bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer
Authors: Janghorban Mahnaz , Farrell Amy S. , Allen-Petersen Brittany L. , Pelz Carl , Daniel Colin J. , Oddo Jessica , Langer Ellen M. , Christensen Dale J. , Sears Rosalie C.
Published: June 2014

Significance

Increased kinase activity and suppressed phosphatase activity are hallmarks of oncogenic signaling. The transcription factor c-MYC, a master driver of human cancer, is stabilized and activated by persistent serine 62 phosphorylation. The tumor suppressor protein phosphatase 2A (PP2A) targets this site and negatively regulates c-MYC. Here, we show that two cellular inhibitors of PP2A, the SET oncoprotein and cancerous inhibitor of PP2A (CIP2A), are overexpressed in breast cancer, and depletion or inhibition of SET or CIP2A reduces c-MYC expression and activity and decreases the tumorigenic potential of breast cancer cells. These findings strongly suggest that inhibiting SET or CIP2A to reactivate PP2A may be an effective therapeutic strategy for targeting c-MYC in breast cancer.
Perilipins 2 and 3 lack a carboxy-terminal domain present in perilipin 1 involved in sequestering ABHD5 and suppressing basal lipolysis
Authors: Patel Satish , Yang Wei , Kozusko Kristina , Saudek Vladimir , Savage David B.
Published: June 2014

Significance

Lipolysis refers to the hydrolysis of triacylglycerol stored within lipid droplets. It is an essential step in the catabolism of triacylglycerol in all cells. Within adipocytes, the regulation is highly dynamic, whereas in other cell types basal lipolytic flux is less effectively suppressed and lipolysis is not as dramatically stimulated. These differences reflect the obviously different functions of adipose tissue, the body’s principle energy store, compared with other sites such as the liver or skeletal muscle, where lipids may be exported within lipoproteins or oxidized. Our data suggest that the molecular differences between perilipins1, 2, and 3 can largely account for these functional differences and thus provide a plausible hypothesis for their preservation in evolution.
Resting GABA and glutamate concentrations do not predict visual gamma frequency or amplitude
Authors: Cousijn Helena , Haegens Saskia , Wallis George , Near Jamie , Stokes Mark G. , Harrison Paul J. , Nobre Anna C.
Published: June 2014

Significance

In vitro and modeling studies have indicated that GABAergic signaling underlies gamma oscillations. It would be valuable to measure this correlation between GABA and gamma oscillations in the human brain, and a recent study [Muthukumaraswamy SD, et al. (2009)Proc Natl Acad Sci USA106(20):8356–8361] indicated that this is possible, using magnetoencephalography and magnetic resonance spectroscopy. If true, such a correlation would make the gamma peak frequency a useful surrogate marker of cortical excitability for studies investigating clinical populations and/or the effects of pharmacological agents. However, magnetic resonance spectroscopy does not measure synaptic GABA specifically, and the results from the current study (n= 50) indicate that GABA, as measured with magnetic resonance spectroscopy, does not correlate with gamma peak frequency.
Proterozoic oxygen rise linked to shifting balance between seafloor and terrestrial weathering
Authors: Mills Benjamin , Lenton Timothy M. , Watson Andrew J.
Published: June 2014

Significance

We investigate the balance between two mechanisms that remove carbon from the atmosphere and oceans over long timescales—weathering of terrestrial silicates and alteration of the ocean floor. We show that this balance should strongly influence atmospheric oxygen concentration, since it dictates the delivery rate of the ultimate limiting nutrient phosphorus to the ocean. Increasing solar luminosity and declining seafloor spreading rates over Proterozoic time are expected to have shifted the balance of carbon removal toward terrestrial weathering. This leads to the prediction of a gradually increasing oxygen concentration over Proterozoic time, with transient higher oxygen concentration in the late Neoproterozoic.
Immersive audiomotor game play enhances neural and perceptual salience of weak signals in noise
Authors: Whitton Jonathon P. , Hancock Kenneth E. , Polley Daniel B.
Published: June 2014

Significance

All sensory systems face two fundamental limitations: (
i
) segregating partially overlapping sensory inputs into separate perceptual objects and (
ii
) raising sensory events that are either weak or noisy to perceptual awareness. The ability of sensory systems to extract information from weak signals in noisy backgrounds can improve with practice, but learning does not typically generalize to untrained stimuli. By training humans and mice with an audio game inspired by sensory foraging behavior, we show that learning to discriminate simple, easily controlled sounds can generalize to improved neural and perceptual processing of “real-world” complex sounds, including speech in noise. These findings suggest new therapeutic options for clinical populations that receive little benefit from conventional sensory rehabilitation strategies.
Global metaanalysis of the nonlinear response of soil nitrous oxide (N
2
O) emissions to fertilizer nitrogen
Authors: Shcherbak Iurii , Millar Neville , Robertson G. Philip
Published: June 2014

Significance

We clarify the response of the greenhouse gas nitrous oxide (N
2
O) to nitrogen (N) fertilizer additions, a topic of considerable debate. Previous analyses have used single N-rate experiments to define a linear response to N additions across climate, management, and soil conditions globally. Here, we provide a first quantitative comparison of N
2
O emissions for all available studies that have used multiple N rates. Results show that a nonlinear emission factor better represents global emission patterns with lower uncertainty, offering more power for balancing the global N
2
O budget and for designing effective mitigation strategies.
Primary cilia control hedgehog signaling during muscle differentiation and are deregulated in rhabdomyosarcoma
Authors: Fu Wenxiang , Asp Patrik , Canter Brian , Dynlacht Brian David
Published: June 2014

Significance

The primary cilium is an organelle emanating from the cell surface, and recent evidence suggests that it regulates various cellular signaling pathways and development and that aberrations in its assembly and function could result in tumorigenesis. Skeletal muscle differentiation proceeds through a temporally defined series of events to form multinucleated myofibers, and in rhabdomyosarcomas (RMS), myoblasts fail to differentiate. However, whether primary cilia are functionally linked to normal muscle differentiation or RMS is not known. In this study we show that in skeletal myoblasts, primary cilia are important for proliferation, hedgehog signaling, and differentiation. Furthermore, the deregulation of cilia and hedgehog in RMS could suggest the utility of therapeutically targeting ciliary components in these tumors.
Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes
Authors: Wang Hao , Fewer David P. , Holm Liisa , Rouhiainen Leo , Sivonen Kaarina
Published: June 2014

Significance

This study demonstrates the widespread distribution of nonribosomal peptide synthetase and modular polyketide synthase biosynthetic pathways across the three domains of life, by cataloging a total of 3,339 gene clusters from 2,699 genomes. Our analysis suggests that noncanonical nonmodular biosynthetic enzymes are common in bacteria.
Proteobacteria
,
Actinobacteria
,
Firmicutes
, and
Cyanobacteria
in bacteria and
Ascomycota
in fungi contained higher number of these gene clusters and are likely to produce a wide variety of nonribosomal peptide and polyketide types of natural products. The data generated here provide a basis for the exploration of nonribosomal peptide and polyketide biosynthetic capacity and present a compelling wealth of new information for natural product discovery.
Influenza hemagglutinin stem-fragment immunogen elicits broadly neutralizing antibodies and confers heterologous protection
Authors: Mallajosyula Vamsee V. A. , Citron Michael , Ferrara Francesca , Lu Xianghan , Callahan Cheryl , Heidecker Gwendolyn J. , Sarma Siddhartha P. , Flynn Jessica A. , Temperton Nigel J. , Liang Xiaoping , Varadarajan Raghavan
Published: June 2014

Significance

Hemagglutinin (HA), the major influenza virus envelope glycoprotein, is the principal target of neutralizing antibodies. Wide diversity and variation of HA entails annual vaccination, as current vaccines typically fail to elicit/boost cross-reactive, broadly neutralizing antibodies (bnAbs). Although several bnAbs bind at the conserved stem of HA making it an attractive universal vaccine candidate, the metastable conformation of this domain imposes challenges in designing a stable, independently folding HA stem immunogen. We rationally designed a stem-fragment immunogen, mimicking the native HA stem that binds conformation-specific bnAbs with high affinity. The immunogen elicited bnAbs and conferred robust protection against lethal, heterologous virus challenge in vivo. Additionally, soluble bacterial expression of such a thermotolerant, disulfide-free immunogen allows for rapid scale-up during pandemic outbreak.
Abrogation of α-synuclein–mediated dopaminergic neurodegeneration in LRRK2-deficient rats
Authors: Daher João P. L. , Volpicelli-Daley Laura A. , Blackburn Jonathan P. , Moehle Mark S. , West Andrew B.
Published: June 2014

Significance

Mutations in the leucine-rich repeat kinase 2 (
LRRK2
) gene are the most common known genetic cause of late-onset Parkinson disease, but the mechanisms underlying LRRK2 action in neurodegeneration are not clear. We demonstrate that rats deficient in LRRK2 expression are protected from dopaminergic neurodegeneration caused by overexpression of α-synuclein or exposure to LPS. LRRK2 expression is induced in proinflammatory brain myeloid cells under pathological conditions. Our results suggest that LRRK2 inhibition may have important neuroprotective effects by critically modulating neuroinflammatory responses. LRRK2 inhibition may therefore be a potentially efficacious approach to slow or stop the progression of brain disorders where myeloid cell activation drives aspects of dysfunction.
Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells
Authors: Kaplinsky Joseph , Li Anthony , Sun Amy , Coffre Maryaline , Koralov Sergei B. , Arnaout Ramy
Published: June 2014

Significance

Antibodies play essential roles in vaccination, infection, autoimmunity, aging, and cancer. A key question is how the antibody repertoire achieves its remarkable diversity. Part of the answer is that B cells, which express antibodies on their surface, are selected for survival based on the specific antigens that their antibodies bind, with antigen specificity determined by the protein sequence of antibodies’ antigen-binding regions. Unexpectedly, we find that B cells are also selected based on whether their antibodies have a loose or tight “elbow joint,” independent of the sequence of their antigen-binding regions. This discovery, enabled by sequencing technology and mathematics, adds a surprising new dimension to our understanding of antibody repertoires, and might one day help us shape them ourselves.
DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin
Authors: Ayrapetov Marina K. , Gursoy-Yuzugullu Ozge , Xu Chang , Xu Ye , Price Brendan D.
Published: June 2014

Significance

Double-strand break (DSB) repair initiates dynamic changes in histone modifications that are required to maintain genome stability. Methylation of histone H3 lysine-9 (H3K9me3) is critical for activating ataxia telangiectasia-mutated (ATM) kinase, but how H3K9 methylation is regulated at DSBs is unknown. We show that a complex containing the suv39h1 methyltransferase is rapidly recruited to DSBs, where it directs H3K9 methylation on large chromatin domains adjacent to the DSB. This process results in transient formation of repressive chromatin and serves to both stabilize the chromatin structure and promote activation of DSB-signaling proteins, including ATM kinase. Dynamic changes in H3K9 modification in euchromatin by suv39h1 are therefore one of the earliest signaling events required for processing and remodeling of the damaged chromatin template.
Evolution of TNF-induced apoptosis reveals 550 My of functional conservation
Authors: Quistad Steven D. , Stotland Aleksandr , Barott Katie L. , Smurthwaite Cameron A. , Hilton Brett Jameson , Grasis Juris A. , Wolkowicz Roland , Rohwer Forest L.
Published: June 2014

Significance

The TNF receptor-ligand superfamily is a central mediator of apoptosis or programmed cell death. Here we show that TNF-induced apoptosis has been functionally maintained for more than half a billion years of evolution. In response to human TNFα, coral cells underwent the classical stages of apoptosis including cellular blebbing, caspase activation, and eventual cell death. Next, the reciprocal experiment showed that coral TNF kills human cells through direct interaction with the death receptor pathway. In addition, corals were found to possess more putative TNF receptors than any organism previously described, including humans. This work provides important insight into the general evolution of apoptosis and demonstrates remarkable conservation of the TNF apoptotic response.
Nod/Ripk2 signaling in dendritic cells activates IL-17A–secreting innate lymphoid cells and drives colitis inT-bet−/−.Rag2−/−(TRUC) mice
Authors: Ermann Joerg , Staton Tracy , Glickman Jonathan N. , de Waal Malefyt Rene , Glimcher Laurie H.
Published: June 2014

Significance

Disease mechanisms in inflammatory bowel disease (IBD) are incompletely understood. In this study, we analyzed the role of IL-17A–secreting innate lymphoid cells (ILCs) in a mouse model of microbiota-driven innate immune-mediated colitis. We report that the pathogenic IL-17A response in ILCs is controlled indirectly by microbial stimulation of dendritic cells (DCs) via the nucleotide-binding oligomerization domain containing (Nod)/receptor-interacting serine-threonine kinase 2 (Ripk2) signaling pathway and requires the cytokines IL-23 and IL-1. Insight into the complex interactions between various immune cells as demonstrated here for DCs and ILCs is a prerequisite for the development of more efficacious therapies in IBD.
Energy landscape of self-assembled superlattices of PbSe nanocrystals
Authors: Quan Zewei , Wu Di , Zhu Jinlong , Evers Wiel H. , Boncella James M. , Siebbeles Laurens D. A. , Wang Zhongwu , Navrotsky Alexandra , Xu Hongwu
Published: June 2014

Significance

Different polymorphs with very similar energetics can be made by slight changes in growth conditions. This is, to our knowledge, the first direct experimental validation of a complex energy landscape for superlattice self-assembly. Our results suggest that fundamental thermodynamic driving forces can be harnessed to tailor specific superlattice assemblies of potential technological significance.
Probing the paramyxovirus fusion (F) protein-refolding event from pre- to postfusion by oxidative footprinting
Authors: Poor Taylor A. , Jones Lisa M. , Sood Amika , Leser George P. , Plasencia Manolo D. , Rempel Don L. , Jardetzky Theodore S. , Woods Robert J. , Gross Michael L. , Lamb Robert A.
Published: June 2014

Significance

The activities of the fusion proteins that mediate virus–cell fusion are an absolute requirement for virus entry and infectivity of enveloped viruses such as HIV, influenza virus, measles virus, and respiratory syncytia virus, among others. Viral fusion proteins are translated initially in a metastable prefusion state and, upon triggering, undergo an extensive and irreversible refolding process. Membrane fusion is coupled to the energy released by the fusion proteins adopting a stable, low-energy postfusion state. Here we use oxidative footprinting of the parainfluenza virus 5 fusion protein to reveal new details of this critical event in the viral lifecycle. A greater understanding of the dynamic nature of these metastable proteins may reveal novel opportunities for the development of targeted therapeutics.
Taxodione and arenarone inhibit farnesyl diphosphate synthase by binding to the isopentenyl diphosphate site
Authors: Liu Yi-Liang , Lindert Steffen , Zhu Wei , Wang Ke , McCammon J. Andrew , Oldfield Eric
Published: June 2014

Significance

There is an ever-present need for new drugs because of drug resistance. An enzyme called “farnesyl diphosphate synthase” (FPPS) is one important drug target, and drugs called “bisphosphonates” that inhibit this enzyme are of interest both as cancer therapeutics and as antibacterial and antiparasitic drug leads. However, they bind avidly to bone and so are ineffective against most tumors and most infectious organisms. Here, we report the discovery of compounds that lack a bone-binding feature that target FPPS in a unique way, as observed at the atomic level. They also can bind to other protein targets, providing a potentially important approach, multitarget inhibition, that is expected to increase efficacy and decrease the likelihood that resistance will develop.
Lexicography in the Philippines (1600–1800)
Authors: Rodríguez Rebeca Fernández
Published: June 2014

Spanish missionary lexicography in America and the Philippines is extensive and deserving of detailed research. In the Philippines, from 1600 up to 1898, more than fifty vocabularies were published in thirteen different languages. Alongside these are numerous vocabularies preserved only as manuscripts and others that are known to be lost. Following some recent publications on Philippine lexicography, in particular bibliographic surveys and studies of specific vocabularies (­García-Medall 2004, 2009; Sueiro Justel 2003; Fernández Rodríguez 2009, 2012), as well as Smith-Stark’s (2009) work on Mexican lexicography, this paper presents a contrastive analysis of the lexicographic styles of seven Philippine vocabularies of five different languages: Tagalog, Visayan, Pampango, ­Bicol and Ilokano. Through examination of the lexicographic characteristics of the most important vocabularies written in the first two centuries of Spanish presence in the Philippines (1600–1800), the present writer tries to establish the lexicographical models used by the missionaries: whether they followed the existing models (mainly Nebrija, Molina and Calepino) or if they created a novel Philippine model. The authors of these vocabularies were missionaries of different Orders: Augustinian, Dominican, Franciscan, and Jesuits. All these vocabularies are bilingual and bidirectional, with the sole exception of the unidirectional Ilokano vocabulary.
Novelty preference in face perception by week-old lambs (Ovis aries)
Authors: Rosa Salva Orsola , Normando Simona , Mollo Antonio , Regolin Lucia
Published: June 2014

An extensive literature has been accumulating, in recent years, on face-processing in sheep and on the relevance of faces for social interaction in this species. In spite of this, spontaneous preferences for face or non-face stimuli in lambs have not been reported. In this study we tested the spontaneous preference of 8-day-old lambs (N = 9) for three pairs of stimuli. In each pair, one stimulus was a face-like display, whereas the other presented the same inner features displaced in unnatural positions. One pair of stimuli was obtained from photographic images of ewes’ faces, the other two pairs were schematic face-like stimuli. Lambs could differentiate the two stimuli obtained by photos of conspecifics, looking longer at the non-face stimulus (p < 0.05). We interpret this as a novelty preference, proving that few day-old lambs have already encoded the structural properties that define a face and recognize violations of those general properties.
DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation
Authors: Ogawa Kana , Tanaka Yoshihiko , Uruno Takehito , Duan Xuefeng , Harada Yosuke , Sanematsu Fumiyuki , Yamamura Kazuhiko , Terasawa Masao , Nishikimi Akihiko , Côté Jean-François , Fukui Yoshinori
Published: June 2014

Mast cells play a key role in the induction of anaphylaxis, a life-threatening IgE-dependent allergic reaction, by secreting chemical mediators that are stored in secretory granules. Degranulation of mast cells is triggered by aggregation of the high-affinity IgE receptor, FcεRI, and involves dynamic rearrangement of microtubules. Although much is known about proximal signals downstream of FcεRI, the distal signaling events controlling microtubule dynamics remain elusive. Here we report that DOCK5, an atypical guanine nucleotide exchange factor (GEF) for Rac, is essential for mast cell degranulation. As such, we found that DOCK5-deficient mice exhibit resistance to systemic and cutaneous anaphylaxis. The Rac GEF activity of DOCK5 is surprisingly not required for mast cell degranulation. Instead, DOCK5 associated with Nck2 and Akt to regulate microtubule dynamics through phosphorylation and inactivation of GSK3β. When DOCK5–Nck2–Akt interactions were disrupted, microtubule formation and degranulation response were severely impaired. Our results thus identify DOCK5 as a key signaling adaptor that orchestrates remodeling of the microtubule network essential for mast cell degranulation.
Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy
Authors: Oricchio Elisa , Ciriello Giovanni , Jiang Man , Boice Michael H. , Schatz Jonathan H. , Heguy Adriana , Viale Agnes , de Stanchina Elisa , Teruya-Feldstein Julie , Bouska Alyssa , McKeithan Tim , Sander Chris , Tam Wayne , Seshan Venkatraman E. , Chan Wing-Chung , Chaganti R.S.K. , Wendel Hans-Guido
Published: June 2014

Loss of cell cycle controls is a hallmark of cancer and has a well-established role in aggressive B cell malignancies. However, the role of such lesions in indolent follicular lymphoma (FL) is unclear and individual lesions have been observed with low frequency. By analyzing genomic data from two large cohorts of indolent FLs, we identify a pattern of mutually exclusive (P = 0.003) genomic lesions that impair the retinoblastoma (RB) pathway in nearly 50% of FLs. These alterations include homozygous and heterozygous deletions of the p16/CDKN2a/b (7%) and RB1 (12%) loci, and more frequent gains of chromosome 12 that include CDK4 (29%). These aberrations are associated with high-risk disease by the FL prognostic index (FLIPI), and studies in a murine FL model confirm their pathogenic role in indolent FL. Increased CDK4 kinase activity toward RB1 is readily measured in tumor samples and indicates an opportunity for CDK4 inhibition. We find that dual CDK4 and BCL2 inhibitor treatment is safe and effective against available models of FL. In summary, frequent RB pathway lesions in indolent, high-risk FLs indicate an untapped therapeutic opportunity.
Derivative estimates of solutions of elliptic systems in narrow regions
Authors: Li HaiGang , Li YanYan , Bao Ellen , Yin Biao
Published: June 2014

In this paper, we establish

C
k

C^k

estimates for a class of elliptic systems, including linear systems of elasticity, in a narrow region. The problem arises from studies of fiber-reinforced elastic composite materials.
Harvesting juveniles of blackspot sea bream (Pagellus bogaraveo) in the Azores (Northeast Atlantic): biological implications, management, and life cycle considerations
Authors: Pinho Mário , Diogo Hugo , Carvalho Joana , Pereira João Gil
Published: June 2014

Blackspot sea bream (Pagellus bogaraveo) is the most important economical resource of Azorean fisheries. Juveniles (age 0 and 1) were detected along island coastlines in nursery grounds that sheltered individuals of up to 13 cm (fork length). Juveniles occurred in coastal areas in all seasons, but higher catch per unit efforts occurred during summer. Larger individuals tended to be caught on the shelves and slopes of the islands and seamounts by the demersal, mixed hook, and line fisheries. Juveniles were exclusively found at inshore areas, while spawners were distributed over offshore areas (islands shelf/slope and seamounts), suggesting an inter-connected cycle of recruitment in coastal areas and ontogenetic migration of juveniles from inshore to offshore areas, while eggs and larvae drift in the opposite direction. Juveniles were found to be targeted by three types of fisheries, amounting to cumulative annual catches of ∼36 t. Shore angling was the most important fishing method, followed by bait fishing for tuna and the coastal pelagic live-bait fishery. Fishery managers have enforced several measures to protect juveniles, although our results indicate that effective interdiction of juvenile catch would provide a long-term increase of 15 and 8% in spawning-stock biomass and catch, respectively, as well as ∼13% increase in the value of landings. Although this measure could improve the protection of a species in an advanced state of overexploitation, our results showed that a decrease in fishing effort would be necessary to achieve sustainability of the stock.
Challenges in mucosal vaccines for the control of infectious diseases
Authors: Azegami Tatsuhiko , Yuki Yoshikazu , Kiyono Hiroshi
Published: June 2014

The mucosal surface is the largest route through which pathogens enter the human body. To control the outbreak of mucosal infectious diseases, we must use our knowledge of the mucosal immune system to create vaccines that elicit protective mucosal and systemic immunity. Mucosal vaccines have advantages over traditional injectable vaccines in that they not only induce effective mucosal immune responses, but they also do not cause physical or psychological discomfort. Mucosal vaccines currently licensed for human use include oral vaccines against Vibrio cholerae, Salmonella typhi, poliovirus and rotavirus, and nasal vaccines against influenza virus. To further improve the existing vaccines, it will be necessary to develop novel vaccine production, storage and delivery systems through innovative strategies derived from interdisciplinary scientific research. Our accumulated knowledge of the innate and acquired arms of the mucosal immune system and the recent scientific and technical advancements in the fields of molecular biology, plant biology, bio-engineering and chemical engineering, genome biology and systems biology have created a unique research and development platform for the development of the next generation of mucosal vaccines. This review summarizes the current perspectives and future directions of mucosal vaccine development with emphasis on oral and nasal vaccines for the control of infectious diseases.
Prospective Clinical Trial of Rifaximin Therapy for Patients With Primary Sclerosing Cholangitis
Authors: Tabibian James H. , Gossard Andrea , El-Youssef Mounif , Eaton John E. , Petz Jan , Jorgensen Roberta , Enders Felicity B. , Tabibian Anilga , Lindor Keith D.
Published: June 2014

Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease in which emerging data suggest that oral antibiotics may offer therapeutic effects. We enrolled patients with PSC in a 12-week, open-label pilot study to investigate the efficacy and safety of 550 mg of oral rifaximin twice daily. The primary end point was serum alkaline phosphatase (ALK) at 12 weeks. Secondary end points included (1) serum bilirubin, gamma-glutamyl transpeptidase, and Mayo PSC risk score; (2) fatigue impact scale, chronic liver disease questionnaire, and short form health survey (SF-36) scores; and (3) adverse effects (AEs). Analyses were performed with nonparametric tests. Sixteen patients were enrolled, among whom the median age was 40 years; 13 (81%) were male, 13 had inflammatory bowel disease, and baseline ALK was 342 IU/mL (interquartile range, 275–520 IU/mL). After 12 weeks of treatment, there were no significant changes in ALK (median increase of 0.9% to 345 IU/mL; P = 0.47) or any of the secondary biochemical end points (all P > 0.05). Similarly, there were no significant changes in fatigue impact scale, chronic liver disease questionnaire, or SF-36 scores (all P > 0.05). Three patients withdrew from the study due to AEs; 4 others reported mild AEs but completed the study. In conclusion, although some antibiotics may have promise in treating PSC, oral rifaximin, based on the results herein, seems inefficacious for this indication. Future studies are needed to understand how the antimicrobial spectra and other properties of antibiotics might determine their utility in treating PSC.
Structural biology at the European X-ray free-electron laser facility
Authors: Altarelli Massimo , Mancuso Adrian P.
Published: June 2014

The European X-ray free-electron laser (XFEL) facility, under construction in the Hamburg region, will provide high-peak brilliance (greater than 10
33
photons s
−1
mm
−2
mrad
−2
per 0.1% BW), ultrashort pulses (approx. 10 fs) of X-rays, with a high repetition rate (up to 27 000 pulses s
−1
) from 2016 onwards. The main features of this exceptional X-ray source, and the instrumentation developments necessary to exploit them fully, for application to a variety of scientific disciplines, are briefly summarized. In the case of structural biology, that has a central role in the scientific case of this new facility, the instruments and ancillary laboratories that are being planned and built within the baseline programme of the European XFEL and by consortia of users are also discussed. It is expected that the unique features of the source and the advanced features of the instrumentation will allow operation modes with more efficient use of sample materials, faster acquisition times, and conditions better approaching feasibility of single molecule imaging.
Fluconazole affects the alkali-metal-cation homeostasis and susceptibility to cationic toxic compounds of Candida glabrata
Authors: Elicharova Hana , Sychrova Hana
Published: June 2014

Candida glabratais a salt-tolerant and fluconazole (FLC)-resistant yeast species. Here, we analyse the contribution of plasma-membrane alkali-metal-cation exporters, a cation/proton antiporter and a cation ATPase to cation homeostasis and the maintenance of membrane potential (ΔΨ). Using a series of single and double mutants lackingCNH1and/orENA1genes we show that the inability to export potassium and toxic alkali-metal cations leads to a slight hyperpolarization of the plasma membrane ofC. glabratacells; this hyperpolarization drives more cations into the cells and affects cation homeostasis. Surprisingly, a much higher hyperpolarization ofC. glabrataplasma membrane was produced by incubating cells with subinhibitory concentrations of FLC. FLC treatment resulted in a substantially increased sensitivity of cells to various cationic drugs and toxic cations that are driven into the cell by negative-inside plasma-membrane potential. The effect of the combination of FLC plus cationic drug treatment was enhanced by the malfunction of alkali-metal-cation transporters that contribute to the regulation of membrane potential and cation homeostasis. In summary, we show that the combination of subinhibitory concentrations of FLC and cationic drugs strongly affects the growth ofC. glabratacells.
Characterization of a rationally engineeredphaCABoperon with a hybrid promoter design
Authors: Bower Iain , Chi Bobby Wenqiang , Chin Matthew Ho Wai , Fan Sisi , Kopniczky Margarita , Pilcher Jemma , Strutt James , Kelwick Richard , Webb Alexander , Jensen Kirsten , Stan Guy-Bart , Kitney Richard , Freemont Paul
Published: June 2014

Biopolymers, such as poly-3-hydroxy-butyrate (P(3HB)) are produced as a carbon store in an array of organisms and exhibit characteristics which are similar to oil-derived plastics, yet have the added advantages of biodegradability and biocompatibility. Despite these advantages, P(3HB) production is currently more expensive than the production of oil-derived plastics, and therefore more efficient P(3HB) production processes are required. In this study, we describe the model-guided design and experimental characterization of several engineered P(3HB) producing operons. In particular, we describe the characterization of a novel hybridphaCABoperon that consists of a dual promoter (native and J23104) and RBS (native and B0034) design. P(3HB) production was around six-fold higher in hybridphaCABengineeredEscherichia coliin comparison toE. coliengineered with the nativephaCABoperon fromRalstonia eutrophaH16. The hybridphaCABoperon represents a step towards the more efficient production of P(3HB), which has an array of applications from 3D printing to tissue engineering.
Dichlorido(5,10,15,20-tetraphenylporphyrinato-κ4N)antimony(V) hexachloridoantimonate(V)
Authors: Soury Raoudha , Belkhiria Mohamed Salah , Giorgi Michel , Nasri Habib
Published: June 2014

The asymmetric unit of the title compound, [Sb(C44H28N4)Cl2][SbCl6], consists of one half of an antimony(V) tetraphenylporphyrin complex cation and one half of an hexachloridoantimonate(V) anion. In the complex cation, the SbVatom lies on an inversion center and is octahedrally coordinated by four N atoms from a macrocyclic tetraphenylporphyrinate ligand and two chloride ions. The complex cation has approximately a planar core with a maximum deviation of 0.018 (5) Å from the porphyrin mean plane. The average Sb—N distance is 2.062 (11) Å, while the Sb—Cl distance is 2.355 (1) Å. The SbVatom of the anion is also located on an inversion center. The [SbCl6]−octahedron exhibits rhombic distortion characterized by the Sb—Cl bond lengths [2.311 (3), 2.374 (2) and 2.393 (4) Å]. In the crystal, the cations and anions are linked C—H... Cl hydrogen bonds, forming a layer parallel to (211).
1-{3-(4-Chlorophenyl)-5-[4-(propan-2-yl)phenyl]-4,5-dihydro-1H-pyrazol-1-yl}propan-1-one
Authors: Narayana B. , Salian Vinutha V. , Sarojini Balladka K. , Jasinski Jerry P.
Published: June 2014

In the title compound, C21H23ClN2O, the dihedral angle between the benzene rings is 83.2 (6)°, while the mean plane of the pyrazole ring [r.m.s. deviation = 0.043 (1) Å] makes dihedral angles of 3.4 (3) and 86.2 (1)° with the benzene rings. In the crystal, a pair of weak C—H...O interactions between the benzene ring and the propan-1-one group link the molecules into an inversion dimer with anR22(16) graph-set motif. In addition, a weak π–π stacking interaction [centroid–centroid distance = 3.959 (4) Å] connects the dimers into a tape running along [201].
β-K3Fe(MoO4)2Mo2O7
Authors: Souilem Amira , Zid Mohamed Faouzi , Driss Ahmed
Published: June 2014

The title compound, tripotassium iron(III) bis(orthomolybdate) dimolybdate, was obtained by a solid-state reaction. The main structural building units are one FeO6octahedron, two MoO4tetrahedra and one Mo2O7dimolybdate group, all with point group symmetriesm. These units are linkedviacorner-sharing to form ribbons parallel to [010]. The three K+cations are located between the ribbons on mirror planes and have coordination numbers of 10 and 12. Two O atoms of one of the MoO4tetrahedra of the dimolybdate group are disordered over two positions in a 0.524 (11):0.476 (11) ratio. The structure of the title compound is compared briefly with that of Rb3FeMo4O15.
Non-centrosymmetric Rb2Mn2(MoO4)3
Authors: Bouzidi Chahira , Zid Mohamed Faouzi , Driss Ahmed , Souilem Amira
Published: June 2014

The title compound, dirubidium dimanganese(II) tris(tetraoxomolybdate), Rb2Mn2(MoO4)3, was prepared by solid-state reactions. The structure can be described as being composed of MnO6octahedra sharing corners with MoO4tetrahedra. The three-dimensional framework contains cavities in which the rubidium ions are located. The Rb+cations are within distorted nine- and 12-vertex polyhedra. The pairs of different Mn2+and Rb+cations are each located on threefold rotation axes.. Rb2Mn2(MoO4)3is isotypic with compounds of the Cs2M2Mo3O12(M= Ni, Fe) family. A comparative structural description is provided between the structure of the title compound and those of related phases. Differences with structures such as alluaudite are discussed.
5′-([1,1′-Biphenyl]-4-yl)-1′,1′′,3′′-trimethyldispiro[indane-2,2′-pyrrolidine-4′,5′′-[1,3]diazinane]-1,3,2′′,4′′,6′′-pentaone
Authors: Subramanyahegde  , Amar Hosamani , Shivaraj Yellappa , Vijayakumar Giriyapura R. , Palakshamurthy Bandrehalli Siddagangaiah
Published: June 2014

In the title compound, C30H25N3O5, the central five-membered heterocyclic ring adopts an envelope conformation, with the N atom as the flap. The dihedral angles between this central ring and the pendant indane ring system, the trione and benzene rings are 87.49 (5), 82.95 (10) and 72.42 (10)°, respectively. The dihedral angle between the rings of the biphenyl group is 45.99 (13)°. In the crystal, molecules are linked by C—H...O hydrogen bonds into [101]C(12) chains.
Data analysis method to achieve sub-10 pm spatial resolution using extended X-ray absorption fine-structure spectroscopy
Authors: Du Yonghua , Wang Jia-ou , Jiang Longhua , Borgna Lucas Santiago , Wang Yanfei , Zheng Yi , Hu Tiandou
Published: June 2014

Obtaining sub-10 pm spatial resolution by extended X-ray absorption fine structure (EXAFS) spectroscopy is required in many important fields of research, such as lattice distortion studies in colossal magnetic resistance materials, high-temperature superconductivity materialsetc.However, based on the existing EXAFS data analysis methods, EXAFS has a spatial resolution limit of π/2Δkwhich is larger than 0.1 Å. In this paper a new data analysis method which can easily achieve sub-10 pm resolution is introduced. Theoretically, the resolution limit of the method is three times better than that normally available. The method is examined by numerical simulation and experimental data. As a demonstration, the LaFe1–xCrxO3system (x= 0, 1/3, 2/3) is studied and the structural information of FeO6octahedral distortion as a function of Cr doping is resolved directly from EXAFS, where a resolution better than 0.074 Å is achieved.
Theoretical consideration of an X-ray Bragg-reflection lens using the eikonal approximation
Authors: Balyan Minas K.
Published: June 2014

On the basis of the eikonal approximation, X-ray Bragg-case focusing by a perfect crystal with parabolic-shaped entrance surface is considered theoretically. Expressions for focal distances, intensity gain and distribution around the focus spot as well as for the focus spot sizes are obtained. The condition of point focusing is presented. The experiment can be performed using X-ray synchrotron radiation sources (particularly free-electron lasers).
Propagation of an X-ray beam modified by a photonic crystal
Authors: Kohn V. G. , Snigireva I. , Snigirev A.
Published: June 2014

A method of calculating the transmission of hard X-ray radiation through a perfect and well oriented photonic crystal and the propagation of the X-ray beam modified by a photonic crystal in free space is developed. The method is based on the approximate solution of the paraxial equation at short distances, from which the recurrent formula for X-ray propagation at longer distances is derived. A computer program for numerical simulation of images of photonic crystals at distances just beyond the crystal up to several millimetres was created. Calculations were performed for Ni inverted photonic crystals with the [111] axis of the face-centred-cubic structure for distances up to 0.4 mm with a step size of 4 µm. Since the transverse periods of the X-ray wave modulation are of several hundred nanometres, the intensity distribution of such a wave is changed significantly over the distance of several micrometres. This effect is investigated for the first time.
Report of the Executive Committee for 2012
Authors: Dacombe M.
Published: June 2014

The report of the Executive Committee for 2012 is presented.
Faces of Platonic solids in all dimensions
Authors: Szajewska Marzena
Published: June 2014

This paper considers Platonic solids/polytopes in the real Euclidean space {\bb R}^n of dimension 3 ≤n< ∞. The Platonic solids/polytopes are described together with their faces of dimensions 0 ≤d≤n− 1. Dual pairs of Platonic polytopes are considered in parallel. The underlying finite Coxeter groups are those of simple Lie algebras of typesAn,Bn,Cn,F4, also called the Weyl groups or, equivalently, crystallographic Coxeter groups, and of non-crystallographic Coxeter groupsH3,H4. The method consists of recursively decorating the appropriate Coxeter–Dynkin diagram. Each recursion step provides the essential information about faces of a specific dimension. If, at each recursion step, all of the faces are in the same Coxeter group orbit,i.e.are identical, the solid is called Platonic. The main result of the paper is found in Theorem 2.1 and Propositions 3.1 and 3.2.
Social media as a political backchannel
Authors: Kalsnes Bente , Krumsvik Arne H. , Storsul Tanja
Published: June 2014

Purpose

– The purpose of this paper is to explore how Twitter is used as a political backchannel and potential agenda setter during two televised political debates during the Norwegian election in 2011. The paper engages with current debates about the role of social media in audience participation and traditional media's changing role as gatekeepers and agenda setter.

Design/methodology/approach

– A combination of quantitative and qualitative methods. By introducing and using the IMSC multiple step analysis model on the Twitter datasets, the authors are able to analyse the flow of thousands of tweets and compare them with topics discussed in the televised debates.

Findings

– The paper finds that the same topics are discussed on Twitter as on TV, but “the debate about the debate” or Meta talk tweets reveal critical scrutiny of the agenda. The paper identifies a clear pattern of political fandom and media criticism in the “debate about the debate”, indicating that Meta talk in social media can function as a critical public sphere, also in real time, which has not been identified in existing studies of Twitter and political TV shows.

Originality/value

– The analysis is unique in the sense that the paper analyses a smaller, national Twitter population in deeper detail than what is common in larger Twitter studies related to political televised debates. The IMSC model can be used in future Twitter studies to uncover layers in the data material and structure the findings.
Reproductive health behaviour of Muslim immigrant women in Canada
Authors: George Pamela , Lennox Terrion Jenepher , Ahmed Rukhsana
Published: June 2014

Purpose

– Reproductive health is critically important for women and yet minority women in Canada are less likely to use preventive health care services. The purpose of this paper is to increase understanding of the health behaviours of this minority population and, in particular, identify barriers to accessing reproductive health care services.

Design/methodology/approach

– This study qualitatively analysed data from focus group discussions with 22 Muslim immigrant women in Ottawa, Canada.

Findings

– The theme of modesty emerged as one of the main barriers in the health seeking behaviour of Muslim immigrant women when it comes to reproductive health and, therefore, the gender of the physician was very important. Focus group participants also discussed a preference for family physicians from the same ethnic and cultural background. Adaptation, or the need to be flexible if there was no alternative to a male doctor, emerged as a theme throughout the focus groups. Emergencies were frequently cited as a reason to adapt.

Practical implications

– The findings reveal that while religious rules do play a predominant role in the health behaviour of Muslim immigrant women, communication by health care providers, government and health agencies can offer strategies to increase the uptake of preventive reproductive care.

Originality/value

– This study offers unique insights into the very personal experience of reproductive health care through rich, qualitative data. Given the impact of culture and religion on perceptions and practices, in particular related to reproductive health, this study contributes to more effective communication strategies with Muslim women.
Development of lean manufacturing implementation drivers for Indian ceramic industry
Authors: Singh Sangwan Kuldip , Bhamu Jaiprakash , Mehta Dhwani
Published: June 2014

Purpose

– The purpose of this paper is to develop a statistically reliable and valid model of lean manufacturing (LM) implementation drivers for the Indian ceramic industry through an empirical study.

Design/methodology/approach

– The research methodology is based on the empirical study of the Indian ceramic industry through a questionnaire specifically developed for the study through literature review and discussions held with practitioners. Exploratory factor analysis, confirmatory factor analysis and structural equation modeling techniques have been used to propose and validate the model. SPSS and AMOS statistical tools have been used for the statistical analysis of the data.

Findings

– The study identified 12 drivers for the LM implementation in Indian ceramic industry. Further, these 12 drivers have been categorized into internal, policy and external drivers (ED). Structural model affirms that ED are positively related to policy drivers (PD) and PD are positively related to internal drivers.

Research limitations/implications

– This study provides casual relationships among the various drivers, which can be leveraged by the managers for the easy and effective implementation of LM in their organizations. It is expected that the model will help the decision makers during LM implementation in taking informed decisions in prioritizing and sequencing the implementation strategy. The results of the research may apply to other industries as well, but this needs to be validated by collecting data and analysing its results.

Practical implications

– The results provide insights into motivating factors that should be focused on while taking lean decisions. The correlation results among drivers will enable the policy makers in government and industry to strategically leverage the resources for the successful implementation of LM in the industry.

Originality/value

– This research empirically develops a model of drivers for LM implementation. The novelty of the study is the causal relationship among the drivers which can be used for decision making to implement lean easily and effectively. Moreover, the categorization of the drivers into internal, external and policy categories and driving/driven relationship among these categories provides the top management an incisive insight into broad improvement areas.