Search Results (59)

The misfolding and aggregation of proteins into amyloidogenic assemblies are key features of several metabolic and neurodegenerative diseases. Human insulin has long been known to form amyloid fibrils under various conditions, which affects its bioavailability and function. Clinically, insulin aggregation at recurrent injection sites poses a challenge for diabetic patients who rely on insulin therapy. Furthermore, decreased responsiveness to insulin in type 2 diabetic (T2D) patients may lead to its overproduction and accumulation as aggregates. Earlier reports have reported that various factors such as pH, temperature, agitation, and the presence of lipids or other proteins influence insulin aggregation. Our present study aims to elucidate the effects of non–micellar anionic DMPG (1,2–dimyristoyl–sn–glycero–3–phosphoglycerol) lipids on insulin aggregation. Distinct pathways of insulin aggregation and intermediate formation were observed in the presence of DMPG using a ThT fluorescence assay. The formation of soluble intermediates alongside large insulin fibrils was observed in insulin incubated with DMPG via TEM, DLS, and NMR as opposed to insulin aggregates generated without lipids. ¹³C magic angle spinning solid–state NMR and FTIR experiments indicated that lipids do not alter the conformation of insulin fibrils but do alter the time scale of motion of aromatic and aliphatic side chains. Furthermore, the soluble intermediates were found to be more cytotoxic than fibrils generated with or without lipids. Overall, our study elucidates the importance of anionic lipids in dictating the pathways and intermediates associated with insulin aggregation. These findings could be useful in determining various approaches to avoid toxicity and enhance the effectiveness of insulin in therapeutic applications. Full article

Bis- and trisphosphines incorporating methylene and aryl spacers readily adsorb on the surface of porous activated carbon (AC). The adsorption can be performed in the absence of solvents, even when the phosphines have high melting points, or from solutions. The diverse phosphines Ph₂PCH₂PPh₂ (dppm), Ph₂P(CH₂)₂PPh₂ (dppe), Ph₂P(CH₂)₃PPh₂ (dppp), Ph₂P(p-C₆H₄)PPh₂ (dppbz), and (Ph₂PCH₂)₃CCH₃ (tdme) were adsorbed in submonolayers on AC. The adsorbed phosphines were studied by ³¹P MAS (magic angle spinning) NMR spectroscopy, and their mobilities on the surface were confirmed by determining the ³¹P T₁ relaxation times. All phosphine groups of each bis- and trisphosphine molecule are in contact with the surface, and the molecules exhibit translational mobility as one unit. All phosphines used here are air-stable. Once a submonolayer is created on the AC surface, oxygen from the air is co-adsorbed and transforms all phosphines quantitatively into phosphine oxides at room temperature. The oxidation proceeds in a consecutive manner with the oxidation of one phosphine group after another until the fully oxidized species are formed. Studies of the kinetics are based on integrating the signals in the solution ³¹P NMR spectra. High temperatures and low surface coverages increase the speed of the oxidation, while light and acid have no impact. The oxidation is fast and complete within one hour for 10% surface coverage at room temperature. In order to study the mechanism and slow down the oxidation, a higher surface coverage of 40% was applied. No unwanted P(V) side products or water adducts were observed. The clean phosphine oxides could be recovered in high yields by washing them off of the AC surface. The oxidation is based on radical activation of O₂ on the AC surface due to delocalized electrons on the AC surface. This is corroborated by the result that AIBN-derived radicals enable the air oxidation of PPh₃ in solution at 65 °C. When the air-stable complex (CO)₂Ni(PPh₃)₂ is applied to the AC surface and exposed to the air, OPPh₃ forms quantitatively. The new surface-assisted air oxidation of phosphines adsorbed on AC renders expensive and hazardous oxidizers obsolete and opens a synthetic pathway to the selective mono-oxidation of bis- and trisphosphines. Full article

Graft-versus-host disease (GVHD) remains a significant barrier to the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT), contributing to long-term morbidity and non-relapse mortality in both pediatric and adult populations. Central to GVHD pathophysiology is the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, where JAK2 mediates key pro-inflammatory cytokines, including IL-6, IFN-γ, and GM-CSF. These cytokines promote donor T cell activation, effector differentiation, and target organ damage. The introduction of ruxolitinib, a selective JAK1/2 inhibitor, has transformed the treatment landscape for steroid-refractory acute and chronic GVHD, leading to improved response rates and durable symptom control. However, its limitations—such as cytopenias, infectious complications, and incomplete responses—have catalyzed the development of next-generation agents. In 2024, the FDA approved axatilimab, a CSF-1R inhibitor that targets monocyte-derived macrophages in fibrotic chronic GVHD, and remestemcel-L, an allogeneic mesenchymal stromal cell therapy, for pediatric steroid-refractory acute GVHD. Both agents offer mechanistically distinct and clinically meaningful additions to the therapeutic armamentarium. In parallel, emerging combination strategies involving JAK2 inhibitors and novel biologics show promise in enhancing immune tolerance while preserving graft-versus-leukemia (GvL) effects. Recent advances in biomarker development, such as the MAGIC Algorithm Probability (MAP), are enabling early risk stratification and response prediction. The integration of these tools with organ-specific and personalized approaches marks a shift toward more precise, durable, and tolerable GVHD therapy. This review highlights the current state and future direction of JAK2 inhibition and complementary therapies in the evolving GVHD treatment paradigm. Full article

This paper proposes a hierarchical framework-based solution to address the challenges of vehicle state estimation and lateral stability control in four-wheel independent drive electric vehicles. First, based on a three-degrees-of-freedom four-wheel vehicle model combined with the Magic Formula Tire model (MF-T), a hierarchical estimation method is designed. The upper layer employs the Kalman Filter (KF) and Extended Kalman Filter (EKF) to estimate the vertical load of the wheels, while the lower layer utilizes EKF in conjunction with the upper-layer results to further estimate the lateral forces, longitudinal velocity, and lateral velocity, achieving accurate vehicle state estimation. On this basis, a hierarchical lateral stability control system is developed. The upper controller determines stability requirements based on driver inputs and vehicle states, switches between handling assistance mode and stability control mode, and generates yaw moment and speed control torques transmitted to the lower controller. The lower controller optimally distributes these torques to the four wheels. Through closed-loop Double Lane Change (DLC) tests under low-, medium-, and high-road-adhesion conditions, the results demonstrate that the proposed hierarchical estimation method offers high computational efficiency and superior estimation accuracy. The hierarchical control system significantly enhances vehicle handling and stability under low and medium road adhesion conditions. Full article

We studied the boron-based composite cluster B₈Al₃⁺ doped with Al atoms. The global minimum structure of the B₈Al₃⁺ cluster is a three-layer structure, consisting of three parts: an Al₂ unit, a B₈ ring and an isolated Al atom. Charge calculations analysis shows that the cluster can be expressed as [Al]⁺[B₈]²⁻[Al₂]²⁺, has 6π/6σ double aromaticity and follows the (4n+2) Hückel rule. Born–Oppenheimer molecular dynamics (BOMD) simulation shows that the B₈Al₃⁺ cluster has dynamic fluxionality properties. Remarkably, at the single-point coupled cluster singles, doubles and triples (CCSD(T)) level, the energy barrier for intramolecular rotation is merely 0.19 kcal mol⁻¹. [B₈]²⁻ molecular wheels have magical 6π/6σ double aromaticity properties, providing a continuous cloud of delocalized electrons, which is a key factor in the dynamic fluxionality of the cluster. The B₈Al₃⁺ cluster provides a new example of dynamic structural fluxionality in molecular systems. Full article

Unique structural and chemical properties, such as ion exchange, developed inner surface, etc., as well as the wide possibilities and flexibility of regulating these properties, cause a keen interest in zeolites. They are widely used in industry as molecular sieves, ion exchangers and catalysts. Current trends in the development of zeolite-based catalysts include the adaptation of their cationic composition, acidity and porosity for a specific catalytic process. Recent studies have shown that mesoporosity is beneficial to the rational design of catalysts with controlled product selectivity and an improved catalyst lifetime due to its efficient mass-transport properties. Nuclear magnetic resonance (NMR) has proven to be a reliable method for studying zeolites. Solid-state NMR spectroscopy allows for the quantification of both Lewis and Brønsted acidity in zeolite catalysts and, nowadays, ²⁷Al and ²⁹Si magic angle spinning NMR spectroscopy has become firmly established in the set of approved methods for characterizing zeolites. The use of probe molecules opens up the possibility for the indirect measurement of the characteristics of acid sites. NMR relaxation is less common, although it is especially informative and enlightening for studying the mobility of guest molecules in the porous matrix. Moreover, the NMR relaxation of guest molecules and NMR cryoporometry can quantify pore size distribution on a broader scale (compared to traditional methods), which is especially important for systems with complex pore organization. Over the last few years, there has been a growing interest in the use of 2D NMR relaxation techniques to probe porous catalysts, such as 2D $T_1$–$T_2$ correlation to study the acidity of the surface of catalysts and 2D $T_2$–$T_2$ exchange to study pore connectivity. This contribution provides a comprehensive review of various NMR relaxation techniques for studying porous media and recent results of their applications in probing micro- and mesoporous zeolites, mainly focused on the mobility of adsorbed molecules, the acidity of the zeolite surface and the pore size distribution and connectivity of zeolites with hierarchical porosity. Full article

Recently, the quest for high-Tc superconductors has evolved from the trial-and-error methodology to the growth of nanostructured artificial high-Tc superlattices (AHTSs) with tailor-made superconducting functional properties by quantum design. Here, we report the growth by molecular beam epitaxy (MBE) of a superlattice of Mott insulator metal interfaces (MIMIs) made of nanoscale superconducting layers of quantum confined-space charge in the Mott insulator La₂CuO₄ (LCO), with thickness L intercalated by normal metal La_1.55Sr_0.45CuO₄ (LSCO) with period d. The critical temperature shows the superconducting dome with Tc as a function of the geometrical parameter L/d showing the maximum at the magic ratio L/d = 2/3 where the Fano–Feshbach resonance enhances the superconducting critical temperature. The normal state transport data of the samples at the top of the superconducting dome exhibit Planckian T-linear resistivity. For L/d > 2/3 and L/d < 2/3, the heterostructures show a resistance following Kondo universal scaling predicted by the numerical renormalization group theory for MIMI nanoscale heterostructures. We show that the Kondo temperature, T_K, and the Kondo scattering amplitude, R_0K, vanish at L/d = 2/3, while T_K and R_0K increase at both sides of the superconducting dome, indicating that the T-linear resistance regime competes with the Kondo proximity effect in the normal phase of MIMIs. Full article

Among the widespread trichothecene mycotoxins, T-2 toxin is considered the most toxic congener. In the present study, we utilized high-resolution magic-angle spinning nuclear magnetic resonance (HRMAS NMR), coupled to the zebrafish (Danio rerio) embryo model, as a toxicometabolomics approach to elucidate the cellular, molecular and biochemical pathways associated with T-2 toxicity. Aligned with previous studies in the zebrafish embryo model, exposure to T-2 toxin was lethal in the high parts-per-billion (ppb) range, with a median lethal concentration (LC₅₀) of 105 ppb. Exposure to the toxins was, furthermore, associated with system-specific alterations in the production of reactive oxygen species (ROS), including decreased ROS production in the liver and increased ROS in the brain region, in the exposed embryos. Moreover, metabolic profiling based on HRMAS NMR revealed the modulation of numerous, interrelated metabolites, specifically including those associated with (1) phase I and II detoxification, and antioxidant pathways; (2) disruption of the phosphocholine lipids of cell membranes; (3) mitochondrial energy metabolism, including apparent disruption of the tricarboxylic acid (TCA) cycle, and the electron transport chain of oxidative phosphorylation, as well as “upstream” effects on carbohydrate, i.e., glucose metabolism; and (4) several compensatory catabolic pathways. Taken together, these observations enabled development of an integrated, system-level model of T-2 toxicity in relation to human and animal health. Full article

This study evaluated the changes in physicochemical properties and appearance quality of long-grain rice during the grinding process using image technologies and aimed to provide reference for future research. The brown rice milling process was divided into three stages, and flatbed scanning, scanning electron microscopy (SEM), X-ray micro-computed tomography (micro-CT), low-field nuclear magic resonance (LF-NMR), and headspace–gas chromatography–ion mobility spectrometry (HS–GC–IMS) were employed to examine the physicochemical and volatile properties of the samples. Results revealed a continuous increase in the degree of milling, with a broken rice rate and a whiteness value increasing by 50.84% and 21.13%, respectively, compared with those during the initial stage; dietary fiber and vitamin B1 contents were reduced by 54.41% and 66.67%, respectively. The image results visualized showed that the cortex of brown rice was gradually peeled off with the increase in milling degree; the cortical thickness was gradually reduced, the endosperm was gradually exposed, and the surface was smoother and shinier. T₂ populations exhibited a shift toward longer relaxation times, followed by a decrease in relaxation time during the milling process. Additionally, 31 target compounds impacting rice flavor, mainly ketones, alcohols, and esters, were identified, and the concentration of volatile substances in the B region decreased with the reduction in the bran layer; the concentration of volatile substances in the C region provided rice flavor, which increased with the milling process. This study showed changes in the physicochemical properties and appearance quality of long-grain brown rice during milling. Furthermore, the use of various image processing techniques offers significant insights for optimizing processing parameters and enhancing overall quality and taste. Full article

We present a computational investigation on the structural arrangements and energetic stabilities of small-size protonated argon clusters, Ar${ }_n$H${ }^{+}$. Using high-level ab initio electronic structure computations, we determined that the linear symmetric triatomic ArH${ }^{+}$Ar ion serves as the molecular core for all larger clusters studied. Through harmonic normal-mode analysis for clusters containing up to seven argon atoms, we observed that the proton-shared vibration shifts to lower frequencies, consistent with measurements in gas-phase IRPD and solid Ar-matrix isolation experiments. We explored the sum-of-potentials approach by employing kernel-based machine-learning potential models trained on CCSD(T)-F12 data. These models included expansions of up to two-body, three-body, and four-body terms to represent the underlying interactions as the number of Ar atoms increases. Our results indicate that the four-body contributions are crucial for accurately describing the potential surfaces in clusters with $n>$ 3. Using these potential models and an evolutionary programming method, we analyzed the structural stability of clusters with up to 24 Ar atoms. The most energetically favored Ar${ }_n$H${ }^{+}$ structures were identified for magic size clusters at n = 7, 13, and 19, corresponding to the formation of Ar-pentagon rings perpendicular to the ArH${ }^{+}$Ar core ion axis. The sequential formation of such regular shell structures is compared to ion yield data from high-resolution mass spectrometry measurements. Our results demonstrate the effectiveness of the developed sum-of-potentials model in describing trends in the nature of bonding during the single proton microsolvation by Ar atoms, encouraging further quantum nuclear studies. Full article

Mefloquine (MQ) is an antimalarial medication prescribed to treat or malaria prevention.. When taken by children, vomiting usually occurs, and new doses of medication frequently need to be taken. So, developing pediatric medicines using taste-masked antimalarial drug complexes is mandatory for the success of mefloquine administration. The hypothesis that binding mefloquine to an ion-exchange resin (R) could circumvent the drug’s bitter taste problem was proposed, and solid-state ¹³C cross-polarization magic angle spinning (CPMAS) NMR was able to follow MQ–R mixtures through chemical shift and relaxation measurements. The nature of MQ–R complex formation could then be determined. Impedimetric electronic tongue equipment also verified the resinate taste-masking efficiency in vitro. Variations in chemical shifts and structure dynamics measured by proton relaxation properties (e.g., T1ρ^H) were used as probes to follow the extension of mixing and specific interactions that would be present in MQ–R. A significant decrease in T1ρ^H values was observed for MQ carbons in MQ–R complexes, compared to the ones in MQ (from 100–200 ms in MQ to 20–50 ms in an MQ–R complex). The results evidenced that the cationic resin interacts strongly with mefloquine molecules in the formulation of a 1:1 ratio complex. Thus, ¹³C CPMAS NMR allowed the confirmation of the presence of a binding between mefloquine and polacrilin in the MQ–R formulation studied. Full article

This paper presents a wideband ridge waveguide Magic-T based on an E- and an H-arm waveguide power divider using a stepped conducting T-junction transition. The Magic-T is designed to cover the full band of 18–40 GHz with a relative bandwidth of 76%. This bandwidth cannot be achieved by a Magic-T based on a conventional rectangular waveguide. Thus, the ridge waveguide ports have been employed and an 18–40 GHz ridge waveguide Magic-T has been fabricated and measured. It is demonstrated that the proposed Magic-T achieves better than 0.3 dB insertion loss and 15 dB return loss, less than 0.2 dB magnitude imbalance, and 2.5° phase imbalance. In addition, the measured data show good agreement with the simulation results, and high isolation is also obtained. Full article

The pseudo-spin symmetry (PSS) provides an important angle to understand nuclear microscopic structure and the novel phenomena found in unstable nuclei. The relativistic Hartree–Fock (RHF) theory, that takes the important degrees of freedom associated with the $\pi$-meson and $\rho$-tensor ($\rho$-T) couplings into account, provides an appropriate description of the PSS restoration in realistic nuclei, particularly for the pseudo-spin (PS) doublets with high angular momenta ($\tilde{l}$). The investigations of the PSS within the RHF theory are recalled in this paper by focusing on the effects of the Fock terms. Aiming at common artificial shell closures appearing in previous relativistic mean-field calculations, the mechanism responsible for the PSS restoration of high-$\tilde{l}$ orbits is stressed, revealing the manifestation of nuclear in-medium effects on the PSS, and thus, providing qualitative guidance on modeling the in-medium balance between nuclear attractions and repulsions. Moreover, the essential role played by the $\rho$-T coupling, that contributes mainly via the Fock terms, is introduced as combined with the relations between the PSS and various nuclear phenomena, including the shell structure and the evolution, novel halo and bubble-like phenomena, and the superheavy magicity. As the consequences of the nuclear force in complicated nuclear many-body systems, the PSS itself and the mechanism therein can not only deepen our understanding of nuclear microscopic structure and relevant phenomena, but also provide special insight into the nature of the nuclear force, which can further enrich our knowledge of nuclear physics. Full article

This study aimed to develop a rapid, 1 mm³ isotropic resolution, whole-brain MRI technique for automatic lesion segmentation and multi-parametric mapping without using contrast by continuously applying balanced steady-state free precession with inversion pulses throughout incomplete inversion recovery in a single 6 min scan. Modified k-means clustering was performed for automatic brain tissue and lesion segmentation using distinct signal evolutions that contained mixed T1/T2/magnetization transfer properties. Multi-compartment modeling was used to derive quantitative multi-parametric maps for tissue characterization. Fourteen patients with contrast-enhancing gliomas were scanned with this sequence prior to the injection of a contrast agent, and their segmented lesions were compared to conventionally defined manual segmentations of T2-hyperintense and contrast-enhancing lesions. Simultaneous T1, T2, and macromolecular proton fraction maps were generated and compared to conventional 2D T1 and T2 mapping and myelination water fraction mapping acquired with MAGiC. The lesion volumes defined with the new method were comparable to the manual segmentations (r = 0.70, p < 0.01; t-test p > 0.05). The T1, T2, and macromolecular proton fraction mapping values of the whole brain were comparable to the reference values and could distinguish different brain tissues and lesion types (p < 0.05), including infiltrating tumor regions within the T2-lesion. Highly efficient, whole-brain, multi-contrast imaging facilitated automatic lesion segmentation and quantitative multi-parametric mapping without contrast, highlighting its potential value in the clinic when gadolinium is contraindicated. Full article

Photosynthetic reaction centers (RCs) are membrane proteins converting photonic excitations into electric gradients. The heliobacterial RCs (HbRCs) are assumed to be the precursors of all known RCs, making them a compelling subject for investigating structural and functional relationships. A comprehensive picture of the electronic structure of the HbRCs is still missing. In this work, the combination of selective isotope labelling of ¹³C and ¹⁵N nuclei and the utilization of photo-CIDNP MAS NMR (photochemically induced dynamic nuclear polarization magic-angle spinning nuclear magnetic resonance) allows for highly enhanced signals from the radical-pair-forming cofactors. The remarkable magnetic-field dependence of the solid-state photo-CIDNP effect allows for observation of positive signals of the electron donor cofactor at 4.7 T, which is interpreted in terms of a dominant contribution of the differential relaxation (DR) mechanism. Conversely, at 9.4 T, the emissive signals mainly originate from the electron acceptor, due to the strong activation of the three-spin mixing (TSM) mechanism. Consequently, we have utilized two-dimensional homonuclear photo-CIDNP MAS NMR at both 4.7 T and 9.4 T. These findings from experimental investigations are corroborated by calculations based on density functional theory (DFT). This allows us to present a comprehensive investigation of the electronic structure of the cofactors involved in electron transfer (ET). Full article