Noble Metals as a Source of Continuous Scattering in Fluoride Glasses

Submicrometer scattering centers in fluorozirconate glasses were analyzed in an analytical electron microscope. Spherical platinum particles were found most frequently; other morphologies and noble metals such as gold, rhodium, and iridium were also observed.     

On the Quantum-Mechanical Kinetic Energy as a Measure of the Information in a Distribution

Standard concepts of information theory, including Shannon's entropy, Fisher's information, Jaynes' principle of entropy maximization, Fisher's locality information matrix, and Kullback and Leibler's information measure, are described and extended to many dimensions as appropriate, to establish precise connections between the many body quantum-mechanical kinetic energy functional T[Ψ] and information measures. Implications for density functional theory of electronic structure are discussed, and elementary examples are displayed to illustrate the argument. Among the several exact relations obtained, one of special interest is the identity where the first term is the intrinsic accuracy or Fisher's information for locality of the one-particle density (normalized to 1), \documentclass{article}\pagestyle{empty}, and the second term is the average over the one-particle density of Fisher's information associated with the conditional density \documentclass{article}\pagestyle{empty} that is, the second term is the average over the marginal distribution ρ(1) of the trace of Fisher's information matrix for the distribution f(2,3, …, N|1). Because of this formula, the quantum mechanical variation principle may be precisely stated as a principle of minimal information.     

Some Results Concerning the Asymptotic Distribution of Sample Fourier Transforms and Periodograms for a Discrete-time Stationary Process with a Continuous Spectrum

We consider a stationary process ( X_t , t = 0, ±1, ...) with a continuous spectrum. Denote by D_n (λ) a tapered Fourier transform of ( X ₀, X ₁, ..., X _{n −1}) at (angular) frequency λ. We obtain the asymptotic distribution of D_n (λ) and the joint asymptotic distribution of { D_n (λ _j ), 1 ≤ j ≤ k } with continuity of the spectral density f (.) at the relevant frequencies as the only assumption concerning the second-order structure of ( X_t ); all other assumptions required are easily stated. The results are extended to processes for which f (.) is continuous except at λ = 0, with lim_λ←0 f (λ)λ^{2 d} = K , a constant, where 0 < d < ½, as is typical of certain types of processes with long-range dependence. Results for the sample periodogram, proportional to | D_n (λ)|², follow immediately.     

Approaches to Evaluate the Impact of a Small-Molecule Binder to a Noncatalytic Site of the Proteasome

Proteasome activity is crucial for cell survival and proliferation. In recent years, small molecules have been discovered that can affect the catalytic activity of the proteasome. Rather than targeting the active sites of the proteasome, it might be possible to affect ubiquitin-dependent degradation of proteins by limiting the association of the 19S regulatory particle (19S RP) with the 20S core particle (20S CP) of the proteasome. We recently described the discovery of TXS-8, a peptoid that binds to Rpn-6. Rpn-6 is a proteasome-associated protein that makes critical contacts with the 19S RP and the 20S CP. Herein, we present a general workflow to evaluate the impact of a small-molecule binder on proteasome activity by using TXS-8 as an example. This workflow contains three steps in which specific probes or overexpressed proteins in cells are used to determine whether the hydrolysis activity of the proteasome is affected. Although, in our case, TXS-8 did not affect proteasome activity, our workflow is highly amenable to studying a variety of small-molecule–proteasome subunit interactions.     

Lighting the world's treasures: Approaches to safer museum lighting

A strategy is reported to optimize lighting to reduce photochemical degradation of works of art and archival documents. The strategy revolves around improving luminous efficiency of the spectral profile to exclude light which doesn't contribute to brightness or color perception, while also trying to maintain color rendering. The work focuses on Old Master Drawings and designing filters for illuminants, but is applicable to the broad range of art and archival documents and the direct design of lighting without filters such as LED. A filter profile is identified which seems to be beneficial, or at worst neutral for all pigments measured. Underlying principles are identified: (1) The best luminous efficiencies arise from multiple band illuminants, and also improves as color rendering is sacrificed. (2) Protection of an object even late in its damage life can significantly extend its remaining life. (3) Protection of an object early in its life can possibly abate some of the light induced damage it may experience across its life, so early intervention in light protection may be advised. This report further goes on to suggest approaches to further enhance the protection, including tailoring the spectral dependence of appearance change. © 2010 Wiley Periodicals, Inc. Col Res Appl, 2010     

Vascular Aspects in Glaucoma: From Pathogenesis to Therapeutic Approaches

Glaucomatous optic neuropathies have been regarded as diseases caused by high intraocular pressure for a long time, despite the concept of vascular glaucoma dating back to von Graefe in 1854. Since then, a tremendous amount of knowledge about the ocular vasculature has been gained; cohort studies have established new vascular risk factors for glaucoma as well as identifying protective measures acting on blood vessels. The knowledge about the physiology and pathophysiology of the choroidal, retinal, as well as ciliary and episcleral circulation has also advanced. Only recently have novel drugs based on that knowledge been approved for clinical use, with more to follow. This review provides an overview of the current vascular concepts in glaucoma, ranging from novel pathogenesis insights to promising therapeutic approaches, covering the supply of the optic nerve head as well as the aqueous humor production and drainage system.     

Microglia and Inhibitory Circuitry in the Medullary Dorsal Horn: Laminar and Time-Dependent Changes in a Trigeminal Model of Neuropathic Pain

Craniofacial neuropathic pain affects millions of people worldwide and is often difficult to treat. Two key mechanisms underlying this condition are a loss of the negative control exerted by inhibitory interneurons and an early microglial reaction. Basic features of these mechanisms, however, are still poorly understood. Using the chronic constriction injury of the infraorbital nerve (CCI-IoN) model of neuropathic pain in mice, we have examined the changes in the expression of GAD, the synthetic enzyme of GABA, and GlyT2, the membrane transporter of glycine, as well as the microgliosis that occur at early (5 days) and late (21 days) stages post-CCI in the medullary and upper spinal dorsal horn. Our results show that CCI-IoN induces a down-regulation of GAD at both postinjury survival times, uniformly across the superficial laminae. The expression of GlyT2 showed a more discrete and heterogeneous reduction due to the basal presence in lamina III of ‘patches’ of higher expression, interspersed within a less immunoreactive ‘matrix’, which showed a more substantial reduction in the expression of GlyT2. These patches coincided with foci lacking any perceptible microglial reaction, which stood out against a more diffuse area of strong microgliosis. These findings may provide clues to better understand the neural mechanisms underlying allodynia in neuropathic pain syndromes.     

Synaptic Alterations in a Transgenic Model of Tuberous Sclerosis Complex: Relevance to Autism Spectrum Disorders

Tuberous sclerosis complex (TSC) is a rare, multi-system genetic disease with serious neurological and mental symptoms, including autism. Mutations in the TSC1/TSC2 genes lead to the overactivation of mTOR signalling, which is also linked to nonsyndromic autism. Our aim was to analyse synaptic pathology in a transgenic model of TSC: two-month-old male B6;129S4-Tsc2^tm1Djk/J mice with Tsc2 haploinsufficiency. Significant brain-region-dependent alterations in the expression of several synaptic proteins were identified. The most prominent changes were observed in the immunoreactivity of presynaptic VAMP1/2 (ca. 50% increase) and phospho-synapsin-1 (Ser62/67) (ca. 80% increase). Transmission electron microscopy demonstrated serious ultrastructural abnormalities in synapses such as a blurred structure of synaptic density and a significantly increased number of synaptic vesicles. The impairment of synaptic mitochondrial ultrastructure was represented by excessive elongation, swelling, and blurred crista contours. Polyribosomes in the cytoplasm and swollen Golgi apparatus suggest possible impairment of protein metabolism. Moreover, the delamination of myelin and the presence of vacuolar structures in the cell nucleus were observed. We also report that Tsc2^+/− mice displayed increased brain weights and sizes. The behavioural analysis demonstrated the impairment of memory function, as established in the novel object recognition test. To summarise, our data indicate serious synaptic impairment in the brains of male Tsc2^+/− mice.     

Approaches to Introduce Helical Structure in Cysteine-Containing Peptides with a Bimane Group

An i−i+4 or i−i+3 bimane-containing linker was introduced into a peptide known to target Estrogen Receptor alpha (ERα), in order to stabilise an α-helical geometry. These macrocycles were studied by CD and NMR to reveal the i−i+4 constrained peptide adopts a 3₁₀-helical structure in solution, and an α-helical conformation on interaction with the ERα coactivator recruitment surface in silico. An acyclic bimane-modified peptide is also helical, when it includes a tryptophan or tyrosine residue; but is significantly less helical with a phenylalanine or alanine residue, which indicates such a bimane modification influences peptide structure in a sequence dependent manner. The fluorescence intensity of the bimane appears influenced by peptide conformation, where helical peptides displayed a fluorescence increase when TFE was added to phosphate buffer, compared to a decrease for less helical peptides. This study presents the bimane as a useful modification to influence peptide structure as an acyclic peptide modification, or as a side-chain constraint to give a macrocycle.     

Trail-following pheromones of the rhinotermitidae: Approaches to their authentication and specificity

A method for determining the authenticity of subterranean termite trail pheromones is suggested and utilized to verify the presence of trail pheromones inReticulitermes virginicus, R. flavipes, andR. tibialis. In addition, a possible trail pheromone has been demonstrated forCoptotermes formosanus. A choice bioassay method shows that the above trail pheromones are species specific.     

Adverse Impact of Diet-Induced Hypercholesterolemia on Cardiovascular Tissue Homeostasis in a Rabbit Model: Time-Dependent Changes in Cardiac Parameters

The present study evaluates a hypothesis that diet-related hypercholesterolemia increases oxidative stress-related burden to cardiovascular tissue, resulting in progressively increased mortality, along with deterioration of electrophysiological and enzymatic function in rabbit myocardium. New Zealand white rabbits were divided into four groups, defined as follows: GROUP I, cholesterol-free rabbit chow for 12 weeks; GROUP II, cholesterol-free chow, 40 weeks; GROUP III, chow supplemented with 2% cholesterol, 12 weeks; GROUP IV, chow supplemented with 2% cholesterol, 40 weeks. At the 12 and 40 weeks time points, animals in each of the aforementioned cohorts were subjected to echocardiographic measurements, followed by sacrifice. Significant deterioration in major outcome variables measured in the present study were observed only in animals maintained for 40 weeks on 2% cholesterol-supplemented chow, with much lesser adverse effects noted in animals fed high cholesterol diets for only 12 weeks. It was observed that rabbits receiving high cholesterol diets for 40 weeks exhibited significantly increased mortality, worsened ejection fraction and general deterioration of cardiac functions, along with increased atherosclerotic plaque formation and infarct size. Additionally, myocardium of GROUP IV animals was observed to contain lower levels of heme oxygenase-1 (HO-1) and cytochrome c oxidase III (COX III) protein relative to the controls.     

微通道反应器中苄亚甲基二氯水解制苯甲醛连续流工艺

以苄亚甲基二氯为原料,盐酸为催化剂,在微通道反应器中连续合成了苯甲醛。考察了苄亚甲基二氯水解反应的温度、盐酸催化剂起始浓度、反应物料摩尔比以及停留时间对反应的影响。实验确定了较优的工艺参数组合：在起始浓度为20%（质量分数）的盐酸催化下,水解反应温度为140 ℃,盐酸与苄亚甲基二氯物料摩尔比为15∶1,停留时间为370 s时,苄亚甲基二氯的转化率达到69.2%,GC选择性超过99.9%。与传统生产工艺相比,实现了连续化操作,缩短了反应时间;采用盐酸作催化剂,避免了传统金属催化剂残留对产品的影响。     

Analysis of Protein Adsorption to Ion Exchangers in a Finite Bath

The adsorption of proteins to ion exchangers was investigated by finite bath experiments and by computer simulations using existing rate models. Experimental data were obtained for the binding of bovine serum albumin at different feed concentrations to both cation and anion exchangers. The results were interpreted together with model predictions and the values of the parameters characterizing the mass transfer mechanisms as well as the interaction rates of the adsorbate–adsorbent complex were estimated. The best agreement between theory and experiment throughout the whole period of adsorption process was obtained with a complex model where several steps of the overall mechanism were simultaneously controlling the overall rate. The simplified models, which offer rapid solution requiring less computational power, can be used at low feed concentrations of the proteins where the mechanisms controlling the adsorption rate are less complex. As the interaction rate mechanism and the intraparticle mass transfer mechanism in the adsorbent particles are the same in both finite bath and column adsorption systems, the information presented in this paper can be used to predict the protein adsorption in a column chromatography system. © 1997 SCI.     

Cells to the Rescue: Emerging Cell-Based Treatment Approaches for NMOSD and MOGAD

Cell-based therapies are gaining momentum as promising treatments for rare neurological autoimmune diseases, including neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody-associated disease. The development of targeted cell therapies is hampered by the lack of adequate animal models that mirror the human disease. Most cell-based treatments, including HSCT, CAR-T cell, tolerogenic dendritic cell and mesenchymal stem cell treatment have entered early stage clinical trials or have been used as rescue treatment in treatment-refractory cases. The development of antigen-specific cell-based immunotherapies for autoimmune diseases is slowed down by the rarity of the diseases, the lack of surrogate outcomes and biomarkers that are able to predict long-term outcomes and/or therapy effectiveness as well as challenges in the manufacturing of cellular products. These challenges are likely to be overcome by future research.     

Various Approaches to Studying the Phase Transition in an Octamethylcyclotetrasiloxane Crystal: From X-ray Structural Analysis to Metadynamics

The structure, thermodynamic parameters, and the character of thermal motion in octamethylcyclotetrasiloxane (D4) were investigated using the combination of experimental (single-crystal X-ray diffraction, thermochemistry) and theoretical (density functional theory calculations, ab initio molecular dynamics and metadynamics) methods. Single crystals of D4 were grown in a glass capillary in situ and the structures of high- (238–270 K) and low-temperature (100–230 K) phases were studied in detail. In the temperature interval 230–238 K, a phase transition with rather low enthalpy (−1.04(7) kcal/mol) was detected. It was found that phase transition is accompanied by change of conformation of cyclosiloxane moiety from boat-saddle (cradle) to chair. According to PBE0/6-311G(d,p) calculation of isolated D4, such conformation changes are characterized by a low barrier (0.07 kcal/mol). The character of molecular thermal motion and the path of phase transition were established with combination of periodic DFT calculations, including molecular dynamics and metadynamics. The effect of crystal field led to an increase in the calculated phase transition barrier (4.27 kcal/mol from low- to high-temperature phase and 3.20 kcal/mol in opposite direction).     

Approaches to enzyme and substrate design of the murine Dnmt3a DNA methyltransferase

Dnmt3a‐C, the catalytic domain of the Dnmt3a DNA‐(cytosine‐C5)‐methyltransferase, is active in an isolated form but, like the full‐length Dnmt3a, shows only weak DNA methylation activity. To improve this activity by directed evolution, we set up a selection system in which Dnmt3a‐C methylated its own expression plasmid in E. coli, and protected it from cleavage by methylation‐sensitive restriction enzymes. However, despite screening about 400 clones that were selected in three rounds from a random mutagenesis library of 60 000 clones, we were not able to isolate a variant with improved activity, most likely because of a background of uncleaved plasmids and plasmids that had lost the restriction sites. To improve the catalytic activity of Dnmt3a‐C by optimization of the sequence of the DNA substrate, we analyzed its flanking‐sequence preference in detail by bisulfite DNA‐methylation analysis and sequencing of individual clones. Based on the enrichment and depletion of certain bases in the positions flanking >1300 methylated CpG sites, we were able to define a sequence‐preference profile for Dnmt3a‐C from the ?6 to the +6 position of the flanking sequence. This revealed preferences for T over a purine at position ?2, A over G at ?1, a pyrimidine at +1, and A and T over G at +3. We designed one “good” substrate optimized for methylation and one “bad” substrate designed not to be efficiently methylated, and showed that the optimized substrate is methylated >20 times more rapidly at its central CpG site. The optimized Dnmt3a‐C substrate can be applied in enzymatic high‐throughput assays with Dnmt3a‐C (e.g., for inhibitor screening), because the increased activity provides an improved dynamic range and better signal/noise ratio.