bluuebunny/crossref_metadata_2025 huggingface dataset:
Endoplasmic Reticulum Degradation–Enhancing α‐Mannosidase–like Protein 1 Targets Misfolded HLA–B27 Dimers for Endoplasmic Reticulum–Associated Degradation
Authors: Guiliano David B. , Fussell Helen , Lenart Izabela , Tsao Edward , Nesbeth Darren , Fletcher Adam J. , Campbell Elaine C. , Yousaf Nasim , Williams Sarah , Santos Susana , Cameron Amy , Towers Greg J. , Kellam Paul , Hebert Daniel N. , Gould Keith G. , Powis Simon J. , Antoniou Antony N.
Published: August 2014

Objective

HLA–B27 forms misfolded heavy chain dimers, which may predispose individuals to inflammatory arthritis by inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). This study was undertaken to define the role of the UPR‐induced ER‐associated degradation (ERAD) pathway in the disposal of HLA–B27 dimeric conformers.

Methods

HeLa cell lines expressing only 2 copies of a carboxy‐terminally Sv5‐tagged HLA–B27 were generated. The ER stress–induced protein ER degradation–enhancing α‐mannosidase–like protein 1 (EDEM1) was overexpressed by transfection, and dimer levels were monitored by immunoblotting. EDEM1, the UPR‐associated transcription factor X‐box binding protein 1 (XBP‐1), the E3 ubiquitin ligase hydroxymethylglutaryl‐coenzyme A reductase degradation 1 (HRD1), and the degradation‐associated proteins derlin 1 and derlin 2 were inhibited using either short hairpin RNA or dominant‐negative mutants. The UPR‐associated ERAD of HLA–B27 was confirmed using ER stress–inducing pharamacologic agents in kinetic and pulse chase assays.

Results

We demonstrated that UPR‐induced machinery can target HLA–B27 dimers and that dimer formation can be controlled by alterations to expression levels of components of the UPR‐induced ERAD pathway. HLA–B27 dimers and misfolded major histocompatibility complex class I monomeric molecules bound to EDEM1 were detected, and overexpression of EDEM1 led to inhibition of HLA–B27 dimer formation. EDEM1 inhibition resulted in up‐regulation of HLA–B27 dimers, while UPR‐induced ERAD of dimers was prevented in the absence of EDEM1. HLA–B27 dimer formation was also enhanced in the absence of XBP‐1, HRD1, and derlins 1 and 2.

Conclusion

The present findings indicate that the UPR ERAD pathway can dispose of HLA–B27 dimers, thus presenting a potential novel therapeutic target for modulation of HLA–B27–associated inflammatory disease.
Regulation of Cytokine Polarization and T Cell Recruitment to Inflamed Paws in Mouse Collagen‐Induced Arthritis by the Chemokine Receptor CXCR6
Authors: Slauenwhite Drew , Gebremeskel Simon , Doucette Carolyn D. , Hoskin David W. , Johnston Brent
Published: August 2014

Objective

The chemokine receptor CXCR6 is highly expressed on lymphocytes isolated from the synovium of patients with rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis, suggesting that CXCR6 regulates immune cell activation or infiltration into arthritic joints. This study was undertaken to examine the role of CXCR6 in T cell activation and arthritis development.

Methods

A collagen‐induced arthritis model was used to examine arthritis development in wild‐type and CXCR6−/− mice. CXCR6 expression, lymphocyte accumulation, and intracellular cytokine production were examined by flow cytometry. Collagen‐specific antibodies were measured in the serum. Collagen‐specific recall responses were examined in vitro via proliferation and cytokine release assays. T cell homing to inflamed joints was examined using competitive adoptive transfer of dye‐labeled lymphocytes from wild‐type and CXCR6−/− mice.

Results

The numbers of CXCR6+ T cells were increased in the paws and draining lymph nodes of arthritic mice. The incidence of arthritis, disease severity, extent of T cell accumulation, and levels of collagen‐specific IgG2a antibodies were significantly reduced in CXCR6−/− mice compared to wild‐type mice. T cells from wild‐type mice exhibited Th1 (interferon‐γ [IFNγ]) polarization in the inguinal lymph nodes following immunization. At disease peak, this shifted to a Th17 (interleukin‐17A [IL‐17A]) response in the popliteal lymph nodes. T cells in CXCR6−/− mice exhibited impaired cytokine polarization, resulting in a decreased frequency and number of IL‐17A– and IFNγ‐producing cells. Recruitment of activated CXCR6−/− mouse T cells to the inflamed paws was impaired compared to recruitment of wild‐type mouse T cells.

Conclusion

These experiments demonstrate that CXCR6 plays important roles in the pathogenesis of arthritis through its effects on both T cell cytokine polarization and homing of T cells to inflamed joints.
Integration of gross anatomy in an organ system‐based medical curriculum: Strategies and challenges
Authors: Brooks William S. , Woodley Kristina T.C. Panizzi , Jackson James R. , Hoesley Craig J.
Published: August 2014

The University of Alabama School of Medicine (UASOM) instituted a fully integrated, organ system‐based preclinical curriculum in 2007. Gross anatomy and embryology were integrated with other basic science disciplines throughout the first two years of undergraduate medical education. Here we describe the methods of instruction and integration of gross anatomy and embryology in this curriculum as well as challenges faced along the way. Gross anatomy and embryology are taught through a combination of didactic lectures, team‐based learning activities, and cadaveric dissection laboratories. Vertical integration occurs through third‐ and fourth‐year anatomy and embryology elective courses. Radiology is integrated with anatomy instruction through self‐study modules and hands‐on ultrasound sessions. Our model of anatomy instruction is time efficient, clinically relevant, and effective as demonstrated by student performance on the United States Medical Licensing Examination® (USMLE®) Step 1 examination. We recommend that medical schools considering full integration of gross anatomy and embryology (1) carefully consider the sequencing of organ system modules, (2) be willing to sacrifice anatomical detail for clinical application, (3) provide additional electives to third‐ and fourth‐year students, and (4) integrate radiology with anatomical education. Anat Sci Educ 8: 266–274. © 2014 American Association of Anatomists.
Glucuronidation of macelignan by human liver microsomes and expressed UGT enzymes: identification of UGT1A1 and 2B7 as the main contributing enzymes
Authors: Liu Hongming , Wu Zhufeng , Ma Zhiguo , Wu Baojian
Published: August 2014

Macelignan is a natural phenolic compound that possesses many types of health benefits such as antiinflammation. This study aimed to characterize the metabolism of macelignan via the glucuronidation pathway and to identify the main UGT enzymes involved in macelignan glucuronidation. The rates of glucuronidation were determined by incubating macelignan with UDPGA‐supplemented microsomes. Kinetic parameters were derived by fitting an appropriate model to the data. Reaction phenotyping, the relative activity factor (RAF) approach and activity correlation analysis were employed to identify the main UGT enzymes contributing to the hepatic metabolism of macelignan. Glucuronidation of macelignan in pooled human liver microsomes (pHLM) was rather efficient with a high CLint (the intrinsic clearance) value of 13.90 ml/min/mg. All UGT enzymes, except UGT1A4, 1A6 and 2B10, showed metabolic activities toward macelignan. UGT1A1 and 2B7 were the enzymes with the highest activities; the CLint values were 4.92 and 2.13 ml/min/mg, respectively. Further, macelignan glucuronidation was significantly correlated with 3‐O‐glucuronidation of β‐estradiol (r = 0.69; p < 0.01) and glucuronidation of zidovudine (r = 0.60; p < 0.05) in a bank of individual HLMs (n = 14). Based on the RAF approach, UGT1A1 and 2B7, respectively, contributed 55.40% and 32.20% of macelignan glucuronidation in pHLM. In conclusion, macelignan was efficiently metabolized via the glucuronidation pathway. It was also shown that UGT1A1 and 2B7 were probably the main contributors to the hepatic glucuronidation of macelignan. Copyright © 2014 John Wiley & Sons, Ltd.
Impact of 60‐GHz millimeter waves and corresponding heat effect on endoplasmic reticulum stress sensor gene expression
Authors: Le Quément Catherine , Nicolaz Christophe Nicolas , Habauzit Denis , Zhadobov Maxim , Sauleau Ronan , Le Dréan Yves
Published: August 2014

Emerging high data rate wireless communication systems, currently under development, will operate at millimeter waves (MMW) and specifically in the 60 GHz band for broadband short‐range communications. The aim of this study was to investigate potential effects of MMW radiation on the cellular endoplasmic reticulum (ER) stress. Human skin cell lines were exposed at 60.4 GHz, with incident power densities (IPD) ranging between 1 and 20 mW/cm2. The upper IPD limits correspond to the ICNIRP local exposure limit for the general public. The expression of ER‐stress sensors, namely BIP and ORP150, was then examined by real‐time RT‐PCR. Our experimental data demonstrated that MMW radiations do not change BIP or ORP150 mRNA basal levels, whatever the cell line, the exposure duration or the IPD level. Co‐exposure to the well‐known ER‐stress inducer thapsigargin (TG) and MMW were then assessed. Our results show that MMW exposure at 20 mW/cm2 inhibits TG‐induced BIP and ORP150 over expression. Experimental controls showed that this inhibition is linked to the thermal effect resulting from the MMW exposure. Bioelectromagnetics. 35:444–451, 2014. © 2014 Wiley Periodicals, Inc.
Wie die Mücke den Menschen findet
Authors: Brennicke Axel
Published: August 2014

Viele Spezies von Stechmücken sind auf den Menschen spezialisiert. Sie finden ihre Opfer durch eine Kombination aus erhöhter CO2‐Konzentration, Duftstoffen wie Milch‐ und Buttersäure sowie einem Temperaturgradienten hin zu 37 °C. Neue Untersuchungen zeigen jetzt, dass die veränderte CO2‐Konzentration das Hauptsignal ist, das die Erkennung der beiden anderen Faktoren verstärkt. Mücken, in denen der CO2‐Sensor ausgeschaltet ist, können dennoch ihre Ziele finden, wenn auch etwas schlechter. Für einen wirksamen Schutz müssen also mindestens zwei der Signale blockiert oder verwirrt werden.
A sensitive and high‐throughput LC‐MS/MS method for inhibition assay of seven major cytochrome P450s in human liver microsomes using an in vitro cocktail of probe substrates
Authors: Liu Li‐Ya , Han Yong‐Long , Zhu Jin‐Hui , Yu Qi , Yang Quan‐Jun , Lu Jin , Guo Cheng
Published: August 2014

A sensitive and high‐throughput LC‐MS/MS method was established and validated for the simultaneous quantification of seven probe substrate‐derived metabolites (cocktail assay) for assessing the in vitro inhibition of cytochrome P450 (CYP) enzymes in pooled human liver microsomes. The metabolites acetaminophen (CYP1A2), hydroxy‐bupropion (CYP2B6), n‐desethyl‐amodiaquine (CYP2C8), 4′‐hydroxy‐diclofenac (CYP2C9), 4′‐hydroxy‐mephenytoin (CYP2C19), dextrorphan (CYP2D6) and 1′‐hydroxy‐midazolam (CYP3A4/5), together with the internal standard verapamil, were eluted on an Agilent 1200 series liquid chromatograph in <7 min. All metabolites were detected by an Agilent 6410B tandem mass spectrometer. The concentration of each probe substrate was selected by substrate inhibition assay that reduced potential substrate interactions. CYP inhibition of seven well‐known inhibitors was confirmed by comparing a single probe substrate assay with cocktail assay. The IC50 values of these inhibitors determined on this cocktail assay were highly correlated (R2 > 0.99 for each individual probe substrate) with those on single assay. The method was selective and showed good accuracy (85.89–113.35%) and between‐day (RSD <13.95%) and within‐day (RSD <9.90%) precision. The sample incubation extracts were stable at 25 °C for 48 h and after three freeze–thaw cycles. This seven‐CYP inhibition cocktail assay significantly increased the efficiency of accurately assessing compounds’ potential inhibition of the seven major CYPs in drug development settings. Copyright © 2014 John Wiley & Sons, Ltd.
Sensitive method for the determination of paricalcitol by liquid chromatography and mass spectrometry and its application to a clinical pharmacokinetic study
Authors: Hotha Kishore Kumar , Mullangi Ramesh , Lakshmanarao Krishnarao Ravindranath , Roychowdhury Swapan
Published: August 2014

A highly sensitive, specific and rapid LC‐ESI‐MS/MS method has been developed and validated for the quantification of paricalcitol (PAR) in human plasma (500 μL) using paricalcitol‐d6 (PAR‐d6) as an internal standard (IS) as per regulatory guidelines. A liquid–liquid extraction method was used to extract the analyte and IS from human plasma. Chromatography was achieved on Zorbax SB C18 column using an isocratic mobile phase in a gradient flow. The total chromatographic run time was 6.0 min and the elution of PAR and PAR‐d6 occurred at ~2.6 min. A linear response function was established for the range of concentrations 10–500 pg/mL in human plasma. The intra‐ and inter‐day accuracy and precision values for PAR met the acceptance criteria. The validated assay was applied to quantitate PAR concentrations in human plasma following oral administration of 4 µg capsules to humans. Copyright © 2014 John Wiley & Sons, Ltd.
Cell culture media supplementation of uncommonly used sugars sucrose and tagatose for the targeted shifting of protein glycosylation profiles of recombinant protein therapeutics
Authors: Hossler Patrick , McDermott Sean , Racicot Christopher , Chumsae Christopher , Raharimampionona Haly , Zhou Yu , Ouellette David , Matuck Joseph , Correia Ivan , Fann John , Li Jianmin
Published: August 2014

Protein glycosylation is an important post‐translational modification toward the structure and function of recombinant therapeutics. The addition of oligosaccharides to recombinant proteins has been shown to greatly influence the overall physiochemical attributes of many proteins. It is for this reason that protein glycosylation is monitored by the developer of a recombinant protein therapeutic, and why protein glycosylation is typically considered a critical quality attribute. In this work, we highlight a systematic study toward the supplementation of sucrose and tagatose into cell culture media for the targeted modulation of protein glycosylation profiles on recombinant proteins. Both sugars were found to affect oligosaccharide maturation resulting in an increase in the percentage of high mannose N‐glycan species, as well as a concomitant reduction in fucosylation. The latter effect was demonstrated to increase antibody‐dependent cell‐mediated cytotoxicity for a recombinant antibody. These aforementioned results were found to be reproducible at different scales, and across different Chinese hamster ovary cell lines. Through the selective supplementation of these described sugars, the targeted modulation of protein glycosylation profiles is demonstrated, as well as yet another tool in the cell culture toolbox for ensuring product comparability. © 2014 American Institute of Chemical Engineers Biotechnol. Prog., 30:1419–1431, 2014
High‐Temperature Capture of CO2 on Lithium‐Based Sorbents Prepared by a Water‐Based Sol‐Gel Technique
Authors: Wang Ke , Wang Xinyong , Zhao Pengfei , Guo Xin
Published: August 2014

A convenient water‐based sol‐gel technique was used to prepare a highly efficient lithium orthosilicate‐based sorbent (Li4SiO4‐G) for CO2 capture at high temperature. The Li4SiO4‐G sorbent was systematically studied and compared with the Li4SiO4‐S sorbent prepared by solid‐state reaction. Both sorbents were characterized by X‐ray diffraction, scanning electron microscopy, nitrogen adsorption, and thermogravimetry. The CO2 sorption stability was investigated in a dual fixed‐bed reactor. Li4SiO4‐G exhibited a special Li4SiO4 structure with smaller crystalline nanoparticles, larger surface area, and higher CO2 adsorption properties as compared with Li4SiO4‐S. The Li4SiO4‐G sorbent also maintained higher capacities during multiple cycles.
Hybrid Process for o‐ and p‐Xylene Production in Aromatics Plants
Authors: Moreira Mariana A. , Ferreira Alexandre F. P. , Santos João C. , Loureiro José M. , Rodrigues Alírio E.
Published: August 2014

A new hybrid process for the production of o‐ and p‐xylene is proposed to replace the traditional plant of aromatics in refineries. The proposed process comprises a simulated moving bed (SMB) unit and two crystallizers. The SMB technology as the first unit of the suggested process is applied for the separation of xylene isomers and was investigated by simulation of an industrial size unit, using experimentally measured adsorption equilibrium data on MIL‐53(Al)‐shaped material. The separation of p‐xylene from o‐xylene with m‐xylene as desorbent is the key characteristic of this method. An industrial‐scale SMB unit could provide extract and raffinate streams with very high purities.
Aberrant synaptic input to retinal ganglion cells varies with morphology in a mouse model of retinal degeneration
Authors: Yee Christopher W. , Toychiev Abduqodir H. , Ivanova Elena , Sagdullaev Botir T.
Published: August 2014

Retinal degeneration describes a group of disorders which lead to progressive photoreceptor cell death, resulting in blindness. As this occurs, retinal ganglion cells (RGCs) begin to develop oscillatory physiological activity. Here we studied the morphological and physiological properties of RGCs in rd1 mice, aged 30–60 days, to determine how this aberrant activity correlates with morphology. Patch‐clamp recordings of excitatory and inhibitory currents were performed, then dendritic structures were visualized by infusion of fluorescent dye. Only RGCs with oscillatory activity were selected for further analysis. Oscillatory frequency and power were calculated using power spectral density analysis of recorded currents. Dendritic arbor stratification, total length, and area were measured from confocal microscope image stacks. These measurements were used to sort RGCs by cluster analysis using Ward's Method. This resulted in a total of 10 clusters, with monostratified and bistratified cells having five clusters each. Both populations exhibited correlations between arbor stratification and aberrant inhibitory input, while excitatory input did not vary with arbor distribution. These findings illustrate the relationship between aberrant activity and RGC morphology at early stages of retinal degeneration. J. Comp. Neurol. 522:4085–4099, 2014. © 2014 Wiley Periodicals, Inc.
Endogenous versus exogenous markers of adult neurogenesis in canaries and other birds: Advantages and disadvantages
Authors: Balthazart Jacques , Ball Gregory F.
Published: August 2014

Although the existence of newborn neurons had originally been suggested, but not broadly accepted, based on studies in adult rodent brains, the presence of an active neurogenesis process in adult homoeothermic vertebrates was first firmly established in songbirds. Adult neurogenesis was initially studied with the tritiated thymidine technique, later replaced by the injection and detection of the marker of DNA replication 5‐bromo‐2′‐deoxyuridine (BrdU). More recently, various endogenous markers were used to identify young neurons or cycling neuronal progenitors. We review here the respective advantages and pitfalls of these different approaches in birds, with specific reference to the microtubule‐associated protein, doublecortin (DCX), that has been extensively used to identify young newly born neurons in adult brains. All these techniques of course have limitations. Exogenous markers label cells replicating their DNA only during a brief period and it is difficult to select injection doses that would exhaustively label all these cells without inducing DNA damage that will also result in some form of labeling during repair. On the other hand, specificity of endogenous markers is difficult to establish due to problems related to the specificity of antibodies (these problems can be, but are not always, addressed) and more importantly because it is difficult, if not impossible, to prove that a given marker exhaustively and specifically labels a given cell population. Despite these potential limitations, these endogenous markers and DCX staining in particular clearly represent a useful approach to the detailed study of neurogenesis especially when combined with other techniques such as BrdU. J. Comp. Neurol. 522:4100–4120, 2014. © 2014 Wiley Periodicals, Inc.
Diethyl Tartrate Linked Chiral Macrocyclic Manganese(III)–Salen Complex for Enantioselective Epoxidation of Olefins and Oxidative Kinetic Resolution of Racemic Secondary Alcohols
Authors: Maity Nabin Ch. , Kumar Bera Prasanta , Saravanan S. , Abdi Sayed H. R. , Kureshy Rukhsana I. , Khan Noor‐ul H. , Bajaj Hari C.
Published: August 2014

Invited for this month’s cover is the group of Dr. Sayed H. R. Abdi from Central Salt and Marine Chemicals Research Institute (CSMCRI), India. The cover picture shows a single metal complex that can catalyse the asymmetric epoxidation of non‐functionalised olefins as well as oxidative kinetic resolution of racemic alcohols, which is carried out with great ease. Read the full text of the article at 10.1002/cplu.201402131
Catalytic Depolymerization of Lignin in Supercritical Ethanol
Authors: Huang Xiaoming , Korányi Tamás I. , Boot Michael D. , Hensen Emiel J. M.
Published: August 2014

Invited for this month′s cover is the group of Emiel Hensen at the Eindhoven University of Technology. The image on the right shows how soda lignin is depolymerized and stabilized under supercritical ethanol over a Cu‐containing mixed oxide catalyst. The Full Paper itself is available at 10.1002/cssc.201402094
Lymphocytes subsets reference values in childhood
Authors: Tosato F. , Bucciol G. , Pantano G. , Putti M. C. , Sanzari M.C. , Basso G. , Plebani M.
Published: August 2014

Immunophenotyping of blood lymphocyte subsets and activation markers is a basic tool in the diagnostic process of primary immunodeficiency diseases, its use becoming more and more widespread as the knowledge about these illnesses increases. However, the availability of reliable reference values, which need to be age‐matched for the pediatric population, is a pre‐requisite for the reliable interpretation of immunophenotyping data. Aim of this study is to analyze the lymphocyte subsets and activation markers distribution in children aged 0–18 years referring to the University Hospital of Padova and to create age‐matched reference values expressed by percentiles, thus providing a valuable guideline for the interpretation of the immunophenotype. © 2014 International Society for Advancement of Cytometry
Performance analysis of distributed underwater wireless acoustic sensor networks systems in the presence of internal solitons
Authors: Mandal Amit Kumar , Misra Sudip , Dash Mihir Kumar , Ojha Tamoghna
Published: August 2014

In this paper, we have analyzed the performance of distributed Underwater Wireless Acoustic Sensor Networks (UWASNs) in the presence of internal solitons in the ocean. Internal waves commonly occur in a layered oceanic environment having differential medium density. So, in a layered shallow oceanic region, the inclusion of the effect of internal solitons on the performance of the network is important. Based on various observations, it is proved that nonlinear internal waves, that is, solitons are one of the major scatterers of underwater sound. If sensor nodes are deployed in such type of environment, internode communication is affected because of the interaction of wireless acoustic signal with these solitons, as a result of which network performance is greatly affected. We have evaluated the performance of UWASNs in the 3‐D deployment scenario of nodes, in which source nodes are deployed in the ocean floor. In this paper, four performance metrics, namely, Signal‐to‐interference‐plus‐noise‐ratio (SINR), bit error rate (BER), Delay (DELAY), and energy consumption are introduced to assess the performance of UWASNs. Simulation studies show that in the presence of internal solitons, SINR decreases by approximately 10%, BER increases by 17%, delay increases by 0.24%, and energy consumption per node increases by 53.05%, approximately. Copyright © 2014 John Wiley & Sons, Ltd.
Family meals and disordered eating in adolescents: Are the benefits the same for everyone?
Authors: Loth Katie , Wall Melanie , Choi Chien‐Wen , Bucchianeri Michaela , Quick Virginia , Larson Nicole , Neumark‐Sztainer Dianne
Published: August 2014

Objective

To examine the association between family meals and disordered eating behaviors within a diverse sample of adolescents and further investigate whether family‐level variables moderate this association.

Method

Data from adolescents (EAT 2010: Eating and Activity in Teens) and their parents (Project F‐EAT: Families and Eating and Activity among Teens) were collected in 2009–2010. Surveys were completed by 2,382 middle and high school students (53.2% girls, mean age = 14.4 years) from Minneapolis/St. Paul, MN, public schools. Parents/guardians (n= 2,792) completed surveys by mail or phone.

Results

Greater frequency of family meals was associated with decreased odds of engaging in unhealthy weight control behaviors in boys, and dieting, unhealthy and extreme weight control behaviors in girls. Results indicate that the protective effects of family meals are, in general, robust to family‐level variables; 64 interactions were examined and only seven were statistically significant. For example, among girls, the protective nature of family meals against dieting and unhealthy weight control behaviors was diminished if they also reported family weight‐related teasing (bothp< .01).

Discussion

The results confirmed previous research indicating that participation in family meals is protective against disordered eating for youth, particularly girls. However, results suggest that in some cases, the protection offered by family meals may be modified by family‐level variables. © 2014 Wiley Periodicals, Inc. (Int J Eat Disord 2015; 48:100–110)
Triggering of NF‐κB in cytokine‐matured human DCs generates superior DCs for T‐cell priming in cancer immunotherapy
Authors: Pfeiffer Isabell A. , Hoyer Stefanie , Gerer Kerstin F. , Voll Reinhard E. , Knippertz Ilka , Gückel Eva , Schuler Gerold , Schaft Niels , Dörrie Jan
Published: August 2014

Understanding the signaling that governs the immunogenicity of human dendritic cells (DCs) is a prerequisite for improving DC‐based therapeutic vaccination strategies, in which the ability of DCs to induce robust and lasting Ag‐specific CTL responses is of critical importance. Cytokine‐matured DCs are regularly used, but to induce memory‐type CTLs, they require additional activation stimuli, such as CD4+ T‐cell help or TLR activation. One common denominator of these stimuli is the activation of NF‐κB. Here, we show that human monocyte‐derived, cytokine cocktail‐matured DCs transfected with constitutively active mutants of IκB kinases (caIKKs) by mRNA electroporation, further upregulated maturation markers, and secreted enhanced amounts of cytokines, including IL‐12p70, which was produced for more than 48 h after transfection. Most importantly, cytotoxic T cells induced by caIKK‐transfected DCs combined high CD27 expression, indicating a more memory‐like phenotype, and a markedly enhanced secondary expandability with a high lytic capacity. In contrast, CTLs primed and expanded with unmodified cytokine cocktail‐matured DCs did not maintain their proliferative capacity upon repetitive stimulations. We hypothesize that “designer” DCs expressing constitutively active IκB kinases will prove highly immunogenic also in vivo and possibly emerge as a new strategy to improve the clinical efficacy of therapeutic vaccinations against cancer and other chronic diseases.
An Efficient Partial Reduction of α,β‐Unsaturated Esters Using DIBAL‐H in Flow
Authors: Yoshida Masahito , Otaka Hiroyuki , Doi Takayuki
Published: August 2014

The partial reduction of α,β‐unsaturated esters and benzoate derivatives to form the corresponding aldehydes was achieved using a flow reactor system within 1 s at a high flow rate (18 mL min–1) under cryogenic conditions (–97 °C). Commercially available diisobutylaluminium hydride (DIBAL‐H) was used as the reductant. The desired enals and benzaldehyde derivatives, except for 4‐methoxycinnamate and 4‐methoxybenzoate, were formed selectively and redox economically in moderate to high yields.
Flow Injection Analysis System Using Magnetic Beads, Screen Printed Electrodes and Magnets
Authors: Biscay Julien , Begoña González García María , García Agustín Costa
Published: August 2014

Here is presented a Flow Injection Analysis (FIA) system using a flow cell with an integrated magnet, applied to biotin determination. The mixture of magnetic beads modified with streptavidin (Strep‐MB), biotin and B‐HRP is left 15 minutes under stirring and then a washing step is performed in an automatic way thanks to the external magnets coupled in the FIA system. After the immobilization of the MBs on the surface of the electrode, 3,3′,5,5′‐Tetramethylbenzidine (TMB) is injected. The linear range obtained is between 0.5 to 10 pM of biotin and the sensitivity is 85 nA/pM.
Clarithromycin as a chiral selector for enantioseparation of basic compounds in nonaqueous capillary electrophoresis
Authors: Lebedeva Margarita V. , Prokhorova Aleksandra F. , Shapovalova Elena N. , Shpigun Oleg A.
Published: August 2014

The first use of macrolide antibiotic clarithromycin (CLM) in nonaqueous media for enantioseparation (partial or baseline) of the following compounds: alprenolol, atenolol, metoprolol, clenbuterol, methoxyphenamine, pindolol, propranolol, sotalol, synephrine, labetalol, and fenoterol is reported. Each analysis took less than 15 min. To find optimal separation conditions, some properties of CLM (adsorption, solubility), as well as the effect of experimental parameters on the enantioseparation of analytes (background electrolyte composition, chiral selector concentration, temperature, and applied voltage) were studied. The best chiral resolution was achieved in methanolic solution of 100 mM citric acid, 10 mM NaOH, 240–300 mM H3BO3, and 60–75 mM CLM. Using the proposed procedure, adsorption of CLM on the capillary wall was negligible and the repeatability of the migration times (RSD) was as good as 1.6%. For the analysis of propranolol, the linearity was achieved in the concentration range 2.5 × 10−2– 3.0 × 10−1 mg/mL with the LODs (3 × S/N) being equal 2.6 × 10−3 mg/mL and 2.8 × 10−3 mg/mL for the first and the second enantiomers, respectively. Linear range for metoprolol enantiomers was 1.0 × 10−2 –1.6 × 10−1 mg/mL. The LODs (3 × S/N) were determined as 2.8 × 10−3 and 3.0 × 10−3 mg/mL for the first and the second enantiomers, respectively.
Chromosomal DNA damage measured using the cytokinesis‐block micronucleus cytome assay is significantly associated with cognitive impairment in South Australians
Authors: Lee Sau Lai , Thomas Philip , Hecker Jane , Faunt Jeffrey , Fenech Michael
Published: August 2014

Loss of genome integrity may be associated with increased risk for neurodegenerative disease. The aim of this study was to investigate whether mild cognitive impairment (MCI) or Alzheimer's disease (AD) individuals have increased DNA damage relative to age‐ and gender‐ matched controls using the cytokinesis‐block micronucleus cytome (CBMN‐Cyt) assay. DNA damage was measured as micronuclei (MN), nucleoplasmic bridges (NPB), and nuclear buds (NBUD) in binucleated cells. The assay was performed on blood samples from 80 participants consisting of (i) MCI cases (N = 20) and age‐ and gender‐ matched controls (N = 20), and (ii) AD cases (N = 20) and age‐ and gender‐ matched controls (N = 20). There was a significant increase in MCI NBUD frequency (P = 0.006) relative to controls, which was also observed in male (P = 0.03) and female (P = 0.04) subgroups. For AD cases, there were no significant differences in assay biomarkers relative to controls. There was a significant negative correlation between Mini Mental State Examination (MMSE) and (i) MN in all controls, (R = −0.3, P = 0.04), and AD cases (R = −0.4, P = 0.03), (ii) NPB in all controls, (R = −0.4, P = 0.006) and AD cases (R = −0.5, P = 0.01), and (iii) NBUD in MCI cases (R = −0.5, P = 0.007) and AD cases (R = −0.7, P = 0.0002). The results suggest that an increase in lymphocyte CBMN‐Cyt DNA damage biomarkers may be associated with cognitive decline. Environ. Mol. Mutagen. 56:32–40, 2015. © 2014 Wiley Periodicals, Inc.
Effects of amphibian chytrid fungus exposure on American toads in the presence of an insecticide
Authors: Wise Rayona S. , Rumschlag Samantha L. , Boone Michelle D.
Published: August 2014

Abiotic factors such as pesticides may alter the impact of a pathogen on hosts, which could have implications for host–pathogen interactions and may explain variation in disease outbreaks in nature. In the present laboratory experiment, American toad (Anaxyrus americanus) metamorphs were exposed to the amphibian chytrid fungal pathogen Batrachochytrium dendrobatidis (Bd) and environmentally relevant concentrations of the insecticide malathion to determine whether malathion altered the effects of Bd exposure on growth and survival of toad metamorphs. Exposure to Bd significantly decreased survival over the 51 d of the experiment, suggesting that Bd could reduce recruitment into the terrestrial life stage when exposure occurs at metamorphosis. Malathion did not impact survival, but a 12-h exposure at metamorphosis significantly reduced terrestrial growth. Toads that were exposed to both Bd and malathion showed a nonsignificant trend toward the smallest growth compared with other treatments. The present study suggests that Bd may pose a threat to American toads even though population declines have not been observed for this species; in addition, the presence of both the insecticide malathion and Bd could reduce terrestrial growth, which could have implications for lifetime fitness and suggests that environmental factors could play a role in pathogen impacts in nature. Environ Toxicol Chem 2014;33:2541–2544. © 2014 SETAC
Accounting for dissociation and photolysis: A review of the algal toxicity of triclosan
Authors: Roberts Jayne , Price Oliver R. , Bettles Nicola , Rendal Cecilie , van Egmond Roger
Published: August 2014

Triclosan, an antimicrobial agent commonly used in down-the-drain consumer products, is toxic to freshwater microalgae. However, the rapid photolysis and pH-dependent dissociation of this compound may give rise to uncertainty in growth inhibition tests with freshwater microalgae, if these are not well characterized. Methods are presented to minimize these uncertainties by stabilizing pH with an organic buffering agent (Bis-Tris) and by the application of ultraviolet (UV) covers to remove UV wavelengths. Toxicity tests with these methods were in compliance with the validity criteria of the Organisation for Economic Co-operation and Development test 201, and no negative effects were seen in controls relative to the unmodified method. The methods were used for toxicity tests with triclosan at pH levels of 7.0, 8.0, and 8.5, yielding effective concentration, 10% values of 0.5 µg/L, 0.6 µg/L, and 12.1 µg/L, respectively. The observed change in toxicity with pH was proportional to the change in bioconcentration factor (BCF) as calculated using the cell model (a dynamic flux model based on the Fick–Nernst–Planck equations, in this case parameterized for an algal cell). Effect concentrations produced with the methods presented in the present study offer robust data on which to base risk assessment, and it is suggested that similar approaches be used to minimize uncertainty when other compounds that dissociate and photolyse are tested. Environ Toxicol Chem 2014;33:2551–2559. © 2014 SETAC
Energy management strategies for base stations in a smart grid environment
Authors: Leithon J. , Sun S. , Lim T. J.
Published: August 2014

In this paper, we propose an optimal energy management strategy that minimises the energy bill incurred by cellular base stations (CBSs) in a smart grid environment. The CBS can harvest renewable energy for local use and is equipped with a limited‐capacity battery that is subject to charging and discharging losses. Because the proposed optimal strategy requires non‐causal information and hence cannot be implemented online, we propose an estimation‐based strategy that only requires causal knowledge of the renewable energy generation and the energy consumption at the CBS. Through simulations, we show that the proposed online estimation‐based strategy has only a small performance gap from the optimal offline strategy. Additionally, we derive and verify three analytical results: an upper bound for the optimal cost, the critical battery capacity, above which no further cost reduction can be achieved, and the conditions on the energy price profile, which ensure that the savings can outweigh both the operational and the per‐cycle battery costs. These analytical results can be used as guidelines in designing energy storage systems for CBSs in a smart grid environment. Copyright © 2014 John Wiley & Sons, Ltd.
Interface control domain decomposition methods for heterogeneous problems
Authors: Discacciati Marco , Gervasio Paola , Quarteroni Alfio
Published: August 2014

This paper is concerned with the solution of heterogeneous problems by the interface control domain decomposition (ICDD) method, a strategy introduced for the solution of partial differential equations in computational domains partitioned into subdomains that overlap. After reformulating the original boundary value problem by introducing new additional control variables, the unknown traces of the solution at internal subdomain interfaces; the latter are determined by requiring that the (a priori) independent solutions in each subdomain undergo the minimization of a suitable cost functional.

We provide an abstract formulation for coupled heterogeneous problems and a general theorem of well‐posedness for the associated ICDD problem. Then, we illustrate and validate an efficient algorithm based on the solution of the Schur‐complement system restricted solely to the interface control variables by considering two kinds of heterogeneous boundary value problems: the coupling between pure advection and advection–diffusion equations and the coupling between Stokes and Darcy equations. In the latter case, we also compare the ICDD method with a classical approach based on the Beavers–Joseph–Saffman conditions. Copyright © 2014 John Wiley & Sons, Ltd.
A water balance approach for quantifying subsurface exchange fluxes and associated errors in hill reservoirs in semiarid regions
Authors: Bouteffeha Maroua , Dages Cécile , Bouhlila Rachida , Molenat Jérôme
Published: August 2014

Hill reservoirs are rain water‐harvesting structures that have been increasingly adopted in arid and semi‐arid regions, such as North Africa, to capture and conserve runoff water and for use as alternative water resources in agricultural development. Currently, process‐based information on reservoir hydrology is needed to improve reservoir management practices.

The study aims to develop an approach to estimate the reservoir–subsurface exchange flux and its associated error at the annual, monthly, and intra‐monthly time scales to better understand the hydrological functioning and dynamics of hill reservoirs. This approach is based on a hydrological water balance of the hill reservoir by considering all water input and output fluxes and their associated errors.

The results demonstrate the ability and relevance of the approach in estimating the net reservoir–subsurface exchange flux and its error estimations at various time scales. Its application on the Kamech catchment (Northern Tunisia) for the 2009–2012 period demonstrates that the net reservoir–subsurface exchange flux is positive, i.e. the infiltration from the hill reservoir to the aquifer dominates over the discharge from the aquifer to the reservoir. Moreover, reservoir–subsurface exchange constitutes the main output component in the water balance. Copyright © 2014 John Wiley & Sons, Ltd.
Tumor genome analysis includes germline genome: Are we ready for surprises?
Authors: Catenacci Daniel V.T. , Amico Andrea L. , Nielsen Sarah M. , Geynisman Daniel M. , Rambo Brittany , Carey George B. , Gulden Cassandra , Fackenthal Jim , Marsh Robert D. , Kindler Hedy L. , Olopade Olufunmilayo I.
Published: August 2014

We sought to describe the spectrum of potential and confirmed germline genomic events incidentally identified during routine medium‐throughput somatic tumor DNA sequencing, and to provide a framework for pre‐ and post‐test consent and counseling for patients and families. Targeted tumor‐only next‐generation sequencing (NGS) had been used to evaluate for possible druggable genomic events obtained from consecutive new patients with metastatic gastroesophageal, hepatobiliary or colorectal cancer seen at the University of Chicago. A panel of medical oncologists, cancer geneticists and genetic counselors retrospectively grouped these patients (N = 111) based on probability of possessing a potentially inherited mutation in a cancer susceptibility gene, both prior to and after incorporating tumor‐only NGS results. High‐risk patients (determined from NGS results) were contacted and counseled in person by a genetic counselor (N = 21). When possible and indicated, germline genetic testing was offered. Of 8 evaluable high‐risk patients, 7 underwent germline testing. Three (37.5%) had confirmed actionable germline mutations (all in the BRCA2 gene). NGS offers promise, but poses significant challenges for oncologists who are ill prepared to handle incidental findings that have clinical implications for at risk family members. In this relatively small cohort of patients undergoing tumor genomic testing for gastrointestinal malignancies, we incidentally identified 3 BRCA2 mutations carriers. This report underscores the need for oncologists to develop a framework for pre‐ and post‐test communication of risks to patients undergoing routine tumor‐only sequencing.
Metalloproteinase‐dependent and ‐independent processes contribute to inhibition of breast cancer cell migration, angiogenesis and liver metastasis by a disintegrin and metalloproteinase with thrombospondin motifs‐15
Authors: Kelwick Richard , Wagstaff Laura , Decock Julie , Roghi Christian , Cooley Lindsay S. , Robinson Stephen D. , Arnold Hugh , Gavrilović Jelena , Jaworski Diane M. , Yamamoto Kazuhiro , Nagase Hideaki , Seubert Bastian , Krüger Achim , Edwards Dylan R.
Published: August 2014

The ADAMTS proteinases are a family of secreted, matrix‐associated enzymes that have diverse roles in the regulation of tissue organization and vascular homeostasis. Several of the 19 human family members have been identified as having either tumor promoting or suppressing roles. We previously demonstrated that decreased ADAMTS15 expression correlated with a worse clinical outcome in mammary carcinoma (e.g., Porter et al., Int J Cancer 2006;118:1241–7). We have explored the effects of A Disintegrin and Metalloproteinase with Thrombospondin motifs‐15 (ADAMTS‐15) on the behavior of MDA‐MB‐231 and MCF‐7 breast cancer cells by stable expression of either a wild‐type (wt) or metalloproteinase‐inactive (E362A) protein. No effects on mammary cancer cell proliferation or apoptosis were observed for either form of ADAMTS‐15. However, both forms reduced cell migration on fibronectin or laminin matrices, though motility on a Type I collagen matrix was unimpaired. Knockdown of syndecan‐4 attenuated the inhibitory effects of ADAMTS‐15 on cell migration. In contrast to its effects on cell migration, wt ADAMTS‐15 but not the E362A inactive mutant inhibited endothelial tubulogenesis in 3D collagen gels and angiogenesis in the aortic ring assay. In experimental metastasis assays in nude mice, MDA‐MB‐231 cells expressing either form of ADAMTS‐15 showed reduced spread to the liver, though lung colonization was enhanced for cells expressing wt ADAMTS‐15. These studies indicate that extracellular ADAMTS‐15 has multiple actions on tumor pathophysiology. Via modulation of cell‐ECM interactions, which likely involve syndecan‐4, it attenuates mammary cancer cell migration independent of its metalloproteinase activity; however, its antiangiogenic action requires catalytic functionality, and its effects on metastasis in vivo are tissue niche‐dependent.
Cisplatin‐Induced Testicular Toxicity in Rats: The Protective Effect of Arjunolic Acid
Authors: Sherif Iman O. , Abdel‐Aziz Azza , Sarhan Osama M.
Published: August 2014

In the present study, the effect of arjunolic acid on testicular damage induced by intraperitoneal injection of rats with 7 mg/kg cisplatin was studied. Cisplatin induced a significant reduction in testicular weights, plasma testosterone, and testicular reduced glutathione levels in addition to a significant elevation of testicular malondialdehyde levels and testicular gene expressions of inducible nitric oxide synthase (iNOS), tumor necrosis factor‐α (TNF‐α), and p38 mitogen‐activated protein kinase (MAPK) when compared with the control group (p < 0.05). Lower tubular diameters and depletion of germ cells and irregular small seminiferous tubules with Sertoli cells only were observed in the cisplatin group. Arjunolic acid administration significantly corrected the changes in both biochemical and histopathological parameters. Arjunolic acid plays a significant protective role against cisplatin‐induced testicular injury by attenuating oxidative stress parameters along with downregulation of iNOS, TNF‐α, and p38‐MAPK testicular expressions.
A Complete Solution to Spectrum Problem for Five‐Vertex Graphs with Application to Traffic Grooming in Optical Networks
Authors: Ge Gennian , Hu Sihuang , Kolotoğlu Emre , Wei Hengjia
Published: August 2014

A G‐design of order n is a decomposition of the complete graph on n vertices into edge‐disjoint subgraphs isomorphic to G. Grooming uniform all‐to‐all traffic in optical ring networks with grooming ratio C requires the determination of graph decompositions of the complete graph on n vertices into subgraphs each having at most C edges. The drop cost of such a grooming is the total number of vertices of nonzero degree in these subgraphs, and the grooming is optimal when the drop cost is minimum. The existence spectrum problem of G‐designs for five‐vertex graphs is a long standing problem posed by Bermond, Huang, Rosa and Sotteau in 1980, which is closely related to traffic groomings in optical networks. Although considerable progress has been made over the past 30 years, the existence problems for such G‐designs and their related traffic groomings in optical networks are far from complete. In this paper, we first give a complete solution to this spectrum problem for five‐vertex graphs by eliminating all the undetermined possible exceptions. Then, we determine almost completely the minimum drop cost of 8‐groomings for all orders n by reducing the 37 possible exceptions to 8. Finally, we show the minimum possible drop cost of 9‐groomings for all orders n is realizable with 14 exceptions and 12 possible exceptions.
Fibroadenomatosis involving bilateral breasts and axillary accessory breast tissues in a renal transplant recipient given cyclosporin A
Authors: Bulakci Mesut , Gocmez Ahmet , Demir Ali Aslan , Salmaslioglu Artur , Tukenmez Mustafa , Yavuz Ekrem , Acunas Gulden
Published: August 2014

We present the mammographic and sonographic findings in a case of fibroadenomatosis involving both breasts and axillae in a renal transplant patient after 16 years of treatment with cyclosporin A. Awareness of the fact that cyclosporin A may induce the formation of fibroadenomas, including in accessory breast tissue, is important for correct diagnosis and preventing unnecessary intervention. © 2014 Wiley Periodicals, Inc. J Clin Ultrasound 42:495–497, 2014