Defining key structural determinants for the pro-osteogenic activity of flavonoids

Epidemiological studies suggest that fruits and vegetables may play a role in promoting bone growth and preventing age-related bone loss, attributable, at least in part, to phytochemicals such as flavonoids stimulating osteoblastogenesis. Through systematically screening the effect of flavonoids on the osteogenic differentiation of human mesenchymal stem cells in vitro, and correlating activity with chemical structure using comparative molecular field analysis, we have successfully identified important structural features which relate to their activity, as well as reliably predicting the activity of compounds with unknown activity. Contour maps emphasised the importance of electronegativity, steric bulk, and a 2-C-3-C double bond at the flavonoid C-ring, as well as overall electropositivity and reduced steric bulk at the flavonoid B-ring. These results support a role for certain flavonoids in promoting osteogenic differentiation, thus their potential for preventing skeletal deterioration, as well as providing a foundation for the lead optimisation of novel bone anabolics.

Achieving customer satisfaction through integrated products and services: an exploratory study

Complex products such as manufacturing equipment have always needed maintenance and repair services. Increasingly, leading manufacturers are integrating products and services to generate increased revenues and achieve customer satisfaction. Designing integrated products and services requires a different approach to new product development and a clear understanding of how customers perceive the value they obtain from actual usage of products and services—so-called value-in-use. However, there is a lack of research on integrated products and services and how they impact customer satisfaction. An exploratory study was undertaken to understand customers’ views on integrated products and services and the value-in-use derived from such offerings. As value-in-use and its impacts are complicated concepts, a technique from psychology—Repertory Grid Technique—was used to gather data in 33 interviews. The interviews allowed a deep understanding of customer views on integrated products and services to be obtained, and a systematic analysis identified the key attributes of value-in-use. In order to probe further, the data were then analyzed using Honey’s procedure, which identified the impact of the attributes of value-in-use on customer satisfaction. Two key attributes—relational dynamic and access—were found to have the most influence on customer satisfaction. This paper contributes to the innovation field by identifying customer needs for integrated products and services and how these impact customer satisfaction. These are key points and need to be fully considered by managers during new product and service development. Similarly, the paper identifies a number of important areas for further research.

Chemoenzymatic Synthesis of alpha-Hydroxy-beta-methyl-gamma-hydroxy Esters: Role of the Keto-Enol Equilibrium To Control the Stereoselective Hydrogenation in a Key Step

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Turbinatine, a potential key intermediate in the biosynthesis of corynanthean-type indole alkaloids

Extraction of the leaves of Chimarrhis turbinata has led to the isolation of turbinatine (1), a new corynanthean-type indole alkaloid, besides four known indole alkaloids, strictosidine, 5alpha-carboxystrictosidine, vallesiachotamine, and isovallesiachotamine. The structural determination of 1 was based on 1D and 2D spectroscopic data. An evaluation of the DNA-damaging activities of the isolates was performed by means of a bioassay using mutant strains of Saccharomyces cerevisiae, which indicated these compounds were weakly active.

Mass-rearing of Mediterranean fruit fly using low-cost yeast products produced in Brazil

Ceratitis capitata is one of the most important pests of fruits for exportation, and Sterile Insect Technique (SIT) has been the most efficient and environmental friendly technique used to control fruit fly populations around the world. A key goal in achieving a successful SIT program is a mass rearing system producing high quality insects at low cost. Providing adults with an artificial diet containing hydrolysed protein has been the major obstacle for bio-production facilities in Brazil, because it is expensive and has to be imported. Two other commercial products, autolysed yeast (AY) and yeast extract (YE), of domestic origin and low cost, were tested as substitutes of the imported hydrolyzed protein. To compare their efficiency we observed the female fecundity, adult survival and egg viability of flies raised on diets containing one of each of the different protein products. Flies reared on the domestic yeast products had equivalent or superior performance to the flies reared on imported protein. Both AY and YE can be a possible substitute for imported hydrolyzed protein for C. capitata mass-rearing, as they are cheaper and are readily available in the national market.

Effect of rearing techniques and feed composition on productive traits, bird welfare and quality of poultry products

The PhD project was focused on the study of the poultry welfare conditions and improvements. The project work was divided into 3 main research activities. A) Field evaluation of chicken meat rearing conditions kept in intensive farms. Considering the lack of published reports concerning the overall Italian rearing conditions of broiler chickens, a survey was carried out to assess the welfare conditions of broiler reared in the most important poultry companies in Italy to verify if they are in accordance with the advices given in the European proposal COM (2005) 221 final. Chicken farm conditions, carcass lesions and meat quality were investigated. 1. The densities currently used in Italy are in accordance with the European proposal COM 221 final (2005) which suggests to keep broilers at a density lower than 30-32 kg live weight/m2 and to not exceed 38-40 kg live weight/m2. 2. The mortality rates in summer and winter agree with the mortality score calculated following the formula reported in the EU Proposal COM 221 final (2005). 3. The incidence of damaged carcasses was very low and did not seem related to the stocking density. 4. The FPD scores were generally above the maximum limit advised by the EU proposal COM 221 final (2005), although the stocking densities were lower than 30-32 kg live weight per m2. 5. It can be stated that the control of the environmental conditions, particularly litter quality, appears a key issue to control the onset of foot dermatitis. B) Manipulation of several farm parameters, such litter material and depth, stocking density and light regimen to improve the chicken welfare conditions, in winter season. 1. Even though 2 different stocking densities were established in this study, the performances achieved from the chickens were almost identical among groups. 2. The FCR was significantly better in Standard conditions contrarily to birds reared in Welfare conditions with lower stocking density, more litter material and with a light program of 16 hours light and 8 hours dark. 3. In our trial, in Standard groups we observed a higher content of moisture, nitrogen and ammonia released from the litter. Therefore it can be assumed that the environmental characteristics have been positively changed by the improvements of the rearing conditions adopted for Welfare groups. 4. In Welfare groups the exhausted litters of the pens were dryer and broilers showed a lower occurrence of FPD. 5. The prevalence of hock burn lesions, like FPD, is high with poor litter quality conditions. 6. The combined effect of a lower stocking density, a greater amount of litter material and a photoperiod similar to the natural one, have positively influenced the chickens welfare status, as a matter of fact the occurrence of FPD in Welfare groups was the lowest keeping the score under the European threshold of the proposal COM 221 final(2005). C) The purpose of the third research was to study the effect of high or low stocking density of broiler chickens, different types of litter and the adoption of short or long lighting regimen on broiler welfare through the evaluation of their productivity and incidence of foot pad dermatitis during the hot season. 1. The feed efficiency was better for the Low Density than for High Density broilers. 2. The appearance of FPD was not influenced by stocking density. 3. The foot examination revealed that the lesions occurred more in birds maintained on chopped wheat straw than on wood shaving. 4. In conclusion, the adoptions of a short light regimen similar to that occurring in nature during summer reduces the feed intake without modify the growth rate thus improving the feed efficiency. Foot pad lesion were not affected neither by stocking densities nor by light regimens whereas wood shavings exerted a favourable effect in preserving foot pad in good condition. D) A study was carried out to investigate more widely the possible role of 25-hydroxycholecalciferol supplemented in the diet of a laying hen commercial strain (Lohmann brown) in comparison of diets supplemented with D3 or with D3 + 25- hydroxycholecalciferol. Egg traits during a productive cycle as well as the bone characteristics of the layers have been as well evaluated to determine if there the vitamin D3 may enhance the welfare status of the birds. 1. The weight of the egg and of its components is often greater in hens fed a diet enriched with 25-hydroxycholecalciferol. 2. Since eggs of treated groups are heavier and a larger amount of shell is needed, a direct effect on shell strength is observed. 3. At 30 and at 50 wk of age hens fed 25 hydroxycholecalciferol exhibited greater values of bone breaking force. 4. Radiographic density values obtained in the trial are always higher in hens fed with 25-hydroxycholecalciferol of both treatments: supplemented for the whole laying cycle (25D3) or from 40 weeks of age onward (D3+25D3).

Natural products as leads for anticancer drug discovery: discovery of new chemotypes of microtubule stabilizers through reengineering of the epothilone scaffold

Epothilones are bacterial macrolides with potent microtubule-stabilizing and antiproliferative activity, which have served as successful lead structures for the discovery of several clinical candidates for cancer treatment. Overall, seven epothilone-type agents have been advanced to clinical evaluation in humans so far and one of these has been approved by the FDA in 2007 for clinical use in breast cancer patients. Notwithstanding these impressive numbers, however, the structural diversity represented by the collection of epothilone analogs that have been (or still are) investigated clinically is rather limited and their individual structures show little divergence from the original natural product leads. In contrast, we have elaborated a series of epothilone-derived macro-lactones, 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 conformationally constrained side chains, the removal of the C(3)-hydroxyl group, and the replacement of C(12) with nitrogen. The latter modification leads to aza-macrolides that may be described as 'non-natural natural products'.

Decomposing Blaschke Products And Polynomials

The goal of this paper is to contribute to the understanding of complex polynomials and Blaschke products, two very important function classes in mathematics. For a polynomial, $f,$ of degree $n,$ we study when it is possible to write $f$ as a composition $f=g\circ h$, where $g$ and $h$ are polynomials, each of degree less than $n.$ A polynomial is defined to be \emph{decomposable }if such an $h$ and $g$ exist, and a polynomial is said to be \emph{indecomposable} if no such $h$ and $g$ exist. We apply the results of Rickards in \cite{key-2}. We show that $$C_{n}=\{(z_{1},z_{2},...,z_{n})\in\mathbb{C}^{n}\,|\,(z-z_{1})(z-z_{2})...(z-z_{n})\,\mbox{is decomposable}\},$$ has measure $0$ when considered a subset of $\mathbb{R}^{2n}.$ Using this we prove the stronger result that $$D_{n}=\{(z_{1},z_{2},...,z_{n})\in\mathbb{C}^{n}\,|\,\mbox{There exists\,}a\in\mathbb{C}\,\,\mbox{with}\,\,(z-z_{1})(z-z_{2})...(z-z_{n})(z-a)\,\mbox{decomposable}\},$$ also has measure zero when considered a subset of $\mathbb{R}^{2n}.$ We show that for any polynomial $p$, there exists an $a\in\mathbb{C}$ such that $p(z)(z-a)$ is indecomposable, and we also examine the case of $D_{5}$ in detail. The main work of this paper studies finite Blaschke products, analytic functions on $\overline{\mathbb{D}}$ that map $\partial\mathbb{D}$ to $\partial\mathbb{D}.$ In analogy with polynomials, we discuss when a degree $n$ Blaschke product, $B,$ can be written as a composition $C\circ D$, where $C$ and $D$ are finite Blaschke products, each of degree less than $n.$ Decomposable and indecomposable are defined analogously. Our main results are divided into two sections. First, we equate a condition on the zeros of the Blaschke product with the existence of a decomposition where the right-hand factor, $D,$ has degree $2.$ We also equate decomposability of a Blaschke product, $B,$ with the existence of a Poncelet curve, whose foci are a subset of the zeros of $B,$ such that the Poncelet curve satisfies certain tangency conditions. This result is hard to apply in general, but has a very nice geometric interpretation when we desire a composition where the right-hand factor is degree 2 or 3. Our second section of finite Blaschke product results builds off of the work of Cowen in \cite{key-3}. For a finite Blaschke product $B,$ Cowen defines the so-called monodromy group, $G_{B},$ of the finite Blaschke product. He then equates the decomposability of a finite Blaschke product, $B,$ with the existence of a nontrivial partition, $\mathcal{P},$ of the branches of $B^{-1}(z),$ such that $G_{B}$ respects $\mathcal{P}$. We present an in-depth analysis of how to calculate $G_{B}$, extending Cowen's description. These methods allow us to equate the existence of a decomposition where the left-hand factor has degree 2, with a simple condition on the critical points of the Blaschke product. In addition we are able to put a condition of the structure of $G_{B}$ for any decomposable Blaschke product satisfying certain normalization conditions. The final section of this paper discusses how one can put the results of the paper into practice to determine, if a particular Blaschke product is decomposable. We compare three major algorithms. The first is a brute force technique where one searches through the zero set of $B$ for subsets which could be the zero set of $D$, exhaustively searching for a successful decomposition $B(z)=C(D(z)).$ The second algorithm involves simply examining the cardinality of the image, under $B,$ of the set of critical points of $B.$ For a degree $n$ Blaschke product, $B,$ if this cardinality is greater than $\frac{n}{2}$, the Blaschke product is indecomposable. The final algorithm attempts to apply the geometric interpretation of decomposability given by our theorem concerning the existence of a particular Poncelet curve. The final two algorithms can be implemented easily with the use of an HTML

Managerial perseptions on corporate social responsbility: A Transatlantic comparison between forest products companies in Europe and North America

Corporate Social Responsibility (CSR) addresses the responsibility of companies for their impacts on society. The concept of strategic CSR is becoming increasingly mainstreamed in the forest industry, but there is, however, little consensus on the definition and implementation of CSR. The objective of this research is to build knowledge on the characteristics of CSR and to provide insights on the emerging trend to increase the credibility and legitimacy of CSR through standardization. The study explores how the sustainability managers of European and North American forest companies perceive CSR and the recently released ISO 26000 guidance standard on social responsibility. The conclusions were drawn from an analysis of two data sets; multivariate survey data based on one subset of 30 European and 13 North American responses, and data obtained through in-depth interviewing of 10 sustainability managers that volunteered for an hour long phone discussion about social responsibility practices at their company. The analysis concluded that there are no major differences in the characteristics of cross-Atlantic CSR. Hence, the results were consistent with previous research that suggests that CSR is a case- and company-specific concept. Regarding the components of CSR, environmental issues and organizational governance were key priorities in both regions. Consumer issues, human rights, and financial issues were among the least addressed categories. The study reveals that there are varying perceptions on the ISO 26000 guidance standard, both positive and negative. Moreover, sustainability managers of European and North American forest companies are still uncertain regarding the applicability of the ISO 26000 guidance standard to the forest industry. This study is among the first to provide a preliminary review of the practical implications of the ISO 26000 standard in the forest sector. The results may be utilized by sustainability managers interested in the best practices on CSR, and also by a variety of forest industrial stakeholders interested in the practical outcomes of the long-lasting CSR debate.

A review and a conceptual framework of the key value drivers of mass customisation

The aim of this paper is to conceptualise the key value drivers of mass customisation in order to provide a structured approach to explain the added value that customers attribute to mass customised products. We assume that the added value of mass customisation is ultimately reflected in an increased willingness to pay. Previous studies show diverse results concerning customers' willingness to pay for mass customised products. We contribute to the existing body of research by suggesting and discussing the influence of general product characteristics and factors of the mass customisation approach on the key value drivers of mass customisation. Furthermore, the development of a conceptual framework offers explanations for the dissimilarity in customers' willingness to pay and advances the knowledge about the value increment of mass customised products as perceived by customers.

Cloning of chlorophyllase, the key enzyme in chlorophyll degradation: Finding of a lipase motif and the induction by methyl jasmonate

Chlorophyllase (Chlase) is the first enzyme involved in chlorophyll (Chl) degradation and catalyzes the hydrolysis of ester bond to yield chlorophyllide and phytol. In the present study, we isolated the Chlase cDNA. We synthesized degenerate oligo DNA probes based on the internal amino acid sequences of purified Chlase from Chenopodium album, screened the C. album cDNA library, and cloned a cDNA (CaCLH, C. album chlorophyll-chlorophyllido hydrolase). The deduced amino acid sequence (347 aa residues) had a lipase motif overlapping with an ATP/GTP-binding motif (P-loop). CaCLH possibly was localized in the extraplastidic part of the cell, because a putative signal sequence for endoplasmic reticulum is at the N terminus. The amino acid sequence shared 37% identity with a function-unknown gene whose mRNA is inducible by coronatine and methyl jasmonate (MeJA) in Arabidopsis thaliana (AtCLH1). We expressed the gene products of AtCLH1 and of CaCLH in Escherichia coli, and they similarly exhibited Chlase activity. Moreover, we isolated another full-length cDNA based on an Arabidopsis genomic fragment and expressed it in E. coli, demonstrating the presence of the second Arabidopsis CLH gene (AtCLH2). No typical feature of signal sequence was identified in AtCLH1, whereas AtCLH2 had a typical signal sequence for chloroplast. AtCLH1 mRNA was induced rapidly by a treatment of MeJA, which is known to promote senescence and Chl degradation in plants, and a high mRNA level was maintained up to 9 h. AtCLH2, however, did not respond to MeJA.

Phylogeny of genes for secretion NTPases: Identification of the widespread tadA subfamily and development of a diagnostic key for gene classification

Macromolecular transport systems in bacteria currently are classified by function and sequence comparisons into five basic types. In this classification system, type II and type IV secretion systems both possess members of a superfamily of genes for putative NTP hydrolase (NTPase) proteins that are strikingly similar in structure, function, and sequence. These include VirB11, TrbB, TraG, GspE, PilB, PilT, and ComG1. The predicted protein product of tadA, a recently discovered gene required for tenacious adherence of Actinobacillus actinomycetemcomitans, also has significant sequence similarity to members of this superfamily and to several unclassified and uncharacterized gene products of both Archaea and Bacteria. To understand the relationship of tadA and tadA-like genes to those encoding the putative NTPases of type II/IV secretion, we used a phylogenetic approach to obtain a genealogy of 148 NTPase genes and reconstruct a scenario of gene superfamily evolution. In this phylogeny, clear distinctions can be made between type II and type IV families and their constituent subfamilies. In addition, the subgroup containing tadA constitutes a novel and extremely widespread subfamily of the family encompassing all putative NTPases of type IV secretion systems. We report diagnostic amino acid residue positions for each major monophyletic family and subfamily in the phylogenetic tree, and we propose an easy method for precisely classifying and naming putative NTPase genes based on phylogeny. This molecular key-based method can be applied to other gene superfamilies and represents a valuable tool for genome analysis.

Asset-backed securities: The key to unlocking Europe's credit markets? Bruegel Policy Contribution 2014/07, 24 July 2014

The European market for asset-backed securities (ABS) has all but closed for business since the start of the economic and financial crisis. ABS (see Box 1) were in fact the first financial assets hit at the onset of the crisis in 2008. The subprime mortgage meltdown caused a deterioration in the quality of collateral in the ABS market in the United States, which in turn dried up overall liquidity because ABS AAA notes were popular collateral for inter-bank lending. The lack of demand for these products, together with the Great Recession in 2009, had a considerable negative impact on the European ABS market. The post-crisis regulatory environment has further undermined the market. The practice of slicing and dicing of loans into ABS packages was blamed for starting and spreading the crisis through the global financial system. Regulation in the post-crisis context has thus been relatively unfavourable to these types of instruments, with heightened capital requirements now necessary for the issuance of new ABS products. And yet policymakers have recently underlined the need to revitalise the ABS market as a tool to improve credit market conditions in the euro area and to enhance transmission of monetary policy. In particular, the European Central Bank and the Bank of England have jointly emphasised that: “a market for prudently designed ABS has the potential to improve the efficiency of resource allocation in the economy and to allow for better risk sharing... by transforming relatively illiquid assets into more liquid securities. These can then be sold to investors thereby allowing originators to obtain funding and, potentially, transfer part of the underlying risk, while investors in such securities can diversify their portfolios... . This can lead to lower costs of capital, higher economic growth and a broader distribution of risk” (ECB and Bank of England, 2014a). In addition, consideration has started to be given to the extent to which ABS products could become the target of explicit monetary policy operations, a line of action proposed by Claeys et al (2014). The ECB has officially announced the start of preparatory work related to possible outright purchases of selected ABS1. In this paper we discuss how a revamped market for corporate loans securitised via ABS products, and how use of ABS as a monetary policy instrument, can indeed play a role in revitalising Europe’s credit market. However, before using this instrument a number of issues should be addressed: First, the European ABS market has significantly contracted since the crisis. Hence it needs to be revamped through appropriate regulation if securitisation is to play a role in improving the efficiency of resource allocation in the economy. Second, even assuming that this market can expand again, the European ABS market is heterogeneous: lending criteria are different in different countries and banking institutions and the rating methodologies to assess the quality of the borrowers have to take these differences into account. One further element of differentiation is default law, which is specific to national jurisdictions in the euro area. Therefore, the pool of loans will not only be different in terms of the macro risks related to each country of origination (which is a ‘positive’ idiosyncratic risk, because it enables a portfolio manager to differentiate), but also in terms of the normative side, in case of default. The latter introduces uncertainties and inefficiencies in the ABS market that could create arbitrage opportunities. It is also unclear to what extent a direct purchase of these securities by the ECB might have an impact on the credit market. This will depend on, for example, the type of securities targeted in terms of the underlying assets that would be considered as eligible for inclusion (such as loans to small and medium-sized companies, car loans, leases, residential and commercial mortgages). The timing of a possible move by the ECB is also an issue; immediate action would take place in the context of relatively limited market volumes, while if the ECB waits, it might have access to a larger market, provided steps are taken in the next few months to revamp the market. We start by discussing the first of these issues – the size of the EU ABS market. We estimate how much this market could be worth if some specific measures are implemented. We then discuss the different options available to the ECB should they decide to intervene in the EU ABS market. We include a preliminary list of regulatory steps that could be taken to homogenise asset-backed securities in the euro area. We conclude with our recommended course of action.

The key role of CD40 ligand in overcoming tumor-induced dendritic cell dysfunction

Overcoming dendritic cell (DC) dysfunction is a prerequisite for successful active immunotherapy against breast cancer. CD40 ligand (CD40L), a key molecule in the interface between T-lymphocytes and DCs, seems to be instrumental in achieving that goal. Commenting on our data that CD40L protects circulating DCs from apoptosis induced by breast tumor products, Lenahan and Avigan highlighted the potential of CD40L for immunotherapy. We expand on that argument by pointing to additional findings that CD40L not only rescues genuine DCs but also functionally improves populations of immature antigen-presenting cells that fill the DC compartment in patients with breast cancer.

Rheumatoid arthritis: links with cardiovascular disease and the receptor for advanced glycation end products

Cardiovascular (CV) disease is increased in patients with chronic inflammatory disease, including rheumatoid arthritis (RA). Furthermore it has become clear at a pathophysiological level, that atherosclerosis has striking similarities with autoimmune disease. This realization has come at a time of paradigm shift in how rheumatologists manage RA, with the availability of biological agents targeting key inflammatory cytokines. This review will focus on the possible causes of increased vascular disease in RA, including the role of traditional CV risk factors. Mechanisms potentially at play, such as C-reactive protein (CRP), altered coagulation, and cyclooxygenase (COX) -2 inhibitors will be covered in brief. The Receptor for Advanced Glycation End Products (RAGE) has been identified as a candidate molecule influencing response to ongoing inflammation and autoimmunity. There will be a focus on the role of RAGE in CV disease and RA. As has been the case with many novel molecules, functional polymorphisms are thought to alter disease expression and assist us in coming to terms with the biological activities of the parent molecule. The review will conclude with a discussion of the potential role of the RAGE Glycine 82 Serine polymorphism