bluuebunny/crossref_metadata_2025 huggingface dataset:
Anticancer Agents That Counteract Tumor Glycolysis
Authors: Granchi Carlotta , Minutolo Filippo
Published: June 2012

Can we consider cancer to be a “metabolic disease”? Tumors are the result of a metabolic selection, forming tissues composed of heterogeneous cells that generally express an overactive metabolism as a common feature. In fact, cancer cells have increased needs for both energy and biosynthetic intermediates to support their growth and invasiveness. However, their high proliferation rate often generates regions that are insufficiently oxygenated. Therefore, their carbohydrate metabolism must rely mostly on a glycolytic process that is uncoupled from oxidative phosphorylation. This metabolic switch, also known as the Warburg effect, constitutes a fundamental adaptation of tumor cells to a relatively hostile environment, and supports the evolution of aggressive and metastatic phenotypes. As a result, tumor glycolysis may constitute an attractive target for cancer therapy. This approach has often raised concerns that antiglycolytic agents may cause serious side effects toward normal cells. The key to selective action against cancer cells can be found in their hyperbolic addiction to glycolysis, which may be exploited to generate new anticancer drugs with minimal toxicity. There is growing evidence to support many glycolytic enzymes and transporters as suitable candidate targets for cancer therapy. Herein we review some of the most relevant antiglycolytic agents that have been investigated thus far for the treatment of cancer.
Synthesis and Antifungal Activities of Glycosylated Derivatives of the Cyclic Peptide Fungicide Caspofungin
Authors: Guo Junxiang , Hu Honggang , Zhao Qingjie , Wang Ting , Zou Yan , Yu Shichong , Wu Qiuye , Guo Zhongwu
Published: June 2012

Diseases caused by systemic fungal infections have become a significant clinical problem in recent decades. A series of glycosyl derivatives of the approved cyclic peptide antifungal drug caspofungin conjugated with β‐D‐glucopyranose, β‐D‐galactopyranose, β‐D‐xylopyranose, β‐L‐rhamnopyranose, β‐maltose and β‐lactose units were designed, synthesized, and evaluated as new potential antifungal drugs. The compounds were obtained by coupling the corresponding glycosyl amines to the free primary amino groups of caspofungin through a bifunctional glutaryl linker. In contrast to caspofungin, these glycosylated derivatives are soluble in water, but are not hygroscopic and moreover, are more stable than caspofungin under high humidity and temperature. CD studies showed that glycosylation has very little impact on the conformation of the cyclic peptide of caspofungin. In vitro antifungal tests against seven human pathogenic fungi revealed that the caspofungin–monosaccharide conjugates, but not the disaccharide conjugates, have increased antifungal activities against the majority of tested fungus species relative to caspofungin. The β‐D‐glucopyranosyl derivative 2 a showed the strongest and broadest antifungal activity, providing a lead for further studies.
Morphology of axonal projections from the high vocal center to vocal motor cortex in songbirds
Authors: Yip Zhiqi C. , Miller‐Sims Vanessa C. , Bottjer Sarah W.
Published: June 2012

Only birds that learn complex vocalizations have telencephalic brain regions that control vocal learning and production, including HVC (high vocal center), a cortical nucleus that encodes vocal motor output in adult songbirds. HVC projects to RA (robust nucleus of the arcopallium), a nucleus in motor cortex that in turn projects topographically onto hindbrain neurons innervating vocal muscles. Individual neurons projecting from HVC to RA (HVCRA) fire sparsely to drive RA activity during song production. To advance understanding of how individual HVC neurons encode production of learned vocalizations, we reconstructed single HVC axons innervating RA in adult male zebra finches. Individual HVCRA axons were not topographically organized within RA: 1) axon arbors of HVC cell bodies located near each other sent branches to different subregions of RA, and 2) branches of single HVC axons terminated in different locations within RA. HVCRA axons also had a simple, sparse morphology, suggesting that a single HVC neuron activates a limited population of postsynaptic RA neurons. These morphological data are consistent with previous work showing that single HVCRA neurons burst sparsely for a brief period of time during the production of a song, indicating that ensembles of HVCRA neurons fire simultaneously to drive small temporal segments of song behavior. We also examined the morphology of axons projecting from HVC to RA cup, a region surrounding RA that receives input from auditory cortex. Axons projecting to RA cup also sent some branches into RA, suggesting direct integration between the sensory and motor circuits for song control. J. Comp. Neurol. 520:2742–2756, 2012. © 2012 Wiley Periodicals, Inc.
Dopamine and full‐field illumination activate D1 and D2‐D5‐type receptors in adult rat retinal ganglion cells
Authors: Ogata Genki , Stradleigh Tyler W. , Partida Gloria J. , Ishida Andrew T.
Published: June 2012

Dopamine can regulate signal generation and transmission by activating multiple receptors and signaling cascades, especially in striatum, hippocampus, and cerebral cortex. Dopamine modulates an even larger variety of cellular properties in retina, yet has been reported to do so by only D1 receptor‐driven cyclic adenosine monophosphate (cAMP) increases or D2 receptor‐driven cAMP decreases. Here, we test the possibility that dopamine operates differently on retinal ganglion cells, because the ganglion cell layer binds D1 and D2 receptor ligands, and displays changes in signaling components other than cAMP under illumination that should release dopamine. In adult rat retinal ganglion cells, based on patch‐clamp recordings, Ca2+ imaging, and immunohistochemistry, we find that 1) spike firing is inhibited by dopamine and SKF 83959 (an agonist that does not activate homomeric D1 receptors or alter cAMP levels in other systems); 2) D1 and D2 receptor antagonists (SCH 23390, eticlopride, raclopride) counteract these effects; 3) these antagonists also block light‐induced rises in cAMP, light‐induced activation of Ca2+/calmodulin‐dependent protein kinase II, and dopamine‐induced Ca2+ influx; and 4) the Ca2+ rise is markedly reduced by removing extracellular Ca2+ and by an IP3 receptor antagonist (2‐APB). These results provide the first evidence that dopamine activates a receptor in adult mammalian retinal neurons that is distinct from classical D1 and D2 receptors, and that dopamine can activate mechanisms in addition to cAMP and cAMP‐dependent protein kinase to modulate retinal ganglion cell excitability. J. Comp. Neurol. 520:4032–4049, 2012. © 2012 Wiley Periodicals, Inc.
Area‐specific substratification of deep layer neurons in the rat cortex
Authors: Watakabe Akiya , Hirokawa Junya , Ichinohe Noritaka , Ohsawa Sonoko , Kaneko Takeshi , Rockland Kathleen S. , Yamamori Tetsuo
Published: June 2012

Gene markers are useful tools to identify cell types for fine mapping of neuronal circuits. Here we report area‐specific sublamina structure of the rat cerebral cortex using cholecystokinin (cck) and purkinje cell protein4 (pcp4) mRNAs as the markers for excitatory neuron subtypes in layers 5 and 6. We found a segregated expression, especially pronounced in layer 6, where corticothalamic and corticocortical projecting neurons reside. To examine the relationship between gene expression and projection target, we injected retrograde tracers into several thalamic subnuclei, ventral posterior (VP), posterior (PO), mediodorsal (MD), medial and lateral geniculate nuclei (MGN and LGN); as well as into two cortical areas (M1 and V1). This combination of tracer‐in situ hybridization (ISH) experiments revealed that corticocortical neurons predominantly express cck and corticothalamic neurons predominantly express pcp4 mRNAs in all areas tested. In general, cck(+) and pcp4(+) cells occupied the upper and lower compartment of layer 6a, respectively. However, the sublaminar distribution and the relative abundance of cck(+) and pcp4(+) cells were quite distinctive across areas. For example, layer 6 of the prelimbic cortex was almost devoid of cck(+) neurons, and was occupied instead by corticothalamic pcp4(+) neurons. In the lateral areas, such as S2, there was an additional layer of cck(+) cells positioned below the pcp4(+) compartment. The claustrum, which has a tight relationship with the cortex, mostly consisted of cck(+)/pcp4(−) cells. In summary, the combination of gene markers and retrograde tracers revealed a distinct sublaminar organization, with conspicuous cross‐area variation in the arrangement and relative density of corticothalamic connections. J. Comp. Neurol. 520:3553–3573, 2012. © 2012 Wiley Periodicals, Inc.
Pattern of calbindin‐D28k and calretinin immunoreactivity in the brain ofXenopus laevisduring embryonic and larval development
Authors: Morona Ruth , González Agustín
Published: June 2012

The present study represents a detailed spatiotemporal analysis of the localization of calbindin‐D28k (CB) and calretinin (CR) immunoreactive structures in the brain ofXenopus laevisthroughout development, conducted with the aim to correlate the onset of the immunoreactivity with the development of compartmentalization of distinct subdivisions recently identified in the brain of adult amphibians and primarily highlighted when analyzed within a segmental paradigm. CR and CB are expressed early in the brain and showed a progressively increasing expression throughout development, although transient expression in some neuronal subpopulations was also noted. Common and distinct characteristics inXenopus, as compared with reported features during development in the brain of mammals, were observed. The development of specific regions in the forebrain such as the olfactory bulbs, the components of the basal ganglia and the amygdaloid complex, the alar and basal hypothalamic regions, and the distinct diencephalic neuromeres could be analyzed on the basis of the distinct expression of CB and CR in subregions. Similarly, the compartments of the mesencephalon and the main rhombencephalic regions, including the cerebellum, were differently highlighted by their specific content in CB and CR throughout development. Our results show the usefulness of the analysis of the distribution of these proteins as a tool in neuroanatomy to interpret developmental aspects of many brain regions. J. Comp. Neurol. 521:79–108, 2013. © 2012 Wiley Periodicals, Inc.
Postnatal development of brain‐derived neurotrophic factor (BDNF) and tyrosine protein kinase B (TrkB) receptor immunoreactivity in multiple brain stem respiratory‐related nuclei of the rat
Authors: Liu Qiuli , Wong‐Riley Margaret T.T.
Published: June 2012

Previously, we found a transient imbalance between suppressed excitation and enhanced inhibition in the respiratory network of the rat around postnatal days (P) 12–13, a critical period when the hypoxic ventilatory response is at its weakest. The mechanism underlying the imbalance is poorly understood. Brain‐derived neurotrophic factor (BDNF) and its tyrosine protein kinase B (TrkB) receptors are known to potentiate glutamatergic and attenuate gamma‐aminobutyric acid (GABA)ergic neurotransmission, and BDNF is essential for respiratory development. We hypothesized that the excitation‐inhibition imbalance during the critical period stemmed from a reduced expression of BDNF and TrkB at that time within respiratory‐related nuclei of the brain stem. An in‐depth, semiquantitative immunohistochemical study was undertaken in seven respiratory‐related brain stem nuclei and one nonrespiratory nucleus in P0–21 rats. The results indicate that the expressions of BDNF and TrkB: 1) in the pre‐Bötzinger complex, nucleus ambiguus, commissural and ventrolateral subnuclei of solitary tract nucleus, and retrotrapezoid nucleus/parafacial respiratory group were significantly reduced at P12, but returned to P11 levels by P14; 2) in the lateral paragigantocellular nucleus and parapyramidal region were increased from P0 to P7, but were strikingly reduced at P10 and plateaued thereafter; and 3) in the nonrespiratory cuneate nucleus showed a gentle plateau throughout the first 3 postnatal weeks, with only a slight decline of BDNF expression after P11. Thus, the significant downregulation of both BDNF and TrkB in respiratory‐related nuclei during the critical period may form the basis of, or at least contribute to, the inhibitory‐excitatory imbalance within the respiratory network during this time. J. Comp. Neurol. 521:109–129, 2013. © 2012 Wiley Periodicals, Inc.
Determination of reactive crystallization kinetics of 5‐(difluromethoxy)‐2‐mercapto‐1H‐benzimidazole in a batch crystallizer
Authors: Wang Yongli , Ma Shuyuan , Lv Xiaodong
Published: June 2012

5‐(difluromethoxy)‐2‐mercapto‐1H‐benzimidazole (DMB) was crystallized via the reaction between sodium salt of DMB and acetic acid. In this work, we firstly measured the solubility data of DMB in binary ethanol‐water mixture at different temperatures. Then, the reactive crystallization kinetics of DMB was determined in the batch crystallizer. Based on the population balance and mass balance, the kinetics model of reactive crystallization process of DMB was established. And the nucleation rate, size‐independent crystal growth and agglomeration kernel were determined by method of classes. Finally, based on the population balance, numeric simulation was done using the above crystallization kinetics in order to verify its reliability.
Critical period for estrogen‐dependent motoneuron dendrite growth is coincident with ERα expression in target musculature
Authors: Rudolph Lauren M. , Sengelaub Dale R.
Published: June 2012

The spinal cord of rats contains the sexually dimorphic, steroid‐sensitive motoneurons of the spinal nucleus of the bulbocavernosus (SNB). In males, SNB dendrite growth is dependent on gonadal steroids: dendrite growth is inhibited after castration, but supported in androgen‐ or estrogen‐treated castrated males. Furthermore, estrogenic support of SNB dendrite growth is mediated by estrogen action at the target musculature, inhibited by estrogen receptor (ER) blockade at the muscle and supported by local estradiol treatment. However, this estrogenic support is restricted to the early postnatal period, after which the morphology of SNB dendrites is insensitive to estrogens. To test if the developmentally restricted effects of estrogens on SNB dendrite growth coincide with the transient expression of ER in the target musculature, ERα expression was assessed during development and in adulthood. ERα expression in extra‐Muscle fiber cells was greatest from postnatal day 7 (P7) to P14 and declined after P21. Because this pattern of ERα expression coincided with the period of estrogen‐dependent dendrite growth, we tested if limiting hormone exposure to the period of maximal ERα expression in extra‐muscle fiber cells could fully support estrogen‐dependent SNB dendrite growth. We restricted estradiol treatment in castrated males from P7 to P21 and assessed SNB dendritic morphology at P28. Treating castrates with estradiol implants at the muscle from P7 to P21 supported dendrite growth to normal levels through P28. These data suggest that the transient ERα expression in target muscle could potentially define the critical period for estrogen‐dependent dendrite growth in SNB motoneurons. © 2011 Wiley Periodicals, Inc. Develop Neurobiol, 2013
Consequences of changing rainfall for fungal pathogen‐induced mortality in tropical tree seedlings
Authors: Swinfield Tom , Lewis Owen T. , Bagchi Robert , Freckleton Robert P.
Published: June 2012

Most general circulation models predict that most tropical forests will experience lower and less frequent rainfall in future as a result of climate change, which may reduce the capacity of fungal pathogens to drive density‐dependent tree mortality. This is potentially significant because fungal pathogens are thought to play a key role in promoting and structuring plant diversity in tropical forests through the Janzen–Connell mechanism. Therefore, we hypothesize that the drying of tropical forests will negatively impact species coexistence. To test one prediction of this hypothesis, we imposed experimental watering regimes on the seedlings of a tropical tree, Pleradenophora longicuspis, and measured mortality induced by fungal pathogens under shade house conditions. The frequency of watering had a strong impact on survival. Seedlings watered daily experienced significantly higher mortality than those watered every three or every six days, while increasing the volume of water applied also led to increased mortality, although this relationship was less pronounced. These results suggest that the capacity of fungal pathogens to drive density‐dependent mortality may be reduced in drier climates and when rainfall is less frequent, with potential implications for the diversity enhancing Janzen–Connell mechanism.
Infectious disease in animal metapopulations: the importance of environmental transmission
Authors: Park Andrew W.
Published: June 2012

Motivated by an array of infectious diseases that threaten wildlife populations, a simple metapopulation model (subpopulations connected by animal movement) is developed, which allows for both movement‐based and environmental transmission. The model demonstrates that for a range of plausible parameterizations of environmental transmission, increased movement rate of animals between discrete habitats can lead to a decrease in the overall proportion of sites that are occupied. This can limit the ability of the rescue effect to ensure locally extinct populations become recolonized and can drive metapopulations down in size so that extinction by mechanisms other than disease may become more likely. It further highlights that, in the context of environmental transmission, the environmental persistence time of pathogens and the probability of acquiring infection by environmental transmission can affect host metapopulations both qualitatively and quantitatively. Additional spillover sources of infection from alternate reservoir hosts are also included in the model and a synthesis of all three types of transmission, acting alone or in combination, is performed revealing that movement‐based transmission is the only necessary condition for a decline in the proportion of occupied sites with increasing movement rate, but that the presence of other types of transmission can reverse this qualitative result. By including the previously neglected role of environmental transmission, this work contributes to the general discussion of when dispersal by wild animals is beneficial or detrimental to populations experiencing infectious disease.
IL‐17 neutralization significantly ameliorates hepatic granulomatous inflammation and liver damage in Schistosoma japonicum infected mice
Authors: Zhang Yuxia , Chen Liuxi , Gao Wenda , Hou Xin , Gu Yuqing , Gui Li , Huang Dake , Liu Miao , Ren Cuiping , Wang Siying , Shen Jijia
Published: June 2012

IL‐17 is a signature cytokine of Th17 cells implicated in the induction and progression of chronic inflammatory diseases. Several studies in C57BL/6 mice, immunized with soluble schistosome egg Ags (SEA) in complete Freund's adjuvant (CFA), and subsequently infected with Schistosoma mansoni (S. mansoni) have shown that severe hepatic granulomatous inflammation is correlated with high levels of IL‐17. Here, using a Schistosoma japonicum (S. japonicum) larvae infection model in C57BL/6 mice, we analyzed the dynamic expression of IL‐17 in infected livers by RT‐qPCR and ELISA. Our results showed that IL‐17 expression was elevated during the course of infection. The temporal expression of IL‐17 and cytokines/chemokines involved in the induction and effector function of Th17 cells was paralleled with hepatic granulomatous inflammation. Treatment of S. japonicum infected mice with IL‐17‐neutralizing mAb resulted in significant downmodulation of granulomatous inflammation and hepatocyte necrosis. The protection was associated with lower expression of proinflammatory cytokines/chemokines, such as IL‐6, IL‐1β, CXCL1, and CXCL2 and a reduced number of infiltrating neutrophils. Anti‐IL‐17 mAb significantly ameliorated hepatic granulomatous inflammation, partly through the downregulation of proinflammatory cytokines/chemokines and recruitment of neutrophils. Our data indicate a pathogenic role of Th17/IL‐17 in hepatic immunopathology in S. japonicum infected mice.
Inefficient exogenous loading of a tapasin‐dependent peptide onto HLA‐B*44:02 can be improved by acid treatment or fixation of target cells
Authors: Stroobant Vincent , Demotte Nathalie , Luiten Rosalie M. , Leonhardt Ralf M. , Cresswell Peter , Bonehill Aude , Michaux Alexandre , Ma Wenbin , Mulder Arend , Van den Eynde Benoît J. , van der Bruggen Pierre , Vigneron Nathalie
Published: June 2012

Antitumor cytolytic T lymphocytes (CTLs) recognize peptides derived from cellular proteins and presented on MHC class I. One category of peptides recognized by these CTLs is derived from proteins encoded by “cancer‐germline” genes, which are specifically expressed in tumors, and therefore represent optimal targets for cancer immunotherapy. Here, we identify an antigenic peptide, which is derived from the MAGE‐A1‐encoded protein (160‐169) and presented to CTLs by HLA‐B*44:02. Although this peptide is encoded by MAGE‐A1, processed endogenously and presented by tumor cells, the corresponding synthetic peptide is hardly able to sensitize target cells to CTL recognition when pulsed exogenously. Endogenous processing and presentation of this peptide is strictly dependent on the presence of tapasin, which is believed to help peptide loading by stabilizing a peptide‐receptive form of HLA‐B*44:02. Exogenous loading of the peptide can be dramatically improved by paraformaldehyde fixation of surface molecules or by peptide loading at acidic pH. Either strategy allows efficient exogenous loading of the peptide, presumably by generating or stabilizing a peptide‐receptive, empty conformation of the HLA. Altogether, our results indicate a potential drawback of short peptide‐based vaccination strategies and offer possible solutions regarding the use of problematic epitopes such as the one described here.
Caveolin‐1 plays a critical role in host immunity against Klebsiella pneumoniae by regulating STAT5 and Akt activity
Authors: Guo Qiang , Shen Nan , Yuan Kefei , Li Jiaxin , Wu Hong , Zeng Yong , Fox John , Bansal Arvind K. , Singh Brij B. , Gao Hongwei , Wu Min
Published: June 2012

Caveolin‐1 (Cav1) is a structural protein of caveolae. Although Cav1 is associated with certain bacterial infections, it is unknown whether Cav1 is involved in host immunity against Klebsiella pneumoniae, the third most commonly isolated microorganism from bacterial sepsis patients. Here, we showed that cav1 knockout mice succumbed to K. pneumoniae infection with markedly decreased survival rates, increased bacterial burdens, intensified tissue injury, hyperactive proinflammatory cytokines, and systemic bacterial dissemination as compared with WT mice. Knocking down Cav1 by a dominant negative approach in lung epithelial MLE‐12 cells resulted in similar outcomes (decreased bacterial clearance and increased proinflammatory cytokine production). Furthermore, we revealed that STAT5 influences the GSK3β−β‐catenin−Akt pathway, which contributes to the intensive inflammatory response and rapid infection dissemination seen in Cav1 deficiency. Collectively, our findings indicate that Cav1 may offer resistance to K. pneumoniae infection, by affecting both systemic and local production of proinflammatory cytokines via the actions of STAT5 and the GSK3β−β‐catenin−Akt pathway.
Pregnancy‐specific glycoprotein 1a activates dendritic cells to provide signals for Th17‐, Th2‐, and Treg‐cell polarization
Authors: Martínez Fernando F. , Knubel Carolina P. , Sánchez Maria C. , Cervi Laura , Motrán Claudia C.
Published: June 2012

Because of their plasticity and central role in orchestrating immunity and tolerance, DCs can respond to pregnancy‐specific signals, thus promoting the appropriate immune response in order to support pregnancy. Here, we show that pregnancy‐specific glycoprotein (PSG1a), the major variant of PSG released into the circulation during pregnancy, targets DCs to differentiate into a subset with a unique phenotype and function. This semi‐mature phenotype is able to secrete IL‐6 and TGF‐β. PSG1a also affected the maturation of DCs, preventing the up‐regulation of some costimulatory molecules, and inducing the secretion of TGF‐β or IL‐10 and the expression of programmed death ligand 1 (PD‐L1) in response to TLR‐9 or CD40 ligation. In addition, PSG1a‐treated DCs promoted the enrichment of Th2‐type cytokines, IL‐17‐producing cells, and Treg cells from CD4+ T cells from DO11.10 Tg mice. Moreover, in vivo expression of PSG1a promoted the expansion of Ag‐specific CD4+CD25+Foxp3+ Treg cells and IL‐17‐, IL‐4‐, IL‐5‐, and IL‐10‐secreting cells able to protect against Listeria monocytogenes infection. Taken together, our data indicate that DCs can be targeted by PSG1a to generate the signals necessary to mount an appropriate, well‐balanced, and effective immune response able to protect against invading pathogens while at the same time being compatible with a successful pregnancy.
Epitope specificity of memory CD8+T cells dictates vaccination‐induced mortality in LCMV‐infected perforin‐deficient mice
Authors: Pham Nhat‐Long L. , Badovinac Vladimir P. , Harty John T.
Published: June 2012

Perforin‐deficient (PKO) mice serve as models for familial hemophagocytic lympho‐histiocytosis, a uniformly fatal disease associated with viral infection of perforin‐deficient humans. Naïve perforin‐deficient BALB/c mice survive while vaccinated PKO mice containing virus‐specific memory CD8+ T cells rapidly succumb to lymphocytic choriomeningitis virus (LCMV) infection. Thus, vaccination converts a nonlethal persistent infection into a fatal disease mediated by virus‐specific memory CD8+ T cells. Here, we determine the extent to which vaccination‐induced mortality in PKO mice following LCMV challenge is due to differences in vaccine modalities, the quantity or epitope specificity of memory CD8+ T cells. We show that LCMV‐induced mortality in immune PKO mice is independent of vaccine modalities and that the starting number of memory CD8+ T cells specific to the immunodominant epitope NP118‐126 dictates the magnitude of secondary CD8+ T‐cell expansion, the inability to regulate production of CD8+ T‐cell‐derived IFN‐γ, and mortality in the vaccinated PKO mice. Importantly, mortality is determined by the epitope specificity of memory CD8+ T cells and the associated degree of functional exhaustion and cytokine dysregulation but not the absolute magnitude of CD8+ T‐cell expansion. These data suggest that deeper understanding of the parameters that influence the outcome of vaccine‐induced diseases would aid rational vaccine design to minimize adverse outcomes after infection.
Short‐term subcutaneous insulin treatment delays but does not prevent diabetes in NOD mice
Authors: Brezar Vedran , Culina Slobodan , Gagnerault Marie‐Claude , Mallone Roberto
Published: June 2012

Despite encouraging results in the NOD mouse, type 1 diabetes prevention trials using subcutaneous insulin have been unsuccessful. To explain these discrepancies, 3‐week‐old NOD mice were treated for 7 weeks with subcutaneous insulin at two different doses: a high dose (0.5 U/mouse) used in previous mouse studies; and a low dose (0.005 U/mouse) equivalent to that used in human trials. Effects on insulitis and diabetes were monitored along with immune and metabolic modifications. Low‐dose insulin did not have any effect on disease incidence. High‐dose treatment delayed but did not prevent diabetes, with reduced insulitis reappearing once insulin discontinued. This effect was not associated with significant immune changes in islet infiltrates, either in terms of cell composition or frequency and IFN‐γ secretion of islet‐reactive CD8+ T cells recognizing the immunodominant epitopes insulin B15‐23 and islet‐specific glucose‐6‐phosphatase catalytic subunit‐related protein (IGRP)206‐214. Delayed diabetes and insulitis were assoc‐iated with lower blood glucose and endogenous C‐peptide levels, which rapidly returned to normal upon treatment discontinuation. In conclusion, high‐ but not low‐dose prophylactic insulin treatment delays diabetes onset and is associated with metabolic changes suggestive of β‐cell “rest” which do not persist beyond treatment. These findings have important implications for designing insulin‐based prevention trials.
Naturally occurring CD1c+ human regulatory dendritic cells: Immunoregulators that are expanded in response to E. coli infection
Authors: Qian Cheng , Cao Xuetao
Published: June 2012

Dendritic cells (DCs) play key roles in initiating and regulating immunity by sensing and integrating signals from a wide range of pathogens and dangers. Although much knowledge has been gained about the origins, phenotypes, and functions of mouse DC subsets, the challenge now is to translate this knowledge to the human immune system and reveal relevant biological significance in human health and disease. Considerably less is known about the phenotype and function of human DC subsets due to their rarity, the lack of distinctive markers, and limited access to human tissues. Initial studies of DCs in human blood revealed that steady‐state myeloid DCs are comprised of the CD141+ and CD1c+ DC subsets as the equivalents to the mouse lymphoid resident CD8+ and CD8− DC subsets, respectively. A new report in this issue of the European Journal of Immunology [Eur. J. Immunol. 2012. 42: 1512–1522] shows that human CD1c+ myeloid DCs secrete IL‐10 and display an immunoregulatory phenotype and function in response to Escherichia coli (E. coli). This finding adds a new element to the current understanding of human CD1c+ DCs and reveals marked differences in human DC subsets during inflammation and microbial infection, as discussed in this Commentary.
Analysis of dietary phytochemicals needs to be applauded: Glycosylated plant sterols
Authors: Jiménez‐Escrig Antonio
Published: June 2012

In this issue of European Journal of Lipid Science and Technology, Lampi and co‐workers [p. 656–669] report the content of glycosylated plant sterols (steryl glycosides and acylated steryl glycosides) as minor glycolipids found in common edible plants.

See accompanying article http://dx.doi.org/10.1002/ejlt.201200033
Direct loading of polymer matrices in plastic microchips for rapid DNA analysis: A comparative study
Authors: Hurth Cedric , Gu Jian , Aboud Maurice , Estes Matthew D. , Nordquist Alan R. , McCord Bruce , Zenhausern Frederic
Published: June 2012

We report the design and performance validation of microfluidic separation technologies for human identification using a disposable plastic device suitable for integration into an automated rapid DNA analysis system. A fabrication process for a 15‐cm long hot‐embossed plastic microfluidic devices with a smooth semielliptical cross section out of cyclic olefin copolymer is presented. We propose a mixed polymer solution of 95% w/v hydroxyethylcellulose and 5% w/v polyvinylpyrrolidone for a final polymer concentration of 2.5 or 3.0% to be used as coating and sieving matrix for DNA separation. This formulation allows preparing the microchip without pretreatment in a single‐loading step and provides high‐resolution separation (≈1.2 bp for fragments <200 bp), which is superior to existing commercial matrices under the same conditions. The hot‐embossed device performance is characterized and compared to injection‐molded devices made out of cyclic olefin copolymer based on their respective injector geometry, channel shape, and surface charges. Each device design is assessed by fluorescence videomicroscopy to evaluate the formation of injection plugs, then by comparing electropherograms for the separation of a DNA size standard relevant to human identification.
Genetic partitioning of interleukin‐6 signalling in mice dissociates Stat3 from Smad3‐mediated lung fibrosis
Authors: O'Donoghue Robert J. J. , Knight Darryl A. , Richards Carl D. , Prêle Cecilia M. , Lau Hui Ling , Jarnicki Andrew G. , Jones Jessica , Bozinovski Steven , Vlahos Ross , Thiem Stefan , McKenzie Brent S. , Wang Bo , Stumbles Philip , Laurent Geoffrey J. , McAnulty Robin J. , Rose‐John Stefan , Zhu Hong Jian , Anderson Gary P. , Ernst Matthias R. , Mutsaers Steven E.
Published: June 2012

Idiopathic pulmonary fibrosis (IPF) is a fatal disease that is unresponsive to current therapies and characterized by excessive collagen deposition and subsequent fibrosis. While inflammatory cytokines, including interleukin (IL)‐6, are elevated in IPF, the molecular mechanisms that underlie this disease are incompletely understood, although the development of fibrosis is believed to depend on canonical transforming growth factor (TGF)‐β signalling. We examined bleomycin‐induced inflammation and fibrosis in mice carrying a mutation in the shared IL‐6 family receptor gp130. Using genetic complementation, we directly correlate the extent of IL‐6‐mediated, excessive Stat3 activity with inflammatory infiltrates in the lung and the severity of fibrosis in corresponding gp130757F mice. The extent of fibrosis was attenuated in B lymphocyte‐deficient gp130757F;µMT−/− compound mutant mice, but fibrosis still occurred in their Smad3−/− counterparts consistent with the capacity of excessive Stat3 activity to induce collagen 1α1 gene transcription independently of canonical TGF‐β/Smad3 signalling. These findings are of therapeutic relevance, since we confirmed abundant STAT3 activation in fibrotic lungs from IPF patients and showed that genetic reduction of Stat3 protected mice from bleomycin‐induced lung fibrosis.
Emergent evaluation and educational reforms in Latin America
Authors: Martinic Sergio
Published: June 2012

The aim of this chapter is to characterize educational reforms in Latin America over the last 25 years, and the way they reflect the role, method, and use of evaluation processes. The main theoretical and methodological tensions that are created by the development of evaluations will be reviewed, concluding with the identification of some of the challenges that are to be resolved in the future. Evaluation has followed educational reform through a number of cycles. ©Wiley Periodicals, Inc., and the American Evaluation Association.
Moving toward a gender equality and human rights perspective in evaluation
Authors: Meléndez Alejandra Faúndez
Published: June 2012

This chapter concerns the emergence of a new perspective on evaluation based on gender equality and human rights in Latin America and the Caribbean. As in other regions of the world, there are many development challenges associated with marginalized and excluded communities. In many Latin American countries, rights failures for indigenous cultures remain unresolved, and the way evaluation serves these peoples may not be immediately obvious, given cultural biases in methodology. Some contributions of this focus on evaluation in general are highlighted in this chapter, as well as both conceptual and methodological challenges faced, and future applications for this region. Finally, this article shares some reflections that contribute to knowledge and debate on empowerment, identity development, and equity in Latin America and the Caribbean. ©Wiley Periodicals, Inc., and the American Evaluation Association.
Evaluation as a learning tool
Authors: Néstor Feinstein Osvaldo
Published: June 2012

Evaluation of programs or projects is often perceived as a threat. This is to a great extent related to the anticipated use of evaluation for accountability, which is often prioritized at the expense of using evaluation as a learning tool. Frequently it is argued that there is a trade‐off between these two evaluation functions. An alternative approach is that accountability complements the role of evaluation as a learning tool, as accountability provides an incentive for learning. This complementarity between learning and accountability is facilitated by the development of an evaluation culture where mistakes are seen as opportunities for learning and learning as an important source for growth and development. © Wiley Periodicals, Inc., and the American Evaluation Association.
Exergoeconomic Analysis of a Combined Ammonia Based Solid Oxide Fuel Cell System
Authors: Baniasadi E. , Dincer I. , Naterer G. F.
Published: June 2012

An exergoeconomic study of an ammonia‐fed solid oxide fuel cell (SOFC) based combined system for transportation applications is presented in this paper. The relations between capital costs and thermodynamic losses for the system components are investigated. The exergoeconomic analysis includes the SOFC stack and system components, including the compressor, microturbine, pressure regulator, and heat exchangers. A parametric study is also conducted to investigate the system performance and costs of the components, depending on the operating temperature, exhaust temperature, and fuel utilization ratio. A parametric study is performed to show how the ratio of the thermodynamic loss rate to capital cost changes with operating parameters. For the devices and the overall system, some practical correlations are introduced to relate the capital cost and total exergy loss. The ratio of exergy consumption to capital cost is found to be strongly dependent on the current density and stack temperature, but less affected by the fuel utilization ratio.
Inflation Derivatives Under Inflation Target Regimes
Authors: Avriel Mordecai , Hilscher Jens , Raviv Alon
Published: June 2012

Inflation targeting—the central bank practice of attempting to keep inflation levels within fixed bounds around a quantitative target—has been adopted by more than 20 economies. Such practice has an important impact on the stochastic nature of inflation and, consequently, on the pricing of inflation derivatives. We develop a flexible model of inflation targeting in which the central bank's intervention to steer inflation toward the target depends on past deviations and the policymaker's ability and will to enforce the target. We use our model to price inflation derivatives and demonstrate the impact of inflation targeting on derivative pricing.
Methylome analysis and integrative profiling of human HCCs identify novel protumorigenic factors
Authors: Neumann Olaf , Kesselmeier Miriam , Geffers Robert , Pellegrino Rossella , Radlwimmer Bernhard , Hoffmann Katrin , Ehemann Volker , Schemmer Peter , Schirmacher Peter , Bermejo Justo Lorenzo , Longerich Thomas
Published: June 2012

To identify new tumor-suppressor gene candidates relevant for human hepatocarcinogenesis, we performed genome-wide methylation profiling and vertical integration with array-based comparative genomic hybridization (aCGH), as well as expression data from a cohort of well-characterized human hepatocellular carcinomas (HCCs). Bisulfite-converted DNAs from 63 HCCs and 10 healthy control livers were analyzed for the methylation status of more than 14,000 genes. After defining the differentially methylated genes in HCCs, we integrated their DNA copy-number alterations as determined by aCGH data and correlated them with gene expression to identify genes potentially silenced by promoter hypermethylation. Aberrant methylation of candidates was further confirmed by pyrosequencing, and methylation dependency of silencing was determined by 5-aza-2′-deoxycytidine (5-aza-dC) treatment. Methylation profiling revealed 2,226 CpG sites that showed methylation differences between healthy control livers and HCCs. Of these, 537 CpG sites were hypermethylated in the tumor DNA, whereas 1,689 sites showed promoter hypomethylation. The hypermethylated set was enriched for genes known to be inactivated by the polycomb repressive complex 2, whereas the group of hypomethylated genes was enriched for imprinted genes. We identified three genes matching all of our selection criteria for a tumor-suppressor gene (period homolog 3 [PER3], insulin-like growth-factor–binding protein, acid labile subunit [IGFALS], and protein Z). PER3 was down-regulated in human HCCs, compared to peritumorous and healthy liver tissues. 5-aza-dC treatment restored PER3 expression in HCC cell lines, indicating that promoter hypermethylation was indeed responsible for gene silencing. Additionally, functional analysis supported a tumor-suppressive function for PER3 and IGFALS

in vitro

.

Conclusion:

The present study illustrates that vertical integration of methylation data with high-resolution genomic and transcriptomic data facilitates the identification of new tumor-suppressor gene candidates in human HCC.
A Preliminary Study on Pace Rating Using Video Technology
Authors: Suwittayaruk Peeradaech , Goubergen Dirk Van , Lockhart Thurmon E.
Published: June 2012

Pace rating has always been recognized and treated as difficult, subjective, and even controversial. Recently, a new idea of pace rating using video technology by showing work motions on a reference video and an actual (real‐life) video simultaneously on a screen has been proposed. By adjusting the speed (and thus the pace) of the reference video, industrial engineers or workers without extensive background in time study can synchronize the motion patterns in both videos, thus quantifying the actual pace of the method under study using their visual sense. However, the impact of motion pattern compatibility between the two stimuli (work motions on the reference video and the actual video) has not been investigated in detail. In this study, we elaborate that motion pattern compatibility between the reference video and the actual video has a significant effect on correct determination of the response (the rated pace) in terms of both the accuracy and the precision. © 2012 Wiley Periodicals, Inc.
Planning to meet the care need challenge in Alberta, Canada
Authors: Duckett Stephen , Bloom Judy , Robertson Andrea
Published: June 2012

The Canadian province of Alberta faces challenges in ensuring an adequate supply of nurses to meet care needs. This paper describes the approach adopted by Alberta Health Services (the public health care provider in Alberta) to address this challenge. Planning was undertaken on the basis of care needs rather than starting from a particular professional perspective and highlighted that the needs could be met by Registered Nurses, Licensed Practical Nurses or Healthcare Aides. Six scenarios, representing different potential mixes of Registered Nurses, Licensed Practical Nurses and Healthcare Aides were identified and used as the basis of stakeholder consultations. The paper identifies the workforce outcomes and needs for the different scenarios and the outcomes of the workforce planning process. Copyright © 2012 John Wiley & Sons, Ltd.
Experiences of Motherhood in Counselor Education
Authors: Trepal Heather C. , Stinchfield Tracy A.
Published: June 2012

This phenomenological study examined 20 tenured and nontenured counselor educators regarding their experiences of motherhood and academia. Two central themes from the interviews emerged: environmental influences (including position flexibility, experienced discrimination, and felt support) and choices and circumstances (including defining and establishing boundaries and accepting decisions). Findings are important for understanding academic mothers’ experiences and underscore the need for additional research in the field that specifically addresses these issues.
Oleanolic acid arrests cell cycle and induces apoptosis via ROS‐mediated mitochondrial depolarization and lysosomal membrane permeabilization in human pancreatic cancer cells
Authors: Wei Jianteng , Liu Ming , Liu Haizhou , Wang Hui , Wang Fengxia , Zhang Yuyan , Han Lijun , Lin Xiukun
Published: June 2012

Oleanolic acid (OA), a pentacyclic triterpenoid, exhibits potential anti‐tumor activity against many tumor cell lines. This study aims to examine the anti‐tumor activity of OA on pancreatic cancer cells and its potential molecular mechanism. The results showed that the proliferation of Panc‐28 cells was inhibited by OA in a concentration‐dependent manner, with an IC50 (The half maximal inhibitory concentration) value of 46.35 µg ml−1, as determined by MTT (3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay. The cell cycle was arrested in S phase and G2/M phase by OA. The study also showed that OA could induce remarkable apoptosis, evidenced by an increased percentage of early/late apoptotic cells, DNA ladder and nuclear morphology change. Further study revealed that OA could induce Reactive Oxygen Species (ROS) generation, mitochondrial depolarization, release of cytochrome C, lysosomal membrane permeabilization and leakage of cathepin B. The expression of apoptosis‐correlated proteins was also affected in cells treated with OA, including activation of caspases‐3/9 and cleavage of PARP. Further study confirmed that ROS scavenger vitamin C could reverse the apoptosis induced by OA in Panc‐28 cells. Our results provide evidence that OA arrests the cell cycle and induces apoptosis, possibly via ROS‐mediated mitochondrial and a lysosomal pathway in Panc‐28 cells. Copyright © 2012 John Wiley & Sons, Ltd.
Hypothesis Holiday sudden cardiac death: food and alcohol inhibition of SULT1A enzymes as a precipitant
Authors: Eagle Ken
Published: June 2012

Sudden cardiac death is a significant health issue, causing millions of deaths worldwide annually. Studies have found that the likelihood of such death is higher in winter. Further studies identified that the highest likelihood occurs on Christmas Day and New Years Day, but not the interim period. Thanksgiving, Independence Day and the Islamic holiday Eid Al‐Fitr also show significant increases in the rate of cardiac events or death. A number of mechanisms have been proposed, but none have satisfactorily explained the evidence. This article reviews the data supporting the existence of a holiday cardiac death phenomenon, the involvement of catecholamines and the normal modes of human catecholamine deactivation. Further evidence is reviewed that supports a hypothesized mechanism whereby critical SULT1A catecholamine deactivation enzymes can in some patients be inhibited by naturally‐occurring phenols and polyphenols in foods and alcohols. If deactivation is inhibited by holiday consumption excesses, holiday stress or excitement could lead to a buildup of catecholamines that can cause fatal arrhythmias. Awareness of this mechanism could reduce deaths, both through doctor/patient education leading to a moderation in consumption and through the potential identification of patients with a predisposition to SULT1A inhibition. This hypothesis also raises parallels between sudden cardiac death in adults and Sudden Infant Death Syndrome (SIDS). The possible involvement of SULT1A inhibition in SIDS is discussed. Copyright © 2012 John Wiley & Sons, Ltd.
Non‐invasive identification of proteoglycans and chondrocyte differentiation state by Raman microspectroscopy
Authors: Pudlas Marieke , Brauchle Eva , Klein Travis J. , Hutmacher Dietmar W. , Schenke‐Layland Katja
Published: June 2012

Proteoglycans (PGs) are crucial extracellular matrix (ECM) components that are present in all tissues and organs. Pathological remodeling of these macromolecules can lead to severe diseases such as osteoarthritis or rheumatoid arthritis. To date, PG‐associated ECM alterations are routinely diagnosed by invasive analytical methods. Here, we employed Raman microspectroscopy, a laser‐based, marker‐free and non‐destructive technique that allows the generation of spectra with peaks originating from molecular vibrations within a sample, to identify specific Raman bands that can be assigned to PGs within human and porcine cartilage samples and chondrocytes. Based on the non‐invasively acquired Raman spectra, we further revealed that a prolonged in vitro culture leads to phenotypic alterations of chondrocytes, resulting in a decreased PG synthesis rate and loss of lipid contents. Our results are the first to demonstrate the applicability of Raman microspectroscopy as an analytical and potential diagnostic tool for non‐invasive cell and tissue state monitoring of cartilage in biomedical research. (© 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)