bluuebunny/crossref_metadata_2025 huggingface dataset:
Growth cone transduction: Go and GAP-43
Authors: Strittmatter Stephen M. , Valenzuela Dario , Vartanian Timothy , Sudo Yoshiaki , Zuber Mauricio X. , Fishman Mark C.
Published: May 2013

The neuronal growth cone plays a crucial role in forming the complex brain architecture achieved during development, and similar nerve terminal mechanisms may operate to modify synaptic structure during adulthood. The growth cone leads the elongating axon towards appropriate synaptic targets by altering motility in response to a variety of extracellular signals. Independently of extrinsic clues, neurons mainfest intrinsic control of their growth and form (Banker and Cowan, 1979). Hence, there must be intracellular proteins which control nerve cell shape, so-called ‘plasticity’ or ‘growth’ genes. GAP-43 may be such a molecule (Skene and Willard, 1981; Benowitz and Lewis, 1983). For example, GAP-43 is localized to the growth cone membrane (Meiri et al. 1986; Skene et al. 1986) and can enhance filopodial formation even in nonneuronal cells (Zuber et al. 1989a). It includes a small region at the amino terminus for membrane association and perhaps growth cone targeting (Zuber et al. 1989b, Liu et al. 1991).

We have found that Go, a member of the G protein family that links receptors and second messengers, is the major non-cytoskeletal protein in the growth cone membrane (Strittmatter et al. 1990). Double staining immunohistochemistry for GAP-43 and Go shows that the distributions of the two proteins are quite similar. Purified GAP-43 regulates the activity of purified Go (Strittmatter et al. 1990), a surprising observation since GAP-43 is an intracellular protein. We have compared the mechanism of GAP-43 activation of Go with that of G protein-linked receptors. GAP-43 resembles receptor activation in that both serve primarily to increase the rate of dissociation of bound GDP, with consequent increase in GTPγS binding and GTPase activity. Neither affects the intrinsic rate of hydrolysis of bound GTP by Go. They differ, however, in that pertussis toxin blocks interaction of the receptor with Go, but not that of GAP-43. Furthermore, whereas GAP-43 activates both isolated αo subunits and α β γ trimers, receptors require the presence of the αγ subunits. Thus like receptors, GAP-43 is a guanine nucleotide release protein, but of a novel class. The interactions between Go and GAP-43 suggest that Go plays a pivotal role in growth cone function, coordinating the effects of both extracellular signals and intracellular growth proteins.
SWI6 is a regulatory subunit of two different cell cycle START-dependent transcription factors in Saccharomyces cerevisiae
Authors: Moll Thomas , Dirick LÉOn , Auer Erbert , Bonkovsky Josh , Nasmyth Kim
Published: May 2013

Most genes involved in DNA replication in the yeast Saccharomyces cerevisiae are transcribed transiently during late Gi as cells undergo START. Their promoters all contain one or more versions of an 8-base pair motif (ACGCGTNA) called the Mlul cell cycle box (MCB). MCBs have been shown to be both necessary and sufficient for the late Gi-specific transcription of the TMP1 thymidylate synthase and POLI DNA polymerase genes. A different late Gi-specific transcription element called the SCB (CACGAAAA) is bound by a factor containing the SWI4 and SWI6 proteins. We describe here the formation in vitro of complexes on TMP1 MCBs that contain the SWI6 protein and, we suggest, a 120 kDa protein that is distinct from SWI4. Transcription due to SCBs and MCBs occurs in the absence of SWI6 but it is no longer correctly cell cycle regulated. We suggest that SWI6 is an essential regulatory subunit of two different START-dependent transcription factors. One factor (SBF) contains SWI4 and binds to SCBs whereas the other (MBF) contains p120 and binds MCBs.
Functional conservation of nematode and vertebrate myogenic regulatory factors
Authors: Krause Michael , Fire Andrew , White-Harrison Susan , Weintraub Harold , Tapscott Stephen
Published: May 2013

The Caenorhabditis elegans protein, CeMyoD, is related to the vertebrate myogenic regulatory factors MyoD, myogenin, MRF-4 and Myf-5. Like its vertebrate counterparts, CeMyoD accumulates in the nucleus of striated muscle cells prior to the onset of terminal differentiation. CeMyoD also shares functional similarities with the vertebrate myogenic regulatory factors. Viral LTR driven expression of CeMyoD in mouse 10T1/2 cells can convert this cell line into myoblasts as well as efficiently Zrans-activate mouse muscle-specific promoters. Furthermore, mouse MyoD expression can activate a CeMyoD-P-galactosidase reporter construct in a 10T1/2 co-transfection assay.
Transcriptional repression by methylation of CpG
Authors: Meehan Richard , Lewis Joe , Cross Sally , Nan Xinsheng , Jeppesen Peter , Bird Adrian
Published: May 2013

Methylated DNA in mammals is associated with transcriptional repression and nuclease resistant chromatin. In this review we discuss how these effects may be mediated by proteins that bind to methylated DNA.
Molecular sorting in polarized and non-polarized cells: common problems, common solutions
Authors: Mellman Ira , Yamamoto Ellen , Whitney J. Andrew , Kim Min , Hunziker Walter , Matter Karl
Published: May 2013

We have been interested in determining how epithelial cells generate and maintain their characteristically polarized distributions of membrane proteins. Our efforts to date strongly indicate that the polarized transport in MDCK cells may be due to a set of discrete targeting determinants often found on a membrane protein’s cytoplasmic domain. Surprisingly, these determinants are widely distributed and are not specific to proteins expressed in polarized cells. They also appear to function in controlling polarized transport along both the biosynthetic and the endocytic (or tran-scytotic) pathways. Signals for basolateral transport have been characterized and, like the cytoplasmic domain signal used by plasma membrane receptors for accumulation at clathrin-coated pits, they often involve a critical tyrosine residue. Although the basolateral and coated pit signals may also be co-linear, they are not identical. The basolateral and apical transport determinants are also hierarchically arranged. Although a single protein may contain one or more signals specifying basolateral transport, inactivation of these signals appears to reveal a determinant that directs efficient apical transport. Given that the sequence determinants responsible for polarized transport are not restricted to epithelial cells and are related to determinants commonly utilized in all cells, it is possible that non-polar-ized cells contain cognate apical and basolateral pathways that are responsible for ‘constitutive’ transport from the Golgi to the plasma membrane. The presence of two cognate pathways might confer a high degree of plasticity to pre-differentiated cells, allowing them rapidly to begin assuming a polarized phenotype in response to extracellular stimuli without requiring the synthesis of epithelial cell-specific transport machinery.
The cytoskeleton in development of epithelial cell polarity
Authors: Fath Karl R. , Mamajiwalla Salim N. , Burgess David R.
Published: May 2013

The polarization of intestinal epithelial cells and the stereotypic arrangement of their actin-based cytoskeleton have made these epithelia an excellent system to explore the organization and formation of a cortical actin-based cytoskeleton. Through a combined morphological and biochemical analysis, the molecular arrangement of many of the components of the brush border has been elucidated. Study of brush border assembly in the Crypts of Lieberkuhn suggests that cytoskeletal mRNA and protein expression, as well as morphological development, occur rapidly following cell differentiation. Protein kinases appear to be important regulators of intestinal cell growth, for differentiating cells in the crypts possess 15-fold higher levels of tyrosine phosphorylated proteins than differentiated cells of the villus. One of these kinases, pp60C STC, has a 4-to 7-fold higher activity in crypts and increased association with the cytoskeleton than it has in villus cells.

The development and maintenance of polarization in epithelial cells require the targeting and transport of specific proteins to the apical and basolateral plasma membrane. It has been proposed that a dynein-like, microtubule-based motor is involved in the transport of apically directed materials from the trans-Golgi to the apical plasma membrane. However, microtubules do not reach the plasma membrane, but terminate below the actin-rich network of filaments comprising the terminal web. We propose that vesicles translocate from the Golgi to the apical cytoplasm along microtubules using dynein, and then move through the terminal web to reach the apical plasma membrane using the actin-based motor myosin-I. Our isolation of Golgi-derived vesicles possessing both myosin-I and dynein on their cytoplasmic surface is consistent with this hypothesis.
Involvement of neurofilaments in motor neuron disease
Authors: Xu Zuoshang , Cork Linda C. , Griffin John W. , Cleveland Don W.
Published: May 2013

Motor neuron disease is clinically characterized by progressive muscle wasting leading to total muscle paralysis. A long history of pathological study of patients has firmly established that the primary lesion site is in spinal and cortical motor neurons. In addition to the widespread loss of these neurons, neuronal abnormalities including massive accumulation of neurofilaments in cell bodies and proximal axons have been also widely observed, particularly in the early stages of the disease. To test whether high accumulation of neurofilaments directly contributes to the pathogenic process, transgenic mice that produce high levels of neurofilaments in motor neurons have been generated. These transgenic mice show most of the hallmarks observed in motor neuron disease, including swollen perikarya with eccentrically localized nuclei, proximal axonal swellings, axonal degeneration and severe skeletal muscle atrophy. These data indicate that extensive accumulation of neurofilaments in motor neurons can trigger a neurodegenerative process and may be a key intermediate in the pathway of pathogenesis leading to neuronal loss.
The retinal pigment epithelium: a versatile partner in vision
Authors: Bok Dean
Published: May 2013

The retinal pigment epithelium (RPE) is a monolayer of cuboidal cells that lies in close association with the rod and cone photoreceptors. This epithelium has diverse features, three of which are discussed in some detail in this review, namely the daily phagocytosis of rod and cone outer segment fragments that are shed from their distal ends; the uptake, processing, transport and release of vitamin A (retinol) and some of its visual cycle intermediates (retinoids); and some of the aspects of its apical and basolateral membrane polarity that are the reverse of most other epithelia.

Phagocytosis takes place at the apical surface via membrane receptor-mediated processes that are not yet well defined. Retinol uptake occurs at both the basolateral and apical surfaces by what appear to be separate receptor-mediated processes. The release of a crucial retinoid, 11-cis retinaldehyde (11-cis retinal), occurs solely across the apical membrane. Delivery of retinol across the basolateral membrane is mediated by a retinol binding protein (RBP) that is secreted by the liver as a complex with retinol (vitamin A). Within the cell, retinol and its derivatives are solubilized by intracellular retinoid binding proteins that are selective for retinol (cellular retinol binding protein, CRBP) and 11-cis retinoids (cellular retinal binding protein, CRALBP). Release of ll-cis retinal across the apical membrane and re-uptake of retinol from the photoreceptors during the visual cycle is promoted by an intercellular retinoid binding protein (IRBP).

Na,K-ATPase, the membrane-integrated enzyme required to set up the ion gradients that drive other ion transporters, is largely localized to the apical membrane. This is the reverse of most epithelia. The RPE expresses the enveloped viral G protein and hemagglutinin on its basolateral and apical surface, respectively and does not appear to possess a general scheme for reversal of memrane protein polarity. Therefore possible alternative mechanisms for this reversal in Na,K-ATPase polarity are discussed. They include unique domains in the primary amino acid sequence of Na,K-ATPase subunits, cytoskeletal elements and components of the extracellular matrix. The precise mechanism remains unresolved.
An electron microscopic study of TGN38/41 dynamics
Authors: Ladinsky Mark S. , Howell Kathryn E.
Published: May 2013

We have used electron microscopy to further characterize details of the dynamics of TGN38/41, a protein found to cycle between the frans-Golgi network and the plasma membrane. Immunogold-labeling of NRK cells under steady-state conditions shows the majority of TGN38/41 is localized to the trans-most Golgi cisternae and the irans-Golgi network. Small amounts of this molecule can be detected in early endosomes. Capture of cycling TGN38/41 molecules at the cell surface altered the steady state distribution. This was accomplished by binding TGN38/41 luminal domain antibodies to solid supports (beads), which were introduced to the culture media of cells. As increasing numbers of antigen-antibody complexes formed, the beads were internalized by the ‘zippering mechanism’ of phagocytosis. This provides a system that can address many questions related to the function of TGN38/41 and the trans-Golgi network itself.
Reliability and reproducibility of spectral and time domain optical coherence tomography images before and after correction for patients with age-related macular degeneration
Authors: Rashid Aymen , Sepah Yasir J , Channa Roomasa , Hatef Elham , Shulman Matthew , Do Diana V , Nguyen Quan Dong
Published: May 2013

Purpose: To evaluate the reproducibility and reliability of Optical Coherence Tomography scans (OCT) obtained using the Time Domain (TD-OCT) StratusTM OCT, and the Spectral Domain (SD-OCT) SpectralisTM and CirrusTM OCT devices before and after manual correction in eyes with either Neovascular (NV-AMD) or Non-Neovascular (NNV-AMD) Age-related Macular Degeneration.

Methods: We conducted a prospective observational study of 36 patients (50 eyes) with NV-AMD or NNV-AMD at a university-based retina practice. OCT scans were taken simultaneously using one TD-OCT and two SD-OCT devices. Macular thickness measurements were assessed before and after correction of the OCT algorithm by constructing Bland-Altman plots for agreement and calculating intraclass correlation coefficients (ICCs) and coefficients of repeatability (COR) to evaluate intraclass repeatability.

Results: The Spectralis device had the highest number of images needing manual correction. All machines had high ICCs, with Spectralis having the highest. Bland-Altman plots indicated that there was low agreement between both Cirrus™ and Stratus™ and Spectralis™ and Stratus™, while there was good agreement between the Cirrus™ and Spectralis™ devices. The CORs were lowest for SpectralisTM and similar with each other and had higher values for CirrusTM and StratusTM. Agreement, CORs, and ICCs generally improved after manual correction, but only minimally.  

Conclusion: Agreement is low between devices, except between both SD-OCT machines. Manual correction tends to improve results.
Cassirer, Benveniste, and Peirce on deictics and "pronominal" communication
Authors: Chang Han-liang
Published: May 2013

For all his profound interest in Secondness and its manifestation in various kinds of indices, including deictics, Peirce rarely addresses the inter-pronominal relationships. Whilst the American founder of semiotics would designate languageas a whole to Thirdness, only within the larger framework of which deictics can work, the German philosopher Cassirer observes that "what characterizes the very first spatial terms that we find in language is their embracing of a definite 'deictic' function". For Cassirer the significance of pronominals, especially the I-Thou relationship, lies in its impact on the development of spatial concept that lays the foundation of symbolic forms. It may look strange why the "designatives" of I, Thou, He, in Peirce's own terms, so obvious in their categorial and empirical differentiation, should fail to be reduceable to the triad of Firstness, Secondness, and Thirdness. It is interesting, however, that in his 1906 correspondence with Lady Welby, Peirce should refer to the strange "Communicational Interpretant", or "the Cominterpretant, which is a determination of that mind into which the minds of utterer and interpreter have to be fused in order that any communication should take place". Peirce asserts that this communication of a Form, say, being in love, is made possible by sign. This paper discusses Peirce's and Cassirer's references to deictics or indexical sign, in particular, inter-personal relationships, in light of Benveniste's concept of discourse, and probes into a possible subtext underlying the Peirce-Welby correspondence.
Cognitive and linguistic underpinnings of deixis am phantasma: Bühler's and Peirce's semiotic
Authors: West Donna E.
Published: May 2013

Th is inquiry outlines Karl Bühle's three kinds of deixis, focusing particularly on his most advanced use – deixis am phantasma (deictics to refer to absent referents). This use is of primary import to the semiosis of index, given the centrality of the object and the interpretant in changing the function of the indexical sign in ontogeny. Employing deictic signs to refer to absent objects (some of which are mental) constitutes a catalyst from more social, conventional, uses to more internal, imaginative, ones. Bühler's analogy of mental objects as a "mimesis" serves as the genesis for the claim that static and more dynamic memories, fuelled by affect, drive deictics to refer to more dynamic objects and more dynamic interpretants, into more constructed realities. Peirce's two types of objects and three types of interpretants complete Bühler's deictic framework; they determine advances in deictic semiosis undeveloped by Bühler, and offer rationale for how it is that deictic use extends the semiosis of index.
Polityka zagraniczna pierwszych czterech lat prezydentury Baracka Obamy
Authors: Wordliczek Łukasz
Published: May 2013

Barack Obama’s Foreign Policy during His First Term. Continuation or Change?
The paper aims at assessing United States foreign policy during Barack Obama’s first term in office. While acknowledging many possible conceptual frameworks, the author uses continuity and change approach. Thus, the following areas are covered: implementation of selected foreign policy decisions, personal dimension, relations with Congress and some projection for future development. Surprisingly, notwithstanding rhetoric of change, it seems to be evident that the United States foreign policy between 2009 and 2012 may be described with considerable amount of continuity.
The Role of Search Engine Optimization in Search Marketing
Authors: Berman Ron , Katona Zsolt
Published: May 2013

This paper examines the impact of search engine optimization (SEO) on the competition between advertisers for organic and sponsored search results. The results show that a positive level of search engine optimization may improve the search engine's ranking quality and thus the satisfaction of its visitors. In the absence of sponsored links, the organic ranking is improved by SEO if and only if the quality provided by a website is sufficiently positively correlated with its valuation for consumers. In the presence of sponsored links, the results are accentuated and hold regardless of the correlation. When sponsored links serve as a second chance to acquire clicks from the search engine, low-quality websites have a reduced incentive to invest in SEO, giving an advantage to their high-quality counterparts. As a result of the high expected quality on the organic side, consumers begin their search with an organic click. Although SEO can improve consumer welfare and the payoff of high-quality sites, we find that the search engine's revenues are typically lower when advertisers spend more on SEO and thus less on sponsored links. Modeling the impact of the minimum bid set by the search engine reveals an inverse U-shaped relationship between the minimum bid and search engine profits, suggesting an optimal minimum bid that is decreasing in the level of SEO activity.
Understanding dynamic milking machine tests
Authors: Allcock James , Postma Epi
Published: May 2013

The milking machine can transmit infection onto teats and disturb normal teat health. Milking-time tests allow advisors to quantify the degree to which the milking machine might be contributing to the risk of new intra-mammary infection.

Cows' teat size and position have changed as have milk flow rates. Milk yields have been rising faster than unit attachment times. Milk flow rate has been shown to be positively associated with risk of new intra-mammary infection.

Vacuum traces collected during milking can illustrate problems with biphasic milk flow or over milking and pressure records can help assess liner function. Lightweight data logging equipment is now available with excellent software to assist with interpretation.
Ear tip necrosis
Authors: White Mark
Published: May 2013

Ear tip necrosis (ETN) in growing pigs is a common condition frequently confused with the vice of ear biting. The underlying infectious cause is discussed including the location, development and progression of the condition along with possible complications.

The economic impact is minimal but this does not lessen the aesthetic and potential welfare issues associated with ETN.
The Soldiers’ City
Authors: Wilkinson Cheryl L.
Published: May 2013

The Pacific Branch of the National Home for Disabled Volunteer Soldiers, a domicile and hospital for Union veterans of the Civil War, opened west of Los Angeles in 1888 on land donated by real-estate developers. Barrett Villa Tract, a development of small plots later renamed Sawtelle, was established outside the south gate of the Soldiers’ Home. There veterans bought homes where they could “live out” and enjoy family life while continuing to avail themselves of the services of the Pacific Branch. Sawtelle incorporated as a city in 1906 but consolidated with Los Angeles in 1922. Issues of Pacific Branch members’ votes, behavior, and community leadership mark Sawtelle’s history. Union veterans played a significant role in the development of West Los Angeles.
An Open-Label Safety Study of Lapatinib Plus Trastuzumab Plus Paclitaxel in First-Line HER2-Positive Metastatic Breast Cancer
Authors: Esteva Francisco J. , Franco Sandra X. , Hagan Maura K. , Brewster Abenaa M. , Somer Robert A. , Williams Will , Florance Allison M. , Turner Simon , Stein Steven , Perez Alejandra
Published: May 2013

Background.

Recent data support the hypothesis that combining lapatinib and trastuzumab with taxane chemotherapy may offer added clinical benefit to patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). This study examined the safety of the triplet combination in first-line HER2-positive MBC.

Patients and Methods.

Patients were enrolled into three sequential cohorts; the last two cohorts were added by protocol amendment following review of safety data from cohort 1. Patients in cohort 1 received lapatinib (1000 mg/day) plus paclitaxel (80 mg/m2 per week, 3 of every 4 weeks); cohort 2 received lapatinib (1000 mg/day) plus paclitaxel (70 mg/m2 per week, 3 of every 4 weeks); and cohort 3 received lapatinib (750 mg/day) plus paclitaxel (80 mg/m2 per week, 3 of every 4 weeks). All received standard trastuzumab dosing. The primary objective was assessment of dose-limiting toxicities, safety, and tolerability of this combination.

Results.

The most frequent adverse events (AEs) for all cohorts were diarrhea (89%), rash (79%), fatigue (73%), alopecia (63%), nausea (63%), and vomiting (40%). In cohorts 1 and 2, the incidence of grade 3 diarrhea was 62% and 50%, respectively; in cohort 3, the incidence was 25% (with prophylactic loperamide). Dehydration was the most frequent serious AE (10%). Across cohorts, overall response rate was 75%.

Conclusions.

The dose-limiting toxicity of paclitaxel, trastuzumab, and lapatinib in first-line HER2-positive MBC was diarrhea. Of the triplet combinations tested, the cohort receiving 750 mg/day dose of lapatinib had the lowest incidence of diarrhea; therefore, this dose should be used in further studies on the treatment of MBC.
On the accuracy of paleodiversity reconstructions: a case study in Antarctic Neogene radiolarians
Authors: Renaudie Johan , Lazarus David B.
Published: May 2013

The deep-sea Cenozoic planktonic microfossil record has the unique characteristics of continuously well-preserved populations of most species, with virtually unlimited sample size, and therefore constitutes, in principle, a major resource for macroevolutionary research. Antarctic Neogene radiolarians in particular, are diverse, abundant and consistently well-preserved and evolved rapidly. This fauna is, in theory, a near-perfect testing ground for paleodiversity reconstructions. In this study we determined the diversity history of these faunas from a new quantitative, taxonomically complete data set from Neogene and Quaternary sections at several Antarctic sites. The pattern retrieved by our whole-fauna data set shows a significant, largely extinctionless ecological change in faunal composition and decrease in the evenness of species' abundances during the late Miocene, followed 3 Myr later, at around 5 Ma, by a significant drop in diversity. We tentatively associate this ecological event with a synchronous, regional change in the composition of the primary producers, but as yet cannot identify any environmental changes associated with the later extinction. Further, our whole-fauna diversity history was compared to diversity computed from much less complete, biostratigraphically oriented studies of species' occurrences, compiled in the Neptune database and reconstructed by using subsampling methodologies. Comparison of our whole-fauna and subsampling-reconstructed diversity patterns shows that the first-order trends are the same in both, suggesting that, to some degree, such literature compilations can be used to explore diversity history of plankton. However, our results also highlight substantial errors and distortions in the reconstructed diversity which make it poorly suited to more-detailed studies (e.g., for comparison of diversity history with paleoenvironmental history). We conclude that detailed studies of plankton diversity, and particularly those attempting to understand the relation between diversity and paleoceanographic change, should be based on taxonomically comprehensive, quantitative data.
CFRP-confined concrete columns under different environmental conditions
Authors: Erdil Barış , Akyüz Uğurhan , Yaman İsmail Özgür
Published: May 2013

The behaviour of carbon fibre reinforced polymer-confined cylindrical and prismatic concrete specimens subjected to several different environmental conditions was investigated in four groups. The first group of specimens was used as a reference. In the second group, specimens were exposed to dry heating–cooling (H–C) cycles in the environmental test chamber (ETC), whereas specimens in the third group were kept in water while simultaneously being subjected to H–C cycles in the ETC. Finally, the last group of specimens was kept outside of the laboratory to determine the outdoor environmental effect. After the ageing phase, specimens were tested under monotonic uniaxial loading to determine the change in their mechanical properties. Cylindrical specimens were observed not to be significantly affected by H–C cycles with the exception of their ultimate strain, which decreased under outdoor conditions. As for the prismatic specimens, dry H–C cycles were found to reduce strength by up to 24% and strain by up to 33%. Wet H–C cycles and outdoor exposure were seen to decrease further the strength and ultimate strain of prismatic specimens.
NEC contracts for design–build–operate contracts
Authors: Patterson Richard L. , Trebes Barry
Published: May 2013

The NEC Engineering and Construction Contract (ECC) is a popular choice for construction and design-and-build contracts in the UK and South Africa. They are also increasingly by being used elsewhere in the world, for example in New Zealand and in Hong Kong. The NEC family of contracts is specifically designed for international use. The NEC Term Service Contract (TSC) is also increasingly being used for contracts to provide a service including, often, the operation and maintenance of an asset. Some clients are increasingly looking to appoint a contractor to design, build and operate an asset and so take a real interest in the operability and operating cost of the asset. This paper looks at key issues specific to design, build and operate contracts and explains how the NEC ECC and NEC TSC could be combined to form the basis of a design, build and operate contract. It is true that changes would be required, but with an NEC base to the contract, all parties would have the benefit of starting from what have become industry standard forms of contract, namely forms that are designed for clarity, flexibility and, most importantly, as a stimulus to good management.
Disturbance regime alters the impact of dispersal on alpha and beta diversity in a natural metacommunity
Authors: Vanschoenwinkel Bram , Buschke Falko , Brendonck Luc
Published: May 2013

Disturbance and dispersal are two fundamental ecological processes that shape diversity patterns, yet their interaction and the underlying mechanisms are still poorly understood, and evidence from natural systems is particularly lacking. Using an invertebrate rock pool metacommunity in South Africa as a natural model system, we studied potential interactive effects of disturbance regime and patch isolation on diversity patterns of species with contrasting dispersal modes (passive vs. active dispersal).

Isolation and disturbance regime had negative synergistic effects on alpha diversity: both directly, by excluding late‐successional species from isolated patches; and indirectly, by modulating establishment success of generalist predators in well‐connected patches. Unimodal relationships between isolation and alpha diversity, as predicted by mass effects, were only detected for passive dispersers in frequently disturbed patches and not in active dispersers. For passive dispersers, indications for a positive effect of isolation and a negative effect of disturbance on beta diversity were found, presumably due to differences in deterministic succession and stochastic colonization–extinction dynamics among different patch types. Our findings illustrate that interactions between dispersal rates and disturbance regime are important when explaining species diversity patterns in metacommunities and support the idea that diversity in frequently disturbed habitats is more sensitive to effects of dispersal‐based processes.
Total Oxidant Status and Bone Resorption Biomarkers in Serum and Gingival Crevicular Fluid of Patients With Periodontitis
Authors: Baltacıoğlu Esra , Kehribar Malike Aslan , Yuva Pınar , Alver Ahmet , Atagün Özlem Saraç , Karabulut Erdem , Akalın Ferda Alev
Published: May 2013

Background: In this study, the relationships between total oxidant status (TOS) and receptor activator of nuclear factor‐κB ligand (RANKL) and osteoprotegerin (OPG) levels and RANKL/OPG ratios in serum and gingival crevicular fluid (GCF) are investigated in patients with chronic (CP) and generalized aggressive (GAgP) periodontitis.

Methods: Thirty patients with CP, 30 patients with GAgP, and 28 periodontally healthy controls were included in the study. After clinical measurements and samplings, serum and GCF TOS, RANKL, and OPG levels were determined by a novel automatic colorimetric method and enzyme‐linked immunosorbent assays.

Results: Serum and GCF TOS, RANKL, and RANKL/OPG values were higher in the periodontitis groups compared with controls, and they were also higher in the GAgP group than the CP group (except serum and GCF RANKL). Furthermore, serum and GCF OPG concentrations were lower in the periodontitis groups than in controls. Strong positive and negative correlations were observed between the periodontal parameters TOS and bone resorption biomarkers.

Conclusions: The present results reveal that TOS, RANKL, and RANKL/OPG values are systemically and locally increased in periodontitis and that this increase is more evident in AgP than CP. These findings further suggest that oxidative stress is closely associated with the severity of periodontitis and bone resorption biomarkers.
Biochemical Basis of the Antidiabetic Activity of Oleanolic Acid and Related Pentacyclic Triterpenes
Authors: Castellano Jose M. , Guinda Angeles , Delgado Teresa , Rada Mirela , Cayuela Jose A.
Published: May 2013

Oleanolic acid (OA), a natural component of many plant food and medicinal herbs, is endowed with a wide range of pharmacological properties whose therapeutic potential has only partly been exploited until now. Throughout complex and multifactorial mechanisms, OA exerts beneficial effects against diabetes and metabolic syndrome. It improves insulin response, preserves functionality and survival of β-cells, and protects against diabetes complications. OA may directly modulate enzymes connected to insulin biosynthesis, secretion, and signaling. However, its major contributions appear to be derived from the interaction with important transduction pathways, and many of its effects are consistently related to activation of the transcription factor Nrf2. Doing that, OA induces the expression of antioxidant enzymes and phase II response genes, blocks NF-κB, and represses the polyol pathway, AGEs production, and hyperlipidemia. The management of type 2 diabetes requires an integrated approach, which includes the early intervention to prevent or delay the disease progression, and the use of therapies to control glycemia and lipidemia in its late stages. In this sense, the use of functional foods or drugs containing OA is, undoubtedly, an interesting path.
Anatomical Locations of Human Brown Adipose Tissue
Authors: Sacks Harold , Symonds Michael E.
Published: May 2013

We will review information about and present hypotheses as to the anatomy of brown adipose tissue (BAT). Why is it located where it is in humans? Its anatomical distribution is likely to confer survival value by protecting critical organs from hypothermia by adaptive thermogenesis. Ultimately, the location and function will be important when considering therapeutic strategies for preventing and treating obesity and type 2 diabetes, in which case successful interventions will need to have a significant effect on BAT function in subjects living in a thermoneutral environment. In view of the diverse locations and potential differences in responsiveness between BAT depots, it is likely that BAT will be shown to have much more subtle and thus previously overlooked functions and regulatory control mechanisms.
Banting Lecture 2012
Authors: Spiegelman Bruce M.
Published: May 2013

The Banting Medal for Scientific Achievement Award is the American Diabetes Association's highest scientific award and honors an individual who has made significant, long-term contributions to the understanding of diabetes, its treatment, and/or prevention.The award is named after Nobel Prize winner Sir Frederick Banting, who codiscovered insulin treatment for diabetes.

Bruce M. Spiegelman, PhD, of Harvard Medical School and the Dana-Farber Cancer Institute in Boston, received the American Diabetes Association's Banting Medal for Scientific Achievement at the Association's 72nd Scientific Sessions, 8–12 June 2012, Philadelphia, Pennsylvania. He presented the Banting Lecture, “Transcriptional Control of Adipogenesis—Toward a New Generation of Therapeutics for Metabolic Disease,” on Sunday, 10 June 2012. In his lecture, Dr. Spiegelman described the discovery of several transcriptional components that control adipose cell development: PPAR-γ, PGC1-α, and PRDM16. He also described the cloning and characterization of beige fat cells, the thermogenic “brown-like” cells that can develop in white fat depots. Lastly, Dr. Spiegelman discussed irisin, a newly discovered regulatory hormone that converts white fat into the more thermogenic beige fat. Dr. Spiegelman’s research has found that irisin, which is induced by exercise, appears to activate some of the same health benefits as exercise, including improvement of glycemic control. Understanding the regulation of adipose tissue, white, brown, and beige, can potentially lead to the development of a new generation of therapeutics for diabetes prevention and treatment.
Ethnic Differences in the Relationship Between Insulin Sensitivity and Insulin Response
Authors: Kodama Keiichi , Tojjar Damon , Yamada Satoru , Toda Kyoko , Patel Chirag J. , Butte Atul J.
Published: May 2013

OBJECTIVE

Human blood glucose levels have likely evolved toward their current point of stability over hundreds of thousands of years. The robust population stability of this trait is called canalization. It has been represented by a hyperbolic function of two variables: insulin sensitivity and insulin response. Environmental changes due to global migration may have pushed some human subpopulations to different points of stability. We hypothesized that there may be ethnic differences in the optimal states in the relationship between insulin sensitivity and insulin response.

RESEARCH DESIGN AND METHODS

We identified studies that measured the insulin sensitivity index (SI) and acute insulin response to glucose (AIRg) in three major ethnic groups: Africans, Caucasians, and East Asians. We identified 74 study cohorts comprising 3,813 individuals (19 African cohorts, 31 Caucasian, and 24 East Asian). We calculated the hyperbolic relationship using the mean values of SI and AIRg in the healthy cohorts with normal glucose tolerance.

RESULTS

We found that Caucasian subpopulations were located around the middle point of the hyperbola, while African and East Asian subpopulations are located around unstable extreme points, where a small change in one variable is associated with a large nonlinear change in the other variable.

CONCLUSIONS

Our findings suggest that the genetic background of Africans and East Asians makes them more and differentially susceptible to diabetes than Caucasians. This ethnic stratification could be implicated in the different natural courses of diabetes onset.
Safety and Tolerability of the Treatment of Youth-Onset Type 2 Diabetes
Authors:   TODAY Study Group
Published: May 2013

OBJECTIVE

Data related to the safety and tolerability of treatments for pediatric type 2 diabetes are limited. The TODAY clinical trial assessed severe adverse events (SAEs) and targeted nonsevere adverse events (AEs) before and after treatment failure, which was the primary outcome (PO).

RESEARCH DESIGN AND METHODS

Obese 10- to 17-year-olds (N = 699) with type 2 diabetes for <2 years and hemoglobin A1c (A1C) ≤8% on metformin monotherapy were randomized to one of three treatments: metformin, metformin plus rosiglitazone (M + R), or metformin plus lifestyle program (M + L). Participants were followed for 2–6.5 years.

RESULTS

Gastrointestinal (GI) disturbance was the most common AE (41%) and was lower in the M + R group (P = 0.018). Other common AEs included anemia (20% before PO, 14% after PO), abnormal liver transaminases (16, 15%), excessive weight gain (7, 9%), and psychological events (10, 18%); the AEs were similar across treatments. Permanent medication reductions/discontinuations occurred most often because of abnormal liver transaminases and were lowest in the M + R group (P = 0.005). Treatment-emergent SAEs were uncommon and similar across treatments. Most (98%) were unrelated or unlikely related to the study intervention. There were no deaths and only 18 targeted SAEs (diabetic ketoacidosis, n = 12; severe hypoglycemia, n = 5; lactic acidosis, n = 1). There were 62 pregnancies occurring in 45 participants, and 6 infants had congenital anomalies.

CONCLUSIONS

The TODAY study represents extensive experience managing type 2 diabetes in youth and found that the three treatment approaches were generally safe and well tolerated. Adding rosiglitazone to metformin may reduce GI side effects and hepatotoxicity.
Treatment Effects on Measures of Body Composition in the TODAY Clinical Trial
Authors:   TODAY Study Group
Published: May 2013

OBJECTIVE

The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial showed superiority of metformin plus rosiglitazone (M+R) over metformin alone (M), with metformin plus lifestyle (M+L) intermediate in maintaining glycemic control. We report here treatment effects on measures of body composition and their relationships to demographic and metabolic variables including glycemia.

RESEARCH DESIGN AND METHODS

Measures of adiposity (BMI, waist circumference, abdominal height, percent and absolute fat, and bone mineral content [BMC] and density [BMD]) were analyzed as change from baseline at 6 and 24 months.

RESULTS

Measures of fat accumulation were greatest in subjects treated with M+R and least in M+L. Although fat measures in M+L were less than those of M+R and M at 6 months, differences from M were no longer apparent at 24 months, whereas differences from M+R persisted at 24 months. The only body composition measure differing by race and/or ethnicity was waist circumference, greater in M+R than either M or M+L at both 6 and 24 months in whites. BMD and BMC increased in all groups, but increased less in M+R compared with the other two groups by 24 months. Measures of adiposity (increases in BMI, waist circumference, abdominal height, and fat) were associated with reduced insulin sensitivity and increased hemoglobin A1c (HbA1c), although effects of adiposity on HbA1c were less evident in those treated with M+R.

CONCLUSIONS

Despite differential effects on measures of adiposity (with M+R resulting in the most and M+L in the least fat accumulation), group differences generally were small and unrelated to treatment effects in sustaining glycemic control.
Personalized Management of Hyperglycemia in Type 2 Diabetes
Authors: Raz Itamar , Riddle Matthew C. , Rosenstock Julio , Buse John B. , Inzucchi Silvio E. , Home Philip D. , Del Prato Stefano , Ferrannini Ele , Chan Juliana C.N. , Leiter Lawrence A. , LeRoith Derek , DeFronzo Ralph , Cefalu William T.
Published: May 2013

In June 2012, 13 thought leaders convened in a Diabetes Care Editors’ Expert Forum to discuss the concept of personalized medicine in the wake of a recently published American Diabetes Association/European Association for the Study of Diabetes position statement calling for a patient-centered approach to hyperglycemia management in type 2 diabetes. This article, an outgrowth of that forum, offers a clinical translation of the underlying issues that need to be considered for effectively personalizing diabetes care. The medical management of type 2 diabetes has become increasingly complex, and its complications remain a great burden to individual patients and the larger society. The burgeoning armamentarium of pharmacological agents for hyperglycemia management should aid clinicians in providing early treatment to delay or prevent these complications. However, trial evidence is limited for the optimal use of these agents, especially in dual or triple combinations. In the distant future, genotyping and testing for metabolomic markers may help us to better phenotype patients and predict their responses to antihyperglycemic drugs. For now, a personalized (“n of 1”) approach in which drugs are tested in a trial-and-error manner in each patient may be the most practical strategy for achieving therapeutic targets. Patient-centered care and standardized algorithmic management are conflicting approaches, but they can be made more compatible by recognizing instances in which personalized A1C targets are warranted and clinical circumstances that may call for comanagement by primary care and specialty clinicians.
Comparison of ice stress records in terms of extreme value analysis
Authors: Lensu Mikko , Elder Bruce C. , Richter-Menge Jackie , Haapala Jari
Published: May 2013

Dynamic ice models use stress tensor to describe the forces arising from internal ice friction. The model stress values are typically one to two magnitudes smaller than values measured by stressmeters deployed on ice floes. The synthesis of the pack-ice stress state from the measurements has been complicated by the peaky character of stress records, and the means to connect them with spatial stress distribution of the floe system have been lacking. Here a reanalysis of Arctic Sea Ice Mechanics Initiative (SIMI) data is made in terms of extreme value statistics. The basic quantity is the maximum stress observed during a time period. The records exhibit self-affine scaling. The statistics are then determined by two parameters, the Hurst exponent H and a reference stress level. Similar analysis is possible for the kinematic data. This establishes the comparability of stress records with each other and with kinematic records. The results suggest that the exponent is related to the stress state of the regional floe system, while the stress level is determined by local floe characteristics. Based on this a characterization of spatial distribution of pack-ice stresses is given.
Metric Structure of the Space of Two-Qubit Gates, Perfect Entanglers and Quantum Control
Authors: Watts Paul , O'Connor Maurice , Vala Jiří
Published: May 2013

We derive expressions for the invariant length element and measure for the simple compact Lie group SU(4) in a coordinate system particularly suitable for treating entanglement in quantum information processing. Using this metric, we compute the invariant volume of the space of two-qubit perfect entanglers. We find that this volume corresponds to more than 84% of the total invariant volume of the space of two-qubit gates. This same metric is also used to determine the effective target sizes that selected gates will present in any quantum-control procedure designed to implement them.
The Dynamics of Concepts in a Homogeneous Community
Authors: Khmelnitsky Eugene , Kagan Eugene
Published: May 2013

The paper addresses informational interactions in a community and considers the dynamics of concepts that represent distribution of knowledge among the individuals. The evolution of a set of concepts maintained by a community is derived by the use of the concepts’ significance in the communication between “cognoscenti” and “dilettanti” and of birth-death processes. The dynamics of concepts depend on the allocation of communication resources and can be governed by an informational principle that requires minimum self-information of the set of concepts over a time horizon. With respect to that principle, the introduction of a new concept into a community’s disposal is shown to lead to a steady-state self-information, which is smaller than that before the introduction of the new concept.