mogrosides. Groups of 20 rats (10/sex/group) were fed diets containing 0, 10,000, 30,000, or 100,000 ppm PureLo for 28 days (OECD, Redbook 2000). PureLo was well tolerated and produced no significant adverse effects. Reduced body weight and body weight gain in high-dose animals of both sexes were related to sporadic reductions in food consumption; there were no overall differences in feed efficiency. Statistically significant changes in clinical chemistry (decreased bilirubin, increased total protein) and relative organ weights of liver, adrenals, ovaries and/or testes, and epididymides were not correlated with any histopathological findings and were not considered adverse. Although a few clinical and pathological findings suggest possible treatment-related effects, particularly in the high-dose group, these findings were transient, not dose-dependent, non-adverse, inconsistent, occurred only in one sex, and/or not supported by histopathological findings. Under the conditions of this study and based on the toxicological endpoints evaluated, the NOAEL for PureLo was 100,000 ppm in the diet, the highest level tested, equivalent to 7.07 and 7.48 g/kg bw/day for male and female rats, respectively.

Acute and subchronic oral toxicity studies in rats of a hydrolyzed chicken sternal cartilage preparation.

Two acute and subchronic oral toxicity studies were conducted in rats to evaluate safety of a patented preparation of hydrolyzed chicken sternal cartilage (BioCell Collagen II) containing collagen type II, chondroitin sulfate, and hyaluronic acid. In the acute oral toxicity study, five males and five females of Sprague-Dawley rats were administered a single dose of 5000 mg of the test product per kg body weight and observed for 14 days. All animals survived and exhibited normal body weight gain throughout the study. Macroscopic necropsy examination conducted on day 15 revealed no gross pathological lesions in any of the animals. In the subchronic study, Sprague-Dawley rats (40 males, 40 females) were divided into four same-sex groups (10 animals/group). Animals in each group were administered daily either 0, 30, 300 or 1000 mg of the test product per kg of body weight for over 90 days. All animals survived and showed no significant changes in their body weights and histopathology. Although some differences were observed between the treated and control animals in several parameters, they were generally not dose-related or considered to be of toxicological significance. In conclusion, the results from the two oral toxicity studies with male and female young adult rats indicated that the test preparation from hydrolyzed chicken sternal cartilage collagen (BioCell Collagen II) was well tolerated at all four doses tested.