Giant nonlinear damping in nanoscale ferromagnets.

Magnetic damping is a key metric for emerging technologies based on magnetic nanoparticles, such as spin torque memory and high-resolution biomagnetic imaging. Despite its importance, understanding of magnetic dissipation in nanoscale ferromagnets remains elusive, and the damping is often treated as a phenomenological constant. Here, we report the discovery of a giant frequency-dependent nonlinear damping that strongly alters the response of a nanoscale ferromagnet to spin torque and microwave magnetic field. This damping mechanism originates from three-magnon scattering that is strongly enhanced by geometric confinement of magnons in the nanomagnet. We show that the giant nonlinear damping can invert the effect of spin torque on a nanomagnet, leading to an unexpected current-induced enhancement of damping by an antidamping torque. Our work advances the understanding of magnetic dynamics in nanoscale ferromagnets and spin torque devices.

[Progress and prospects of metabolic therapy in multiple sclerosis]. / Dostizheniia i perspektivy metabolicheskoi terapii rasseiannogo skleroza.

Side-effects and incomplete response to standard therapy of patients with multiple sclerosis (MS) stimulate the development of an alternative therapy, that influences, in particular, metabolic functions of MS patients. Metabolic therapy (vitamins, antioxidants and others) have been used for a long time in neurologic practice for the treatment of MS on the basis of pathophysiological mechanisms, positive clinical experience, low rate of side-effects and practical availability. Recent objective scientific data explain the necessity of correction of the disturbed metabolic profile (metabolome) in MS, and the first evidence of the efficacy of several metabolic agents, particularly, biotin and vitamin D, was shown. Taking into account the mechanisms of action and clinical experience, the authors consider the prospects of using the combined medicine cytoflavin, that contains succinate, nicotinamide, riboflavin and inosine, in metabolic therapy of MS.

Oscillatory interlayer coupling in spin Hall systems.

Many spintronics applications consist of ultrathin magnetic and nonmagnetic multilayers and require an in-depth understanding of interfacial magnetism and spin transport. Here, we study permalloy/copper/platinum multilayer systems. We find that magnetic damping, perpendicular anisotropy, and proximity magnetization exhibit correlated oscillations as a function of the copper thickness. We ascribe these observations to an oscillatory interlayer coupling between permalloy and platinum. Such interlayer coupling may have a significant impact on the performance of spintronics applications.

Spin Hall-induced auto-oscillations in ultrathin YIG grown on Pt.

We experimentally study nanowire-shaped spin-Hall nano-oscillators based on nanometer-thick epitaxial films of Yttrium Iron Garnet grown on top of a layer of Pt. We show that, although these films are characterized by significantly larger magnetic damping in comparison with the films grown directly on Gadolinium Gallium Garnet, they allow one to achieve spin current-driven auto-oscillations at comparable current densities, which can be an indication of the better transparency of the interface to the spin current. These observations suggest a route for improvement of the flexibility of insulator-based spintronic devices and their compatibility with semiconductor technology.

Targeting SxIP-EB1 interaction: An integrated approach to the discovery of small molecule modulators of dynamic binding sites.

End binding protein 1 (EB1) is a key element in the complex network of protein-protein interactions at microtubule (MT) growing ends, which has a fundamental role in MT polymerisation. EB1 is an important protein target as it is involved in regulating MT dynamic behaviour, and has been associated with several disease states, such as cancer and neuronal diseases. Diverse EB1 binding partners are recognised through a conserved four amino acid motif, (serine-X-isoleucine-proline) which exists within an intrinsically disordered region. Here we report the use of a multidisciplinary computational and experimental approach for the discovery of the first small molecule scaffold which targets the EB1 recruiting domain. This approach includes virtual screening (structure- and ligand-based design) and multiparameter compound selection. Subsequent studies on the selected compounds enabled the elucidation of the NMR structures of the C-terminal domain of EB1 in the free form and complexed with a small molecule. These structures show that the binding site is not preformed in solution, and ligand binding is fundamental for the binding site formation. This work is a successful demonstration of the combination of modelling and experimental methods to enable the discovery of compounds which bind to these challenging systems.

Spin caloritronic nano-oscillator.

Energy loss due to ohmic heating is a major bottleneck limiting down-scaling and speed of nano-electronic devices, and harvesting ohmic heat for signal processing is a major challenge in modern electronics. Here, we demonstrate that thermal gradients arising from ohmic heating can be utilized for excitation of coherent auto-oscillations of magnetization and for generation of tunable microwave signals. The heat-driven dynamics is observed in Y3Fe5O12/Pt bilayer nanowires where ohmic heating of the Pt layer results in injection of pure spin current into the Y3Fe5O12 layer. This leads to excitation of auto-oscillations of the Y3Fe5O12 magnetization and generation of coherent microwave radiation. Our work paves the way towards spin caloritronic devices for microwave and magnonic applications.Harvesting ohmic heat for signal processing is one of major challenges in modern electronics and spin caloritronics, but not yet well accomplished. Here the authors demonstrate a spin torque oscillator device driven by pure spin current arising from thermal gradient across an Y3Fe5O12/Pt interface.

Parallel evolution or purifying selection, not introgression, explains similarity in the pyrethroid detoxification linked GSTE4 of Anopheles gambiae and An. arabiensis.

Insecticide resistance is a major impediment to the control of vectors and pests of public health importance and is a strongly selected trait capable of rapid spread, sometimes even between closely related species. Elucidating the mechanisms generating insecticide resistance in mosquito vectors of disease, and understanding the spread of resistance within and between populations and species are vital for the development of robust resistance management strategies. Here, we studied the mechanisms of resistance in two sympatric members of the Anopheles gambiae species complex-the major vector of malaria in sub-Saharan Africa-to understand how resistance has developed and spread in eastern Uganda, a region with some of the highest levels of malaria. In eastern Uganda, where the mosquitoes Anopheles arabiensis and An. gambiae can be found sympatrically, low levels of hybrids (0.4 %) occur, offering a route for introgression of adaptively important variants between species. In independent microarray studies of insecticide resistance, Gste4, an insect-specific glutathione S-transferase, was among the most significantly up-regulated genes in both species. To test the hypothesis of interspecific introgression, we sequenced 2.3 kbp encompassing Gste4. Whilst this detailed sequencing ruled out introgression, we detected strong positive selection acting on Gste4. However, these sequences, followed by haplotype-specific qPCR, showed that the apparent up-regulation in An. arabiensis is a result of allelic variation across the microarray probe binding sites which artefactually elevates the gene expression signal. Thus, face-value acceptance of microarray data can be misleading and it is advisable to conduct a more detailed investigation of the causes and nature of such signal. The identification of positive selection acting on this locus led us to functionally express and characterise allelic variants of GSTE4. Although the in vitro data do not support a direct role for GSTE4 in metabolism, they do support a role for this enzyme in insecticide sequestration. Thus, the demonstration of a role for an up-regulated gene in metabolic resistance to insecticides should not be limited to simply whether it can metabolise insecticide; such a strict criterion would argue against the involvement of GSTE4 despite the weight of evidence to the contrary.

Prevalence of diabetes mellitus in patients with acromegaly.

Early carbohydrate metabolism disorders (ECMDs) and diabetes mellitus (DM) are frequently associated with acromegaly. We aimed to assess the prevalence of ECMDs in patients with acromegaly and to compare the results with those in adults without acromegaly using two population-based epidemiologic surveys. We evaluated 97 patients with acromegaly in several phases of their disease (mean age, 56 years and estimated duration of acromegaly, 12.5 years). An oral glucose tolerance test was done in those not yet diagnosed with DM to reveal asymptomatic DM or ECMDs (impaired glucose tolerance+impaired fasting glucose). Comparisons were made between patients with acromegaly and participants from the general adult population (n=435) and an adult population with multiple type 2 diabetes risk factors (n=314), matched for gender, age and BMI. DM was diagnosed in 51 patients with acromegaly (52.5%) and 14.3% of the general population (P<0.001). The prevalence of ECMDs was also higher in patients with acromegaly than in the general population and in the high-risk group; only 22% of patients with acromegaly were normoglycaemic. The prevalence of newly diagnosed ECMDs or DM was 1.3-1.5 times higher in patients with acromegaly compared with the high-risk group. Patients with acromegaly having ECMDs or DM were older, more obese and had longer disease duration and higher IGF1 levels (Z-score). Logistic regression showed that the severity of glucose derangement was predicted by age, BMI and IGF1 levels. In patients with acromegaly, the prevalence of DM and ECMDs considerably exceeds that of the general population and of a high-risk group, and development of DM depends on age, BMI and IGF1 levels.

[Risk of type 2 diabetes mellitus and acute cardiovascular disorders in patients with early disturbances of carbohydrate metabolism].

The aim of this work was to estimate the relative risk (RR) of type 2 diabetes mellitus (DM2) and cardiovascular diseases, total and cardiovascular mortality in patients with disturbances of carbohydrate metabolism revealed in the prospective study carried out in 2009 that included patients found to have disturbances of carbohydrate metabolism in 2006. We analysed the 3-year risk of development of type 2 diabetes mellitus, total and cardiovascular mortality. RR of DM2 was significantly increased in association with practically all early disturbances of carbohydrate metabolism. The most unfavourable combination is fasting glycemia and impaired glucose tolerance. Within 3 years after its determination, 33.3% of the patients developed DM2 while RR of DM2 increased 11-fold. Newly diagnosed DM2 increased RR of total mortality by 2.3 times. Fasting glycemia during 3 years increased RR of cardiovascular mortality by 3.2 times. Results of the study suggest the necessity of not only timely diagnosis of fasting glycemia and impaired glucose tolerance but also further monitoring and correction of carbohydrate metabolism in patients with this pathology as well as of the elaboration and implementation of a comprehensive program for the screening of disturbed carbohydrate metabolism in high-risk groups.

[Major risk factors of glucose metabolism abnormalities].

Using the data of population base study of adult residents of 2 districts of Moscow Region (2638 persons), prevalence is studied and influence on occurrence of glucose metabolism abnormalities of major risk factors is estimated. Influence of risk factors was estimated with Cox regression analyses. High prevalence undiagnosed glucose metabolism abnormalities among persons (24,9%) is taped; it is established that relative risk of diabetes mellitus type 2 significantly raised at persons is more than 50 years of age independently of BMI, at the same time first-degree obesity increased relative risk of diabetes mellitus type 2 in 4,3 times and third-degree obesity--in 9,0 times independently of age.

Magnetism of single-crystalline Fe nanostructures.

The quantitative investigation of magnetic nanostructures by means of ferromagnetic resonance is demonstrated for single-crystalline iron nanostructures. It is shown that the single-crystalline nature leads to effects not being present in polycrystalline ones and helps to quantitatively interpret the results. First a method is presented that enables one to fabricate epitaxial Fe nanowires starting from a thin film of Fe grown under ultrahigh vacuum conditions on GaAs (110). The system allows, due to the combination of cubic and twofold magnetic anisotropy, to prepare wires whose easy axis in remanence is oriented perpendicular to the wires axis. This unique feature is only achievable in epitaxial systems. Furthermore, nearly perfect Fe nanocubes with 13.6 nm edge length prepared by wet-chemical methods are studied. While the shell of the particles is composed of either Fe3O4 or gamma-Fe2O3, the core consists of metallic Fe. Oxygen and hydrogen plasma are used to remove the ligand system and the oxide shell. The single-crystalline nature of the cubes enables one to quantitatively determine the magnetic properties of the individual particle by means of ferromagnetic resonance measurements on an ensemble together with a model based on the Landau-Lifshitz equation. The measurements reveal a magneto-crystalline anisotropy of K4 = 4.8. 10(4) J/m3 being equal to bulk value and a saturation magnetization which is reduced to M(5K) = (1.2 +/- 0.12). 10(6) A/m (70% of bulk value). The effective damping parameter alpha = 0.03 is increased by one order of magnitude with respect to bulk Fe, showing that magnetic damping in nanostructures differs from the bulk.

[Influence of age and body weight on plasma glucose levels during an oral glucose tolerance test in subjects without carbohydrate metabolic disturbances].

AIM: To evaluate the influence of age and body mass index (BMI) on fasting and postprandial (2 hours after glucose load) plasma glucose (FPG and PPG) levels in males and females. SUBJECTS AND METHODS: A screening for carbohydrate metabolic disturbances (by using an oral glucose tolerance test) was made in the stratified adult sample from two municipal districts of the Moscow Region. The data were statistically processed by the computer program SPSS 11.0. RESULTS: The mean FPG level in normoglycemic subjects was 5.26 +/- 0.43 mmol/l. There was a significant (p < 0.001) positive correlation between age and FPG: r = 0.11 in men and r = 0.17 in women. The mean PPG was 6.15 +/- 1.35 mmol/l; in males it was significantly lower than that in females. There was a significant correlation between age and PPG: r = 0.30 in males and r = 0.13 in females. A weak, but statistically significant correlation was found between FPG and body mass index (BMI) in women: r = 0.02. There was no significant correlation between FPG and BMI in men. No significant correlation was found between PPG and BMI in both males and females. A lower PPG level was 2 times more frequently observed in men than that in women (37.70 and 17.57%, respectively). CONCLUSION: Fasting and postprandial (2 hours after glucose load) plasma glucose levels increase with age in subjects without carbohydrate metabolic disturbances. A predictable plasma glucose level increase depending on age is described by the cubic regression model equation.

Low relaxation rate in epitaxial vanadium-doped ultrathin iron films.

The longest relaxation time and sharpest frequency content in ferromagnetic precession is determined by the intrinsic (Gilbert) relaxation rate G. For many years, pure iron (Fe) has had the lowest known value of G = 57 MHz for all pure ferromagnetic metals or binary alloys. We show that an epitaxial iron alloy with vanadium (V) possesses values of G which are significantly reduced to 35 +/- 5 MHz at 27% V. The result can be understood as the role of spin-orbit coupling in generating relaxation, reduced through the atomic number Z.

Crystal structure of pentaerythritol tetranitrate reductase: "flipped" binding geometries for steroid substrates in different redox states of the enzyme.

Pentaerythritol tetranitrate reductase (PETN reductase) degrades high explosive molecules including nitrate esters, nitroaromatics and cyclic triazine compounds. The enzyme also binds a variety of cyclic enones, including steroids; some steroids act as substrates whilst others are inhibitors. Understanding the basis of reactivity with cyclic enones requires structural information for the enzyme and key complexes formed with steroid substrates and inhibitors. The crystal structure of oxidised and reduced PETN reductase at 1.5 A resolution establishes a close structural similarity to the beta/alpha-barrel flavoenzyme, old yellow enzyme. In complexes of oxidised PETN reductase with progesterone (an inhibitor), 1,4-androstadiene-3,17-dione and prednisone (both substrates) the steroids are stacked over the si-face of the flavin in an orientation different from that reported for old yellow enzyme. The specifically reducible 1,2 unsaturated bonds in 1,4-androstadiene-3,17-dione and prednisone are not optimally aligned with the flavin N5 in oxidised enzyme complexes. These structures suggest either relative "flipping" or shifting of the steroid with respect to the flavin when bound in different redox forms of the enzyme. Deuterium transfer from nicotinamide coenzyme to 1,4-androstadiene-3,17-dione via the enzyme bound FMN indicates 1alpha addition at the steroid C2 atom. These studies rule out lateral motion of the steroid and indicate that the steroid orientation is "flipped" in different redox states of the enzyme.

Structural consequences of site-directed mutagenesis in flexible protein domains: NMR characterization of the L(55,56)S mutant of RhoGDI.

The guanine dissociation inhibitor RhoGDI consists of a folded C-terminal domain and a highly flexible N-terminal region, both of which are essential for biological activity, that is, inhibition of GDP dissociation from Rho GTPases, and regulation of their partitioning between membrane and cytosol. It was shown previously that the double mutation L55S/L56S in the flexible region of RhoGDI drastically decreases its affinity for Rac1. In the present work we study the effect of this double mutation on the conformational and dynamic properties of RhoGDI, and describe the weak interaction of the mutant with Rac1 using chemical shift mapping. We show that the helical content of the region 45-56 of RhoGDI is greatly reduced upon mutation, thus increasing the entropic penalty for the immobilization of the helix, and contributing to the loss of binding. In contrast to wild-type RhoGDI, no interaction with Rac1 could be identified for amino-acid residues of the flexible domain of the mutant RhoGDI and only very weak binding was observed for the folded domain of the mutant. The origins of the effect of the L55S/L56S mutation on the binding constant (decreased by at least three orders of magnitude relative to wild-type) are discussed with particular reference to the flexibility of this part of the protein.

Structure-activity relationships in flexible protein domains: regulation of rho GTPases by RhoGDI and D4 GDI.

The guanine dissociation inhibitors RhoGDI and D4GDI inhibit guanosine 5'-diphosphate dissociation from Rho GTPases, keeping these small GTPases in an inactive state. The GDIs are made up of two domains: a flexible N-terminal domain of about 70 amino acid residues and a folded 134-residue C-terminal domain. Here, we characterize the conformation of the N-terminal regions of both RhoGDI and D4GDI using a series of NMR experiments which include (15)N relaxation and amide solvent accessibility measurements. In each protein, two regions with tendencies to form helices are identified: residues 36 to 58 and 9 to 20 in RhoGDI, and residues 36 to 57 and 20 to 25 in D4GDI. To examine the functional roles of the N-terminal domain of RhoGDI, in vitro and in vivo functional assays have been carried out with N-terminally truncated proteins. These studies show that the first 30 amino acid residues are not required for inhibition of GDP dissociation but appear to be important for GTP hydrolysis, whilst removal of the first 41 residues completely abolish the ability of RhoGDI to inhibit GDP dissociation. The combination of structural and functional studies allows us to explain why RhoGDI and D4GDI are able to interact in similar ways with the guanosine 5'-diphosphate-bound GTPase, but differ in their ability to regulate GTP-bound forms; these functional differences are attributed to the conformational differences of the N-terminal domains of the guanosine 5'-diphosphate dissociation inhibitors. Therefore, the two transient helices, appear to be associated with different biological effects of RhoGDI, providing a clear example of structure-activity relationships in a flexible protein domain.

Mapping the binding site for the GTP-binding protein Rac-1 on its inhibitor RhoGDI-1.

BACKGROUND: Members of the Rho family of small GTP-binding proteins, such as Rho, Rac and Cdc42, have a role in a wide range of cell responses. These proteins function as molecular switches by virtue of a conformational change between the GTP-bound (active) and GDP-bound (inactive) forms. In addition, most members of the Rho and Rac subfamilies cycle between the cytosol and membrane. The cytosolic guanine nucleotide dissociation inhibitors, RhoGDIs, regulate both the GDP/GTP exchange cycle and the membrane association/dissociation cycle. RESULTS: We have used NMR spectroscopy and site-directed mutagenesis to identify the regions of human RhoGDI-1 that are involved in binding Rac-1. The results emphasise the importance of the flexible regions of both proteins in the interaction. At least one specific region (residues 46-57) of the flexible N-terminal domain of RhoGDI, which has a tendency to form an amphipathic helix in the free protein, makes a major contribution to the binding energy of the complex. In addition, the primary site of Rac-1 binding on the folded domain of RhoGDI involves the beta4-beta5 and beta6-beta7 loops, with a slight movement of the 3(10) helix accompanying the interaction. This binding site is on the same face of the protein as the binding site for the isoprenyl group of post-translationally modified Rac-1, but is distinct from this site. CONCLUSIONS: Isoprenylated Rac-1 appears to interact with three distinct sites on RhoGDI. The isoprenyl group attached to the C terminus of Rac-1 binds in a pocket in the folded domain of RhoGDI. This is distinct from the major site on this domain occupied by Rac-1 itself, which involves two loops at the opposite end to the isoprenyl-binding site. It is probable that the flexible C-terminal region of Rac-1 extends from the site at which Rac-1 contacts the folded domain of RhoGDI to allow the isoprenyl group to bind in the pocket at the other end of the RhoGDI molecule. Finally, the flexible N terminus of RhoGDI-1, and particularly residues 48-58, makes a specific interaction with Rac-1 which contributes substantially to the binding affinity.

The solution structure of the complex of Lactobacillus casei dihydrofolate reductase with methotrexate.

We have determined the three-dimensional solution structure of the complex of Lactobacillus casei dihydrofolate reductase (18.3 kDa, 162 amino acid residues) formed with the anticancer drug methotrexate using 2531 distance, 361 dihedral angle and 48 hydrogen bond restraints obtained from analysis of multidimensional NMR spectra. Simulated annealing calculations produced a family of 21 structures fully consistent with the constraints. The structure has four alpha-helices and eight beta-strands with two other regions, comprising residues 11 to 14 and 126 to 127, also interacting with each other in a beta-sheet manner. The methotrexate binding site is very well defined and the structure around its glutamate moiety was improved by including restraints reflecting the previously determined specific interactions between the glutamate alpha-carboxylate group with Arg57 and the gamma-carboxylate group with His28. The overall fold of the binary complex in solution is very similar to that observed in the X-ray studies of the ternary complex of L. casei dihydrofolate reductase formed with methotrexate and NADPH (the structures of the binary and ternary complexes have a root-mean-square difference over the backbone atoms of 0.97 A). Thus no major conformational change takes place when NADPH binds to the binary complex. In the binary complex, the loop comprising residues 9 to 23 which forms part of the active site has been shown to be in the "closed" conformation as defined by M. R. Sawaya & J. Kraut, who considered the corresponding loops in crystal structures of complexes of dihydrofolate reductases from several organisms. Thus the absence of the NADPH does not result in the "occluded" form of the loop as seen in crystal studies of some other dihydrofolate reductases in the absence of coenzyme. Some regions of the structure in the binary complex which form interaction sites for NADPH are less well defined than other regions. However, in general terms, the NADPH binding site appears to be essentially pre-formed in the binary complex. This may contribute to the tighter binding of coenzyme in the presence of methotrexate.

1H, 15N and 13C NMR resonance assignment, secondary structure and global fold of the FMN-binding domain of human cytochrome P450 reductase.

The FMN-binding domain of human NADPH-cytochrome P450 reductase, corresponding to exons 3-7, has been expressed at high level in an active form and labelled with 13C and 15N. Most of the backbone and aliphatic side-chain 1H, 15N and 13C resonances have been assigned using heteronuclear double- and triple-resonance methods, together with a semiautomatic assignment strategy. The secondary structure as estimated from the chemical shift index and NOE connectivities consists of six alpha-helices and five beta-strands. The global fold was deduced from the long-range NOEs unambiguously assigned in a 4D 13C-resolved HMQC-NOESY-HMQC spectrum. The fold is of the alternating alpha/beta type, with the five beta-strands arranged into a parallel beta-sheet. The secondary structure and global fold are very similar to those of the bacterial flavodoxins, but the FMN-binding domain has an extra short helix in place of a loop, and an extra helix at the N-terminus (leading to the membrane anchor domain in the intact P450 reductase). The experimental constraints were combined with homology modelling to obtain a structure of the FMN-binding domain satisfying the observed NOE constraints. Chemical shift comparisons showed that the effects of FMN binding and of FMN reduction are largely localised at the binding site.