Approaches to Identify Inhibitors of Melanin Biosynthesis via the Quality Control of Tyrosinase

Tyrosinase, a copper-containing glycoprotein, is the rate-limiting enzyme critical for melanin biosynthesis in specialized organelles termed melanosomes that are produced only by melanocytic cells. Inhibitors of tyrosinase activity have long been sought as therapeutic means to treat cutaneous hyperpigmentary disorders. Multiple potential approaches exist that could control pigmentation via the regulation of tyrosinase activity, for example: the transcription of its messenger RNA, its maturation via glycosylation, its trafficking to melanosomes, as well as modulation of its catalytic activity and/or stability. However, relatively little attention has been paid to regulating pigmentation via the stability of tyrosinase, which depends on its processing and maturation in the endoplasmic reticulum and Golgi, its delivery to melanosomes and its degradation via the ubiquitin-proteasome pathway and/or the endosomal/lysosomal system. Recently, it has been shown that carbohydrate modification, molecular chaperone engagement, and ubiquitylation all play pivotal roles in regulating the degradation/stability of tyrosinase. While such processes affect virtually all proteins, such effects on tyrosinase have immediate and dramatic consequences on pigmentation. In this review, we classify melanogenic inhibitory factors in terms of their modulation of tyrosinase function and we summarize current understanding of how the quality control of tyrosinase processing impacts its stability and melanogenic activity

Optimized Synthesis, Structural Investigations, Ligand Tuning and Synthetic Evaluation of Silyloxy-Based Alkyne Metathesis Catalysts

Nitride- and alkylidyne complexes of molybdenum endowed with triarylsilanolate ligands are excellent (pre)catalysts for alkyne-metathesis reactions of all sorts, since they combine high activity with an outstanding tolerance toward polar and/or sensitive functional groups. Structural and reactivity data suggest that this promising application profile results from a favorable match between the characteristics of the high-valent molybdenum center and the electronic and steric features of the chosen Ar3SiO groups. This interplay ensures a well-balanced level of Lewis acidity at the central atom, which is critical for high activity. Moreover, the bulky silanolates, while disfavoring bimolecular decomposition of the operative alkylidyne unit, do not obstruct substrate binding. In addition, Ar3SiO groups have the advantage that they are more stable within the coordination sphere of a high-valent molybdenum center than tert-alkoxides, which commonly served as ancillary ligands in previous generations of alkyne metathesis catalysts. From a practical point of view it is important to note that complexes of the general type [(Ar3SiO)3MoΞX] (X = N, CR; R = aryl, alkyl, Ar = aryl) can be rendered air-stable with the aid of 1,10-phenanthroline, 2,2′-bipyridine or derivatives thereof. Although the resulting adducts are themselves catalytically inert, treatment with Lewis acidic additives such as ZnCl2 or MnCl2 removes the stabilizing N-donor ligand and gently releases the catalytically active template into the solution. This procedure gives excellent results in alkyne metathesis starting from air-stable and hence user-friendly precursor complexes. The thermal and hydrolytic stability of representative molybdenum alkylidyne and -nitride complexes of this series was investigated and the structure of several decomposition products elucidated

The cross-species immunity during acute Babesia co-infection in mice

Babesiosis causes high morbidity and mortality in immunocompromised individuals. An earlier study suggested that lethal Babesia rodhaini infection in murine can be evaded by Babesia microti primary infection via activated macrophage-based immune response during the chronic stage of infection. However, whether the same immune dynamics occur during acute B. microti co-infection is not known. Hence, we used the mouse model to investigate the host immunity during simultaneous acute disease caused by two Babesia species of different pathogenicity. Results showed that B. microti primary infection attenuated parasitemia and conferred immunity in challenge-infected mice as early as day 4 post-primary infection. Likewise, acute Babesia co-infection undermined the splenic immune response, characterized by the significant decrease in splenic B and T cells leading to the reduction in antibody levels and decline in humoral immunity. Interestingly, increased macrophage and natural killer splenic cell populations were observed, depicting their subtle role in the protection. Pro-inflammatory cytokines (i.e. IFN-γ, TNF-α) were downregulated, while the anti-inflammatory cytokine IL-10 was upregulated in mouse sera during the acute phase of Babesia co-infection. Herein, the major cytokines implicated in the lethality caused by B. rodhaini infection were IFN- γ and IL-10. Surprisingly, significant differences in the levels of serum IFN- γ and IL-10 between co-infected survival groups (day 4 and 6 challenge) indicated that even a two-day delay in challenge infection was crucial for the resulting pathology. Additionally, oxidative stress in the form of reactive oxygen species contributed to the severity of pathology during acute babesiosis. Histopathological examination of the spleen showed that the erosion of the marginal zone was more pronounced during B. rodhaini infection, while the loss of cellularity of the marginal zone was less evident during co-infection. Future research warrants investigation of the roles of various immune cell subtypes in the mechanism involved in the protection of Babesia co-infected hosts

Determining biosensing modes in SH-SAW device using 3D finite element analysis

Surface acoustic wave (SAW) sensors are electromechanical devices that exploit the piezoelectric effect to induce elastic (acoustic) waves which are sensitive to small perturbations: for example specific binding and recognition of disease biomarkers. Shear horizontal surface acoustic waves (SH-SAWs) are particularly suited to biosample analysis as the wave is not completely radiated and lost into the liquid medium (e.g., blood, saliva) as is the case, for example, in a device implementing Rayleigh waves. Here, using 3D finite element analysis (FEA) the nature of waves launched on a particular quartz device is investigated with respect to the cut of the quartz, the addition of gold guiding layers, and the addition of other linear elastic materials of contrasting acoustic properties. It is demonstrated that 3D FEA analysis showing the device's frequency shift with added guiding layer height reveals a proportional relationship in agreement with the Sauerbrey equation from perturbation theory. It is directly shown, given certain device parameters and a gold guiding layer, that shear horizontally polarized waves are launched on the surface with a dominant mode frequency around 250 MHz. This would be an appropriate biosensing mode in Point of Care (POC) testing for the particular properties of certain disease biomarkers delivered via a liquid medium

Vectorial Control of Magnetization by Light

Coherent light-matter interactions have recently extended their applications to the ultrafast control of magnetization in solids. An important but unrealized technique is the manipulation of magnetization vector motion to make it follow an arbitrarily designed multi-dimensional trajectory. Furthermore, for its realization, the phase and amplitude of degenerate modes need to be steered independently. A promising method is to employ Raman-type nonlinear optical processes induced by femtosecond laser pulses, where magnetic oscillations are induced impulsively with a controlled initial phase and an azimuthal angle that follows well defined selection rules determined by the materials' symmetries. Here, we emphasize the fact that temporal variation of the polarization angle of the laser pulses enables us to distinguish between the two degenerate modes. A full manipulation of two-dimensional magnetic oscillations is demonstrated in antiferromagnetic NiO by employing a pair of polarization-twisted optical pulses. These results have lead to a new concept of vectorial control of magnetization by light

Large oxygen-isotope effect in Sr_{0.4}K_{0.6}BiO_{3}: Evidence for phonon-mediated superconductivity

Oxygen-isotope effect has been investigated in a recently discovered superconductor Sr_{0.4}K_{0.6}BiO_{3}. This compound has a distorted perovskite structure and becomes superconducting at about 12 K. Upon replacing ^{16}O with ^{18}O by 60-80%, the T_c of the sample is shifted down by 0.32-0.50 K, corresponding to an isotope exponent of alpha_{O} = 0.40(5). This isotope exponent is very close to that for a similar bismuthate superconductor Ba_{1-x}K_{x}BiO_{3} with T_c = 30 K. The very distinctive doping and T_c dependencies of alpha_{O} observed in bismuthates and cuprates suggest that bismuthates should belong to conventional phonon-mediated superconductors while cuprates might be unconventional supercondutors.Comment: 9 pages, 5 figure

Networked buffering: a basic mechanism for distributed robustness in complex adaptive systems

A generic mechanism - networked buffering - is proposed for the generation of robust traits in complex systems. It requires two basic conditions to be satisfied: 1) agents are versatile enough to perform more than one single functional role within a system and 2) agents are degenerate, i.e. there exists partial overlap in the functional capabilities of agents. Given these prerequisites, degenerate systems can readily produce a distributed systemic response to local perturbations. Reciprocally, excess resources related to a single function can indirectly support multiple unrelated functions within a degenerate system. In models of genome:proteome mappings for which localized decision-making and modularity of genetic functions are assumed, we verify that such distributed compensatory effects cause enhanced robustness of system traits. The conditions needed for networked buffering to occur are neither demanding nor rare, supporting the conjecture that degeneracy may fundamentally underpin distributed robustness within several biotic and abiotic systems. For instance, networked buffering offers new insights into systems engineering and planning activities that occur under high uncertainty. It may also help explain recent developments in understanding the origins of resilience within complex ecosystems. \ud \u