Insulin in motion: The A6-A11 disulfide bond allosterically modulates structural transitions required for insulin activity

The structural transitions required for insulin to activate its receptor and initiate regulation of glucose homeostasis are only partly understood. Here, using ring-closing metathesis, we substitute the A6-A11 disulfide bond of insulin with a rigid, non-reducible dicarba linkage, yielding two distinct stereo-isomers (cis and trans). Remarkably, only the cis isomer displays full insulin potency, rapidly lowering blood glucose in mice (even under insulin-resistant conditions). It also posseses reduced mitogenic activity in vitro. Further biophysical, crystallographic and molecular-dynamics analyses reveal that the A6-A11 bond configuration directly affects the conformational flexibility of insulin A-chain N-terminal helix, dictating insulin's ability to engage its receptor. We reveal that in native insulin, contraction of the Cα-Cα distance of the flexible A6-A11 cystine allows the A-chain N-terminal helix to unwind to a conformation that allows receptor engagement. This motion is also permitted in the cis isomer, with its shorter Cα-Cα distance, but prevented in the extended trans analogue. These findings thus illuminate for the first time the allosteric role of the A6-A11 bond in mediating the transition of the hormone to an active conformation, significantly advancing our understanding of insulin action and opening up new avenues for the design of improved therapeutic analogues.A.J.R., B.E.F. and M.C.L. acknowledge funding from National Health and Medical Research Council (Project Grant APP1069328 and Project Grant APP1058233) and Australian Research Council. Te Walter and Eliza Hall Institute of Medical Research acknowledges Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS

Separation of static and dynamic disorder in magnetic materials

Conventional transmission Mossbauer, selective excitation double Mossbauer (SEDM), and zero-field muon spin relaxation (ZF-muSR) spectroscopy were used to identify static and dynamic magnetic disorder. With the construction of an efficient SEDM spectrometer, a consistent description of static magnetic disorder in an amorphous alloy (a-Fe80B 20) was developed using transmission Mossbauer and SEDM spectroscopy. Both methods measure the effects of the random static distribution of local magnetic environments around the Mossbauer nuclei. Magnetic fine particle systems (Fe3O4 ferrofluids, polysaccharide iron complex) were examined using transmission Mossbauer spectroscopy, and a model was developed that describes the entire range of dynamic magnetic behavior, from blocked moments on towards collective excitations and superparamagnetic moments. SEDM has measured 180° moment flips in the ferrofluids, determining a model independent relaxation rate of superparamagnetic moments. With the spectral signatures of static and dynamic magnetic phenomena identified, SEDM spectroscopy has been used to unambiguously verify the existence (a-Fe 92Zr8) and absence (Fe65Ni35) of magnetic relaxation in chemically disordered alloys. Additionally, the static and dynamic disorder in a magnetic fine particle system (a polysaccharide iron complex) and a frustrated magnet system (a-FexZr100- x), have been measured with ZF-muSR spectroscopy. The effects of collective excitations have been independently verified with ZF-muSR and moment fluctuation rates are in agreement with transmission Mossbauer spectra fit results. Two magnetic transitions have been identified with ZF-muSR in the a-FexZr100- x system, one at TC and another at Txy corresponding to transverse spin freezing, in both static and fluctuating magnetic components of muSR spectra. SEDM has been used to verify the existence of a fluctuation peak at T xy, and the time-dependent hyperfine interactions due to transverse spin freezi

Using Ion-Beam-Assisted Deposition and Ion Implantation for the Rational Control of Nanomagnetism in Thin Film and Nanostructured Systems

The applications of low energy argon or oxygen ion-beam assisted deposition and high energy oxygen ion implantation for thin film fabrication and modification of the microstructural, compositional and magnetic properties are demonstrated. Five representative model systems are discussed with the state-of-the art characterization tools such as atomic force microscopy, X-ray diffraction, transmission electron microscopy and electron energy loss spectroscopy, X-ray synchrotron-based spectroscopy techniques, and SQUID magnetometry. For example, (i) in nanostructured Fe/Cu thin films, by tuning the amount of interfacial Fe-Cu alloy, the control of the magnetic ordering temperature and the nature of the nanocrystallite dynamical freezing processes have been achieved. (ii) In NiFe/NiO bilayers, the exchange coupling was enhanced when the interface roughness was reduced and the interface texture was changed to a striped configuration. (iii) [Pt/Co]/NiO multilayers could be grown so that the origin of perpendicular magnetic anisotropy was identified as coming from mixed CoPt phases driven by negative heat of mixing when Co thickness was reduced. (iv) In Mn/NiFe thin films, a structural phase transformation from Mn to MnO via ion implantation gave rise to the modifications that can determine the magnetic properties. (v) NiO/NiFe antidot arrays were made with a unidirectional bias that resulted in an induced asymmetric microwave response, which was linked to an unbalanced distribution of the demagnetizing fields around the hole edges

Micromagnetic modeling of experimental hysteresis loops for heterogeneous electrodeposited cobalt films

Micromagnetic modeling provides a realistic description of the magnetic switching behavior in electrodeposited Co thin films that are either uniform (untemplated) or templated with an array of sub-micron spheres. Quantitative agreement between experimental results and simulations based on the Landau-Lifshitz-Gilbert equations is achieved for both in-plane and perpendicular MH loops at two temperatures. By accounting for the sweep-rate dependence in coercivity values from simulated loops (with sweep rates 104–10�1 Oe/ns) and then extrapolating to the experimental regime (measurement times of 10–100 s), a self-consistent set of microscopic parameters is established to accommodate the complexity of the electrodeposited films

Correlating uncompensated antiferromagnetic moments and exchange coupling interactions in interface ion-beam bombarded Co90Fe 10/CoFe-oxide bilayers

The coercivity and exchange bias field of ferro-/antiferromagnetic Co 90Fe10/CoFe-oxide bilayers were studied as function of the surface morphology of the bottom CoFe-oxide layer. The CoFe-oxide surface structure was varied systematically by low energy (0-70 V) Argon ion-beam bombardment before subsequent deposition of the Co90Fe10 layer. Transmission electron microscopy results showed that the bilayer consisted of hcp Co90Fe10 and rock-salt CoFe-oxide. At low temperatures, enhanced coercivities and exchange bias fields with increasing ion-beam bombardment energy were observed, which are attributed to defects and uncompensated moments created near the CoFe-oxide surface in increasing amounts with larger ion-beam bombardment energies. Magnetometry results also showed an increasing divergence of the low field temperature dependent magnetization [ΔM(T)] between field-cooling and zero-field-cooling processes, and an increasing blocking temperature with increasing ion-beam bombardment energy. © 2012 The Japan Society of Applied Physics

Modifying exchange bias effects of Mn/NiFe bilayers by in-situ Ar\u3csup\u3e+\u3c/sup\u3e bombardment

In this work, we present a procedure to modify the exchange bias (EB) properties of antiferromagnetic Mn/ferromagnetic NiFe bilayers by in-situ low energy Ar+ bombardment of the Mn layer during sample deposition. We present structural and magnetic results for unassisted and Ar+ assisted Mn/NiFe bilayers. X-ray diffraction, transmission electron microscopy and electron diffraction results establish different preferred Mn orientation directions between the two samples as a result of the Ar+ bombardment process. Hysteresis loops taken over several temperatures reveal that samples assisted with Ar+ ions during the Mn layer deposition had suppressed EB properties at low temperature as compared to samples grown without Ar+ assistance

The magnetic interfacial properties of an exchange biased nanocrystalline Ni80Fe20/α-Fe2O3 bilayer studied by polarized neutron reflectometry and Monte Carlo simulation

2019 The Japan Society of Applied Physics. The strength of exchange bias can be influenced by interface roughness and antiferromagnetic morphology. Here, we studied the interface profile of an exchange biased, nanocrystalline Ni80Fe20/α-Fe2O3 bilayer. Magnetometry determined the bilayer\u27s exchange bias is observed below a blocking temperature of 75 K. Polarized neutron reflectometry measurements revealed the Ni80Fe20 layer was fully saturated to yield a net-moment of 0.95 μ B/atom, while the majority of the Fe2O3 layer exhibited zero net-magnetization with the exception of the interfacial region with an uncompensated moment between 0.5 and 1.0 μ B/Fe2O3. Monte Carlo simulations of a ferromagnetic/antiferromagnetic bilayer incorporating a granular antiferromagnet indicate that an extrinsic uncompensated moment of ∼1.0 μ B/Fe2O3 can arise from grain boundary disorder. The size of the modeled moment is equivalent to the experimental value, and comparable with previous calculations. Furthermore, unlike intrinsic uncompensated spins, it is found that the disorder-induced moment in the granular antiferromagnet is not destroyed by interface roughness

Spontaneously Formed Interfacial Metal Silicates and Their Effect on the Magnetism of Superparamagnetic FeCo/SiO₂ Core/Shell Nanoparticles

The integration of superparamagnetic core/shell nanoparticles into devices and other nanoscale technological applications requires a detailed understanding of how the intimate contact between core and shell nanophases affects the magnetism. We report how, for single-domain FeCo nanoparticles, an FeCo phase unique to the nanoscale with silica shells of increasing thicknesses spontaneously formed interfacial metal silicates between the core and shell (such as Fe₂SiO₄ and Co₂SiO₄) and altered the overall magnetism of the nanomaterial significantly. The influence of this previously overlooked phenomenon on magnetic properties is reported. Evidence of these metal silicate interfacial layers was observed by X-ray absorption spectroscopy (XAS) collected over the L_3,2 absorption edges of Fe and X-ray photoelectron spectra (XPS) collected over the 2p transitions of Fe and Co. Through the correlation of magnetometry and XPS data, the evolution of nanoparticle magnetic anisotropy is shown to increase with the metal silicate