bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancement of Lipolytic Responsiveness of Adipocytes by Novel Plant Extract in Rat
Authors: Mori Shinobu , Takizawa Minoru , Satou Mayumi , Sakasai Mitsuyoshi , Kusuoku Hiroshi , Nojiri Hiroshi , Yoshizuka Naonobu , Hotta Mitsuyuki , Kitahara Takashi , Hase Tadashi , Takema Yoshinori , Saito Masayuki , Yada Toshihiko
Published: November 2009

Subcutaneous adipocytes accumulate excess energy as triglycerides, but lipolytic response is less sensitive to catecholamines than visceral adipocytes. Obesity also induces catecholamine resistance of adipocytes. We have searched for crude drugs that could enhance the lipolytic response to noradrenalin. In this study, the lipolysis-promoting activities and action mechanisms of a novel plant extract from Hemerocallis fulva (HE) were investigated in isolated adipocytes from rat subcutaneous fat. HE exhibited no lipolysis-promoting activity alone but markedly promoted lipolysis when combined with noradrenaline; however, this synergistic activity was accompanied by no increase of intracellular cAMP production. This activity of HE was also observed when combined with cAMP analogue and was further enhanced by phosphodiesterase inhibitor. PKA inhibitor could reduce these activities of HE. These results indicate that HE is a novel lipolysis-promoting material that can sensitize the lipolytic response of adipocytes to catecholamine and suggest that HE can amplify the intra-cellular signaling pathway related to PKA or modify the other mechanism-regulating lipase activity. This characteristic material could contribute to improvement of adipose mobility in obesity-related disorder or in subcutaneous adiposity and to suppression of body fat accumulation.
Comparative Impacts of Knockouts of Two Antioxidant Enzymes on Acetaminophen-Induced Hepatotoxicity in Mice
Authors: Zhu Jian-Hong , McClung James P. , Zhang Xiaomei , Aregullin Manuel , Chen Chi , Gonzalez Frank J. , Kim Tae-Wan , Lei Xin Gen
Published: November 2009

We have previously shown a more potent impact of knockout of Cu,Zn-superoxide dismutase (SOD1) than that of Se-dependent glutathione peroxidase-1 (GPX1) on murine hepatotoxicity induced by an intraperitoneal (ip) injection of a high dose of acetaminophen (APAP, 600 mg/kg). The objective of this experiment was to compare the temporal impacts of knockouts of GPX1 and SOD1 alone or together on mouse susceptibility to an injection of a low dose of APAP (300 mg/kg). The APAP-mediated rises in plasma alanine aminotransferase activity and nitrate/nitrite concentrations, hepatic GSH depletion, and hepatic protein nitration at 5 and (or) 24 h were nearly abolished ( P < 0.05) in SOD1−/− or GPX1 and SOD1 double-knockout (DKO) mice, while GPX1−/− mice exerted only moderate or no change compared with the WT. Despite an increased ( P < 0.05) APAP- N-acetylcysteine and decreased APAP-glucuronide ( P < 0.05) relative to the total APAP metabolites in urine collected for 24 h after the APAP injection, the SOD1−/− mice displayed no shift in urinary APAP-cysteine compared with the WT mice. Knockout of SOD1 prevented the APAP-induced hepatic GPX inactivation ( P < 0.05), whereas knockout of GPX1 aggravated the APAP-induced hepatic SOD activity loss ( P < 0.05). However, the APAP-mediated activity changes of these enzymes in liver accompanied no protein alterations. In conclusion, knockout of GPX1 or SOD1 exerted differential impact on mouse susceptibility to this low dose of APAP, but neither shifted urinary APAP-cysteine formation.
Semantic values in Translating from English to Bangla
Authors: Huq Mohammad Daniul
Published: November 2009

Translating from other languages to Bangla is confronted with multiple factors. Hindrance seems hidden within the system, or to say, with the applied discipline of this very language, pivot of all may be examined as the transference of semantic values from SL to TL. This paper tries to depict the nature of Bangla while examining the peripheral aspects related to a meaningful and ostensive translated version. Discussion with appropriate examples forms the main burden of the paper. Concerns of translation theories vs. problems will ultimately be taken up exposing Bangla in particular trivial examples. It is expected that, subjectivity and individual traits of an author will find expression in style register.  DOI: 10.3329/dujl.v1i2.3716 The Dhaka University Journal of Linguistics: Vol. 1 No. 2 August, 2008 Page: 45-66
Bengali Noun Phrase complex: A minimalist approach
Authors: Bhattacharja Shishir
Published: November 2009

In this article, we show, following the Minimalist approach, how features like definiteness and specificity are checked either through Probe-Goal or through overt movement to different projections situated in the left periphery of Noun Phrase complex (NPC) constituated of, as we suggest, the NP itself and the traditonal DP split into four different projections: Deixis Phrase, Determiner Phrase, Classifier Phrase and Quantifier Phrase. At the end of this article we point out some of the limitations of this approach and show how they can be handled in the Substantivist or similar approaches. Key words: Definiteness, Specificity, Deixis, Classifier, Quantifier, SubstantiveDOI: 10.3329/dujl.v1i2.3717  The Dhaka University Journal of Linguistics: Vol. 1 No.2 August, 2008 Page: 67-86
An analysis of the sounds and words used in Pali Language
Authors: Barua Shantu
Published: November 2009

Pali is the name of the language of Theravada Buddhist literature. It belongs to Indo-European language family, especially to Middle Indo-Aryan. Tripitaka, the sacred text of the Buddhist, was first handed down in this language, and from then Pali was recognized as the language of literature. After the Tripitaka many religious and secular books were written in this language and thus, Pali became the language of a vast literature. It was originated in India, however, with the spread of Buddhism, it was accrosed the boundary of India and practiced in Sri Lanka, Thailand, Myanmar (Burma), Cambodia, Vietnam and Bangladesh; and a noteworthy number of books were written in those countries in this language. Pali contains many elements or characteristics of other languages, such as Vedic, Classical Sanskrit, Shinhalese, Dravidan etc. Hence, scholars termed it as compromising speech'. The main objective of this article is to present a clear conception of the phonological and morphological characteristics of Pali language.DOI: 10.3329/dujl.v1i2.3720 The Dhaka University Journal of Linguistics: Vol. 1 No.2 August: 2008 Page: 125-146
Bengali Upasarga: A morphological analysis
Authors: Khairunnahar Khondokar
Published: November 2009

In Bengali an upasarga- a special kind of prefx- is a vibrant element which is determined as bound morpheme in a morphological consideration. If words are analyzed structurally, the result is outnumbered words, which are mainly constructed by such a prefix. More specifically, most of the terms in Bengali are created with the help of these prefixes. Thus, the main goal of this paper is to provide a structural interpretation of such bound morphemes enriching the words in Bengali. Key words: prefix, bound morpheme, class changing, class maintaining, morphologyDOI: 10.3329/dujl.v1i2.3722 The Dhaka University Journal of Linguistics: Vol.1 No.2 August, 2008 Page: 157-168
Developing Professionally
Authors: Khan Rubina
Published: November 2009

Teaching is a challenging job and teachers need to perform well in order to deliver their lessons effectively. One major prerequisite for effective performance is the need for teachers to engage in continuous professional development (CPD). Professional development (PD) includes a cluster of activities related to the enhancement of career growth and refinement of the skills of the practitioner. It may range from activities like attending pre-service and in-service training, participating in conferences, seminars, workshops, joining teacher associations, reading books and articles etc. This article briefly highlights the key ingredients of professional development, outlines the sources of PD and argues that professional development is essential for promoting individual and professional growth. Keywords: Professional Development (PD), Continuous Professional Development (CPD), Teacher Development (TD), knowledge base, ELT professional, facets of Continuous Professional Development.DOI: 10.3329/dujl.v1i2.3723 The Dhaka University Journal of Linguistics: Vol. 1 No .2 August, 2008 Page: 169-180
Hydration and microstructure of Portland cement partially substituted with ultrafine silica
Authors: Gómez-Zamorano L. Y. , Escalante J. I.
Published: November 2009

Geothermal waste, a by-product of steam power plants that use geothermal underground resources, was studied as a possible replacement for Portland cement. This waste consists primarily in amorphous nanometric silica with traces of sodium and potassium chlorides. The replacement ratios studied were 0, 10 and 20% in cements cured at 20 and 60 ºC. X-ray diffraction analysis showed that clinker phase hydration took place earlier in the presence of the geothermal waste. Scanning electron microscopy, in turn, revealed a reduction in porosity and intense calcium hydroxide consumption as a result of the pozzolanic reaction. The pastes containing 20% waste, however, an intense cracking was observed due to the formation of alkali silica reaction gel and ettringite. Cracking was more prominent at 60 ºC but was not observed in either the neat cement or the blend with 10 % waste. The presence of these detrimental phases was attributed to the formation of Friedel’s salt in the initial hydration stages, induced by the chlorides in the geothermal material.
A Remote Laboratory for Real-Time Digital Image Processing on Embedded Systems
Authors: Kalantzopoulos Athanasios , Markonis Dimitrios , Zigouris Evangelos
Published: November 2009

The purpose of this paper is to present a Remote Laboratory on embedded systems focused in real-time digital image processing. This laboratory consists of a Main Web Server and several Workstations which are designed for digital image retrieval from a CMOS Image Sensor and real-time image processing on a Digital Signal Processor development platform. The Main Web Server redirects the authorised remote users to available Workstations in order to execute and verify their image processing algorithms or test their system designs using a developed Application Programming Interface. Through user-friendly web pages users can interfere with the hardware parameters and observe the results of their solutions.
A Virtual Environment for Studying Flexible Robot Manipulators
Authors: Azad Abul K. M. , Tokhi Osman , Shaheed Hasan
Published: November 2009

The paper presents a virtual environment for simulation and modeling a single-link flexible robotic manipulator. Simulation algorithm is based on the finite difference method where the systems governing dynamic equation is discretized and implemented. Intelligent modeling techniques are developed using neural network and genetic algorithm based techniques. All these have been developed and realized within a virtual environment using the Matlab, Simulink, and associated toolboxes. An interactive user friendly graphical user interface has also been presented. This environment has proven to be a valuable educational tool for understanding the behavior of flexible manipulator systems and can also be used as a computer aided teaching facility and a testbed for controller designs.
Caspase-1, Caspase-8, and Calpain Are Dispensable for IL-33 Release by Macrophages
Authors: Ohno Tatsukuni , Oboki Keisuke , Kajiwara Naoki , Morii Eiichi , Aozasa Katsuyuki , Flavell Richard A. , Okumura Ko , Saito Hirohisa , Nakae Susumu
Published: November 2009

In addition to IL-1 and IL-18, IL-33 was recently identified as a member of the IL-1 cytokine family. rIL-33 can promote production of Th2-type cytokines by Th2 cells and mast cells in vitro. Administration of rIL-33 to mice results in increases in IgE secretion and eosinophilic inflammation. However, the precise immune cell source of IL-33 remains unclear. Moreover, although recombinant pro-IL-33 is cleaved by recombinant caspase-1 in vitro, as are pro-IL-1β and pro-IL-18, the involvement of caspase-1 in pro-IL-33 cleavage remains controversial. In this study, we show that mouse peritoneal macrophages, but not splenic dendritic cells, produced IL-33 upon stimulation with LPS. Likewise, mouse bone marrow cell-derived cultured mast cells also produced a small, but significant amount of IL-33 via FcεRI cross-linking, but not in response to stimulation with LPS. To our surprise, IL-33 release was found even in caspase-1-deficient, caspase-8 inhibitor-treated, and calpain inhibitor-treated macrophages. These observations suggest that caspase-1-, caspase-8-, and calpain-independent IL-33 production by macrophages and/or mast cells may contribute to the pathogenesis of Th2-type allergic inflammation.
Siglec-E Is Up-Regulated and Phosphorylated Following Lipopolysaccharide Stimulation in Order to Limit TLR-Driven Cytokine Production
Authors: Boyd Caroline R. , Orr Selinda J. , Spence Shaun , Burrows James F. , Elliott Joanne , Carroll Helen P. , Brennan Kiva , Gabhann Joan Ní , Coulter Wilson A. , Johnston James A. , Jefferies Caroline A.
Published: November 2009

Although production of cytokines by TLR is essential for viral and bacterial clearance, overproduction can be detrimental, thus controlling these responses is essential. CD33-related sialic acid binding Ig-like lectin receptors (Siglecs) have been implicated in the control of leukocyte responses. In this study, we report that murine Siglec-E is induced by TLRs in a MyD88-specific manner, is tyrosine phosphorylated following LPS stimulation, and negatively regulates TLR responses. Specifically, we demonstrate the Siglec-E expression inhibits TLR-induced NF-κB and more importantly, the induction of the antiviral cytokines IFN-β and RANTES. Siglec-E mediates its inhibitory effects on TIR domain containing adaptor inducing IFN-β (TRIF)-dependent cytokine production via recruitment of the serine/threonine phosphatase SHP2 and subsequent inhibition of TBK1 activity as evidenced by enhanced TBK1 phosphorylation in cells following knockdown of Siglec-E expression. Taken together, our results demonstrate a novel role for Siglec-E in controlling the antiviral response to TLRs and thus helping to maintain a healthy cytokine balance following infection.
Macro and micro challenges for talent retention in South Africa
Authors: Kerr-Phillips Berenice , Thomas Adèle
Published: November 2009

The aim of the study was to explore the challenges presented in retaining South Africa’s talent at both macro (country) and micro (organisational) levels. Using a web-based survey placed on eight New Zealand sites, the reasons for emigration of South African talent during the period 1994–2006 were explored with 84 respondents. Utilising a purposive sampling technique, 20 semi-structured interviews were undertaken with identified ‘top talent’ in two financial services companies. Content analysis of the responses from both samples was employed. Reasons for emigration (macro issues) included uncertainty about the future of the country, job insecurity and fears regarding both corruption and violent crime. Reasons for talent loss amongst identified top talent (micro issues) were found to be linked to leadership, organisational culture and employment equity.
Study on Crack‐like Pores of Al Foams Made via the Powder‐Metallurgy Route
Authors: Wang Lei , Yao Guangchun , Liu Yihan , Zu Guoyin
Published: November 2009

Mechanisms for the formation and disappearance of the crack‐like pores generated during the early stage of Al foaming are investigated. A model for their disappearance process is proposed for the first time. The stress, perpendicular to the compaction direction in uniaxial cold compaction, is caused by the interaction of the Al powder under a high compaction pressure and is the main reason for the formation of the crack‐like pores. The results of the model analysis and theoretical calculations suggest that the pressure difference ΔP between the initial, round bubbles and the crack‐like pores is the driving force for their disappearance. The rapid reduction of ΔP is attributed to the decomposition characteristics of the TiH2 powder.
High Velocity Oxy Fuel Spraying of Cold Work Tool Steels‐ A Novel Approach to Thick Coatings for Wear Protection Applications
Authors: Röttger Arne , Weber Sebastian L. , Theisen Werner , Rajasekaran Balasundaram , Vaßen Robert
Published: November 2009

Within this work, HVOF sprayed coatings based on X220CrVMo13‐4 cold work steel were applied to a S235JR construction steel substrate. The investigations focus on the influence of particle size and spray parameters on the coating microstructure, analyzed by means of optical microscope (OM) and scanning electron microscopy (SEM). Additional XRD measurements and micro hardness plots across the interface between substrate material and coating were carried out. Furthermore, the influence of particle size on the detected phases and coating porosity was studied. The results were compared with an X220CrMoV13‐4 reference sample produced by HIP.
General Zinc‐Catalyzed Conia‐Ene Reactions of 1,3‐Dicarbonyl Compounds with Alkynes Including the Classically Challenging Substrates under Neat Conditions
Authors: Deng Chen‐Liang , Song Ren‐Jie , Liu Yi‐Lin , Li Jin‐Heng
Published: November 2009

A simple, versatile new approach to four‐membered ring to six‐membered ring products has been developed by zinc‐catalyzed intramolecular Conia‐ene reactions of 1,3‐dicarbonyl compounds with alkynes. This new route allows a wide range of dicarbonyl compounds, including the classically challenging 1,3‐diesters and N,N′‐disubstituted 1,3‐keto amides, to be used for the Conia‐ene reaction with inexpensive zinc chloride (ZnCl2) under neat conditions.
A matrix method for multicomponent distillation sequences
Authors: Shah Vishesh H. , Agrawal Rakesh
Published: November 2009

We describe a simple‐to‐use “matrix” method for obtaining all the basic distillation configurations and additional thermally coupled configurations that separate a zeotropic multicomponent feed into essentially pure product streams. This provides an opportunity to rank‐list the configurations for a given application subject to criteria of interest. The only information needed to generate the configurations is the number of components in the feed. We have successfully enumerated all the configurations for feeds containing up to eight components. The method can also be used to generate nondistillation and hybrid separation configurations, and even easy‐to‐retrofit configurations. We illustrate the use of this method by applying it to the highly energy‐intensive problem of petroleum crude distillation. We have identified more than 70 new configurations that could potentially have lower heat duty than the existing configuration. A significant number of these could reduce the heat demand by nearly 50%. © 2009 American Institute of Chemical Engineers AIChE J, 56: 1759–1775, 2010
Costs by industry and diagnosis among musculoskeletal claims in a state workers compensation system: 1999–2004
Authors: Dunning Kari K. , Davis Kermit G. , Cook Chad , Kotowski Susan E. , Hamrick Chris , Jewell Gregory , Lockey James
Published: November 2009

Background

Musculoskeletal disorders (MSDs) are a tremendous burden on industry in the United States. However, there is limited understanding of the unique issues relating to specific industry sectors, specifically the frequency and costs of different MSDs.

Methods

Claim data from 1999 to 2004 from the Ohio Bureau of Workers' Compensation were analyzed as a function of industry sector (NAICS industry‐sector categories) and anatomical region (ICD‐9 codes).

Results

Almost 50% of the claims were lumbar spine (26.9%) or hand/wrist (21.7%). The majority of claims were from manufacturing (25.1%) and service (32.8%) industries. The industries with the highest average costs per claim were transportation, warehouse, and utilities and construction. Across industries, the highest costs per claim were consistently for the lumbar spine, shoulder, and cervical spine body regions.

Conclusion

This study provides insight into the severity (i.e., medical and indemnity costs) of MSDs across multiple industries, providing data for prioritizing of resources for research and interventions. Am. J. Ind. Med. 53:276–284, 2010. © 2009 Wiley‐Liss, Inc.
Mardini–Nyhan association (lung agenesis, congenital heart, and thumb anomalies): Three new cases and possible recurrence in a sib—Is there a distinct recessive syndrome?
Authors: Hastings Rob , Harding David , Donaldson Alan , Liebling Rachel , Hayes Alison , Kraus Alison , Joss Shelagh , Narayanaswamy Shuba , Turnpenny Peter , Smithson Sarah
Published: November 2009

In 1985, Mardini and Nyhan described three patients from consanguineous families with unilateral complete/partial lung agenesis, congenital cardiac defects, and ipsilateral thumb anomalies. Although there have been many reports of lung agenesis with other malformations, especially hemifacial microsomia and radial ray anomalies, very few demonstrate this triad of defects. We describe three patients with the Mardini–Nyhan association which may represent a distinct entity, although this remains uncertain at present. A fourth patient is also described, the sister of one of the other patients, with complex congenital cardiac disease and bilateral lung lobation abnormalities. This is the first reported incidence of a possible recurrence within a family and suggests, together with the consanguinity observed by Mardini and Nyhan, that recessive inheritance should be considered in genetic counseling for this disorder. © 2009 Wiley‐Liss, Inc.
Two adults with Rubinstein–Taybi syndrome with mild mental retardation, glaucoma, normal growth and skull circumference, and camptodactyly of third fingers
Authors: Wieczorek Dagmar , Bartsch Oliver , Lechno Stanislav , Kohlhase Jürgen , Peters Dorien J.M. , Dauwerse Hans , Gillessen‐Kaesbach Gabriele , Hennekam Raoul C.M. , Passarge Eberhard
Published: November 2009

The Rubinstein–Taybi syndrome (RTS; OMIM 180849) is a well‐defined mental retardation/multiple congenital anomalies (MR/MCA) syndrome characterized by postnatal growth retardation, microcephaly, specific facial features, broad thumbs and halluces, and MR of variable degree. Ten percent of patients with RTS have a microdeletion 16p13.3, 40–50% carry a mutation of theCREBBPgene and another 3% have a mutation in theEP300gene. In the remaining patients with clinically suspected RTS no mutation can be detected. Here we describe two patients with an RTS phenotype, one with a mutation in theCREBBPgene and the other without a detectableCREBBPorEP300mutation and without a chromosomal imbalance on high‐resolution arrays. Both patients present with the characteristic facial RTS phenotype, broad thumbs and big toes, mild MR, formation of keloids and glaucoma, but without postnatal growth retardation or microcephaly. In addition, they have both congenital camptodactyly of third (and fourth) fingers, which has not reported in RTS previously. We suggest that they represent a clinical subtype of RTS. © 2009 Wiley‐Liss, Inc.
Genome‐wide linkage scan of nonsyndromic orofacial clefting in 91 families of central European origin
Authors: Mangold Elisabeth , Reutter Heiko , Birnbaum Stefanie , Walier Maja , Mattheisen Manuel , Henschke Henning , Lauster Carola , Schmidt Gül , Schiefke Franziska , Reich Rudolf H. , Scheer Martin , Hemprich Alexander , Martini Markus , Braumann Bert , Krimmel Michael , Opitz Charlotte , Lenz Jan‐Hendrik , Kramer Franz‐Josef , Wienker Thomas F. , Nöthen Markus M. , Diaz Lacava Amalia
Published: November 2009

Orofacial clefts are among the most common of all congenital disorders. Nonsyndromic cases of cleft lip with or without cleft palate (NSCL/P) and cleft palate only (NSCPO) are considered to have a multifactorial etiology which involves both genetic and environmental factors. We present the results of a genome‐wide linkage scan in 91 families of central European descent with nonsyndromic orofacial clefts (NSC). The sample included 74 NSCL/P families, 15 NSCPO families, and 2 mixed families (a total of 217 affected and 230 unaffected individuals were genotyped). We genotyped 542 microsatellite markers (average intermarker distance = 6.9 cM). Multipoint nonparametric linkage analysis was performed using Allegro 2.0f. In addition to the factors investigated in previous genome‐wide linkage analyses, we searched for sex‐specific susceptibility loci, loci demonstrating parental imprinting and loci that are shared by NSCL/P and NSCPO. Several genomic regions likely to contain susceptibility loci for NSC were identified at the level of nominal significance. Some of these overlap with regions identified in previous studies. Suggestive evidence of linkage was obtained for the loci 4q21‐q26 and 1p31‐p21, with the chromosome 1 locus showing a male‐specific genetic effect. Our study has identified promising chromosomal regions for the identification of NSC‐associated genes, and demonstrates the importance of performing detailed statistical analyses which take into account complex genetic mechanisms such as sex‐specific effects and genomic imprinting. Further research in large patient samples is necessary to identify factors common to NSCL/P and NSCPO. © 2009 Wiley‐Liss, Inc.
Exudativory in the Bengal slow loris (Nycticebus bengalensis) in Trishna Wildlife Sanctuary, Tripura, northeast India
Authors: Swapna N. , Radhakrishna Sindhu , Gupta Atul K. , Kumar Ajith
Published: November 2009

In this study we estimated the extent of exudativory in Nycticebus bengalensis and examined whether exudates can be considered as fallback foods. This study was carried out in Trishna Wildlife Sanctuary, northeastern India, in winter (December–February) and summer (March and April). We estimated time–activity budget using instantaneous sampling and used continuous focal animal sampling to record all instances and durations of feeding, over a total of 177 hr. Feeding accounted for 22.3±2.2% of the activity budget, with no seasonal difference. Bengal slow lorises fed on exudates, nectar, fruit, bark, invertebrates and avian eggs. In addition to scraping they also obtained exudates by gouging holes into the bark of trees. In winter, lorises almost exclusively fed on exudates (94.3% of winter feeding time). In summer, exudates (67.3%) and nectar from one species (22.3%) dominated the diet. This study identifies the Bengal slow loris as the most exudativorous loris. Exudates rather than being a staple fallback food, seem to be a preferred, patchily distributed and common food in the diet of the Bengal slow loris. Exudativory in this species is characterized by high selectivity among species and seasonal variation, which may be related to variations in productivity of exudates and their chemical composition. An understanding of these factors is necessary for predicting the response of this species to human disturbance such as logging. This study also underscores the importance of protecting some of the common species such as Terminalia belerica on which the loris feeds during periods of scarcity. Am. J. Primatol. 72:113–121, 2010. © 2009 Wiley‐Liss, Inc.
Die Renaissance der α‐Methylen‐γ‐butyrolactone: neue Syntheseansätze
Authors: Kitson Russell R. A. , Millemaggi Alessia , Taylor Richard J. K.
Published: November 2009

Seit einigen Jahren erlebt die Forschung an α‐Methylen‐γ‐butyrolactonen einen enormen Aufschwung. Diese Übersicht beschreibt die Strukturen, die biologische Aktivität und die Biosynthese der Substanzen mit dem Schwerpunkt auf Veröffentlichungen aus den letzten zehn Jahren. Thematisiert werden sowohl die klassischen Herstellungsmethoden von α‐Methylen‐γ‐butyrolactonen und α‐Alkyliden‐γ‐butyrolactonen als auch neue Syntheseansätze, die unter anderem von uns entwickelt worden sind.
Expression of Lymphatic Markers During Avian and Mouse Cardiogenesis
Authors: Karunamuni Ganga , Yang Ke , Doughman Yong Qiu , Wikenheiser Jamie , Bader David , Barnett Joey , Austin Anita , Parsons‐Wingerter Patricia , Watanabe Michiko
Published: November 2009

The adult heart has been reported to have an extensive lymphatic system, yet the development of this important system during cardiogenesis is still largely unexplored. The nuclear‐localized transcription factor Prox‐1 identified a sheet of Prox‐1‐positive cells on the developing aorta and pulmonary trunk in avian and murine embryos just before septation of the four heart chambers. The cells coalesced into a branching lymphatic network that spread within the epicardium to cover the heart. These vessels eventually expressed the lymphatic markers LYVE‐1, VEGFR‐3, and podoplanin. Before the Prox‐1‐positive cells were detected in the mouse epicardium, LYVE‐1, a homologue of the CD44 glycoprotein, was primarily expressed in individual epicardial cells. Similar staining patterns were observed for CD44 in avian embryos. The proximity of these LYVE‐1/CD44‐positive mesenchymal cells to Prox‐1‐positive vessels suggests that they may become incorporated into the lymphatics. Unexpectedly, we detected LYVE‐1/PECAM/VEGFR‐3‐positive vessels within the embryonic and adult myocardium, which remained Prox‐1/podoplanin‐negative. Lymphatic markers were surprisingly found in adult rat and embryonic mouse epicardial cell lines, with Prox‐1 also exhibiting nuclear‐localized expression in primary cultures of embryonic avian epicardial cells. Our data identified three types of cells in the embryonic heart expressing lymphatic markers: (1) Prox‐1‐positive cells from an extracardiac source that migrate within the serosa of the outflow tract into the epicardium of the developing heart, (2) individual LYVE‐1‐positive cells in the epicardium that may be incorporated into the Prox‐1‐positive lymphatic vasculature, and (3) LYVE‐1‐positive cells/vessels in the myocardium that do not become Prox‐1‐positive even in the adult heart. Anat Rec, 2010. © 2009 Wiley‐Liss, Inc.
Anatomical Sciences Education vol.2, issue 6, 2009 cover image
Authors: Kinnison Tierney , Forrest Neil David , Frean Stephen Philip , Baillie Sarah
Published: November 2009

Veterinary students at the Royal Veterinary College, University of London learn about bovine abdominal anatomy using a virtual reality simulator, the Haptic Cow. A haptic device is positioned inside a fiberglass model of the rear‐half of a cow, allowing students to palpate virtual abdominal structures via a robotic arm. The Haptic Cow helps to address some of the practical and ethical issues around sourcing and using cadavers and live animals in teaching. Kinnison and her co‐authors discuss use of this simulator in anatomy classes in the current issue of ASE.
L1Penalized Estimation in the Cox Proportional Hazards Model
Authors: Goeman Jelle J.
Published: November 2009

This article presents a novel algorithm that efficiently computesL1penalized (lasso) estimates of parameters in high‐dimensional models. The lasso has the property that it simultaneously performs variable selection and shrinkage, which makes it very useful for finding interpretable prediction rules in high‐dimensional data. The new algorithm is based on a combination of gradient ascent optimization with the Newton–Raphson algorithm. It is described for a general likelihood function and can be applied in generalized linear models and other models with anL1penalty. The algorithm is demonstrated in the Cox proportional hazards model, predicting survival of breast cancer patients using gene expression data, and its performance is compared with competing approaches. AnRpackage,penalized, that implements the method, is available on CRAN.
Illustrating the steady‐state condition and the single‐molecule kinetic method with the NMDA receptor
Authors: Kosman Daniel J.
Published: November 2009

The steady‐state is a fundamental aspect of biochemical pathways in cells; indeed, the concept of steady‐state is a definition of life itself. In a simple enzyme kinetic scheme, the steady‐state condition is easy to define analytically but experimentally often difficult to capture because of its evanescent quality; the initial, constant velocity condition that signifies the steady‐state of the Ef and ES system is often short‐lived. The recording of electrophysiologic events through a receptor channel is used here to illustrate the steady‐state and to introduce the single‐molecule approach to the quantification of biologic kinetic schemes. This article first briefly reviews the Michaelis‐Menten and Briggs‐Haldane formulations for the simple enzyme kinetic scheme. The salient structural features of the NMDA (N‐methyl‐D‐aspartic acid) receptor are introduced as is the single NMDA molecule patch‐clamp method; this is a high‐resolution method for recording charge (ion) transfer through this and other ionotropic (ion‐conducting) receptors. The concept of a time constant is related directly to a rate constant in showing that durations of channel opening and closing directly provide values for the rate constants that link the various conformation states adopted by the receptor when it is at a steady state. These rate constants provide the basis for illustrating the energy relationships between the multiple protein conformation states that the receptor populates during steady‐state ion conduction across the cell membrane. The article emphasizes the advantages of collecting the mean behavior of a single molecule over time in comparison to the mean behavior of a large collection of independent molecules at a single time point.
Escherichia coli
Authors: Goodsell David S.
Published: November 2009

Diverse biological data may be used to create illustrations of molecules in their cellular context. I describe the scientific results that support a recent textbook illustration of an Escherichia coli cell. The image magnifies a portion of the bacterium at one million times, showing the location and form of individual macromolecules. Results from biochemistry, electron microscopy, and X‐ray crystallography were used to create the image.
Sex offender registration and recidivism risk in juvenile sexual offenders
Authors: Caldwell Michael F. , Dickinson Casey
Published: November 2009

Juvenile sex offenders are increasingly included in sex offender registration laws, based, in part, on the assumption that they pose a distinctively high risk for future sexual violence and registration may help to mitigate this risk. To test this assumption, the current study compares risk scores on the static scales of the Juvenile Sex Offender Assessment Protocol—II (JSOAP‐II; Prentky & Righthand, 2003) and the Youth Level of Service/Case Management Inventory (YLS/CMI; Hoge, Andrews, & Leschied, 2002), between samples of 106 registered and 66 unregistered juvenile sex offenders. New criminal charges, including sexually based crimes, were examined over a mean follow‐up of 49.2 months (SD = 29.6 months). Results indicated that registered youth had lower risk scores on scales that most accurately predicted recidivism and registered youth were charged with new crimes at rates similar to those of unregistered youth. Reoffense risk, as measured by the risk scales, was not moderated by registration. The findings did not support the assumption that registration can effectively lower the risk for reoffense in juvenile offenders. Copyright © 2009 John Wiley & Sons, Ltd.
Bootstrapping persistence risk indicators for juveniles who sexually offend
Authors: Knight Raymond A. , Ronis Scott T. , Zakireh Barry
Published: November 2009

This research was supported by research grants MH54263‐01 from the National Institute of Mental Health and 94‐IJ‐CX‐0049 from the National Institute of Justice. The authors wish to express their deep appreciation to the staff in the numerous institutions at which we have tested for their considerable commitment of time and energy to our research program. We also thank all the offenders who participated in our research. Special thanks are due to David Cerce and Alison Martino for coordinating the coding of files and organizing all of our data, to Nick Fadden and Karen Fadden for help in coordinating and collecting the Minnesota data, and to Karen Locke for her programming and data processing skills. Copyright © 2009 John Wiley & Sons, Ltd.
Application of near‐infrared (NIR) spectroscopy for screening of raw materials used in the cell culture medium for the production of a recombinant therapeutic protein
Authors: Kirdar Alime Ozlem , Chen Guoxiang , Weidner James , Rathore Anurag S.
Published: November 2009

Control of raw materials based on an understanding of their impact on product attributes has been identified as a key aspect of developing a control strategy in the Quality by Design (QbD) paradigm. This article presents a case study involving use of a combined approach of Near‐infrared (NIR) spectroscopy and Multivariate Data Analysis (MVDA) for screening of lots of basal medium powders based on their impact on process performance and product attributes. These lots had identical composition as per the supplier and were manufactured at different scales using an identical process. The NIR/MVDA analysis, combined with further investigation at the supplier site, concluded that grouping of medium components during the milling and blending process varied with the scale of production and media type. As a result, uniformity of blending, impurity levels, chemical compatibility, and/or heat sensitivity during the milling process for batches of large‐scale media powder were deemed to be the source of variation as detected by NIR spectra. This variability in the raw materials was enough to cause unacceptably large variability in the performance of the cell culture step and impact the attributes of the resulting product. A combined NIR/MVDA approach made it possible to finger print the raw materials and distinguish between good and poor performing media lots. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2010
Out of control? An ethnographic analysis of the disposal of collectable objects through auction
Authors: Cheetham Fiona
Published: November 2009

This research contributes to our understanding of disposal by attempting to foreground the journey of the disposed object rather than examining disposal from the perspective of the seller as previous consumer researchers have done. Drawing on ideas taken from anthropological analyses of objects and markets the paper provides a glimpse of the cultural biographies of a number of collectable objects as they are disposed of through the public arena of auction. Analysing the disposal of meaningful possessions through auction provides a different context and associated dynamics to that studied in previous research on disposal. Ethnographic analysis indicates that in spite of the fact that the practices and rituals of auction facilitate a process of commoditisation which erases the cultural biography of objects, still traces of their previous cultural history transfer with these objects to their new owners. The objects themselves are implicated in this transfer of meaning indicating that objects do have some kind of social agency.

Copyright © 2009 John Wiley & Sons, Ltd.
Drug Metabolism for the Perplexed Medicinal Chemist
Authors: Testa Bernard
Published: November 2009

Two related and significant issues may elicit perplexity in medicinal chemists and are discussed here. First, a broad presentation of the pharmacological and toxicological consequences of drug metabolism should justify the significance of drug metabolism and serve as an incentive to further study. When comparing the pharmacological activities of a drug and its metabolite(s), a continuum is found which ranges from soft drugs (no active metabolites) to prodrugs (inactiveper se, as illustrated here with clopidogrel and prasugrel). Innumerable intermediate cases document drugs whose activity is shared by one or more metabolites, as exemplified with tamoxifen. The toxicological consequences of metabolism at the molecular, macromolecular, and macroscopic levels are manyfold. A brief overview is offered together with a summary of the reactions of toxification and detoxification of the antiepileptic valproic acid.

The second issue discussed in the review is a comparison of the relative significance of cytochromes P450 and other oxidoreductases (EC 1), hydrolases (EC 3), and transferases (EC 2) in drug metabolism, based on a ‘guesstimate’ of the number of drug metabolites that are known to be produced by them. The conclusion is that oxidoreductases are the main enzymes responsible for the formation of toxic or active metabolites, whereas transferases play the major role in producing inactive and nontoxic metabolites.
Impact of Acute Streptozotocin‐Induced Diabetes on ABC Transporter Expression in Rats
Authors: Anger Gregory J. , Magomedova Lilia , Piquette‐Miller Micheline
Published: November 2009

Hepatic ABC efflux transporters control the cellular uptake (in basolateral membranes) and excretion (in apical membranes) of many substrates. Since type‐1 diabetes mellitus (T1DM) is associated with altered hepatobiliary excretion of many endogenous and exogenous substances, we examined key hepatic ABC transporters and levels of the endogenous substrate glutathione in rats with acute streptozotocin‐induced T1DM. Renal transporters and inflammatory markers were also examined.Abcb1, Abcc1–4, andAbcg2were measured using qRT‐PCR. Glutathione was measured in liver tissue, plasma, and urine. Inflammatory markers, including C‐reactive protein (CRP), were measured in plasmaviaELISA. In diabetic rats,Abcb1a, Abcc2, andAbcg2(apical) were decreased, whileAbcc4(basolateral) was increased.Abcb1aandAbcc2inversely correlated with plasma CRP. Diabetic and control rats exhibited similar hepatic glutathione, but levels in diabetic plasma were lower. When standardized to urinary output, diabetic rats excreted 6.7‐fold more glutathione in urine than controls. Renal transporter levels were normal in diabetic rats. Results show apical transporters involved in hepatobiliary excretion are downregulated in T1DM, possibly through an inflammation‐mediated process. Findings suggest that there may be a vectorial shift from hepatic to renal excretion for some substrates in T1DM.
Probabilistic Prediction of the Human CYP3A4 and CYP2D6 Metabolism Sites
Authors: Dapkunas Justas , Sazonovas Andrius , Japertas Pranas
Published: November 2009

This article briefly introduces the results ofin silicoprediction of the most probable metabolism sites for the human cytochrome P450 3A4 and 2D6 isoforms. Ligand‐based QSAR models have been developed using a novel GALAS modeling approach, and provide probabilities of being a target of CYP3A4 or CYP2D6 for any atom in a molecule. The GALAS‐model development methodology allows evaluation of the reliability of predictions in the form of estimated prediction Reliability Indices (RIs). For all the models considered in this study, the number of misclassifications and inconclusive results was reduced significantly when only predictions of high quality (RI>0.5) were taken into account, demonstrating thatRIreflects accuracy of prediction. The applicability domain of regioselectivity models is shown to be easily expandable to cover compound classes of interest to the user. The results obtained so far show promising perspectives for the utilization of the GALAS modeling in the analysis of regioselectivity for other important biotransformation enzymes – a work currently in progress.
Lipophilicity Determination of Highly Lipophilic Compounds by Liquid Chromatography
Authors: Guillot Amandine , Henchoz Yveline , Moccand Cyril , Guillarme Davy , Veuthey Jean‐Luc , Carrupt Pierre‐Alain , Martel Sophie
Published: November 2009

Different experimental strategies using short columns in both conventional liquid chromatography (HPLC) and ultra‐high pressure liquid chromatography (UHPLC) were evaluated to allow, for the first time with these techniques, the lipophilicity determination of compounds with log P>5. Various organic modifiers, stationary phases, and elution modes were tested on 14 rigid compounds with a CLogP between 5 and 8, and 38 compounds with log Poct from 0 to 5. The best results in HPLC were obtained with the 20‐mm Discovery ® RP Amide C16 stationary phase in isocratic mode using MeOH as organic modifier. To improve analysis time, the UHPLC approach was then evaluated. Consequently, a generic method was developed with a 30‐mm Acquity BEH Shield RP18 column in gradient mode using MeOH as organic modifier, allowing a fourfold gain of time compared to the HPLC method, for the highly lipophilic compounds tested. Finally, the most rapid and accurate results were obtained with a 10‐mm HypersilTM GOLD Javelin HTS stationary phase in UHPLC, enabling an eightfold gain of time compared to the HPLC method.
Prediction of Pharmacokinetic Profile of Valsartan in Humans Based onin vitroUptake‐Transport Data
Authors: Poirier Agnès , Cascais Anne‐Christine , Funk Christoph , Lavé Thierry
Published: November 2009

The aim of this study was to evaluate a physiologically based pharmacokinetic (PBPK) model for predicting PK profiles in humans based on a model refined in rats and humansin vitrouptake‐transport data using valsartan as a probe substrate. Valsartan is eliminated unchanged, mostly through biliary excretion, both in humans and rats. It was, therefore, chosen as model compound to predictin vivoelimination based onin vitrohepatic uptake‐transport data using a fully mechanistic PBPK model. Plated rat and human hepatocytes, and cell lines overexpressing human OATP1B1 and OATP1B3 were used forin vitrouptake experiments. A mechanistic two‐compartment model was used to derive the active and passive transport parameters, namely uptakeMichaelis–Mentenparameters (VmaxandKm,u) together with passive diffusion (Pdif). These transport parameters were then used as input in a whole body physiologically based pharmacokinetic (PBPK) model. The uptake rate of valsartan was higher for rat hepatocytes (Km,u=28.4±3.7 μM,Vmax=1320±180 pmol/mg/min, andPdif =1.21±0.42 μl/mg/min) compared to human hepatocytes (Km,u=44.4±14.6 μM,Vmax=304±85 pmol/mg/min, andPdif=0.724±0.271 μl/mg/min). OATP1B1 and ‐1B3 parameters were correlated to human hepatocyte data, using experimentally established relative activity factors (RAF). Resulting PBPK simulations were compared for plasma‐ (humans and rats) and bile‐ (rats) concentration–time profiles following iv bolus administration of valsartan. Plasma clearances (CLP) for rats and humans were predicted within twofold relative to predictions based on respectivein vitrodata. The simulations were extended to simulate the impact of either OATP1B1 or ‐1B3 inhibition on plasma profile. The limited data set indicates that the mechanistic model allowed for accurate evaluation ofin vitrotransport data; and the resulting hepatic uptake transport kinetic parameters enabled the prediction ofin vivoPK profiles and plasma clearances, using PBPK modelling. Moreover, the interspecies difference in elimination rate observedin vivowas correctly reflected in the transport parameters determinedin vitro.
Recent Advances in Physicochemical and ADMET Profiling in Drug Discovery
Authors: Wang Jianling , Skolnik Suzanne
Published: November 2009

The drastic increase in the cost for discovering and developing a new drug along with the high attrition rate of development candidates led to shifting drug‐discovery strategy to parallel assessment of comprehensive drug physicochemical, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties alongside efficacy. With the proposal of a profiling paradigm and utilization of integrated risk assessment, one can exponentially enhance the predictive power of in vitro tools by taking into consideration the interplay among profiling parameters. In particular, this article will review recent advances in accurate assessment of solubility and other physicochemical parameters. The proper interpretation of these experimental data is crucial for rapid and meaningful risk assessment and rational optimization of drug candidates in drug discovery. The impact of these tools on assisting drug‐discovery teams in establishing in vitro–in vivo correlation (IVIVC) as well as structure–property relationship (SPR) will be presented.