bluuebunny/crossref_metadata_2025 huggingface dataset:
Fiscal Federalism and Long-Run Macroeconomic Performance: A Survey of Recent Research
Authors: Feld Lars P , Schnellenbach Jan
Published: April 2011

In this paper we offer both a broad survey of the literature on fiscal federalism and long-run economic performance, and a detailed report of some of our own recent studies in this field. We look at the difference between study types (cross-country versus single-country studies), and at the relevance of the broader institutional framework into which fiscal decentralization is embedded. We also look into structural change and intergovernmental transfers as a detailed mechanism through which federalism may have an impact on aggregate economic performance. It turns out that fiscal decentralization has no robust effect on growth, but the evidence hints at a positive effect on overall productivity, conditional on the broader institutional framework.
Decentralization and Corruption: New Cross-Country Evidence
Authors: Ivanyna Maksym , Shah Anwar
Published: April 2011

We attempt to improve the understanding and measurement of decentralization and its relationship with corruption in a worldwide context. This is done by presenting the conceptual underpinnings of such a relationship as well as using more defensible measures of both decentralization in its various dimensions as well as corruption for a sample of 158 countries. It is the first paper that treats various tiers of local governments (below the intermediate order of government) as the unit of comparative analysis. By pursuing rigorous econometric analysis we demonstrate that decentralization, when properly measured to mean moving government closer to people by empowering local governments, is shown to have a significant negative effect on the incidence of corruption regardless of the choice of the estimation procedures or the measures of corruption used. In terms of various dimensions of decentralized local governance, political decentralization matters even when we control for fiscal decentralization. Further voice (political accountability) is empirically shown to be more important in combating corruption than exit options made available though competition among jurisdictions.
AMP kinase-related kinase NUAK2 affects tumor growth, migration, and clinical outcome of human melanoma
Authors: Namiki Takeshi , Tanemura Atsushi , Valencia Julio C. , Coelho Sergio G. , Passeron Thierry , Kawaguchi Masakazu , Vieira Wilfred D. , Ishikawa Masashi , Nishijima Wataru , Izumo Toshiyuki , Kaneko Yasuhiko , Katayama Ichiro , Yamaguchi Yuji , Yin Lanlan , Polley Eric C. , Liu Hongfang , Kawakami Yutaka , Eishi Yoshinobu , Takahashi Eishi , Yokozeki Hiroo , Hearing Vincent J.
Published: April 2011

The identification of genes that participate in melanomagenesis should suggest strategies for developing therapeutic modalities. We used a public array comparative genomic hybridization (CGH) database and real-time quantitative PCR (qPCR) analyses to identify the AMP kinase (AMPK)-related kinase
NUAK2
as a candidate gene for melanomagenesis, and we analyzed its functions in melanoma cells. Our analyses had identified a locus at 1q32 where genomic gain is strongly associated with tumor thickness, and we used real-time qPCR analyses and regression analyses to identify
NUAK2
as a candidate gene at that locus. Associations of relapse-free survival and overall survival of 92 primary melanoma patients with NUAK2 expression measured using immunohistochemistry were investigated using Kaplan–Meier curves, log rank tests, and Cox regression models. Knockdown of NUAK2 induces senescence and reduces S-phase, decreases migration, and down-regulates expression of mammalian target of rapamycin (mTOR). In vivo analysis demonstrated that knockdown of NUAK2 suppresses melanoma tumor growth in mice. Survival analysis showed that the risk of relapse is greater in acral melanoma patients with high levels of NUAK2 expression than in acral melanoma patients with low levels of NUAK2 expression (hazard ratio = 3.88; 95% confidence interval = 1.44–10.50;
P
= 0.0075). These data demonstrate that NUAK2 expression is significantly associated with the oncogenic features of melanoma cells and with the survival of acral melanoma patients. NUAK2 may provide a drug target to suppress melanoma progression. This study further supports the importance of NUAK2 in cancer development and tumor progression, while AMPK has antioncogenic properties.
Transmission of endoplasmic reticulum stress and pro-inflammation from tumor cells to myeloid cells
Authors: Mahadevan Navin R. , Rodvold Jeffrey , Sepulveda Homero , Rossi Steven , Drew Angela F. , Zanetti Maurizio
Published: April 2011

Metabolic, infectious, and tumor cell-intrinsic
noxae
can all evoke the endoplasmic reticulum (ER) stress response in tumor cells, which is critical for tumor cell growth and cancer progression. Evidence exists that the ER stress response can drive a proinflammatory program in tumor cells and macrophages but, to our knowledge, a role for the tumor ER stress response in influencing macrophages and inflammation in the tumor microenvironment has not been suggested. Here we show that macrophages cultured in conditioned medium from ER-stressed tumor cells become activated, and themselves undergo ER stress with the up-regulation of
Grp78
,
Gadd34
,
Chop,
and
Xbp-1
splicing, suggesting a general activation of the ER stress-signaling pathways. Furthermore, these macrophages recapitulate, amplify and expand the proinflammatory response of tumor cells. We term this phenomenon “transmissible” ER stress. Although neither Toll-like receptor (TLR)2 nor interleukin 6 receptor (IL6R) signaling is involved, a reduction was observed in the transmission of ER stress to TLR4 KO macrophages, consistent with the fact that a second signal through TLR4 combined with exposure to tumor ER stress-conditioned medium results in a faster ER stress response and an enhancement of proinflammatory cytokine production in macrophages. The injection of tumor ER stress-conditioned medium into WT mice elicited a generalized ER stress response in the liver. We suggest that transmissible ER stress is a mechanism through which tumor cells can control myeloid cells by directing them toward a proinflammatory phenotype, thus facilitating tumor progression.
Experimental illumination of a fitness landscape
Authors: Hietpas Ryan T. , Jensen Jeffrey D. , Bolon Daniel N. A.
Published: April 2011

The genes of all organisms have been shaped by selective pressures. The relationship between gene sequence and fitness has tremendous implications for understanding both evolutionary processes and functional constraints on the encoded proteins. Here, we have exploited deep sequencing technology to experimentally determine the fitness of all possible individual point mutants under controlled conditions for a nine-amino acid region of Hsp90. Over the past five decades, limited glimpses into the relationship between gene sequence and function have sparked a long debate regarding the distribution, relative proportion, and evolutionary significance of deleterious, neutral, and advantageous mutations. Our systematic experimental measurement of fitness effects of Hsp90 mutants in yeast, evaluated in the light of existing population genetic theory, are remarkably consistent with a nearly neutral model of molecular evolution.
Quantum nature of the hydrogen bond
Authors: Li Xin-Zheng , Walker Brent , Michaelides Angelos
Published: April 2011

Hydrogen bonds are weak, generally intermolecular bonds, which hold much of soft matter together as well as the condensed phases of water, network liquids, and many ferroelectric crystals. The small mass of hydrogen means that they are inherently quantum mechanical in nature, and effects such as zero-point motion and tunneling must be considered, though all too often these effects are not considered. As a prominent example, a clear picture for the impact of quantum nuclear effects on the strength of hydrogen bonds and consequently the structure of hydrogen bonded systems is still absent. Here, we report ab initio path integral molecular dynamics studies on the quantum nature of the hydrogen bond. Through a systematic examination of a wide range of hydrogen bonded systems we show that quantum nuclear effects weaken weak hydrogen bonds but strengthen relatively strong ones. This simple correlation arises from a competition between anharmonic intermolecular bond bending and intramolecular bond stretching. A simple rule of thumb is provided that enables predictions to be made for hydrogen bonded materials in general with merely classical knowledge (such as hydrogen bond strength or hydrogen bond length). Our work rationalizes the influence of quantum nuclear effects, which can result in either weakening or strengthening of the hydrogen bonds, and the corresponding structures, across a broad range of hydrogen bonded materials. Furthermore, it highlights the need to allow flexible molecules when anharmonic potentials are used in force field-based studies of quantum nuclear effects.
Magnetic evidence for a partially differentiated carbonaceous chondrite parent body
Authors: Carporzen Laurent , Weiss Benjamin P. , Elkins-Tanton Linda T. , Shuster David L. , Ebel Denton , Gattacceca Jérôme
Published: April 2011

The textures of chondritic meteorites demonstrate that they are not the products of planetary melting processes. This has long been interpreted as evidence that chondrite parent bodies never experienced large-scale melting. As a result, the paleomagnetism of the CV carbonaceous chondrite Allende, most of which was acquired after accretion of the parent body, has been a long-standing mystery. The possibility of a core dynamo like that known for achondrite parent bodies has been discounted because chondrite parent bodies are assumed to be undifferentiated. Resolution of this conundrum requires a determination of the age and timescale over which Allende acquired its magnetization. Here, we report that Allende’s magnetization was acquired over several million years (Ma) during metasomatism on the parent planetesimal in a >  ∼ 20 μT field up to approximately 9—10 Ma after solar system formation. This field was present too recently and directionally stable for too long to have been generated by the protoplanetary disk or young Sun. The field intensity is in the range expected for planetesimal core dynamos, suggesting that CV chondrites are derived from the outer, unmelted layer of a partially differentiated body with a convecting metallic core.
Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y
2
receptor stimulation through S-nitrosylation of NF-κB
Authors: Nishida Motohiro , Ogushi Mariko , Suda Reiko , Toyotaka Miyuki , Saiki Shota , Kitajima Naoyuki , Nakaya Michio , Kim Kyeong-Man , Ide Tomomi , Sato Yoji , Inoue Kazuhide , Kurose Hitoshi
Published: April 2011

Cross-talk between G protein-coupled receptor (GPCR) signaling pathways serves to fine tune cellular responsiveness by neurohumoral factors. Accumulating evidence has implicated nitric oxide (NO)-based signaling downstream of GPCRs, but the molecular details are unknown. Here, we show that adenosine triphosphate (ATP) decreases angiotensin type 1 receptor (AT
1
R) density through NO-mediated S-nitrosylation of nuclear factor κB (NF-κB) in rat cardiac fibroblasts. Stimulation of purinergic P2Y
2
receptor by ATP increased expression of inducible NO synthase (iNOS) through activation of nuclear factor of activated T cells, NFATc1 and NFATc3. The ATP-induced iNOS interacted with p65 subunit of NF-κB in the cytosol through flavin-binding domain, which was indispensable for the locally generated NO-mediated S-nitrosylation of p65 at Cys38. β-Arrestins anchored the formation of p65/IκBα/β-arrestins/iNOS quaternary complex. The S-nitrosylated p65 resulted in decreases in NF-κB transcriptional activity and AT
1
R density. In pressure-overloaded mouse hearts, ATP released from cardiomyocytes led to decrease in AT
1
R density through iNOS-mediated S-nitrosylation of p65. These results show a unique regulatory mechanism of heterologous regulation of GPCRs in which cysteine modification of transcriptional factor rather than protein phosphorylation plays essential roles.
Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase
Authors: Hicklin Tianna R. , Wu Peter H. , Radcliffe Richard A. , Freund Ronald K. , Goebel-Goody Susan M. , Correa Paulo R. , Proctor William R. , Lombroso Paul J. , Browning Michael D.
Published: April 2011

Alcohol's deleterious effects on memory are well known. Acute alcohol-induced memory loss is thought to occur via inhibition of NMDA receptor (NMDAR)-dependent long-term potentiation in the hippocampus. We reported previously that ethanol inhibition of NMDAR function and long-term potentiation is correlated with a reduction in the phosphorylation of Tyr
1472
on the NR2B subunit and ethanol's inhibition of the NMDAR field excitatory postsynaptic potential was attenuated by a broad spectrum tyrosine phosphatase inhibitor. These data suggested that ethanol's inhibitory effect may involve protein tyrosine phosphatases. Here we demonstrate that the loss of striatal-enriched protein tyrosine phosphatase (STEP) renders NMDAR function, phosphorylation, and long-term potentiation, as well as fear conditioning, less sensitive to ethanol inhibition. Moreover, the ethanol inhibition was “rescued” when the active STEP protein was reintroduced into the cells. Taken together, our data suggest that STEP contributes to ethanol inhibition of NMDAR function via dephosphorylation of tyrosine sites on NR2B receptors and lend support to the hypothesis that STEP may be required for ethanol's amnesic effects.
Intracellular invasion of green algae in a salamander host
Authors: Kerney Ryan , Kim Eunsoo , Hangarter Roger P. , Heiss Aaron A. , Bishop Cory D. , Hall Brian K.
Published: April 2011

The association between embryos of the spotted salamander (
Ambystoma maculatum
) and green algae (“
Oophila amblystomatis
” Lamber ex Printz) has been considered an ectosymbiotic mutualism. We show here, however, that this symbiosis is more intimate than previously reported. A combination of imaging and algal 18S rDNA amplification reveals algal invasion of embryonic salamander tissues and cells during development. Algal cells are detectable from embryonic and larval Stages 26–44 through chlorophyll autofluorescence and algal 18S rDNA amplification. Algal cell ultrastructure indicates both degradation and putative encystment during the process of tissue and cellular invasion. Fewer algal cells were detected in later-stage larvae through FISH, suggesting that the decline in autofluorescent cells is primarily due to algal cell death within the host. However, early embryonic egg capsules also contained encysted algal cells on the inner capsule wall, and algal 18S rDNA was amplified from adult reproductive tracts, consistent with oviductal transmission of algae from one salamander generation to the next. The invasion of algae into salamander host tissues and cells represents a unique association between a vertebrate and a eukaryotic alga, with implications for research into cell–cell recognition, possible exchange of metabolites or DNA, and potential congruence between host and symbiont population structures.
Late Miocene to Pliocene carbon isotope record of differential diet change among East African herbivores
Authors: Uno Kevin T. , Cerling Thure E. , Harris John M. , Kunimatsu Yutaka , Leakey Meave G. , Nakatsukasa Masato , Nakaya Hideo
Published: April 2011

Stable isotope and molecular data suggest that C
4
grasses first appeared globally in the Oligocene. In East Africa, stable isotope data from pedogenic carbonate and fossil tooth enamel suggest a first appearance between 15–10 Ma and subsequent expansion during the Plio-Pleistocene. The fossil enamel record has the potential to provide detailed information about the rates of dietary adaptation to this new resource among different herbivore lineages. We present carbon isotope data from 452 fossil teeth that record differential rates of diet change from C
3
to mixed C
3
/C
4
or C
4
diets among East African herbivore families at seven different time periods during the Late Miocene to the Pliocene (9.9–3.2 Ma). Significant amounts of C
4
grasses were present in equid diets beginning at 9.9 Ma and in rhinocerotid diets by 9.6 Ma, although there is no isotopic evidence for expansive C
4
grasslands in this part of the Late Miocene. Bovids and hippopotamids followed suit with individuals that had C
4
-dominated (>65%) diets by 7.4 Ma. Suids adopted C
4
-dominated diets between 6.5 and 4.2 Ma. Gomphotheriids and elephantids had mostly C
3
-dominated diets through 9.3 Ma, but became dedicated C
4
grazers by 6.5 Ma. Deinotheriids and giraffids maintained a predominantly C
3
diet throughout the record. The sequence of differential diet change among herbivore lineages provides ecological insight into a key period of hominid evolution and valuable information for future studies that focus on morphological changes associated with diet change.
Site-specific integrase-mediated transgenesis in mice via pronuclear injection
Authors: Tasic Bosiljka , Hippenmeyer Simon , Wang Charlene , Gamboa Matthew , Zong Hui , Chen-Tsai Yanru , Luo Liqun
Published: April 2011

Microinjection of recombinant DNA into zygotic pronuclei has been widely used for producing transgenic mice. However, with this method, the insertion site, integrity, and copy number of the transgene cannot be controlled. Here, we present an integrase-based approach to produce transgenic mice via pronuclear injection, whereby an intact single-copy transgene can be inserted into predetermined chromosomal loci with high efficiency (up to 40%), and faithfully transmitted through generations. We show that neighboring transgenic elements and bacterial DNA within the transgene cause profound silencing and expression variability of the transgenic marker. Removal of these undesirable elements leads to global high-level marker expression from transgenes driven by a ubiquitous promoter. We also obtained faithful marker expression from a tissue-specific promoter. The technique presented here will greatly facilitate murine transgenesis and precise structure/function dissection of mammalian gene function and regulation in vivo.
Impact of gene expression noise on organismal fitness and the efficacy of natural selection
Authors: Wang Zhi , Zhang Jianzhi
Published: April 2011

Gene expression noise is a universal phenomenon across all life forms. Although beneficial under certain circumstances, expression noise is generally thought to be deleterious. However, neither the magnitude of the deleterious effect nor the primary mechanism of this effect is known. Here, we model the impact of expression noise on the fitness of unicellular organisms by considering the influence of suboptimal expressions of enzymes on the rate of biomass production and the energetic cost associated with imprecise amounts of protein synthesis. Our theoretical modeling and empirical analysis of yeast data show four findings. (
i
) Expression noise reduces the mean fitness of a cell by at least 25%, and this reduction cannot be substantially alleviated by gene overexpression. (
ii
) Higher sensitivity of fitness to the expression fluctuations of essential genes than nonessential genes creates stronger selection against noise in essential genes, resulting in a decrease in their noise. (
iii
) Reduction of expression noise by genome doubling offers a substantial fitness advantage to diploids over haploids, even in the absence of sex. (
iv
) Expression noise generates fitness variation among isogenic cells, which lowers the efficacy of natural selection similar to the effect of population shrinkage. Thus, expression noise renders organisms both less adapted and less adaptable. Because expression noise is only one of many manifestations of the stochasticity in cellular molecular processes, our results suggest a much more fundamental role of molecular stochasticity in evolution than is currently appreciated.
Algae and humans share a molybdate transporter
Authors: Tejada-Jiménez Manuel , Galván Aurora , Fernández Emilio
Published: April 2011

Almost all living organisms need to obtain molybdenum from the external medium to achieve essential processes for life. Activity of important enzymes such as sulfite oxidase, aldehyde oxidase, xanthine dehydrogenase, and nitrate reductase is strictly dependent on the presence of Mo in its active site. Cells take up Mo in the form of the oxianion molybdate, but the molecular nature of the transporters is still not well known in eukaryotes. MOT1 is the first molybdate transporter identified in plant-type eukaryotic organisms, but it is absent in animal genomes. Here we report a molybdate transporter different from the MOT1 family, encoded by the
Chlamydomonas reinhardtii
gene
MoT2
, that is also present in animals including humans. The knockdown of
CrMoT2
transcription leads to the deficiency of molybdate uptake activity in
Chlamydomonas
. In addition, heterologous expression in
Saccharomyces cerevisiae
of
MoT2
genes from
Chlamydomonas
and humans support the functionality of both proteins as molybdate transporters. Characterization of CrMOT2 and HsMOT2 activities showed an apparent Km of about 550 nM that, though higher than the Km reported for MOT1, still corresponds to high affinity systems.
CrMoT2
transcription is activated when extracellular molybdate concentration is low but in contrast to
MoT1
is not activated by nitrate. Analysis of protein databases revealed the presence of four motifs present in all the proteins with high similarity to MOT2, that label a previously undescribed family of proteins probably related to molybdate transport. Our results open the way toward the understanding of molybdate transport as part of molybdenum homeostasis and Moco biosynthesis in animals.
Organic synthesis toward small-molecule probes and drugs
Authors: Schreiber Stuart L.
Published: April 2011

“Organic synthesis” is a compound-creating activity often focused on biologically active small molecules. This special issue of PNAS explores innovations and trends in the field that are enabling the synthesis of new types of small-molecule probes and drugs. This perspective article frames the research described in the special issue but also explores how these modern capabilities can both foster a new and more extensive view of basic research in the academy and promote the linkage of life-science research to the discovery of novel types of small-molecule therapeutics [Schreiber SL (2009)
Chem Bio Chem
10:26–29]. This new view of basic research aims to bridge the chasm between basic scientific discoveries in life sciences and new drugs that treat the root cause of human disease—recently referred to as the “valley of death” for drug discovery. This perspective article describes new roles that modern organic chemistry will need to play in overcoming this challenge.
Learning new color names produces rapid increase in gray matter in the intact adult human cortex
Authors: Kwok Veronica , Niu Zhendong , Kay Paul , Zhou Ke , Mo Lei , Jin Zhen , So Kwok-Fai , Tan Li Hai
Published: April 2011

The human brain has been shown to exhibit changes in the volume and density of gray matter as a result of training over periods of several weeks or longer. We show that these changes can be induced much faster by using a training method that is claimed to simulate the rapid learning of word meanings by children. Using whole-brain magnetic resonance imaging (MRI) we show that learning newly defined and named subcategories of the universal categories green and blue in a period of 2 h increases the volume of gray matter in V2/3 of the left visual cortex, a region known to mediate color vision. This pattern of findings demonstrates that the anatomical structure of the adult human brain can change very quickly, specifically during the acquisition of new, named categories. Also, prior behavioral and neuroimaging research has shown that differences between languages in the boundaries of named color categories influence the categorical perception of color, as assessed by judgments of relative similarity, by response time in alternative forced-choice tasks, and by visual search. Moreover, further behavioral studies (visual search) and brain imaging studies have suggested strongly that the categorical effect of language on color processing is left-lateralized, i.e., mediated by activity in the left cerebral hemisphere in adults (hence “lateralized Whorfian” effects). The present results appear to provide a structural basis in the brain for the behavioral and neurophysiologically observed indices of these Whorfian effects on color processing.
Genetic correction and analysis of induced pluripotent stem cells from a patient with gyrate atrophy
Authors: Howden Sara E. , Gore Athurva , Li Zhe , Fung Ho-Lim , Nisler Benjamin S. , Nie Jeff , Chen Goukai , McIntosh Brian E. , Gulbranson Daniel R. , Diol Nicole R. , Taapken Seth M. , Vereide David T. , Montgomery Karen Dyer , Zhang Kun , Gamm David M. , Thomson James A.
Published: April 2011

Gene-corrected patient-specific induced pluripotent stem (iPS) cells offer a unique approach to gene therapy. Here, we begin to assess whether the mutational load acquired during gene correction of iPS cells is compatible with use in the treatment of genetic causes of retinal degenerative disease. We isolated iPS cells free of transgene sequences from a patient with gyrate atrophy caused by a point mutation in the gene encoding ornithine-δ-aminotransferase (
OAT
) and used homologous recombination to correct the genetic defect. Cytogenetic analysis, array comparative genomic hybridization (aCGH), and exome sequencing were performed to assess the genomic integrity of an iPS cell line after three sequential clonal events: initial reprogramming, gene targeting, and subsequent removal of a selection cassette. No abnormalities were detected after standard G-band metaphase analysis. However, aCGH and exome sequencing identified two deletions, one amplification, and nine mutations in protein coding regions in the initial iPS cell clone. Except for the targeted correction of the single nucleotide in the
OAT
locus and a single synonymous base-pair change, no additional mutations or copy number variation were identified in iPS cells after the two subsequent clonal events. These findings confirm that iPS cells themselves may carry a significant mutational load at initial isolation, but that the clonal events and prolonged cultured required for correction of a genetic defect can be accomplished without a substantial increase in mutational burden.
Plastid gene expression and plant development require a plastidic protein of the mitochondrial transcription termination factor family
Authors: Babiychuk Elena , Vandepoele Klaas , Wissing Josef , Garcia-Diaz Miguel , De Rycke Riet , Akbari Hana , Joubès Jérôme , Beeckman Tom , Jänsch Lothar , Frentzen Margrit , Van Montagu Marc C. E. , Kushnir Sergei
Published: April 2011

Plastids are DNA-containing organelles unique to plant cells. In
Arabidopsis
, one-third of the genes required for embryo development encode plastid-localized proteins. To help understand the role of plastids in embryogenesis and postembryonic development, we characterized proteins of the mitochondrial transcription termination factor (mTERF) family, which in animal models, comprises DNA-binding regulators of mitochondrial transcription. Of 35
Arabidopsis
mTERF proteins, 11 are plastid-localized. Genetic complementation shows that at least one plastidic mTERF, BELAYA SMERT' (BSM), is required for embryogenesis. The main postembryonic phenotypes of genetic mosaics with the
bsm
mutation are severe abnormalities in leaf development. Mutant
bsm
cells are albino, are compromised in growth, and suffer defects in global plastidic gene expression. The
bsm
phenotype could be phenocopied by inhibition of plastid translation with spectinomycin. Plastid translation is essential for cell viability in dicotyledonous species such as tobacco but not in monocotyledonous maize. Here, genetic interactions between
BSM
and the gene encoding plastid homomeric acetyl-CoA carboxylase ACC2 suggest that there is a functional redundancy in malonyl-CoA biosynthesis that permits
bsm
cell survival in
Arabidopsis
. Overall, our results indicate that biosynthesis of malonyl-CoA and plastid-derived systemic growth-promoting compounds are the processes that link plant development and plastid gene expression.
Targeting kidney mesangium by nanoparticles of defined size
Authors: Choi Chung Hang J. , Zuckerman Jonathan E. , Webster Paul , Davis Mark E.
Published: April 2011

Nanoparticles are being investigated for numerous medical applications and are showing potential as an emerging class of carriers for drug delivery. Investigations on how the physicochemical properties (e.g., size, surface charge, shape, and density of targeting ligands) of nanoparticles enable their ability to overcome biological barriers and reach designated cellular destinations in sufficient amounts to elicit biological efficacy are of interest. Despite proven success in nanoparticle accumulation at cellular locations and occurrence of downstream therapeutic effects (e.g., target gene inhibition) in a selected few organs such as tumor and liver, reports on effective delivery of engineered nanoparticles to other organs still remain scarce. Here, we show that nanoparticles of ~75 ± 25-nm diameters target the mesangium of the kidney. These data show the effects of particle diameter on targeting the mesangium of the kidney. Because many diseases originate from this area of the kidney, our findings establish design criteria for constructing nanoparticle-based therapeutics for targeting diseases that involve the mesangium of the kidney.
Differential transformation capacity of Src family kinases during the initiation of prostate cancer
Authors: Cai Houjian , Smith Daniel A. , Memarzadeh Sanaz , Lowell Clifford A. , Cooper Jonathan A. , Witte Owen N.
Published: April 2011

Src family kinases (SFKs) are pleiotropic activators that are responsible for integrating signal transduction for multiple receptors that regulate cellular proliferation, invasion, and metastasis in a variety of human cancers. Independent groups have identified increased expression of individual SFK members during prostate cancer progression, raising the question of whether SFKs display functional equivalence. Here, we show that Src kinase, followed by Fyn kinase and then Lyn kinase, exhibit ranked tumorigenic potential during both paracrine-induced and cell-autonomous–initiated prostate cancer. This quantitative variation in transformation potential appears to be regulated in part by posttranslational palmitoylation. Our data indicate that development of inhibitors against specific SFK members could provide unique targeted therapeutic strategies.
NFATc1 affects mouse splenic B cell function by controlling the calcineurin–NFAT signaling network
Authors: Bhattacharyya Sankar , Deb Jolly , Patra Amiya K. , Thuy Pham Duong Anh , Chen Wen , Vaeth Martin , Berberich-Siebelt Friederike , Klein-Hessling Stefan , Lamperti Edward D. , Reifenberg Kurt , Jellusova Julia , Schweizer Astrid , Nitschke Lars , Leich Ellen , Rosenwald Andreas , Brunner Cornelia , Engelmann Swen , Bommhardt Ursula , Avots Andris , Müller Martin R. , Kondo Eisaku , Serfling Edgar
Published: April 2011

By studying mice in which the Nfatc1 gene was inactivated in bone marrow, spleen, or germinal center B cells, we show that NFATc1 supports the proliferation and suppresses the activation-induced cell death of splenic B cells upon B cell receptor (BCR) stimulation. BCR triggering leads to expression of NFATc1/αA, a short isoform of NFATc1, in splenic B cells. NFATc1 ablation impaired Ig class switch to IgG3 induced by T cell–independent type II antigens, as well as IgG3+ plasmablast formation. Mice bearing NFATc1−/− B cells harbor twofold more interleukin 10–producing B cells. NFATc1−/− B cells suppress the synthesis of interferon-γ by T cells in vitro, and these mice exhibit a mild clinical course of experimental autoimmune encephalomyelitis. In large part, the defective functions of NFATc1−/− B cells are caused by decreased BCR-induced Ca2+ flux and calcineurin (Cn) activation. By affecting CD22, Rcan1, CnA, and NFATc1/αA expression, NFATc1 controls the Ca2+-dependent Cn–NFAT signaling network and, thereby, the fate of splenic B cells upon BCR stimulation.
Theory for island induced neoclassical toroidal plasma viscosity in tokamaks
Authors: Shaing K.C. , Tsai T.H. , Chu M.S. , Sabbagh S.A.
Published: April 2011

Error fields and resistive magnetohydrodynamic modes are ubiquitous in real tokamaks. They break the toroidal symmetry in |
B
| in tokamaks. Here,
B
is the magnetic field. There are two mechanisms that break the symmetry on the perturbed magnetic surface: one is the perturbed field itself and the other results from the distortion of the magnetic surface due to the perturbed field. The broken toroidal symmetry leads to enhanced neoclassical toroidal plasma viscosity and consequently the rate of the toroidal flow damping. The neoclassical toroidal plasma viscosity also results in a steady-state toroidal plasma flow. In addition, the neoclassical toroidal plasma viscosity in the vicinity of the magnetic islands provides a mechanism to determine the island rotation frequency, which is an important quantity for the island stability. Here, the theory for neoclassical toroidal plasma viscosity in the vicinity of the magnetic island is extended to include the effects of the collisional boundary layer that lead to
scaling in the transport fluxes, where ν is the collision frequency.
The Brauer group of moduli spaces of vector bundles over a real curve
Authors: Biswas Indranil , Hoffmann Norbert , Hogadi Amit , Schmitt Alexander
Published: April 2011

LetXXbe a geometrically connected smooth projective curve of genusgX≥2g_X \geq 2overR\mathbb {R}. LetM(r,ξ)M(r, \xi )be the coarse moduli space of geometrically stable vector bundlesEEoverXXof rankrrand determinantξ\xi, whereξ\xiis a real point of the Picard varietyPic_d(X)\underline {\mathrm {Pic}}^d( X). IfgX=r=2g_X = r = 2, then letddbe odd. We compute the Brauer group ofM(r,ξ)M(r,\xi ).
Planar loops with prescribed curvature: Existence, multiplicity and uniqueness results
Authors: Musina Roberta
Published: April 2011

Let

k
:

C

→

R

k:\mathbb {C}\to \mathbb {R}

be a smooth given function. A

k
k

-loop is a closed curve

u
u

in

C

\mathbb {C}

having prescribed curvature

k
(
p
)

k(p)

at every point

p
∈
u

p\in u

. We use variational methods to provide sufficient conditions for the existence of

k
k

-loops. Then we show that a breaking symmetry phenomenon may produce multiple

k
k

-loops, in particular when

k
k

is radially symmetric and somewhere increasing. If

k
>
0

k>0

is radially symmetric and non-increasing, we prove that any embedded

k
k

-loop is a circle; that is, round circles are the only convex loops in

C

\mathbb {C}

whose curvature is a non-increasing function of the Euclidean distance from a fixed point. The result is sharp, as there exist radially increasing curvatures

k
>
0

k>0

which have embedded

k
k

-loops that are not circles.
Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner
Authors: He Kunyan , Jang Sung-Wuk , Joshi Jayashree , Yoo Min-Heui , Ye Keqiang
Published: April 2011

UNC5B acts as a tumor suppressor, and it induces apoptosis in the absence of its cognate ligand netrins. UNC5B is a direct transcriptional target of p53 upon UV stimulation. Here we show that Akt phosphorylates PIKE-A and regulates its association with UNC5B and inhibits UNC5B-provoked apoptosis in a p53-dependent manner. PIKE-A GTPase binds active Akt and stimulates its kinase activity in a guanine-nucleotide–dependent way. Akt feeds back and phosphorylates PIKE-A on Ser-472 and subsequently enhances its stimulatory effect on Akt kinase activity. Akt activity is significantly reduced in PIKE −/− Mouse Embryonic Fibroblast (MEF) cells as compared to wild-type cells. PIKE-A directly interacts with UNC5B, which is regulated by netrin-1–activated Akt. Overexpression of PIKE-A diminishes UNC5B expression through down-regulation of p53. Knocking down PIKE-A stabilizes p53, increases UNC5B, and escalates UV-triggered apoptosis. Depletion of Akt abrogates PIKE-A's inhibitory effect on both p53 and UNC5B. Hence our findings support the notion that Akt-­phosphorylated PIKE-A inhibits UNC5B-elicited apoptosis and reduces its expression level through inactivation of p53.
Mitochondria can recognize and assemble fragments of a β-barrel structure
Authors: Müller Jonas E.N. , Papic Drazen , Ulrich Thomas , Grin Iwan , Schütz Monika , Oberhettinger Philipp , Tommassen Jan , Linke Dirk , Dimmer Kai S. , Autenrieth Ingo B. , Rapaport Doron
Published: April 2011

β-barrel proteins are found in the outer membranes of eukaryotic organelles of endosymbiotic origin as well as in the outer membrane of Gram-negative bacteria. Precursors of mitochondrial β-barrel proteins are synthesized in the cytosol and have to be targeted to the organelle. Currently, the signal that assures their specific targeting to mitochondria is poorly defined. To characterize the structural features needed for specific mitochondrial targeting and to test whether a full β-barrel structure is required, we expressed in yeast cells the β-barrel domain of the trimeric autotransporter Yersinia adhesin A (YadA). Trimeric autotransporters are found only in prokaryotes, where they are anchored to the outer membrane by a single 12-stranded β-barrel structure to which each monomer is contributing four β-strands. Importantly, we found that YadA is solely localized to the mitochondrial outer membrane, where it exists in a native trimeric conformation. These findings demonstrate that, rather than a linear sequence or a complete β-barrel structure, four β-strands are sufficient for the mitochondria to recognize and assemble a β-barrel protein. Remarkably, the evolutionary origin of mitochondria from bacteria enables them to import and assemble even proteins belonging to a class that is absent in eukaryotes.
Rigid substructure search
Authors: Shirvanyants David , Alexandrova Anastassia N. , Dokholyan Nikolay V.
Published: April 2011

Motivation: Identifying the location of binding sites on proteins is of fundamental importance for a wide range of applications, including molecular docking, de novo drug design, structure identification and comparison of functional sites. Here we present Erebus, a web server that searches the entire Protein Data Bank for a given substructure defined by a set of atoms of interest, such as the binding scaffolds for small molecules. The identified substructure contains atoms having the same names, belonging to same amino acids and separated by the same distances (within a given tolerance) as the atoms of the query structure. The accuracy of a match is measured by the root-mean-square deviation or by the normal weight with a given variance. Tests show that our approach can reliably locate rigid binding scaffolds of drugs and metal ions.

Availability and Implementation: We provide this service through a web server at http://erebus.dokhlab.org.

Contact:  dokh@unc.edu
ROS-DET: robust detector of switching mechanisms in gene expression
Authors: Kayano Mitsunori , Takigawa Ichigaku , Shiga Motoki , Tsuda Koji , Mamitsuka Hiroshi
Published: April 2011

A switching mechanism in gene expression, where two genes are positively correlated in one condition and negatively correlated in the other condition, is a key to elucidating complex biological systems. There already exist methods for detecting switching mechanisms from microarrays. However, current approaches have problems under three real cases: outliers, expression values with a very small range and a small number of examples. ROS-DET overcomes these three problems, keeping the computational complexity of current approaches. We demonstrated that ROS-DET outperformed existing methods, under that all these three situations are considered. Furthermore, for each of the top 10 pairs ranked by ROS-DET, we attempted to identify a pathway, i.e. consecutive biological phenomena, being related with the corresponding two genes by checking the biological literature. In 8 out of the 10 pairs, we found two parallel pathways, one of the two genes being in each of the two pathways and two pathways coming to (or starting with) the same gene. This indicates that two parallel pathways would be cooperatively used under one experimental condition, corresponding to the positive correlation, and the two pathways might be alternatively used under the other condition, corresponding to the negative correlation. ROS-DET is available from http://www.bic.kyoto-u.ac.jp/pathway/kayano/ros-det.htm.
Tenacibaculum dicentrarchi sp. nov., a marine bacterium of the family Flavobacteriaceae isolated from European sea bass
Authors: Piñeiro-Vidal Maximino , Gijón Daniel , Zarza Carles , Santos Ysabel
Published: April 2011

A novel Gram-stain-negative rod-shaped gliding bacterial strain, designated 35/09T, was isolated from diseased European sea bass (Dicentrarchus labrax L.) in Spain. Colonies were pale-yellow-pigmented with uneven edges and did not adhere to the agar. The DNA G+C content of the isolate was 31.3 mol%. 16S rRNA gene sequence analysis indicated affiliation to the genus Tenacibaculum (family Flavobacteriaceae, phylum ‘Bacteroidetes’). Sequence similarities between the isolate and type strains of other members of the genus were 93.1–97.3 %. The major fatty acids (>5 % of the total fatty acids) were iso-C15 : 0 (24.8 %), iso-C15 : 0 3-OH (18.0 %), anteiso-C15 : 0 (8.1 %), C15 : 1ω6c (6.9 %) and iso-C15 : 1 (6.2 %). Genotypic and phenotypic data indicate that strain 35/09T should be classified as a representative of a novel species in the genus Tenacibaculum, for which the name Tenacibaculum dicentrarchi sp. nov. is proposed; the type strain is 35/09T ( = CECT 7612T = NCIMB 14598T).
Pseudomonas litoralis sp. nov., isolated from Mediterranean seawater
Authors: Pascual Javier , Lucena Teresa , Ruvira María A. , Giordano Assunta , Gambacorta Agata , Garay Esperanza , Arahal David R. , Pujalte María J. , Macián M. Carmen
Published: April 2011

Strains 2SM5Tand 2SM6, two strictly aerobic chemo-organotrophic gammaproteobacteria, were isolated from Mediterranean seawater off the coast of Vinaroz, Castellón, Spain, in February, 1990. They were extensively characterized by a polyphasic study that placed them in the genusPseudomonas. Phylogenetic analysis of 16S rRNA gene sequences showed that both strains shared 100 % sequence similarity and were closely related to members of thePseudomonas pertucinogenaclade, with less than 97.3 % similarity to strains of established species;Pseudomonas xiamenensiswas the closest relative. Analysis of sequences of three housekeeping genes,rpoB,rpoDandgyrB, further confirmed the phylogenetic assignment of the Mediterranean isolates. Chemotaxonomic traits such as quinone and polar lipid composition also corroborated the placement of strains 2SM5Tand 2SM6 in the gammaproteobacteria. Other phenotypic traits, including fatty acid composition, enabled clear differentiation of both isolates from other species ofPseudomonas. We therefore conclude that strains 2SM5Tand 2SM6 represent a novel species ofPseudomonas, for which the namePseudomonas litoralisis proposed; the type strain is 2SM5T( = CECT 7670T = KCTC 23093T).
Telmatobacter bradus gen. nov., sp. nov., a cellulolytic facultative anaerobe from subdivision 1 of the Acidobacteria, and emended description of Acidobacterium capsulatum Kishimoto et al. 1991
Authors: Pankratov Timofey A. , Kirsanova Lilia A. , Kaparullina Elena N. , Kevbrin Vadim V. , Dedysh Svetlana N.
Published: April 2011

A Gram-negative, facultatively anaerobic, chemo-organotrophic, non-pigmented, slow-growing bacterium was isolated from acidic Sphagnum peat and designated strain TPB6017T. Cells of this strain were long rods that multiplied by normal cell division and were motile by means of a single flagellum. Cells grew under reduced oxygen tension and under anoxic conditions and were able to ferment sugars and several polysaccharides, including amorphous and crystalline cellulose. Strain TPB6017T was a psychrotolerant acidophile capable of growth between pH 3.0 and 7.5 (optimum 4.5–5.0) and at 4–35 °C (optimum 20–28 °C). It was extremely sensitive to salt stress; growth was inhibited at NaCl concentrations above 0.1 % (w/v). The major fatty acids were iso-C15 : 0 and iso-C17 : 1ω9c; the polar lipids were phosphatidylethanolamine and a number of phospholipids and aminophospholipids with an unknown structure. The quinone was MK-8. The DNA G+C content was 57.6 mol%. Comparative 16S rRNA gene sequence analysis revealed that strain TPB6017T was a member of subdivision 1 of the phylum Acidobacteria and belonged to a phylogenetic lineage defined by the acidophilic aerobic chemo-organotroph Acidobacterium capsulatum (92.3 % sequence similarity). However, cell morphology, type of flagellation, the absence of pigment, differences in fatty acid and polar lipid composition, possession of a cellulolytic capability, inability to grow under fully oxic conditions and good growth in anoxic conditions distinguished strain TPB6017T from A. capsulatum. Therefore, it is proposed that strain TPB6017T represents a novel acidobacterium species in a new genus, Telmatobacter bradus gen. nov., sp. nov.; strain TPB6017T ( = DSM 23630T = VKM B-2570T) is the type strain.
Algoriphagus jejuensis sp. nov., isolated from seawater
Authors: Lee Dong-Heon , Kahng Hyung-Yeel , Lee Sun Bok
Published: April 2011

A Gram-negative, pink-pigmented, non-motile, strictly aerobic rod, designated CNU040T, was isolated from seawater from the coast of Jeju Island in Korea. The temperature, pH and NaCl ranges for growth were 4–30 °C, pH 5.5–10.0 and 0–5.0 % NaCl. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain CNU040T belonged to a distinct lineage in the genus Algoriphagus and exhibited high sequence similarity with Algoriphagus terrigena DS-44T (98.3 %) and Algoriphagus alkaliphilus AC-74T (96.6 %) and lower sequence similarity (<96.0 %) with all other members of the genus Algoriphagus. DNA–DNA relatedness between strain CNU040T and A. terrigena KCTC 12545T was 44.5 %. The DNA G+C content of the isolate was 48.5 mol% and the major respiratory quinone was menaquinone-7. The major cellular fatty acids were iso-C15 : 0 (28.6 %) and summed feature 3 (consisting of iso-C15 : 0 2-OH and/or C16 : 1ω7c; 24.0 %). The polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, one unknown amino lipid, one unknown aminophospholipid and three unknown polar lipids. On the basis of phenotypic, phylogenetic and genotypic data, strain CNU040T represents a novel species within the genus Algoriphagus, for which the name Algoriphagus jejuensis sp. nov. is proposed. The type strain is CNU040T ( = KCTC 22647T  = JCM 16112T).