New players on the center stage: sphingosine 1-phosphate and its receptors as drug targets

The recent identification of a cellular balance between ceramide and sphingosine 1-phosphate (S1P) as a critical regulator of cell growth and death has stimulated increasing research effort to clarify the role of ceramide and S1P in various diseases associated with dysregulated cell proliferation and apoptosis. S1P acts mainly, but not exclusively, by binding to and activating specific cell surface receptors, the so-called S1P receptors. These receptors belong to the class of G protein-coupled receptors that constitute five subtypes, denoted as S1P(1)-S1P(5), and represent attractive pharmacological targets to interfere with S1P action. Whereas classical receptor antagonists will directly block S1P action, S1P receptor agonists have also proven useful, as recently shown for the sphingolipid-like immunomodulatory substance FTY720. When phosphorylated by sphingosine kinase to yield FTY720 phosphate, it acutely acts as an agonist at S1P receptors, but upon prolonged presence, it displays antagonistic activity by specifically desensitizing the S1P(1) receptor subtype. This commentary will cover the most recent developments in the field of S1P receptor pharmacology and highlights the potential therapeutic benefit that can be expected from these novel drug targets in the future.

Epothilones as lead structures for the synthesis-based discovery of new chemotypes for microtubule stabilization

Epothilones are macrocyclic bacterial natural products with potent microtubule-stabilizing and antiproliferative activity. They have served as successful lead structures for the development of several clinical candidates for anticancer therapy. However, the structural diversity of this group of clinical compounds is rather limited, as their structures show little divergence from the original natural product leads. Our own research has explored the question of whether epothilones can serve as a basis for the development of new structural scaffolds, or chemotypes, for microtubule stabilization that might serve as a basis for the discovery of new generations of anticancer drugs. We have elaborated a series of epothilone-derived macrolactones whose overall structural features significantly deviate from those of the natural epothilone scaffold and thus define new structural families of microtubule-stabilizing agents. Key elements of our hypermodification strategy are the change of the natural epoxide geometry from cis to trans, the incorporation of a conformationally constrained side chain, the removal of the C3-hydroxyl group, and the replacement of C12 with nitrogen. So far, this approach has yielded analogs 30 and 40 that are the most advanced, the most rigorously modified, structures, both of which are potent antiproliferative agents with low nanomolar activity against several human cancer cell lines in vitro. The synthesis was achieved through a macrolactone-based strategy or a high-yielding RCM reaction. The 12-aza-epothilone ("azathilone" 40) may be considered a "non-natural" natural product that still retains most of the overall structural characteristics of a true natural product but is structurally unique, because it lies outside of the general scope of Nature's biosynthetic machinery for polyketide synthesis. Like natural epothilones, both 30 and 40 promote tubulin polymerization in vitro and at the cellular level induce cell cycle arrest in mitosis. These facts indicate that cancer cell growth inhibition by these compounds is based on the same mechanistic underpinnings as those for natural epothilones. Interestingly, the 9,10-dehydro analog of 40 is significantly less active than the saturated parent compound, which is contrary to observations for natural epothilones B or D. This may point to differences in the bioactive conformations of N-acyl-12-aza-epothilones like 40 and natural epothilones. In light of their distinct structural features, combined with an epothilone-like (and taxol-like) in vitro biological profile, 30 and 40 can be considered as representative examples of new chemotypes for microtubule stabilization. As such, they may offer the same potential for pharmacological differentiation from the original epothilone leads as various newly discovered microtubule-stabilizing natural products with macrolactone structures, such as laulimalide, peloruside, or dictyostatin.

THE USE OF LIFE-CYCLE ANALYSIS TO REDUCE THE ENVIRONMENTAL IMPACT OF MATERIALS IN MANUFACTURING

This thesis is composed of three life-cycle analysis (LCA) studies of manufacturing to determine cumulative energy demand (CED) and greenhouse gas emissions (GHG). The methods proposed could reduce the environmental impact by reducing the CED in three manufacturing processes. First, industrial symbiosis is proposed and a LCA is performed on both conventional 1 GW-scaled hydrogenated amorphous silicon (a-Si:H)-based single junction and a-Si:H/microcrystalline-Si:H tandem cell solar PV manufacturing plants and such plants coupled to silane recycling plants. Using a recycling process that results in a silane loss of only 17 versus 85 percent, this results in a CED savings of 81,700 GJ and 290,000 GJ per year for single and tandem junction plants, respectively. This recycling process reduces the cost of raw silane by 68 percent, or approximately $22.6 and $79 million per year for a single and tandem 1 GW PV production facility, respectively. The results show environmental benefits of silane recycling centered around a-Si:H-based PV manufacturing plants. Second, an open-source self-replicating rapid prototype or 3-D printer, the RepRap, has the potential to reduce the environmental impact of manufacturing of polymer-based products, using distributed manufacturing paradigm, which is further minimized by the use of PV and improvements in PV manufacturing. Using 3-D printers for manufacturing provides the ability to ultra-customize products and to change fill composition, which increases material efficiency. An LCA was performed on three polymer-based products to determine the CED and GHG from conventional large-scale production and are compared to experimental measurements on a RepRap producing identical products with ABS and PLA. The results of this LCA study indicate that the CED of manufacturing polymer products can possibly be reduced using distributed manufacturing with existing 3-D printers under 89% fill and reduced even further with a solar photovoltaic system. The results indicate that the ability of RepRaps to vary fill has the potential to diminish environmental impact on many products. Third, one additional way to improve the environmental performance of this distributed manufacturing system is to create the polymer filament feedstock for 3-D printers using post-consumer plastic bottles. An LCA was performed on the recycling of high density polyethylene (HDPE) using the RecycleBot. The results of the LCA showed that distributed recycling has a lower CED than the best-case scenario used for centralized recycling. If this process is applied to the HDPE currently recycled in the U.S., more than 100 million MJ of energy could be conserved per annum along with significant reductions in GHG. This presents a novel path to a future of distributed manufacturing suited for both the developed and developing world with reduced environmental impact. From improving manufacturing in the photovoltaic industry with the use of recycling to recycling and manufacturing plastic products within our own homes, each step reduces the impact on the environment. The three coupled projects presented here show a clear potential to reduce the environmental impact of manufacturing and other processes by implementing complimenting systems, which have environmental benefits of their own in order to achieve a compounding effect of reduced CED and GHG.

An Isopach Map and a Discussion of the Permian in Wyoming and Adjacent Areas

The accelerated post-war demand for petroleum products with resultant high prices and dwindling reserves has spurred producers to an extensive search for new fields and for ad­ditional production in known fields. Exploration and discov­ery is dependent on the collection and correlation of vast amounts of data both in the field and that found in liter­ature.

[Casein phosphopeptide--amorphous calcium phosphate (CPP-ACP) and its effect on dental hard tissues]

Dental products with casein phosphopeptide--amorphous calcium phosphate-nanocomplexes (CPP-ACP) are used in several tooth products (toothpastes, chewing gums, mouthrinses) and are as well used in dental filling material. CPP-ACP containing products are supposed to enhance remineralisation of dental hard tissues und thus might play a major role in prevention and therapy of initial caries or erosively dissolved enamel. Furthermore, also in hypersensitive teeth and even cases of hyposalivation, CPP-ACP containig products are supposed to improve the clinical condition. This article aims at three goals: point out the evolvement of CPP-ACP out of milk casein; description of possible biochemical effects of CPP-ACP on dental hard tissues; critical review of the current literature.

Properties comparison of Injected and SLS material

Most of the plastic injection companies are focused in the production of some products with a high exigency standard levels. That is why, to compete and gain some market share in front of the concurrency of companies from other countries, they need to be able to introduce new rapid prototyping techniques and product development.

Diseases in neonatal foals. Part 2: potential risk factors for a higher incidence of infectious diseases during the first 30 days post partum

REASON FOR PERFORMING STUDY: The development of clinical illness in foals is usually predetermined by perinatal history, management or stressful environmental conditions. OBJECTIVES: To determine potential risk factors for an increased incidence of infectious diseases during the first 30 days post partum. METHODS: The population consisted of Thoroughbred foals born on stud farms in the Newmarket (UK) area in 2005 (n = 1031). They were followed for their first 30 days. Factors suspected to influence the incidence of infectious neonatal diseases were examined in a logistic regression approach for each of the 3 outcomes (total infectious diseases, systemic disease with diarrhoea and total infectious diseases excluding diarrhoea). All 28 factors were either foal or mare or stud farm related. RESULTS: Several significant risk factors for a higher disease incidence, such as birth complications, colostrum intake by stomach tube and leucocytosis 12-48 h post partum were identified. The factor 'boarding stud' seemed to be protective against disease. CONCLUSION: Some factors, such as the mare's time at stud before foaling, the mare's rotavirus vaccination schedule and fibrinogen-values that empirically had been linked to the outcome previously were not confirmed as relevant. This included the reported useful prophylactic treatment with antimicrobial drugs. POTENTIAL RELEVANCE: Factors to be considered when evaluating newborn foals include: stud management, the birth process, route of colostrum intake, white and red blood cells, and the date of birth. These may help to detect foals at risk to develop an infection so that targeted prophylactic measures can be initiated.

Asymmetric cyclopropanation of olefins catalysed by Cu(I) complexes of chiral pyridine-containing macrocyclic ligands (Pc-L*)

The synthesis and characterisation of copper(I) complexes of chiral pyridine-containing macrocyclic ligands (Pc-L*) and their use as catalysts in asymmetric cyclopropanation reactions are reported. All ligands and metal complexes were fully characterised, including crystal structures of some species determined by X-ray diffraction on single crystals. This allowed characterising the very different conformations of the macrocycles which could be induced by different substituents or by metal complexation. The strategy adopted for the ligand synthesis is very flexible allowing several structural modifications. A small library of macrocyclic ligands possessing the same donor properties but with either C-1 or C-2 symmetry was synthesized. Cyclopropane products with both aromatic and aliphatic olefins were obtained in good yields and enantiomeric excesses up to 99%.

Two new flavonol glycosides and a metabolite profile of Bryophyllum pinnatum, a phytotherapeutic used in obstetrics and gynaecology

Bryophyllum pinnatum is a succulent perennial plant native to Madagascar which is used in anthroposophical medicine to treat psychiatric disorders and as a tocolytic agent to prevent premature labour. We performed a metabolite profiling study in order to obtain a comprehensive picture of the constituents in B. pinnatum leaves and to identify chromatographic markers for quality control and safety assessment of medicinal preparations. Preliminary HPLC-PDA-ESIMS analyses revealed that flavonoid glycosides were the main UV-absorbing constituents in the MeOH extract of B. pinnatum. Two phenolic glucosides, syringic acid β-D-glucopyranosyl ester (1) and 4'-O-β-D-glucopyranosyl-cis-p-coumaric acid (2), as well as nine flavonoids (3-11) including kaempferol, quercetin, myricetin, acacetin, and diosmetin glycosides were unambiguously identified by 1H and 2D NMR analysis after isolation from a MeOH extract. The flavonol glycosides quercetin 3-O-α-L-arabinopyranosyl-(1 → 2)-α-L-rhamnopyranoside 7-O-β-D-glucopyranoside (3) and myricetin 3-O-α-L-arabinopyranosyl-(1 → 2)-α-L-rhamnopyranoside (4) were new natural products. With the aid of HPLC-PDA-APCIMS and authentic references isolated from the related species B. daigremontianum, the presence of four bufadienolides, bersaldegenin-1-acetate (12), bryophyllin A (13), bersaldegenin-3-acetate (14), and bersaldegenin-1,3,5-orthoacetate (15) was detected in B. pinnatum.

Spider Ecophysiology

With over 43,000 species, spiders are the largest predacious arthropod group. They have developed key characteristics such as multi-purpose silk types, venoms consisting of hundreds of components, locomotion driven by muscles and hydraulic pressure, a highly evolved key-lock mechanism between the complex genital structures, and many more unique features. After 300 million years of evolutionary refinement, spiders are present in all land habitats and represent one of the most successful groups of terrestrial organisms. Ecophysiology combines functional and evolutionary aspects of morphology, physiology, biochemistry and molecular biology with ecology. Cutting-edge science in spiders focuses on the circulatory and respiratory system, locomotion and dispersal abilities, the immune system, endosymbionts and pathogens, chemical communication, gland secretions, venom components, silk structure, structure and perception of colours as well as nutritional requirements. Spiders are valuable indicator species in agroecosystems and for conservation biology. Modern transfer and application technologies research spiders and their products with respect to their value for biomimetics, material sciences, and the agrochemical and pharmaceutical industries.

Erosion in relation to nutrition and the environment.

When considering the erosive potential of a food or drink, a number of factors must be taken into account. pH is arguably the single most important parameter in determining the rate of erosive tissue dissolution. There is no clear-cut critical pH for erosion as there is for caries. At low pH, it is possible that other factors are sufficiently protective to prevent erosion, but equally erosion can progress in acid of a relatively high pH in the absence of mitigating factors. Calcium and phosphate concentration, in combination with pH, determine the degree of saturation with respect to tooth minerals. Solutions supersaturated with respect to enamel or dentine will not cause them to dissolve, meaning that given sufficient common ion concentrations erosion will not proceed, even if the pH is low. Interestingly, the addition of calcium is more effective than phosphate at reducing erosion in acid solutions. Today, several calcium-enriched soft drinks are on the market, and acidic products with high concentrations of calcium and phosphorus are available (such as yoghurt), which do not soften the dental hard tissues. The greater the buffering capacity of the drink or food, the longer it will take for the saliva to neutralize the acid. A higher buffer capacity of a drink or foodstuff will enhance the processes of dissolution because more release of ions from the tooth mineral is required to render the acid inactive for further demineralization. Temperature is also a significant physical factor; for a given acidic solution, erosion proceeds more rapidly the higher the temperature of that solution. In recent years, a number of interesting potentially erosion-reducing drink and food additives have been investigated.

Electrospray tandem mass spectrometry of mixed-sequence RNA/DNA oligonucleotides

The fragmentation of electrospray-generated multiply deprotonated RNA and mixed-sequence RNA/DNA pentanucleotides upon low-energy collision-induced dissociation (CID) in a hybrid quadrupole time-of-flight mass spectrometer was investigated. The goal of unambiguous sequence identification of mixed-sequence RNA/DNA oligonucleotides requires detailed understanding of the gas-phase dissociation of this class of compounds. The two major dissociation events, base loss and backbone fragmentation, are discussed and the unique fragmentation behavior of oligoribonucleotides is demonstrated. Backbone fragmentation of the all-RNA pentanucleotides is characterized by abundant c-ions and their complementary y-ions as the major sequence-defining fragment ion series. In contrast to the dissociation of oligodeoxyribonucleotides, where backbone fragmentation is initiated by the loss of a nucleobase which subsequently leads to the formation of the w- and [a-base]-ions, backbone dissociation of oligoribonucleotides is essentially decoupled from base loss. The different behavior of RNA and DNA oligonucleotides is related to the presence of the 2'-hydroxyl substituent, which is the only structural alteration between the DNA and RNA pentanucleotides studied. CID of mixed-sequence RNA/DNA pentanucleotides results in a combination of the nucleotide-typical backbone fragmentation products, with abundant w-fragment ions generated by cleavage of the phosphodiester backbone adjacent to the deoxy building blocks, whereas backbone cleavage adjacent to ribonucleotides induces the formation of c- and y-ions. (C) 2002 American Society for Mass Spectrometry.

Impact of Taylor-Aris diffusivity on analyte and system zone dispersion in CZE assessed by computer simulation and experimental validation.

Application of pressure-driven laminar flow has an impact on zone and boundary dispersion in open tubular CE. The GENTRANS dynamic simulator for electrophoresis was extended with Taylor-Aris diffusivity which accounts for dispersion due to the parabolic flow profile associated with pressure-driven flow. Effective diffusivity of analyte and system zones as functions of the capillary diameter and the amount of flow in comparison to molecular diffusion alone were studied for configurations with concomitant action of imposed hydrodynamic flow and electroosmosis. For selected examples under realistic experimental conditions, simulation data are compared with those monitored experimentally using modular CE setups featuring both capacitively coupled contactless conductivity and UV absorbance detection along a 50 μm id fused-silica capillary of 90 cm total length. The data presented indicate that inclusion of flow profile based Taylor-Aris diffusivity provides realistic simulation data for analyte and system peaks, particularly those monitored in CE with conductivity detection.

The Role of Forest Soils in a Northern New England Effluent Management System

The Carrabassett Valley Sanitary District in Carrabassett Valley, Maine has utilized both a forest spray irrigation system and a Snowfluent™ system for the treatment of their wastewater effluent. This study was designed to evaluate potential changes in soil properties after approximately 20 years of treatment in the forested spray irrigation site and three years of treatment in the field Snowfluent™ site. In addition, grass yield and composition were evaluated on the field study sites. After treatment with effluent or Snowfluent™, soils showed an increase in soil exchangeable Ca, Mg, Na, and K, base saturation, and pH. While most constituents were higher in treated soils, available P was lower in treated soils compared to the controls. This difference was attributed to higher rates of P mineralization from soil organic matter due to an irrigation effect of the treatment, depleting available P pools despite the P addition with the treatment. Most of the differences due to treatment were greatest at the surface and diminished with depth. Depth patterns in soil properties mostly reflected the decreasing influence of organic matter and its decomposition products with depth as evidenced by significantly higher total C in the surface compared to lower horizons. There were decreasing concentrations of total N, and exchangeable or extractable Ca, Mg, Na, K, Mn, Zn, and P with depth. In addition, there was decreasing BS with depth, driven primarily by declining exchangeable Ca and Mg. Imgation with Snowfluent™ altered the chemical composition of the grass on the site. All element concentrations were significantly higher in the grass foliage except for Ca. The differences were attributed to the additional nutrients and moisture derived from the Snowfluent™. The use of forest spray imgation and Snowfluent™ as a wastewater treatment strategy appears to work well. The soil and vegetation were able to retain most of the applied nutrients, and do not appear to be moving toward saturation. Vegetation management may be a key tool for managing nutrient accumulation on the grass sites as the system ages.

What Is Known about Testing for Discrimination: Lessons Learned by Comparing across Different Markets

The paper provides a fairly comprehensive examination of recent empirical work on discrimination within economics. The three major analytical approaches considered are traditional regression analysis of outcomes, paired testing or audits, and finally analysis of performance where higher group performance suggests that a group has been treated disfavorably. The review covers research in the labor, credit, and consumption markets, as well as recent studies of discrimination within the legal system. The review suggests that the validity of interpreting observed racial differences as discrimination depends heavily on whether the analysis is based on a sample that is representative of a population of individuals or households or based on a sample of market transactions, as well as the analyst?s ability to control for heterogeneity within that sample. Heterogeneous firm behavior and differentiated products, such as those found in labor and housing markets, also can confound empirical analyses of discrimination by confusing the allocation of individuals across firms or products with disparate treatment or by ignoring disparate impacts that might arise based on that allocation.