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Knee osteoarthritis (KOA) is the most common form of joint degeneration with increasing prevalence and incidence in recent decades. KOA is a molecular disorder characterized by the interplay of numerous molecules, a considerable number of which can be detected in body fluids, including synovial fluid, urine, and blood. However, the current diagnosis and treatment of KOA mainly rely on clinical and imaging manifestations, neglecting its molecular pathophysiology. The mismatch between participants’ molecular characteristics and drug therapeutic mechanisms might explain the failure of some disease-modifying drugs in clinical trials. Hence, according to the temporal alteration of representative molecules, we propose a novel molecular classification of KOA divided into pre-KOA, early KOA, progressive KOA, and end-stage KOA. Then, progressive KOA is furtherly divided into four subtypes as cartilage degradation-driven, bone remodeling-driven, inflammation-driven, and pain-driven subtype, based on the major pathophysiology in patient clusters. Multiple clinical findings of representatively investigated molecules in recent years will be reviewed and categorized. This molecular classification allows for the prediction of high-risk KOA individuals, the diagnosis of early KOA patients, the assessment of therapeutic efficacy, and in particular, the selection of homogenous patients who may benefit most from the appropriate therapeutic agents.

An improved preconditioned multiple-relaxation-time lattice Boltzmann equation model for incompressible flow (IPMRT-LBE) in porous media is proposed. Motivated by previous LBE models [Guo et al., Phys. Rev. E 70, 066706 (2004); Premnath et al., J. Comput. Phys. 228, 746 (2009); Guo et al., J. Comput. Phys. 165, 288 (2000)], the current model is demonstrated to have the advantages of accurate implementation of the no-slip boundary condition, reducing the compressible effect as well as fast convergence rate compared with standard LBE models. To validate the IPMRT-LBE model, flows in two- and three-dimensional synthetic porous media (square array of cylinders and body-centered cubic array of spheres) are simulated. The results show that the current model can predict the macroscopic property (such as permeability) accurately with significantly accelerated convergence rate. Furthermore, simulations of flow through a three-dimensional sandpack confirm the applicability and advantages of the IPMRT-LBE model. [ABSTRACT FROM AUTHOR]

We have studied new superconductors prepared by metal doping of two-dimensional (2D) layered materials, FeSe and FeSe0.5Te0.5, using ethylenediamine (EDA). The superconducting transition temperatures (Tcs) of metal-doped FeSe and metal-doped FeSe0.5Te0.5, i.e., (EDA)yMxFeSe and (EDA)yMxFeSe0.5Te0.5 (M: Li, Na, and K), were 31-45 K and 19-25 K, respectively. The stoichiometry of each sample was clarified by energy dispersive x-ray (EDX) spectroscopy, and the x-ray powder diffraction pattern indicated a large expansion of lattice constant c, indicating the cointercalation of metal atoms and EDA. The pressure dependence of superconductivity in (EDA)yNaxFeSe0.5Te0.5 has been investigated at a pressure of 0-0.8GPa, showing negative pressure dependence in the same manner as (NH3)yNaxFeSe0.5Te0.5 The Tc-c phase diagrams of MxFeSe and MxFeSe0.5Te0.5 were drawn afresh from the Tc and c of (EDA)yMxFeSe and (EDA)yMxFeSe0.5Te0.5, showing that the Tc increases with increasing c but that extreme expansion of c reverses the Tc trend. [ABSTRACT FROM AUTHOR]

The prion protein (PrP)4 has been implicated both in prion diseases such as Creutzfeldt-Jakob disease (CJD), where its monomeric cellular isoform (PrPC) is recruited into pathogenic self-propagating polymers of misfolded protein, and in Alzheimer's disease (AD) where PrPC may act as a receptor for synaptotoxic oligomeric forms of amyloid beta (Aβ). There has been considerable interest in identification of compounds which bind to PrPC, stabilising its native fold and thereby acting as pharmacological chaperones to block prion propagation and pathogenesis. However, compounds binding PrPC could also inhibit the binding of toxic Aβ species and may have a role in treating AD, a highly prevalent dementia for which there are currently no disease-modifying treatments. However, the absence of a unitary, readily measurable, physiological function of PrP makes screening for ligands challenging, and the highly heterogeneous nature of Aβ oligomer preparations makes conventional competition binding assays difficult to interpret. We have therefore developed a high-throughput screen which utilises site-specifically fluorescently labelled protein to identify compounds which bind to PrP and inhibit both Aβ binding and prion propagation. Following a screen of 1,200 approved drugs we identified Chicago Sky Blue 6B as the first small molecule PrP ligand capable of inhibiting Aβ binding, demonstrating the feasibility of development of drugs to block this interaction. The interaction of Chicago Sky Blue 6B was characterised by isothermal titration calorimetry and its ability to inhibit Aβ binding and reduce prion levels established in cell-based assays. [ABSTRACT FROM AUTHOR]

The new complex, [Zr(pda)2]n (1, pda2- = N,N′-bis(neo-pentyl)-ortho-phenylenediamide, n = 1 or 2), prepared by the reaction of 2 equiv of pdaLi2 with ZrCl4, reacts rapidly with halogen oxidants to afford the new product ZrX2(disq)2 (3, X = Cl, Br, I; disq- = N,N′-bis(neo-pentyl)-ortho-diiminosemiquinonate) in which each redox-active ligand has been oxidized by one electron. The oxidation products 3a-c have been structurally characterized and display an unusual parallel stacked arrangement of the disq- ligands in the solid state, with a separation of ~3 Å. Density functional calculations show a bonding-type interaction between the SOMOs of the disq- ligands to form a unique HOMO while the antibonding linear combination forms a unique LUMO. This orbital configuration leads to a closed-shell-singlet ground-state electron configuration (S = 0). Temperature-dependent magnetism measurements indicate a low-lying triplet excited state at ~750 cm-1. In solution, 3a-c show strong disq-based absorption bands that are invariant across the halide series. Taken together these spectroscopic measurements provide experimental values for the one- and two-electron energies that characterize the π-stacked bonding interaction between the two disq- ligands. [ABSTRACT FROM AUTHOR]

Pore-scale simulation is an essential tool to understand complex physical process in many environmental problems. However, structural heterogeneity and data scarcity render the porous medium, and in turn its macroscopic properties, uncertain. Meanwhile, direct numerical simulation of the medium at the fine scale often incurs high computational cost, which further limits efforts to quantify the parametric uncertainty over those macroscopic properties. To address this challenge, we propose a framework to compute the probabilistic density function (PDF) of the macroscopic property based on the generalized polynomial chaos expansion method and the Minkowski functionals. To illustrate the effectiveness of our approach, we conduct numerical experiments for one macroscopic property, namely the permeability, and we compare its PDF with that obtained from Monte Carlo simulations. Both two- and three-dimensional cases show that our framework requires much fewer realizations while maintaining the desired accuracy. [ABSTRACT FROM AUTHOR]