Estimation of distal arm joint angles from EMG and shoulder orientation for transhumeral prostheses

In this paper, we quantify the extent to which shoulder orientation, upper-arm electromyography (EMG), and forearm EMG are predictors of distal arm joint angles during reaching in eight subjects without disability as well as three subjects with a unilateral transhumeral amputation and targeted reinnervation. Prior studies have shown that shoulder orientation and upper-arm EMG, taken separately, are predictors of both elbow flexion/extension and forearm pronation/supination. We show that, for eight subjects without disability, shoulder orientation and upper-arm EMG together are a significantly better predictor of both elbow flexion/extension during unilateral ($R^2=0.72$) and mirrored bilateral ($R^2=0.72$) reaches and of forearm pronation/supination during unilateral ($R^2=0.77$) and mirrored bilateral ($R^2=0.70$) reaches. We also show that adding forearm EMG further improves the prediction of forearm pronation/supination during unilateral ($R^2=0.82$) and mirrored bilateral ($R^2=0.75$) reaches. In principle, these results provide the basis for choosing inputs for control of transhumeral prostheses, both by subjects with targeted motor reinnervation (when forearm EMG is available) and by subjects without target motor reinnervation (when forearm EMG is not available). In particular, we confirm that shoulder orientation and upper-arm EMG together best predict elbow flexion/extension ($R^2=0.72$) for three subjects with unilateral transhumeral amputations and targeted motor reinnervation. However, shoulder orientation alone best predicts forearm pronation/supination ($R^2=0.88$) for these subjects, a contradictory result that merits further study.     

Structural Analysis of a Trimer of β2-Microgloblin Fragment by Molecular Dynamics Simulations

A peptide ${\beta }_2$-${\text{m}}_{21?31}$, which is a fragment from residue 21 to residue 31 of ${\beta }_2$-microgloblin, is experimentally known to self-assemble and form amyloid fibrils. In order to understand the mechanism of amyloid fibril formations, we applied the replica-exchange molecular dynamics method to the system consisting of three fragments of ${\beta }_2$-${\text{m}}_{21?31}$. From the analyses on the temperature dependence, we found that there is a clear phase transition temperature in which the peptides aggregate with each other. Moreover, we found by the free energy analyses that there are two major stable states: One of them is like amyloid fibrils and the other is amorphous aggregates.     

A convenient synthesis of bis(phosphino)methanes: Formation of a nickel(II) bis(phosphino)methane monoxide complex

The reaction of (trimethylsilyl)methyl phosphines R₂PCH₂SiMe₃ with chlorophosphines ${\mathrm{ClPR}}_2^{\prime }$ provides ready access to a range of symmetrical or non-symmetrical diphosphinomethanes ${\mathrm{R}}_2{\mathrm{PCH}}_2{\mathrm{PR}}_2^{\prime }$. The products are obtained cleanly and can be used directly in the synthesis of transition metal complexes. This is illustrated by the preparation and structural characterization of the corresponding NiCl₂(P–P) derivatives.     

Tocopheramine succinate and tocopheryl succinate: Mechanism of mitochondrial inhibition and superoxide radical production

Tocopherols (TOH) are lipophilic antioxidants which require the phenolic OH group for their redox activity. In contrast, non-redox active esters of α-TOH with succinate (α-TOS) were shown to possess proapoptotic activity in cancer cells. It was suggested that this activity is mediated via mitochondrial inhibition with subsequent ${\text{O}}_2^{\text{<mglyph src="https://sdfestaticassets-us-east-1.sciencedirectassets.com/shared-assets/16/entities/rad"></mglyph>}-}$ production triggering apoptosis and that the modification of the linker between the succinate and the lipophilic chroman may modulate this activity. However, the specific mechanism and the influence of the linker are not clear yet on the level of the mitochondrial respiratory chain. Therefore, this study systematically compared the effects of α-TOH acetate (α-TOA), α-TOS and α-tocopheramine succinate (α-TNS) in cells and submitochondrial particles (SMP). The results showed that not all cancer cell lines are highly sensitive to α-TOS and α-TNS. In HeLa cells α-TNS did more effectively reduce cell viability than α-TOS. The complex I activity of SMP was little affected by α-TNS and α-TOS while the complex II activity was much more inhibited (IC₅₀ = 42 ± 8 μM α-TOS, 106 ± 8 μM α-TNS, respectively) than by α-TOA (IC₅₀ >1000 μM). Also the complex III activity was inhibited by α-TNS (IC₅₀ = 137 ± 6 μM) and α-TOS (IC₅₀ = 315 ± 23 μM). Oxygen consumption of NADH- or succinate-respiring SMP, involving the whole electron transfer machinery, was dose-dependently decreased by α-TOS and α-TNS, but only marginal effects were observed in the presence of α-TOA. In contrast to the similar inhibition pattern of α-TOS and α-TNS, only α-TOS triggered ${\text{O}}_2^{\text{<mglyph src="https://sdfestaticassets-us-east-1.sciencedirectassets.com/shared-assets/16/entities/rad"></mglyph>}-}$ formation in succinate- and NADH-respiring SMP. Inhibitor studies excluded complex I as ${\text{O}}_2^{\text{<mglyph src="https://sdfestaticassets-us-east-1.sciencedirectassets.com/shared-assets/16/entities/rad"></mglyph>}-}$ source and suggested an involvement of complex III in ${\text{O}}_2^{\text{<mglyph src="https://sdfestaticassets-us-east-1.sciencedirectassets.com/shared-assets/16/entities/rad"></mglyph>}-}$ production. In cancer cells only α-TOS was reproducibly able to increase ${\text{O}}_2^{\text{<mglyph src="https://sdfestaticassets-us-east-1.sciencedirectassets.com/shared-assets/16/entities/rad"></mglyph>}-}$ levels above the background level but neither α-TNS nor α-TOA. Furthermore, the stability of α-TNS in liver homogenates was significantly lower than that of α-TOS. In conclusion, this suggests that α-TNS although it has a structure similar to α-TOS is not acting via the same mechanism and that for α-TOS not only complex II but also complex III interactions are involved.     

Potent covalent inhibitors of bacterial urease identified by activity-reactivity profiling

Covalent enzyme inhibitors constitute a highly important group of biologically active compounds, with numerous drugs available on the market. Although the discovery of inhibitors of urease, a urea hydrolyzing enzyme crucial for the survival of some human pathogens, is a field of medicinal chemistry that has grown in recent years, covalent urease inhibitors have been rarely investigated until now. Forty Michael acceptor-type compounds were screened for their inhibitory activities against bacterial urease, and several structures exhibited high potency in the nanomolar range. The correlation between chemical reactivity towards thiols and inhibitory potency indicated the most valuable compound — acetylenedicarboxylic acid, with $K_i^1=42.5$ nM and $\text{log}{k}_{\mathit{GSH}}=-2.14$. Molecular modelling studies revealed that acetylenedicarboxylic acid is the first example of highly effective mode of binding based on simultaneous bonding to a cysteine residue and interaction with nickel ions present in the active site. Activity-reactivity profiling of reversible covalent enzyme inhibitors is a general method for the identification of valuable drug candidates.     

The consequences of dominance and gene flow for local adaptation and differentiation at two linked loci

For a subdivided population the consequences of dominance and gene flow for the maintenance of multilocus polymorphism, local adaptation, and differentiation are investigated. The dispersing population inhabits two demes in which selection acts in opposite direction. Fitness is determined additively by two linked diallelic loci with arbitrary intermediate dominance (no over- or underdominance). For weak as well as strong migration, the equilibrium structure is derived. As a special case, a continuous-time continent–island model (CI model) is analyzed, with one-way migration from the continent to the island. For this CI model, the equilibrium and stability configuration is obtained explicitly for weak migration, for strong migration, for independent loci, and for complete linkage. For independent loci, the possible bifurcation patterns are derived as functions of the migration rate. These patterns depend strongly on the degree of dominance. The effects of dominance, linkage, and migration on the amount of linkage disequilibrium (LD) and the degree of local adaptation are explored. Explicit formulas are obtained for $D$   $(=x_1{x}_4-x_2{x}_3)$ and $r^2$ (the squared correlation in allelic state). They demonstrate that dominant island alleles increase $D$ and decrease $r^2$. Local adaptation is elevated by dominance of the locally adaptive alleles. The effective migration rate at a linked neutral locus is calculated. If advantageous alleles are dominant, it is decreased only slightly below the actual migration rate. For a quantitative trait that is determined by two additive loci, the influence of dominance on measures of differentiation is studied. Explicit expressions for $Q_{ST}$ and two types of $F_{ST}$ at equilibrium are deduced and their relation is discussed.