bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic studies provide clues on the pathogenesis of idiopathic pulmonary fibrosis
Authors: Kropski Jonathan A. , Lawson William E. , Young Lisa R. , Blackwell Timothy S.
Published: December 2012

Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal lung disease for which there is no known treatment. Although the traditional paradigm of IPF pathogenesis emphasized chronic inflammation as the primary driver of fibrotic remodeling, more recent insights have challenged this view. Linkage analysis and candidate gene approaches have identified four genes that cause the inherited form of IPF, familial interstitial pneumonia (FIP). These four genes encode two surfactant proteins, surfactant protein C (encoded by SFTPC) and surfactant protein A2 (SFTPA2), and two components of the telomerase complex, telomerase reverse transcriptase (TERT) and the RNA component of telomerase (TERC). In this review, we discuss how investigating these mutations, as well as genetic variants identified in other inherited disorders associated with pulmonary fibrosis, are providing new insights into the pathogenesis of common idiopathic interstitial lung diseases, particularly IPF. Studies in this area have highlighted key roles for epithelial cell injury and dysfunction in the development of lung fibrosis. In addition, genetic approaches have uncovered the importance of several processes – including endoplasmic reticulum stress and the unfolded protein response, DNA-damage and -repair pathways, and cellular senescence – that might provide new therapeutic targets in fibrotic lung diseases.
A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations
Authors: Abrahamsen Greger , Fan Yongjun , Matigian Nicholas , Wali Gautam , Bellette Bernadette , Sutharsan Ratneswary , Raju Jyothy , Wood Stephen A. , Veivers David , Sue Carolyn M. , Mackay-Sim Alan
Published: December 2012

Hereditary spastic paraplegia (HSP) leads to progressive gait disturbances with lower limb muscle weakness and spasticity. Mutations in SPAST are a major cause of adult-onset, autosomal-dominant HSP. Spastin, the protein encoded by SPAST, is a microtubule-severing protein that is enriched in the distal axon of corticospinal motor neurons which degenerate in HSP patients. Animal and cell models have identified functions of spastin and mutated spastin but these models lack the gene dosage, mutation variability and genetic background that characterize patients with the disease. In this study, this genetic variability is encompassed by comparing neural progenitor cells derived from biopsies of the olfactory mucosa from healthy controls with similar cells from HSP patients with SPAST mutations, in order to identify cell functions altered in HSP. Patient-derived cells were similar to control-derived cells in proliferation and multiple metabolic functions but had major dysregulation of gene expression, with 57% of all mRNA transcripts affected, including many associated with microtubule dynamics. Compared to control cells, patient-derived cells had 50% spastin, 50% acetylated α-tubulin and 150% stathmin, a microtubule-destabilising enzyme. Patient-derived cells were smaller than control cells. They had altered intracellular distributions of peroxisomes and mitochondria and they had slower moving peroxisomes. These results suggest that patient-derived cells might compensate for reduced spastin, but their increased stathmin expression reduced stabilised microtubules and altered organelle trafficking. Sub-nanomolar concentrations of the microtubule-binding drugs, paclitaxel and vinblastine, increased acetylated α-tubulin levels in patient cells to control levels, indicating the utility of this cell model for screening other candidate compounds for drug therapies.
Modelling how initiating and transforming oncogenes cooperate to produce a leukaemic cell state
Authors: Richardson Simon E.
Published: December 2012

Summary of and comment on a recent Cell Stem Cell paper entitled ‘Gene sets identified with oncogene cooperativity analysis regulate in vivo growth and survival of leukemia stem cells’ (Ashton et al., 2012).
Poly(ADP-ribosyl)ation links the chromatin remodeler SMARCA5/SNF2H to RNF168-dependent DNA damage signaling
Authors: Smeenk Godelieve , Wiegant Wouter W. , Marteijn Jurgen A. , Luijsterburg Martijn S. , Sroczynski Nicholas , Costelloe Thomas , Romeijn Ron J. , Pastink Albert , Mailand Niels , Vermeulen Wim , van Attikum Haico
Published: December 2012

Ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) arising in native chromatin elicit an RNF8/RNF168-dependent ubiquitylation response, which triggers the recruitment of various repair factors. Precisely how this response is regulated in the context of chromatin remains largely unexplored. Here, we show that SMARCA5/SNF2H, the catalytic subunit of ISWI chromatin remodeling complexes, is recruited to DSBs in a poly(ADP-ribose) polymerase 1 (PARP1)-dependent manner. Remarkably, PARP activity, although dispensable for the efficient spreading of γH2AX into damaged chromatin, selectively promotes spreading of SMARCA5, the E3 ubiquitin ligase RNF168, ubiquitin conjugates and the ubiquitin-binding factors RAD18 and the RAP80-BRCA1 complex throughout DSB-flanking chromatin. This suggests that PARP regulates the spatial organization of the RNF168-driven ubiquitin response to DNA damage. In support of this, we show that SMARCA5 and RNF168 interact in a DNA damage- and PARP-dependent manner. RNF168 becomes poly(ADP-ribosyl)ated after DNA damage, while RNF168 and poly(ADP-ribose) chains were required for SMARCA5 binding in vivo, explaining how SMARCA5 is linked to the RNF168 ubiquitin cascade. Moreover, SMARCA5 regulates the ubiquitin response by promoting RNF168 accumulation at DSBs, which subsequently facilitates efficient ubiquitin conjugation and BRCA1 assembly. Underlining the importance of these findings, we show that SMARCA5 depletion renders cells sensitive to IR and results in DSB repair defects. Our study unveils a functional link between DNA damage-induced poly(ADP-ribosyl)ation, SMARCA5-mediated chromatin remodeling and RNF168-dependent signaling and repair of DSBs.
Interplay between Rab35 and Arf6 controls cargo recycling to coordinate cell adhesion and recycling
Authors: Allaire Patrick D. , Seyed Sadr Mohamed , Chaineau Mathilde , Seyed Sadr Emad , Konefal Sarah , Fotouhi Maryam , Maret Deborah , Ritter Brigitte , Del Maestro Rolando F , McPherson Peter S.
Published: December 2012

Cells inversely adjust the plasma membrane levels of integrins and cadherins during cell migration and cell-cell adhesion but the regulatory mechanisms that coordinate these trafficking events remain unknown. Here, we demonstrate that the small GTPase Rab35 maintains cadherins at the cell surface to promote cell-cell adhesion. Simultaneously, Rab35 supresses the activity of the GTPase Arf6 to down regulate an Arf6-dependent recycling pathway for β1-integrin and EGF receptors, resulting in inhibition of cell migration and attenuation of signaling downstream of these receptors. Importantly, the phenotypes observed following Rab35 knock down are consistent with the epithelial-mesenchymal transition, a feature of invasive cancer cells, and we show that Rab35 expression is suppressed in a subset of cancers characterized by Arf6 hyperactivity. Our data thus identify a key molecular mechanism that efficiently coordinates the inverse intracellular sorting and cell surface levels of cadherin and integrin receptors for cell migration and differentiation.
Separate roles of PKA and EPAC in renal function unraveled by the optogenetic control of cAMP levels in vivo
Authors: Efetova Marina , Petereit Linda , Rosiewicz Kamil , Overend Gayle , Haußig Florian , Hovemann Bernhard T. , Cabrero Pablo , T. Dow Julian A. , Schwärzel Martin
Published: December 2012

Cyclic AMP (cAMP) is a ubiquitous second messenger that regulates a variety of essential processes in diverse cell types, functioning via cAMP-dependent effectors such as PKA and/or EPAC. In an intact tissue it is difficult to separate the contribution of each cAMP effector in a particular cell type using genetic or pharmacological approaches alone. Here, we utilized optogenetics to overcome the difficulties associated with examining a multicellular tissue. The transgenic photoactive adenylyl cyclase bPAC can be activated to rapidly and reversibly generate cAMP pulses in a cell-type specific manner. This optogenetic approach to cAMP manipulation was validated in vivo using GAL4-driven UAS-bPAC in a simple epithelium, the Drosophila renal (Malpighian) tubules. As bPAC was expressed under the control of cell-type specific promoters, each cAMP signal could be directed to either the stellate or principal cells, the two major cell-types of the Drosophila renal tubule. By combining the bPAC transgene with genetic and pharmacological manipulation of either PKA or EPAC it was possible to investigate the functional impact of PKA and EPAC independently of each other. The results of this investigation suggest that both PKA and EPAC are involved in cAMP sensing, but are engaged in very different downstream physiological functions in each cell type: PKA is necessary for basal secretion in principal cells only, and for stimulated fluid secretion in stellate cells only. By contrast, EPAC is important in stimulated fluid secretion in both cell types. We propose that such optogenetic control of cellular cAMP levels can be applied to other systems, for example the heart or the central nervous system, to investigate the physiological impact of cAMP-dependent signaling pathways with unprecedented precision.
PDGFRα signaling in the primary cilium regulates NHE1-dependent fibroblast migration via coordinated differential activity of MEK1/2-ERK1/2-p90RSK and AKT signaling pathways
Authors: Clement Ditte L. , Mally Sabine , Stock Christian , Lethan Mette , Satir Peter , Schwab Albrecht , Pedersen Stine F. , Christensen Søren T.
Published: December 2012

In fibroblasts, Platelet-Derived Growth Factor alpha (PDGFRα) is upregulated during growth arrest and compartmentalized to the primary cilium. PDGF-AA activation of the dimerized ciliary receptor produces a phosphorylation cascade through the PI3K-AKT and MEK1/2-ERK1/2 pathways leading to the activation of the Na+/H+ exchanger, NHE1, cytoplasmic alkalinization and actin nucleation at the lamellipodium that supports directional cell migration. We here show that AKT and MEK1/2-ERK1/2-p90RSK inhibition reduced PDGF-AA-induced cell migration by distinct mechanisms: AKT inhibition reduced NHE1 activity by blocking the translocation of NHE1 to the cell membrane. MEK1/2 inhibition did not affect NHE1 activity but influenced NHE1 localization, causing NHE1 to localize discontinuously in patches along the plasma membrane, rather than preferentially at the lamellipodium. We also provide direct evidence of NHE1 translocation through the cytoplasm to the leading edge. In conclusion, signals initiated at the primary cilium through the PDGFRαα cascade reorganize the cytoskeleton to regulate cell migration differentially through the AKT and the MEK1/2-ERK1/2-p90RSK pathways, with the AKT pathway necessary for initiation of NHE1 translocation, presumably in vesicles, to and activation at the leading edge. In contrast, the MEK1/2-ERK1/2-p90RSK pathway controls the spatial organization of NHE1 translocation and incorporation and therefore specifies the direction in which the leading edge forms.
Molecular chaperones protect against JNK- and Nmnat-regulated axon degeneration in Drosophila
Authors: Rallis Andrew , Lu Bingwei , Ng Julian
Published: December 2012

Axon degeneration is observed at the early stages of many neurodegenerative conditions and this often leads to subsequent neuronal loss. We previously showed that inactivating the c-Jun N-terminal kinase (JNK) pathway leads to axon degeneration in Drosophila mushroom body (MB) neurons. To understand this process, we screened through candidate suppressor genes and found that the Wallerian degeneration slow (WldS) protein blocked JNK axonal degeneration. Although the nicotinamide mononucleotide adenylyltransferase (NMNAT1) portion of WldS is required, unlike axotomy models of neurodegeneration, we find that its nicotinamide adenine dinucleotide (NAD+) enzyme activity and the WldS N-terminus (N70) are dispensable. Instead, we suggest that WldS-Nmnat protects against axonal degeneration through chaperone activity. Furthermore, ectopically expressed heat shock proteins (hsp26 and hsp70) also protect against JNK and Nmnat degeneration phenotypes. These results suggest molecular chaperones are key in JNK- and Nmnat-regulated axonal protective functions.
RARγ is Essential for Retinoic Acid Induced Chromatin Remodeling and Transcriptional Activation in Embryonic Stem Cells
Authors: Kashyap Vasundhra , Laursen Kristian B. , Brenet Fabienne , Viale Agnes J. , Scandura Joseph M. , Gudas Lorraine J.
Published: December 2012

We have utilized retinoic acid receptor γ knockout (RARγ−/−) embryonic stem (ES) cells as a model system to analyze RARγ mediated transcriptional regulation of stem cell differentiation. Most of the transcripts regulated by all-trans retinoic acid (RA) in ES cells are dependent upon functional RARγ signaling. Notably, many of these RA-RARγ target genes are implicated in retinoid uptake and metabolism. For instance, Lrat (lecithin∶retinol acyltransferase), Stra6 (stimulated by retinoic acid 6), Crabp2 (cellular retinoic acid binding protein 2), and Cyp26a1 (cytochrome p450 26a1) transcripts are induced in wild type (WT), but not in RARγ−/− cells. Transcripts for the transcription factors Pbx1 (pre-B cell leukemia homeobox-1), Wt1 (Wilm's tumor gene-1), and Meis1 (myeloid ecotropic viral integration site-1) increase upon RA treatment of WT, but not RARγ−/− cells. In contrast, Stra8, Dleu7, Leftb, Pitx2, and Cdx1 mRNAs are induced by RA even in the absence of RARγ. Mapping of the epigenetic signature of Meis1 revealed that RA induces a rapid increase in the H3K9/K14ac epigenetic mark at the proximal promoter and at two sites downstream of the transcription start site in WT, but not in RARγ−/− cells. Thus, RA-associated increases in H3K9/K14ac epigenetic marks require RARγ and are associated with increased Meis1 transcript levels, whereas H3K4me3 is present at the Meis1 proximal promoter even in the absence of RARγ. In contrast, at the Lrat proximal promoter primarily the H3K4me3 mark, and not the H3K9/K14ac mark, increases in response to RA independently of the presence of RARγ. Our data show major epigenetic changes associated with addition of the RARγ agonist RA in ES cells.
ifet-1 is a broad scale translational repressor required for normal P granule formation in C. elegans
Authors: Sengupta Madhu S. , Low Wai Yee , Patterson Joseph R. , Kim Hyun-Min , Traven Ana , Beilharz Traude H. , Colaiácovo Monica P. , Schisa Jennifer A. , Boag Peter R.
Published: December 2012

Large cytoplasmic ribonucleoprotein germ granule complexes are a common feature in germ cells. In C. elegans these are called P granules and for much of the life-cycle they associate with nuclear pore complexes in germ cells. P granules are rich in proteins that function in diverse RNA pathways. Here we report that the C. elegans homologue of the eIF4E-transporter IFET-1 is required for oogenesis but not spermatogenesis. We show IFET-1 is required for translational repression of several maternal mRNAs in the distal gonad and functions in conjunction with the broad-scale translational regulators CGH-1, CAR-1 and PATR-1 to regulate germ cell sex determination. Furthermore we have found that IFET-1 localises to P granules throughout the gonad and in the germ cell lineage in the embryo. Interestingly, IFET-1 is required for the normal ultrastructure of P granules and for the localization of CGH-1 and CAR-1 to P granules. Our findings suggest that IFET-1 is a key translational regulator and is required for normal P granule formation.
Par6γ is at the mother centriole and controls centrosomal protein composition through a Par6α-dependent pathway
Authors: Dormoy Valérian , Tormanen Kati , Sütterlin Christine
Published: December 2012

The centrosome contains two centrioles that differ in age, protein composition and function. This non-membrane bound organelle is known to regulate microtubule organization in dividing cells and ciliogenesis in quiescent cells. These specific roles depend on protein appendages at the older, or mother, centriole. In this study, we present the identification of the polarity protein Par6γ as a novel component of the mother centriole. This specific localization required the Par6γ C-terminus, but was independent of intact microtubules, the dynein/dynactin complex and the components of the PAR polarity complex. Par6γ depletion resulted in altered centrosomal protein composition, with the loss of multiple proteins, including Par6α and p150Glued, from the centrosome. As a consequence, there were defects in ciliogenesis, microtubule organization and centrosome reorientation during migration. Par6γ interacted with Par3 or aPKC, but these proteins were not required for the regulation of centrosomal protein composition. Par6γ also associated with Par6α, which controls protein recruitment to the centrosome through p150Glued. Our study is the first to identify Par6γ as a component of the mother centriole and to report a role of a mother centriole protein in the regulation of centrosomal protein composition.
The repeatability of metabolic rate declines with time
Authors: White Craig R. , Schimpf Natalie G. , Cassey Phillip
Published: December 2012

The evolutionary causes of variation in metabolic rate within and among species are a topic of enduring interest. Since variation between individuals is the raw material on which natural selection acts, recent years have seen an increase in the number of studies that examine the consequences of inter-individual differences in metabolic rate for organismal performance. A minimum requirement for a trait to evolve is that it must differ consistently between individuals, and these differences must be heritable. The time constancy of a trait is assessed by estimating its repeatability, which represents the ratio of the between-individual component of phenotypic variance to total phenotypic variance. A previous meta-analysis of repeatability concluded that metabolic rate is, on average, repeatable. Here we expand on this earlier analysis by including extra data published in the intervening years and demonstrate that the repeatability of metabolic rate decreases as the interval between measurements increases.
The contribution of the lateral line to 'hearing' in fish
Authors: Higgs Dennis M. , Radford Craig A.
Published: December 2012

In the underwater environment, sound propagates as both a pressure wave and as particle displacement, with particle displacement dominating close to the source (the nearfield). At the receptor level, both the fish ear and the neuromast hair cells act as displacement detectors and both are potentially stimulated by the particle motion component of sound sources, especially in the nearfield. A now common way to test 'hearing' in fish involves auditory evoked potentials (AEP), with recordings made from electrodes implanted near the auditory brainstem. These AEP recordings are typically conducted in enclosed acoustic environments with the fish well within the nearfield, especially for lower frequencies. We tested the contribution of neuromast hair cells to AEP by first testing intact goldfish (Carassius auratus), then ablating their neuromasts with streptomycin sulfate — disabling superficial and canal neuromasts — and retesting the same goldfish. We did a similar experiment where only the superficial neuromasts were physically ablated. At 100 and 200 Hz, there was a 10-15 dB increase in threshold after streptomycin treatment but no significant difference at higher frequencies. There was no difference in threshold in control fish or in fish that only had superficial neuromasts removed, indicating that the differential responses were driven by canal neuromasts. Taken together these results indicate that AEP results at lower frequencies should be interpreted as multimodal responses, rather than 'hearing'. The results also suggest that in natural situations both the ear and lateral line likely play an integrative role in detecting and localising many types of 'acoustic' stimuli.
Response of a free-flying songbird to an experimental shift of the light polarization pattern around sunset
Authors: Schmaljohann Heiko , Rautenberg Tobias , Muheim Rachel , Naef-Daenzer Beat , Bairlein Franz
Published: December 2012

The magnetic field, the sun, the stars and the polarization pattern of visible light during twilight are important cues for orientation in nocturnally migrating songbirds. As these cues change with time and location on Earth, the polarization pattern was put forward as a likely key reference system calibrating the other compass systems. Whether this applies generally to migratory birds is, however, controversially discussed. We used an experimental approach in free-flying birds to study the role of polarization for their departure direction in autumn. Experimental birds experienced a 90° shift of the band of maximum polarization during sunset, whereas control-birds experienced the polarization pattern as under natural condition. Full view of the sunset cues near the horizon was provided during the cue conflict exposure. Here we show both the experimental and the control-birds being released after nautical twilight departed consistently towards south-southeast. Radio telemetry allowed tracking first 15 km of birds' way out, thus the intrinsic migration direction as chosen by the birds was measured. We found no recalibration of the magnetic compass after pre-exposure to a cue conflict between the natural magnetic field and the artificially shifted polarization pattern at sunset. The lacking difference in the departure direction of both groups may suggests that birds did not recalibrate any of the compass systems during the experiment. As free-flying migrants can use all available orientation cues after release, it remains unknown whether our birds might have used the magnetic and/or star compass to determine their departure direction.
A long life in the fast lane: positive association between peak metabolic rate and lifespan in a butterfly
Authors: Niitepõld Kristjan , Hanski Ilkka
Published: December 2012

High peak metabolic may provide performance advantage, but it may also entail a physiological cost. A long-held assumption is that high mass-specific energy expenditure is associated with short lifespan. To examine the relationship between energy expenditure and lifespan we asked two questions. First, do individuals have a consistent rate of metabolism throughout their life? Second, is metabolic rate correlated with lifespan? We analysed the repeatability of measurements of resting (RMR) and peak flight metabolic rate (MRpeak) throughout the life of the Glanville fritillary butterfly (Melitaea cinxia). Measurements of MRpeak showed significant repeatability. Senescence occurred only shortly before death. RMR showed a U-shaped relationship with age and very low repeatability. Intraspecific association between metabolic rates and lifespan was tested under three conditions: in the laboratory, under field conditions, and in a laboratory experiment with repeated flight treatments. There was a significant correlation between MRpeak and lifespan in all three experiments, but the correlation was positive, not negative. RMR was not correlated with lifespan. Both MRpeak and lifespan may reflect physiological condition and be therefore positively correlated. Individuals with a large resource pool may be able to invest in mechanisms that slow down ageing. Individuals with high metabolic capacity may also possess adaptations against ageing. Molecular polymorphism in the gene phosphoglucose isomerase (Pgi) was significantly associated with both MRpeak and lifespan, and may have coevolved with defence mechanisms against senescence. Generalisations such as 'live fast, die young' may be too simple to explain the complex processes affecting ageing and lifespan.
Biodynamics of climbing: effects of substrate orientation on the locomotion of a highly arboreal lizard (Chamaeleo calyptratus)
Authors: Krause Cornelia , Fischer Martin
Published: December 2012

Arboreal substrates differ not only in diameter, but also continuity and orientation. To gain more insight into the dynamics of small-branch locomotion in tetrapods we studied the veiled chameleon walking on inclined and declined perches of up to 60° slope. Inclines and declines are characterized by fore- and hind limbs that equally contribute to body’s progression. The higher-positioned limb's vertical impulses decreased with slope. And while in the lower-positioned limb vertical impulses increased with substrate slope, peak vertical forces decreased. The decrease in peak vertical forces in the lower-positioned limb can be explained by a considerable increase of tensile forces in the higher-positioned limb the steeper the slope gets. In addition, limbs were more crouched on slopes while no changes in fore- and backward reach were observed. Mediolateral impulses were the smallest amongst the force components, and lateral impulses (medially-directed limb forces) exceeded medial impulses (laterally-directed limb forces). On inclines and declines limb placement was more variable than on level substrates. The tail never contacted the substrate during level locomotion. On inclines and declines the tail was held closer to the substrate, with short substrate contacts in one third of the analyzed trials. Regardless of substrate orientation the tail was always held straight above the branch, rotational moments induced by the tail were, therefore, minimized.
Divide-and-Conquer Electronic-Structure Study on the Mechanism of the West Nile Virus NS3 Protease Inhibitor
Authors: Saparpakorn Patchreenart , Kobayashi Masato , Nakai Hiromi
Published: December 2012

An effective tripeptide inhibitor, 2-naphthoyl–Lys–Lys–Arg–H (Naph-KKR-H), acts as an inhibitor against West Nile Virus (WNV) NS3 protease (NS3pro). Two conformations of Naph-KKR-H were found in the crystal structure of WNV NS2B cofactor and NS3pro. In this study, divide-and-conquer-based density functional theory and second-order Møller–Plesset perturbation theory calculations were applied in order to clarify the binding mechanism of both conformations. The solvent effect was also examined. In addition, bond energy density analysis (BEDA) was performed to investigate the binding interaction. Interestingly, even though conformations 1 and 2 revealed the difference of interaction energies, energy barriers, reaction energies, and type of reaction, the energy differences of tetrahedral intermediate forms as compared to their separated systems were close to each other with the energy difference of ca. 4 kcal mol−1. These results clearly indicated why both conformations existed in the crystal structure. The bond energy also showed the important interaction to the amino acids and role of water molecules in the active site. Furthermore, according to the high correlation between the changes of bond distance and bond energy, it was found that the BEDA technique is useful to study the binding mechanism.
Design and Synthesis of Gramicidin S Analogs with High Antibiotic Activity
Authors: Sato Kazuki , Yamaguchi Yoko , Nagai Ukon
Published: December 2012

Based on the β-turn preference of tetrapeptide sequences as analyzed by CD spectra of their chromophoric derivatives, 10 analogs of gramicidin S (GS) were designed and synthesized with general formula cyclo(–d-Leu1,1′–d-Lys2,2′–d-Leu3,3′–l-Pro4,4′–X5,5′–)2, where X is l-Asn, l-Ala, l-Leu, l-Phe, l-cyclohexylalanine, Gly, d-Ala, d-Leu, d-Phe, or d-cyclohexylalanine. Several analogs with high hydrophobicity showed antibiotic activity as strong as GS. CD spectra of the analogs with d-amino acid or Gly at the X position and their dinitrophenyl derivatives suggested that they have β-sheet conformation that is antipodal to that of GS.
Spectral Fitting of Action Spectra for Motions and Reactions of Single Molecules on Metal Surfaces
Authors: Motobayashi Kenta , Katano Satoshi , Kim Yousoo , Kawai Maki
Published: December 2012

We demonstrate the spectral fitting analysis of action spectroscopy with a scanning tunneling microscope (STM-AS) that enables us to determine the existence of two vibrational modes that overlap in energy and also the modes which exist in lower energy region than the actually observed spectral region. These hidden properties obtained only by spectral fitting are essential for the quantitative understanding of the action spectra. The assignment of vibrational signals in the analysis follows the approximate rule of which vibrational mode is active in STM-AS that was previously proposed based on the resonant tunneling model and supporting experimental results.
Kinetics of Charge Transfer through DNA across Guanine–Cytosine Repeats Intervened by Adenine–Thymine Base Pair(s)
Authors: Osakada Yasuko , Kawai Kiyohiko , Majima Tetsuro
Published: December 2012

Charge transfer (CT) in DNA has been studied extensively in the past decade. Several reasonable models, concerning delocalized charge over guanines (G’s) as well as localized charge on individual G’s, such as polaron and hopping mechanisms, are proposed based on theoretical and experimental research. It is likely that the dynamic nature of DNA such as electronic coupling and dynamic motion is important to promote this process. We previously reported the kinetic features of CT across the G and cytosine (C) repetitive sequence (GC repeats). Temperature-dependent experiments in GC repeats suggested the importance of the conformational flexibility and structure of DNA toward CT in DNA. In the present paper, we look further into the dynamic mechanisms of CT in DNA across GC repeats. Based on the nanosecond transient absorption measurement, we monitored the migration of a charge in DNA having GC repeats separated by A/T intervening base pair(s). Interestingly, the migration time of the charge varies depending on the position, where A/T base pair(s) are located among GC repeats. Thus, the data obtained here are not simply explained by G-hopping mechanisms, in which the charge localizes on individual G’s. These results possibly indicate that CT in DNA across GC repeats proceeds via delocalization of the charge over G’s to some extent, rather than localized G-hopping mechanisms.
Bioinspired Supramolecular Materials
Authors: Ikeda Masato
Published: December 2012

In biological systems, noncovalent interactions of molecular building blocks such as lipids, proteins, and nucleic acids play important roles in creating diverse complex structure and dynamic function. Inspired by such biological systems, we have designed a variety of functional supramolecular materials on the basis of self-assembly of covalently prefabricated small molecules. Among them, the following three topics are described in this account: (1) supramolecular self-assembled materials based on π-conjugated disk-shaped molecules, (2) supramolecular materials based on helical-shaped molecules, and (3) biofunctions of supramolecular materials based on amphiphilic molecules.
Plasmonic Photoelectrochemistry: Functional Materials Based on Photoinduced Reversible Redox Reactions of Metal Nanoparticles
Authors: Tatsuma Tetsu
Published: December 2012

Plasmonic metal nanoparticles absorb and scatter visible light due to localized surface plasmon resonance (LSPR). The optical properties including resonance wavelength and absorption intensity depend on particle size, shape, orientation, spacing, and dielectric environments. If silver nanoparticles are placed on TiO2, plasmonic excitation of the particles by visible or near-infrared light results in their oxidation due to plasmon-induced charge separation. Silver ions thus released are reduced back to silver nanoparticles by UV-excitation of TiO2. These pseudo-reversible processes induced by visible and UV light between silver nanoparticles and silver ions are applied to various photoelectrochemical devices and materials. Multicolor photochromism is a typical example, in which an ensemble of silver nanoparticles on TiO2 is colored by monochromated light to a color corresponding to the excitation wavelength. The use of silver nanorods allows infrared and polarization photochromism. The photoinduced oxidation is also applied to size, shape, and orientation control of silver nanoparticles. A photomorphing gel is an additional application of the reversible processes.
A Case of Breathlessness during Pregnancy: The Difficulty in Diagnosing Heart Failure
Authors: Snow Timothy A C , Wasywich Cara A , Stewart Fiona M
Published: December 2012

We present the case of a 33-year-old woman in her second pregnancy who was transferred to our unit following a one-month history of worsening fatigue and a three-day history of worsening symptoms of heart failure. Shortly after presentation she developed ventricular fibrillation and arrested. At an emergency caesarean section a placental abruption was noted and the baby was stillborn, unable to be resuscitated. The patient required a prolonged intensive and coronary care stay. Echocardiographic findings were consistent with dilated cardiomyopathy and as all investigations to ascertain a cause were negative she was diagnosed with peripartum cardiomyopathy. Her case highlights a potential fatal cause of breathlessness during pregnancy and the role of B-type natriuretic peptide to assist in the differential diagnosis of these cases.
Protein Analytical Assays for Diagnosing, Monitoring, and Choosing Treatment for Cancer Patients
Authors: Powers Alicia D. , Palecek Sean P.
Published: December 2012

Cancer treatment is often hindered by inadequate methods for diagnosing the disease or insufficient predictive capacity regarding therapeutic efficacy. Targeted cancer treatments, including Bcr‐Abl and EGFR kinase inhibitors, have increased survival for some cancer patients but are ineffective in other patients. In addition, many patients who initially respond to targeted inhibitor therapy develop resistance during the course of treatment. Molecular analysis of cancer cells has emerged as a means to tailor treatment to particular patients. While DNA analysis can provide important diagnostic information, protein analysis is particularly valuable because proteins are more direct mediators of normal and diseased cellular processes. In this review article, we discuss current and emerging protein assays for improving cancer treatment, including trends toward assay miniaturization and measurement of protein activity.
Applications of Nanotechnology in Bladder Cancer Therapy
Authors: Hsu Jong-Wei , King Michael R.
Published: December 2012

Effective therapies can prevent superficial bladder cancer from developing into muscle‐invasive stage or more severe stages which require radical cystectomy and negatively affect life quality. In terms of therapeutic approaches against superficial bladder cancer, intravesical (regional) therapy has several advantages over oral (systemic) therapy. Though urologists can directly deliver drugs to bladder lesions by intravesical instillation after transurethral resection, the efficacy of conventional drug delivery is usually low due to the bladder permeability barrier and bladder periodical discharge. Nanoparticles have been well developed as pharmaceutical carriers. By their versatile properties, nanoparticles can greatly improve the interactions between urothelium and drugs and also enhance the penetration of drugs into urothelium with lesions, which dramatically improves therapeutic efficacy. In this review, we discuss the advances of nanotechnology in bladder cancer therapy by different types of nanoparticles with different encapsulating materials.
Statistics‐Based Prediction Analysis for Head and Neck Cancer Tumor Deformation
Authors: Azimi Maryam , Kamrani Ali K. , Smadi Hazem J.
Published: December 2012

Most of the current radiation therapy planning systems, which are based on pre‐treatment Computer Tomography (CT) images, assume that the tumor geometry does not change during the course of treatment. However, tumor geometry is shown to be changing over time. We propose a methodology to monitor and predict daily size changes of head and neck cancer tumors during the entire radiation therapy period. Using collected patients′ CT scan data, MATLAB routines are developed to quantify the progressive geometric changes occurring in patients during radiation therapy. Regression analysis is implemented to develop predictive models for tumor size changes through entire period. The generated models are validated using leave‐one‐out cross validation. The proposed method will increase the accuracy of therapy and improve patient′s safety and quality of life by reducing the number of harmful unnecessary CT scans.
Analysis of Steel Structures in Fire with Force-Based Frame Elements
Authors: Jeffers Ann , Sotelino Elisa
Published: December 2012

This paper considers the extension of the force-based element formulation to simulate the nonlinear, temperature-dependent response of structural frames exposed to fire. The two-dimensional formulation presented here accounts for thermal expansion, temperature-dependent material properties, and residual stresses. The element utilizes a fiber discretization to simulate the gradual plastification of the section. Geometric nonlinearities are included through coordinate transformations of the corotational reference frame. Analyses of benchmark experimental tests demonstrate that the force-based element formulation is computationally stable and provides accurate results for structures exposed to fire. In addition, comparisons to traditional displacement-based elements indicate that the force-based element may offer improved computational efficiency because fewer elements are needed per member.
Strength Characteristics of Concrete Exposed to Elevated Temperatures and Cooled Under Different Regimes
Authors: Yaragal Subhash , Narayan K , S Adari
Published: December 2012

Concrete loses strength in the event of accidental fires. The residual strength of normal strength concrete is of vital importance for ascertaining serviceability of buildings after the event of fires. Strength loss in concrete is dependent on the temperature of exposure, its duration and the way it gets cooled. In this study concrete cubes of size 100 mm have been cast for M25 grade of concrete, 28 days water cured. The specimens were subjected to elevated temperatures of 150°C, 250°C, 350°C, 450°C and 550°C with a retention period of 1 hour. After 1 hour of exposure, specimens were allowed to cool under different cooling regimes to ambient temperature. Later their appearance, colour and cracks were observed and also weight losses were determined. Further, destructive tests were conducted to estimate residual compressive and split tensile strengths. Important performance changes have been presented and discussed. Split tensile strengths are related to compressive strengths for all the cases of cooling regimes.
Fire Performance of Corrosion-Damaged Reinforced Concrete Beams
Authors: Porcari Gian-Luca , Zalok Ehab , Isgor O.
Published: December 2012

This experimental study examines the effects of fire on corrosion-damaged reinforced concrete beams. Nine beams were cast with the same external dimensions and amount of reinforcement. Corrosion was induced in the beams by a constant current source. The beams were tested at constant service load while being exposed to the CAN/ULC-S101 time-temperature curve. The results indicated that the deflection of reinforced concrete beams increased during a fire exposure as the level of corrosion damage increased. The corrosion products within the pores of the concrete provided a limited insulating effect on the heat front penetration through the concrete cover. Temperature differential developed at the steel level was shown to help delay failure of the beams by the development of the axial thrust force. A major factor affecting the performance of corrosion damaged beams during a fire exposure was the ability of the concrete cover to remain in place.
Residual Compressive Stress-Strain Relationship for Concrete Subjected to Elevated Temperatures
Authors: Sharma Umesh , Zaidi Kaleem , Bhandari Navratan
Published: December 2012

This study attempts to investigate the post-fire residual stress-strain behaviour of unconfined plain and fibrous concretes under axial compression. The experimental variables of the study were concrete strength levels, volume fractions of flat crimped steel fibres and polypropylene fibres, inclusion of hybrid fibres and temperature of exposure. A total of 147 cylindrical specimens (150 x 450 mm) were cast and tested under this study. The specimens were first exposed to temperatures ranging from room temperature to 800°C and then tested under uni-axial compression after cooling to obtain complete residual stress-strain response. Based on the test data obtained, a simple empirical model is proposed to describe the complete residual stress-strain relationships of plain and fibre reinforced concrete after exposure at elevated temperatures. Important observations have been made in the paper about the influence of temperature on various mechanical properties namely strength, stress-strain curves, compressive toughness and modulus of elasticity of both plain and fibrous concretes.
Exploitation of Ambiguous Cues to Infer Terrorist Activity
Authors: Ni Kevin S. , Faissol Daniel , Edmunds Thomas , Wheeler Richard
Published: December 2012

To aid intelligence analysts in processing ambiguous data regarding nuclear terrorism threats, we develop a methodology that captures and accounts for the uncertainty in new information and incorporates prior beliefs on likely nuclear terrorist activity. This methodology can guide the analyst when making difficult decisions regarding what data are most critical to examine and what threats require greater attention. Our methodology is based on a Bayesian statistical approach that incorporates ambiguous cues to update prior beliefs of adversary activity. We characterize the general process of a nuclear terrorist attack on the United States and describe, using a simplified example, how this can be represented by an event tree. We then define hypothetical cues for the example and give notional strengths to each cue. We also perform sensitivity analysis and show how cue strengths can affect inference. The method can be used to help support decisions regarding resource allocation and interdiction.
Ascending Combinatorial Auctions with Allocation Constraints: On Game Theoretical and Computational Properties of Generic Pricing Rules
Authors: Petrakis Ioannis , Ziegler Georg , Bichler Martin
Published: December 2012

Combinatorial auctions are used in a variety of application domains, such as transportation or industrial procurement, using a variety of bidding languages and different allocation constraints. This flexibility in the bidding languages and the allocation constraints is essential in these domains but has not been considered in the theoretical literature so far. In this paper, we analyze different pricing rules for ascending combinatorial auctions that allow for such flexibility: winning levels and deadness levels. We determine the computational complexity of these pricing rules and show that deadness levels actually satisfy an ex post equilibrium, whereas winning levels do not allow for a strong game theoretical solution concept. We investigate the relationship of deadness levels and the simple price update rules used in efficient ascending combinatorial auction formats. We show that ascending combinatorial auctions with deadness level pricing rules maintain a strong game theoretical solution concept and reduce the number of bids and rounds required at the expense of higher computational effort. The calculation of exact deadness levels is a [Formula: see text]-complete problem. Nevertheless, numerical experiments show that for mid-sized auctions this is a feasible approach. The paper provides a foundation for allocation constraints in combinatorial auctions and a theoretical framework for recent Information Systems contributions in this field.
Social Media and Firm Equity Value
Authors: Luo Xueming , Zhang Jie , Duan Wenjing
Published: December 2012

Companies have increasingly advocated social media technologies to transform businesses and improve organizational performance. This study scrutinizes the predictive relationships between social media and firm equity value, the relative effects of social media metrics compared with conventional online behavioral metrics, and the dynamics of these relationships. The results derived from vector autoregressive models suggest that social media-based metrics (Web blogs and consumer ratings) are significant leading indicators of firm equity value. Interestingly, conventional online behavioral metrics (Google searches and Web traffic) are found to have a significant yet substantially weaker predictive relationship with firm equity value than social media metrics. We also find that social media has a faster predictive value, i.e., shorter “wear-in” time, than conventional online media. These findings are robust to a consistent set of volume-based measures (total blog posts, rating volume, total page views, and search intensity). Collectively, this study proffers new insights for senior executives with respect to firm equity valuations and the transformative power of social media.
Engineering Optimal Network Effects via Social Media Features and Seeding in Markets for Digital Goods and Services
Authors: Dou Yifan , Niculescu Marius F. , Wu D. J.
Published: December 2012

Firms nowadays are increasingly proactive in trying to strategically capitalize on consumer networks and social interactions. In this paper, we complement an emerging body of research on the engineering of word-of-mouth effects by exploring a different angle through which firms can strategically exploit the value-generation potential of the user network. Namely, we consider how software firms should optimize the strength of network effects at utility level by adjusting the level of embedded social media features in tandem with the right market seeding and pricing strategies in the presence of seeding disutility. We explore two opposing seeding cost models where seeding-induced disutility can be either positively or negatively correlated with customer type. We consider both complete and incomplete information scenarios for the firm. Under complete information, we uncover a complementarity relationship between seeding and building social media features that holds for both disutility models. When the cost of any of these actions increases, rather than compensating by a stronger action on the other dimension to restore the overall level of network effects, the firm will actually scale back on the other initiative as well. Under incomplete information, this complementarity holds when seeding disutility is negatively correlated with customer type but may not always hold in the other disutility model, potentially leading to fundamentally different optimal strategies. We also discuss how our insights apply to asymmetric networks.