bluuebunny/crossref_metadata_2025 huggingface dataset:
GABA‐mediated spatial and temporal asymmetries that contribute to the directionally selective light responses of starburst amacrine cells in retina
Authors: Dmitriev Andrey V. , Gavrikov Konstantin E. , Mangel Stuart C.
Published: January 2012

Key points 

Starburst amacrine cells (SACs), interneurons that are essential to the generation of direction selectivity in the retina, depolarize to light stimuli that move centrifugally away from them, but hyperpolarize to stimuli that move centripetally towards them.

These directionally selective light responses are dependent on the differential distribution of the Cl− cotransporters NKCC (which mediates GABA‐evoked depolarizations by increasing intracellular Cl−) and KCC2 (which mediates GABA‐evoked hyperpolarizations by decreasing intracellular Cl−) on SAC proximal and distal dendrites, respectively.

We show computationally that directionally selective light responses can be produced in both starburst cell bodies and distal dendrites if (1) there is an intracellular Cl− concentration gradient along SAC dendrites and (2) the response of the dendrites to GABA is relatively long lasting.

The location of NKCC and KCC2 in different compartments of individual neuronal processes may be an important means by which the brain encodes information.
Ascorbate prevents placental oxidative stress and enhances birth weight in hypoxic pregnancy in rats
Authors: Richter H. G. , Camm E. J. , Modi B. N. , Naeem F. , Cross C. M. , Cindrova‐Davies T. , Spasic‐Boskovic O. , Dunster C. , Mudway I. S. , Kelly F. J. , Burton G. J. , Poston L. , Giussani D. A.
Published: January 2012

Key points 

High‐altitude pregnancy is associated with reduced oxygenation and placental complications, which can affect maternal and fetal outcome. However, most high‐altitude populations are also impoverished and because maternal undernutrition itself is known to promote placental problems, the extent to which complications during high‐altitude pregnancy could be due to maternal oxygen and/or nutrient restriction remains unclear.

The aim of the study was to investigate whether reduced placental oxygenation, independent of maternal undernutrition, increases maternal and placental oxidative stress and whether maternal treatment with vitamin C is protective.

The study shows that hypoxic pregnancy increased maternal circulating and placental molecular indices of oxidative stress.

Maternal vitamin C treatment was protective and increased birth weight.

The study offers insight to mechanism and intervention against the effects of high altitude on pregnancy.
Chronic maternal infusion of full‐length adiponectin in pregnant mice down‐regulates placental amino acid transporter activity and expression and decreases fetal growth
Authors: Rosario Fredrick J , Schumacher Michael A. , Jiang Jean , Kanai Yoshikatsu , Powell Theresa L. , Jansson Thomas
Published: January 2012

Key points 

Fetal growth is positively correlated to maternal adiposity, but the underlying mechanisms remain largely unknown.

Maternal circulating levels of adiponectin, a hormone secreted by adipose tissue, are negatively correlated to maternal adiposity and fetal growth, suggesting that maternal adiponectin may limit fetal growth.

Here we report that chronic administration of adiponectin to pregnant mice inhibits placental insulin and mammalian target of rapamycin (mTOR) signalling, down‐regulates the activity and expression of key placental nutrient transporters, and decreases fetal growth.

We have identified a novel physiological mechanism by which the endocrine functions of maternal adipose tissue influence fetal growth by altering placental function.

These findings may help us better understand the factors determining birth weight in normal pregnancies and in pregnancy complications associated with altered maternal adiponectin levels such as obesity and gestational diabetes.
PAS Kinase Promotes Cell Survival and Growth Through Activation of Rho1
Authors: Cardon Caleb M. , Beck Thomas , Hall Michael N. , Rutter Jared
Published: January 2012

The Rho1-activating complex formed by yPASK-phosphorylated Ugp1 enables yeast to overcome loss of Tor2 function.
Therapeutic Amprenavir Concentrations in Cerebrospinal Fluid
Authors: Croteau David , Letendre Scott , Best Brookie M. , Rossi Steven S. , Ellis Ronald J. , Clifford David B. , Collier Ann C. , Gelman Benjamin B. , Marra Christina M. , McArthur Justin , McCutchan J. Allen , Morgello Susan , Simpson David M. , Way Lauren , Capparelli Edmund , Grant Igor ,   for the CHARTER Group
Published: January 2012

Antiretrovirals that reach higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV in CSF and possibly better neurocognitive performance. The objective of this study was to determine whether amprenavir (APV) concentrations in CSF are in the therapeutic range. Individuals were selected based on the use of regimens that included fosamprenavir (FPV), a prodrug of APV, and the availability of stored CSF and matched plasma. Total APV was measured in 119 matched CSF-plasma pairs from 75 subjects by high-performance liquid chromatography (HPLC) (plasma) or liquid chromatography tandem mass spectrometry (LC/MS/MS) (CSF). Concentrations were compared to the 50% inhibitory concentration (IC
50
) for wild-type HIV (5.6 ng/ml). Subjects were predominantly middle-aged (median 44 years) white (57%) men (78%) with AIDS (77%). APV was detected in all but 4 CSF specimens, with a median concentration of 24.8 ng/ml (interquartile range [IQR], 16.2 to 44.0). The median CSF-to-plasma ratio was 0.012 (IQR, 0.008 to 0.018). CSF concentrations correlated with plasma concentrations (rho = 0.61;
P
< 0.0001) and with postdose sampling interval (rho = −0.29;
P
= 0.0019). APV concentrations in CSF exceeded the median IC
50
for wild-type HIV in more than 97% of CSF specimens with detectable APV by a median of 4.4-fold (IQR, 2.9 to 7.9). We conclude that administration of fosamprenavir should contribute to control of HIV replication in the central nervous system (CNS) as a component of effective antiretroviral regimens.
Deletion of Tn
AbaR23
Results in both Expected and Unexpected Antibiogram Changes in a Multidrug-Resistant Acinetobacter baumannii Strain
Authors: Kochar Mandira , Crosatti Marialuisa , Harrison Ewan M. , Rieck Barbara , Chan Jacqueline , Constantinidou Chrystala , Pallen Mark , Ou Hong-Yu , Rajakumar Kumar
Published: January 2012

Since the 2006 discovery of the
Acinetobacter baumannii
strain AYE AbaR1 resistance island, similar elements have been reported in numerous members of this species. As AbaR1 is distantly related to Tn
7
, we have renamed it Tn
AbaR1
. Tn
AbaR
transposons are known to carry multiple antibiotic resistance- and efflux-associated genes, although none have been experimentally studied
en bloc
. We deleted the Tn
AbaR
transposon in
A. baumannii
A424, which we have designated Tn
AbaR23
, and characterized independent deletion mutants DCO163 and DCO174. The NotI pulsed-field gel electrophoresis (PFGE) profile of strain DCO174 was consistent with targeted deletion of Tn
AbaR23
alone, but strain DCO163 apparently harbored a second large genomic deletion. Nevertheless, “subtractive amplification” targeting 52 Tn
AbaR
and/or resistance-associated loci yielded identical results for both mutants and highlighted genes lost relative to strain A424. PCR mapping and genome sequencing revealed the entire 48.3-kb sequence of Tn
AbaR23
. Consistent with Tn
AbaR23
carrying two copies of
sul1
, both mutants exhibited markedly increased susceptibility to sulfamethoxazole. In contrast, loss of
tetAR
(A) resulted in only a minor and variable increase in tetracycline susceptibility. Despite not exhibiting a growth handicap, strain DCO163 was more susceptible than strain DCO174 to 9 of 10 antibiotics associated with mutant-to-mutant variation in susceptibility, suggesting impairment of an undefined resistance-associated function. Remarkably, despite all three strains sharing identical
gyrA
and
parC
sequences, the ciprofloxacin MIC of DCO174 was >8-fold that of DCO163 and A424, suggesting a possible paradoxical role for Tn
AbaR23
in promoting sensitivity to ciprofloxacin. This study highlights the importance of experimental scrutiny and challenges the assumption that resistance phenotypes can reliably be predicted from genotypes alone.
Nosocomial Outbreak of Klebsiella pneumoniae Carbapenemase-Producing Klebsiella oxytoca in Austria
Authors: Hoenigl Martin , Valentin Thomas , Zarfel Gernot , Wuerstl Benjamin , Leitner Eva , Salzer Helmut J. F. , Posch Josefa , Krause Robert , Grisold Andrea J.
Published: January 2012

To date, no outbreak of carbapenemase-producing bacteria has been reported for Austria. While outbreaks of
Klebsiella pneumoniae
carbapenemase (KPC)-producing
K. pneumoniae
have been increasingly reported, no outbreak caused by KPC-producing
Klebsiella oxytoca
has been described yet, to the best of our knowledge. We report an outbreak of KPC-producing
K. oxytoca
. In 5 months, 31 KPC-producing
Klebsiella oxytoca
strains were isolated from five patients. All patients were admitted to the same medical intensive care unit in Austria.
First Human Isolate of Salmonella enterica Serotype Enteritidis Harboring
bla
CTX-M-14
in South America
Authors: Bado Inés , García-Fulgueiras Virginia , Cordeiro Nicolás F. , Betancor Laura , Caiata Leticia , Seija Verónica , Robino Luciana , Algorta Gabriela , Chabalgoity José A. , Ayala Juan A. , Gutkind Gabriel O. , Vignoli Rafael
Published: January 2012

We studied a clinical isolate of
Salmonella enterica
serotype Enteritidis showing resistance to oxyiminocephalosporins. PCR analysis confirmed the presence of
bla
CTX-M-14
linked to IS
903
in a 95-kb IncI1 conjugative plasmid. Such a plasmid is maintained on account of the presence of a
pndAC
addiction system. Multilocus sequence typing (MLST) analysis indicated that the strain belongs to ST11. This is the first report of
bla
CTX-M-14
in
Salmonella
Enteritidis of human origin in South America.
Deciphering the Magainin Resistance Process of Escherichia coli Strains in Light of the Cytosolic Proteome
Authors: Maria-Neto Simone , Cândido Elizabete de Souza , Rodrigues Diana Ribas , de Sousa Daniel Amaro , da Silva Ezequiel Marcelino , de Moraes Lidia Maria Pepe , Otero-Gonzalez Anselmo de Jesus , Magalhães Beatriz Simas , Dias Simoni Campos , Franco Octávio Luiz
Published: January 2012

Antimicrobial peptides (AMPs) are effective antibiotic agents commonly found in plants, animals, and microorganisms, and they have been suggested as the future of antimicrobial chemotherapies. It is vital to understand the molecular details that define the mechanism of action of resistance to AMPs for a rational planning of the next antibiotic generation and also to shed some light on the complex AMP mechanism of action. Here, the antibiotic resistance of
Escherichia coli
ATCC 8739 to magainin I was evaluated in the cytosolic subproteome. Magainin-resistant strains were selected after 10 subsequent spreads at subinhibitory concentrations of magainin I (37.5 mg · liter
−1
), and their cytosolic proteomes were further compared to those of magainin-susceptible strains through two-dimensional electrophoresis analysis. As a result, 41 differentially expressed proteins were detected by
in silico
analysis and further identified by tandem mass spectrometry
de novo
sequencing. Functional categorization indicated an intense metabolic response mainly in energy and nitrogen uptake, stress response, amino acid conversion, and cell wall thickness. Indeed, data reported here show that resistance to cationic antimicrobial peptides possesses a greater molecular complexity than previously supposed, resulting in cell commitment to several metabolic pathways.
Genetic and Biochemical Characterization of a Novel Metallo-β-Lactamase, TMB-1, from an Achromobacter xylosoxidans Strain Isolated in Tripoli, Libya
Authors: El Salabi Allaaeddin , Borra Pardha Saradhi , Toleman Mark A. , Samuelsen Ørjan , Walsh Timothy R.
Published: January 2012

An
Achromobacter xylosoxidans
strain from the Tripoli central hospital produced a unique metallo-β-lactamase, designated TMB-1, which is related to DIM-1 (62%) and GIM-1 (51%).
bla
TMB-1
was embedded in a class 1 integron and located on the chromosome. The TMB-1 β-lactamase has lower
k
cat
values than both DIM-1 and GIM-1 with cephalosporins and carbapenems. The

K
m

values were more similar to those of GIM-1 than those of DIM-1, with the overall
k
cat
/

K
m

values being lower than those for GIM-1 and DIM-1.
Antigen 85C Inhibition Restricts Mycobacterium tuberculosis Growth through Disruption of Cord Factor Biosynthesis
Authors: Warrier Thulasi , Tropis Marielle , Werngren Jim , Diehl Anne , Gengenbacher Martin , Schlegel Brigitte , Schade Markus , Oschkinat Hartmut , Daffe Mamadou , Hoffner Sven , Eddine Ali Nasser , Kaufmann Stefan H. E.
Published: January 2012

The antigen 85 (Ag85) protein family, consisting of Ag85A, -B, and -C, is vital forMycobacterium tuberculosisdue to its role in cell envelope biogenesis. The mycoloyl transferase activity of these proteins generates trehalose dimycolate (TDM), an envelope lipid essential forM. tuberculosisvirulence, and cell wall arabinogalactan-linked mycolic acids. Inhibition of these enzymes through substrate analogs hinders growth of mycobacteria, but a link to mycolic acid synthesis has not been established. In this study, we characterized a novel inhibitor of Ag85C, 2-amino-6-propyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonitrile (I3-AG85). I3-AG85 was isolated from a panel of four inhibitors that exhibited structure- and dose-dependent inhibition ofM. tuberculosisdivision in broth culture. I3-AG85 also inhibitedM. tuberculosissurvival in infected primary macrophages. Importantly, it displayed an identical MIC against the drug-susceptible H37Rv reference strain and a panel of extensively drug-resistant/multidrug-resistantM. tuberculosisstrains. Nuclear magnetic resonance analysis indicated binding of I3-AG85 to Ag85C, similar to its binding to the artificial substrate octylthioglucoside. Quantification of mycolic acid-linked lipids of theM. tuberculosisenvelope showed a specific blockade of TDM synthesis. This was accompanied by accumulation of trehalose monomycolate, while the overall mycolic acid abundance remained unchanged. Inhibition of Ag85C activity also disrupted the integrity of theM. tuberculosisenvelope. I3-AG85 inhibited the division of and reduced TDM synthesis in anM. tuberculosisstrain deficient in Ag85C. Our results indicate that Ag85 proteins are promising targets for novel antimycobacterial drug design.
Anti-Human Immunodeficiency Virus Type 1 Activity of Novel 6-Substituted 1-Benzyl-3-(3,5-Dimethylbenzyl)Uracil Derivatives
Authors: Ordonez Paula , Hamasaki Takayuki , Isono Yohei , Sakakibara Norikazu , Ikejiri Masahiro , Maruyama Tokumi , Baba Masanori
Published: January 2012

Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are important components of current combination therapies for human immunodeficiency virus type 1 (HIV-1) infection. In screening of chemical libraries, we found 6-azido-1-benzyl-3-(3,5-dimethylbenzyl)uracil (AzBBU) and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl)uracil (AmBBU) to be highly active and selective inhibitors of HIV-1 replicationin vitro. To determine the resistance profiles of these compounds, we conducted a long-term culture of HIV-1-infected MT-4 cells with escalating concentrations of each compound. After serial passages of the infected cells, escape viruses were obtained, and they were more than 500-fold resistant to the uracil derivatives compared to the wild type. Sequence analysis was conducted for RT of the escape viruses at passages 12 and 24. The amino acid mutation Y181C in the polymerase domain of RT was detected for all escape viruses. Docking studies using the crystal structure of RT showed that AmBBU requires the amino acid residues Leu100, Val106, Tyr181, and Trp229 for exerting its inhibitory effect on HIV-1. Four additional amino acid changes (K451R, R461K, T468P, and D471N) were identified in the RNase H domain of RT; however, their precise role in the acquisition of resistance is still unclear. In conclusion, the initial mutation Y181C seems sufficient for the acquisition of resistance to the uracil derivatives AzBBU and AmBBU. Further studies are required to determine the precise role of each mutation in the acquisition of HIV-1 resistance.
Involvement of the Mannose Receptor and p38 Mitogen-Activated Protein Kinase Signaling Pathway of the Microdomain of the Integral Membrane Protein after Enteropathogenic Escherichia coli Infection
Authors: Liu Zhihua , Ma Yanlei , Moyer Mary Pat , Zhang Peng , Shi Chenzhang , Qin Huanlong
Published: January 2012

The microdomain of the integral membrane protein (MIMP) has been shown to adhere to mucin and to antagonize the adhesion of enteropathogenicEscherichia coli(EPEC) to epithelial cells; however, the mechanism has not been fully elucidated. In this study, we further identified the receptor of MIMP on NCM460 cells and investigated the mechanism (the p38 mitogen-activated protein kinase [MAPK] pathway) following the interaction of MIMP and its corresponding receptor, mannose receptor. We first identified the target receptor of MIMP on the surfaces of NCM460 cells using immunoprecipitation-mass spectrometry technology. We also verified the mannose receptor and examined the degradation and activation of the p38 MAPK signaling pathway. The results indicated that MIMP adhered to NCM460 cells by binding to the mannose receptor and inhibited the phosphorylation of p38 MAPK stimulated after EPEC infection via inhibition of the Toll-like receptor 5 pathway. These findings indicated that MIMPs relieve the injury of NCM460 cells after enteropathogenicE. coliinfection through the mannose receptor and inhibition of the p38 MAPK signaling pathway, both of which may therefore be potential therapeutic targets for intestinal diseases, such as inflammatory bowel disease.
Association between the Haptoglobin and Heme Oxygenase 1 Genetic Profiles and Soluble CD163 in Susceptibility to and Severity of Human Malaria
Authors: Mendonça Vitor R. R. , Luz Nívea F. , Santos Nadja J. G. , Borges Valéria M. , Gonçalves Marilda S. , Andrade Bruno B. , Barral-Netto Manoel
Published: January 2012

Intravascular hemolysis is a hallmark event in the immunopathology of malaria that results in increased systemic concentrations of free hemoglobin (Hb). The oxidation of Hb by free radicals causes the release of heme, which amplifies inflammation. To circumvent the detrimental effects of free heme, hosts have developed several homeostatic mechanisms, including the enzyme haptoglobin (Hp), which scavenges cell-free Hb, the monocyte receptor CD163, which binds to Hb-Hp complexes, and heme oxygenase-1 (HO-1), which degrades intracellular free heme. We tested the association between these three main components of the host response to hemolysis and susceptibility to malaria in a Brazilian population. The genetic profiles of theHMOX1andHpgenes and the plasma levels of a serum inflammatory marker, the soluble form of the CD163 receptor (sCD163), were studied in 264 subjects, including 78 individuals with symptomatic malaria, 106 individuals with asymptomatic malaria, and 80 uninfected individuals. We found that long (GT)nrepeats in the microsatellite polymorphism region of theHMOX1gene, theHp2allele, and theHp2.2genotype were associated with symptomatic malaria. Moreover, increased plasma concentrations of heme, Hp, HO-1, and sCD163 were associated with susceptibility to malaria. The validation of these results could support the development of targeted therapies and aid in reducing the severity of malaria.
Microevolution in
fimH
Gene of Mucosa-Associated Escherichia coli Strains Isolated from Pediatric Patients with Inflammatory Bowel Disease
Authors: Iebba Valerio , Conte Maria Pia , Lepanto Maria Stefania , Di Nardo Giovanni , Santangelo Floriana , Aloi Marina , Totino Valentina , Checchi Monica Proietti , Longhi Catia , Cucchiara Salvatore , Schippa Serena
Published: January 2012

Several studies reported increased numbers of mucosa-associated
Escherichia coli
strains in patients with inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC). The majority of
E. coli
strains possess type 1 fimbriae, whose tip fibrillum protein, FimH, naturally undergoes amino acid replacements, an important process in the adaptation of commensal
E. coli
strains to environmental changes, like those observed in IBD and urinary tract infections. In this study, we analyzed mutational patterns in the
fimH
gene of 52 mucosa-associated
E. coli
strains isolated from IBD and non-IBD pediatric patients, in order to investigate microevolution of this genetic trait. FimH-positive strains were also phylogenetically typed and tested for their adhesive ability on Caco-2 cells. Specific FimH alleles for each grouping feature were found. Mutations G66S and V27A were related to CD, while mutations A242V, V163A, and T74I were attributed to UC. Otherwise, the G66S, N70S, and S78N mutations were specifically attributed to B2/D phylogroups. The N70S and A119V mutations were related to adhesive
E. coli
strains. Phylogroup B2, adhesive, and IBD
E. coli
strains showed a higher site substitution rate (SSR) in the
fimH
gene, together with a higher number of mutations. The degree of naïve mucosal inflammation was related to specific FimH alleles. Moreover, we could suggest that the V27A mutation is pathoadaptive for the CD intestinal habitat, while we could also suggest that both the N70S and S78N mutations are related to the more virulent
E. coli
B2 phylogroup. In conclusion, we found some FimH variants that seem to be more involved than others in the evolution of IBD pathogenesis.
Characterization of a Novel Inactivated Salmonella enterica Serovar Enteritidis Vaccine Candidate Generated Using a Modified cI857/λ PR/GeneEExpression System
Authors: Jawale Chetan V. , Chaudhari Atul A. , Jeon Byung Woo , Nandre Rahul M. , Lee John Hwa
Published: January 2012

A new strategy to develop an effective vaccine is essential to control food-borneSalmonella entericaserovar Enteritidis infections. Bacterial ghosts (BGs), which are nonliving, Gram-negative bacterial cell envelopes, are generated by expulsion of the cytoplasmic contents from bacterial cells through controlled expression using the modified cI857/λ PR/geneEexpression system. In the present study, the pJHL99 lysis plasmid carrying the mutated lambda pR37-cI857 repressor and PhiX174 lysis geneEwas constructed and transformed inS. Enteritidis to produce a BG. Temperature induction of the lysis gene cassette at 42°C revealed quantitative killing ofS. Enteritidis. TheS. Enteritidis ghost was characterized using scanning and transmission electron microscopy to visualize the transmembrane tunnel structure and loss of cytoplasmic materials, respectively. The efficacy of the BG as a vaccine candidate was evaluated in a chicken model using 60 10-day-old chickens, which were divided into four groups (n= 15), A, B, C, and D. Group A was designated as the nonimmunized control group, whereas the birds in groups B, C, and D were immunized via the intramuscular, subcutaneous, and oral routes, respectively. The chickens from all immunized groups showed significant increases in plasma IgG and intestinal secretory IgA levels. The lymphocyte proliferation response and CD3+CD4+and CD3+CD8+T cell subpopulations were also significantly increased in all immunized groups. The data indicate that both humoral and cell-mediated immune responses are robustly stimulated. Based on an examination of the protection efficacy measured by observations of gross lesions in the organs and bacterial recovery, the candidate vaccine can provide efficient protection against virulent challenge.
Hyperinduction of Host Beta Interferon by a Listeria monocytogenes Strain Naturally Overexpressing the Multidrug Efflux Pump MdrT
Authors: Schwartz Kierstyn T. , Carleton Joshua D. , Quillin Sarah J. , Rollins Stuart D. , Portnoy Daniel A. , Leber Jess H.
Published: January 2012

Many pathogens regulate or modify their immune-stimulating ligands to avoid detection by their infected hosts.
Listeria monocytogenes
, a facultative intracellular bacterial pathogen, interacts with multiple components of mammalian innate immunity during its infection cycle. During replication within the cytosol of infected cells,
L. monocytogenes
utilizes two multidrug efflux pumps, MdrM and MdrT, to secrete the small nucleic acid second messenger cyclic-di-AMP (c-di-AMP). Host recognition of c-di-AMP triggers the production of type I interferons, including beta interferon (IFN-β), which, surprisingly, promote
L. monocytogenes
virulence. In this study, we have examined the capacity of multiple laboratory and clinical isolates of
L. monocytogenes
to stimulate host production of IFN-β. We have identified the
L. monocytogenes
strain LO28 as able to hyperinduce IFN-β production in infected cells ∼30-fold more than the common laboratory clone
L. monocytogenes
strain 10403S. Genomic analyses determined that LO28 contains a naturally occurring loss-of-function allele of the transcriptional regulator BrtA and correspondingly derepresses expression of MdrT. Surprisingly, while derepression of MdrT resulted in hyperstimulation of IFN-β, it results in significant attenuation in multiple mouse models of infection. While type I interferons may promote
L. monocytogenes
virulence, this study demonstrates that unregulated expression of the c-di-AMP-secreting efflux pump MdrT significantly restricts virulence
in vivo
by an unknown mechanism.
Chlamydia muridarum T Cell Antigens and Adjuvants That Induce Protective Immunity in Mice
Authors: Yu Hong , Karunakaran Karuna P. , Jiang Xiaozhou , Shen Caixia , Andersen Peter , Brunham Robert C.
Published: January 2012

Major impediments to aChlamydiavaccine lie in discovering T cell antigens and polarizing adjuvants that stimulate protective immunity. We previously reported the discovery of three T cell antigens (PmpG, PmpF, and RplF) via immunoproteomics that elicited protective immunity in the murine genital tract infection model againstChlamydiainfection after adoptive transfer of antigen-pulsed dendritic cells. To expand the T cell antigen repertoire necessary for aChlamydiavaccine, we evaluated 10 newChlamydiaT cell antigens discovered via immunoproteomics in addition to the 3 antigens reported earlier as a molecular subunit vaccine. We first tested five adjuvants, including three cationic liposome formulations (dimethyldioctadecylammonium bromide-monophosphoryl lipid A [DDA-MPL], DDA-trehalose 6,6′-dibehenate [DDA-TDB {CAF01}], and DDA-monomycolyl glycerol [DDA-MMG {CAF04}]), Montanide ISA720–CpG-ODN1826, and alum using the PmpG protein as a model T cell antigen in the mouse genital tract infection model. The results showed that the cationic liposomal adjuvants DDA-MPL and DDA-TDB elicited the best protective immune responses, characterized by multifunctional CD4+T cells coexpressing gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α), and reduced infection by more than 3 logs. Using DDA-MPL as an adjuvant, we found that 7 of 13ChlamydiaT cell antigens (PmpG, PmpE, PmpF, Aasf, RplF, TC0420, and TC0825) conferred protection better than or equal to that of the reference vaccine antigen, major outer membrane protein (MOMP). Pools of membrane/secreted proteins, cytoplasmic proteins, and hypothetical proteins were tested individually or in combination. Immunization with combinations protected as well as the best individual protein in that combination. The T cell antigens and adjuvants discovered in this study are of further interest in the development of a molecularly definedChlamydiavaccine.
ON THE CLASSIFICATION OF QUANDLES OF LOW ORDER
Authors: VENDRAMIN L.
Published: January 2012

Using the classification of transitive groups we classify indecomposable quandles of size < 36. This classification is available in Rig, a GAP package for computations related to racks and quandles. As an application, the list of all indecomposable quandles of size < 36 not of type D is computed.
VirE2-DEPENDENT PORES FOR ssDNA TRANSFER ACROSS ARTIFICIAL AND CELL MEMBRANES
Authors: VOLOKHINA IRINA , GUSEV YURY , MAZILOV SVYATOSLAV , CHUMAKOV MIKHAIL
Published: January 2012

The transfer of single-stranded (ss) T-DNA from soil bacteria of the genus Agrobacterium with the help of the VirE2 protein, which possibly mediates the delivery of ss-T-DNA across the cell membrane, was demonstrated earlier, but how VirE2 participates in ssDNA transfer across artificial and natural membranes is not known. Using computational methods, we reconstructed model structures composed of two and four VirE2 proteins and showed by the MOLE program the formation of pores with channel diameters of 1.2–1.6 and 1.4–4.6 nm in a model structure formed from two and four VirE2 molecules, respectively. Using light scattering, we recorded the size distribution for recombinant VirE2-dependent complexes in aqueous solutions and found that VirE2 in a buffer solution is present as a complex made up of two or more proteins. We revealed single, long-lived jumps in voltage-dependent membrane conductance during coincubation of planar black membranes with the VirE2 protein. On the addition of VirE2 and FAM-labeled oligonucleotides to HeLa cells, the fluorescence intensity for the cells increased by 56% as compared to that for cells incubated only with oligonucleotides.
Easy Formal Specification and Validation of Unbounded Networks-on-Chips Architectures
Authors: Verbeek Freek , Schmaltz Julien
Published: January 2012

This article presents a formal specification and validation environment to prove safety and liveness properties of parametric -- unbounded -- NoCs architectures described at a high-level of abstraction. The environment improves the GeNoC approach with two new theorems, proving evacuation and starvation freedom. The application of the validation methodology is illustrated on a HERMES NoC with adaptive west-first routing and wormhole switching. This case study illustrates the strong compositional aspect of the GeNoC environment. The complete specification of this HERMES instance, together with the proof that the specification is deadlock-free, starvation free, and all messages eventually leave the network at their correct destination, could be achieved in about a week. Approximately 86% of this proof is automatically derived from the GeNoC model.
Coverage-Directed Test Generation Automated by Machine Learning -- A Review
Authors: Ioannides Charalambos , Eder Kerstin I.
Published: January 2012

The increasing complexity and size of digital designs, in conjunction with the lack of a potent verification methodology that can effectively cope with this trend, continue to inspire engineers and academics in seeking ways to further automate design verification. In an effort to increase performance and to decrease engineering effort, research has turned to artificial intelligence (AI) techniques for effective solutions. The generation of tests for simulation-based verification can be guided by machine-learning techniques. In fact, recent advances demonstrate that embedding machine-learning (ML) techniques into a coverage-directed test generation (CDG) framework can effectively automate the test generation process, making it more effective and less error-prone. This article reviews some of the most promising approaches in this field, aiming to evaluate the approaches and to further stimulate more directed research in this area.
Topological and Simplicial Models of Identity Types
Authors: van den Berg Benno , Garner Richard
Published: January 2012

In this paper we construct new categorical models for the identity types of Martin-Löf type theory, in the categories
Top
of topological spaces and
SSet
of simplicial sets. We do so building on earlier work of Awodey and Warren [2009], which has suggested that a suitable environment for the interpretation of identity types should be a category equipped with a weak factorization system in the sense of Bousfield--Quillen. It turns out that this is not quite enough for a sound model, due to some subtle coherence issues concerned with stability under substitution; and so our first task is to introduce a slightly richer structure, which we call a
homotopy-theoretic model of identity types
, and to prove that this is sufficient for a sound interpretation.

Now, although both
Top
and
SSet
are categories endowed with a weak factorization system---and indeed, an entire Quillen model structure---exhibiting the additional structure required for a homotopy-theoretic model is quite hard to do. However, the categories we are interested in share a number of common features, and abstracting these leads us to introduce the notion of a
path object category
. This is a relatively simple axiomatic framework, which is nonetheless sufficiently strong to allow the construction of homotopy-theoretic models. Now by exhibiting suitable path object structures on
Top
and
SSet
, we endow those categories with the structure of a homotopy-theoretic model and, in this way, obtain the desired topological and simplicial models of identity types.
Reachability Problems in Piecewise FIFO Systems
Authors: Ghafari Naghmeh , Gurfinkel Arie , Klarlund Nils , Trefler Richard
Published: January 2012

Systems consisting of several finite components that communicate via unbounded perfect FIFO channels (i.e., FIFO systems) arise naturally in modeling distributed systems. Despite well-known difficulties in analyzing such systems, they are of significant interest as they can describe a wide range of communication protocols.

In this article, we study the problem of computing the set of reachable states of a FIFO system composed of
piecewise
components. This problem is closely related to calculating the set of all possible channel contents, that is, the
limit language
, for each control location. We present an algorithm for calculating the limit language of a system with a single communication channel. For multichannel systems, we show that the limit language is piecewise if the initial language is piecewise. Our construction is not effective in general; however, we provide algorithms for calculating the limit language of a restricted class of multichannel systems in which messages are not passed around in cycles through different channels. We show that the worst case complexity of our algorithms for single-channel and important subclasses of multichannel systems is exponential in the size of the initial content of the channels.
Flow Logic for Process Calculi
Authors: Nielson Hanne Riis , Nielson Flemming , Pilegaard Henrik
Published: January 2012

Flow Logic is an approach to statically determining the behavior of programs and processes. It borrows methods and techniques from Abstract Interpretation, Data Flow Analysis and Constraint Based Analysis while presenting the analysis in a style more reminiscent of Type Systems. Traditionally developed for programming languages, this article provides a tutorial development of the approach of Flow Logic for process calculi based on a decade of research.

We first develop a simple analysis for the
π
-calculus; this consists of the specification, semantic soundness (in the form of subject reduction and adequacy results), and a Moore Family result showing that a least solution always exists, as well as providing insights on how to implement the analysis. We then show how to strengthen the analysis technology by introducing reachability components, interaction points, and localized environments, and finally, we extend it to a relational analysis.

A Flow Logic is a program logic---in the same sense that a Hoare’s logic is. We conclude with an executive summary presenting the highlights of the approach from this perspective including a discussion of theoretical properties as well as implementation considerations.

The electronic supplements present an application of the analysis techniques to a version of the
π
-calculus incorporating distribution and code mobility; also the proofs of the main results can be found in the electronic supplements.
Context-aware web search in ubiquitous sensor environments
Authors: Maekawa Takuya , Yanagisawa Yutaka , Sakurai Yasushi , Kishino Yasue , Kamei Koji , Okadome Takeshi
Published: January 2012

This article proposes a new concept for a context-aware Web search method that automatically retrieves a webpage related to the daily activity that a user currently is engaged in and displays the page on nearby Internet-connected home appliances such as televisions. For example, when a user is washing a coffeemaker, a webpage is retrieved that includes tips such as “cleaning a coffee maker with vinegar removes stains well,” and the page is displayed on a nearby appliance. In this article, we design and implement a Web search method that employs ubiquitous sensors to monitor a user's daily life. Our proposed method automatically searches for a webpage related to a daily activity by using a query constructed from the use of daily objects employed in the activity that is detected with object-attached sensors. We evaluate the search method with real datasets collected from vast numbers of sensors and achieve very accurate webpage retrieval. We then investigate the usefulness and effectiveness of a daily life Web search with Wizard-of-Oz (WOz)-like experiments. We confirm that the presentation of webpages related to daily activities improves participants' future daily lives and triggers communication among the participants in the experiment.
A smart web service based on the context of things
Authors: He Jing , Zhang Yanchun , Huang Guangyan , Cao Jinli
Published: January 2012

Combining the Semantic Web and the Ubiquitous Web, Web 3.0 is for
things
. The Semantic Web enables human knowledge to be machine-readable and the Ubiquitous Web allows Web services to serve any thing, forming a bridge between the virtual world and the real world. By using context, Web services can become smarter—that is, aware of the target things' or applications' physical environments, or situations and respond proactively and intelligently. Existing methods for implementing context-aware Web services on Web 2.0 mainly enumerate different implementations corresponding to different attribute values of the context, in order to improve the Quality of Services (QoS). However, things in the physical world are extremely diverse, which poses new problems for Web services: it is difficult to unify the context of things and to implement a flexible smart Web service for things. This article proposes a novel smart Web service based on the context of things, which is implemented using a REpresentational State Transfer for Things (Thing-REST) style, to tackle the two problems. In a smart Web service, the user's description (semantic context) and sensor reports (sensing context) are two channels for acquiring the context of things which are then employed by ontology services to make the context of things machine-readable. With guidance of domain knowledge services, event detection services can analyze things' needs particularly, well through the context of things. We then propose a Thing-REST style to manage the context of things and user context, and to mashup Web services through three structures (i.e., chain, select, and merge) to implement smart Web services. A smart plant watering-service application demonstrates the effectiveness of our method.
Making the common case the only case with anticipatory memory allocation
Authors: Sundararaman Swaminathan , Zhang Yupu , Subramanian Sriram , Arpaci-Dusseau Andrea C. , Arpaci-Dusseau Remzi H.
Published: January 2012

We present
anticipatory memory allocation
(AMA), a new method to build kernel code that is robust to memory-allocation failures. AMA avoids the usual difficulties in handling allocation failures through a novel combination of static and dynamic techniques. Specifically, a developer, with assistance from AMA static analysis tools, determines how much memory a particular call into a kernel subsystem will need, and then preallocates said amount immediately upon entry to the kernel; subsequent allocation requests are serviced from the preallocated pool and thus guaranteed never to fail. We describe the static and runtime components of AMA, and then present a thorough evaluation of Linux ext2-mfr, a case study in which we transform the Linux ext2 file system into a memory-failure robust version of itself. Experiments reveal that ext2-mfr avoids memory-allocation failures successfully while incurring little space or time overhead.
Sequential Modeling of Topic Dynamics with Multiple Timescales
Authors: Iwata Tomoharu , Yamada Takeshi , Sakurai Yasushi , Ueda Naonori
Published: January 2012

We propose an online topic model for sequentially analyzing the time evolution of topics in document collections. Topics naturally evolve with multiple timescales. For example, some words may be used consistently over one hundred years, while other words emerge and disappear over periods of a few days. Thus, in the proposed model, current topic-specific distributions over words are assumed to be generated based on the multiscale word distributions of the previous epoch. Considering both the long- and short-timescale dependency yields a more robust model. We derive efficient online inference procedures based on a stochastic EM algorithm, in which the model is sequentially updated using newly obtained data; this means that past data are not required to make the inference. We demonstrate the effectiveness of the proposed method in terms of predictive performance and computational efficiency by examining collections of real documents with timestamps.
Learning Incoherent Sparse and Low-Rank Patterns from Multiple Tasks
Authors: Chen Jianhui , Liu Ji , Ye Jieping
Published: January 2012

We consider the problem of learning incoherent sparse and low-rank patterns from multiple tasks. Our approach is based on a linear multitask learning formulation, in which the sparse and low-rank patterns are induced by a cardinality regularization term and a low-rank constraint, respectively. This formulation is nonconvex; we convert it into its convex surrogate, which can be routinely solved via semidefinite programming for small-size problems. We propose employing the general projected gradient scheme to efficiently solve such a convex surrogate; however, in the optimization formulation, the objective function is nondifferentiable and the feasible domain is nontrivial. We present the procedures for computing the projected gradient and ensuring the global convergence of the projected gradient scheme. The computation of the projected gradient involves a constrained optimization problem; we show that the optimal solution to such a problem can be obtained via solving an unconstrained optimization subproblem and a Euclidean projection subproblem. We also present two projected gradient algorithms and analyze their rates of convergence in detail. In addition, we illustrate the use of the presented projected gradient algorithms for the proposed multitask learning formulation using the least squares loss. Experimental results on a collection of real-world data sets demonstrate the effectiveness of the proposed multitask learning formulation and the efficiency of the proposed projected gradient algorithms.
Connecting Two (or Less) Dots
Authors: Shahaf Dafna , Guestrin Carlos
Published: January 2012

Finding information is becoming a major part of our daily life. Entire sectors, from Web users to scientists and intelligence analysts, are increasingly struggling to keep up with the larger and larger amounts of content published every day. With this much data, it is often easy to miss the big picture.

In this article, we investigate methods for automatically connecting the dots---providing a structured, easy way to navigate within a new topic and discover hidden connections. We focus on the news domain: given two news articles, our system automatically finds a coherent chain linking them together. For example, it can recover the chain of events starting with the decline of home prices (January 2007), and ending with the health care debate (2009).

We formalize the characteristics of a good chain and provide a fast search-driven algorithm to connect two fixed endpoints. We incorporate user feedback into our framework, allowing the stories to be refined and personalized. We also provide a method to handle partially-specified endpoints, for users who do not know both ends of a story. Finally, we evaluate our algorithm over real news data. Our user studies demonstrate that the objective we propose captures the users’ intuitive notion of coherence, and that our algorithm effectively helps users understand the news.
New software for computing asymptotics of multivariate generating functions
Authors: Raichev Alexander
Published: January 2012

I introduce amgf, a new Sage software package for computing asymptotics of multivariate generating functions. It implements recent algorithms developed by Mark C. Wilson and me. The current version of amgf is under peer review for incorporation into Sage and is available from my website at www.cs.auckland.ac.nz/~raichev/research.html.
Mathemagix
Authors: van der Hoeven Joris , Lecerf Grégoire , Mourrain Bernard , Trébuchet Philippe , Berthomieu Jérémy , Diatta Daouda Niang , Mantzaflaris Angelos
Published: January 2012

We describe the goals and architecture of the software project Mathemagix, the main list of packages it contains, the main characteristics of its programming language, and connections with existing frontends.
Macular Hole Progression after Intravitreal Bevacizumab for Hemicentral Retinal Vein Occlusion
Authors: Nagpal Manish , Mehta Vikram , Nagpal Kamal
Published: January 2012

Macular edema secondary to retinal vein occlusion is commonly being treated with off-label intravitreal bevacizumab with good outcomes. A significant reduction in macular edema and improvement in visual acuity is seen following such a treatment with no serious adverse effects. In the reported case, a full-thickness macular hole was noticed one month after intravitreal bevacizumab for macular edema secondary to hemicentral retinal vein occlusion. On a detailed review of the pre- and postoptical coherence tomography scans, it was realized that there was a preexisting stage 2-3 macular hole which was masked by the hemorrhages and edema at the fovea and the macular hole had progressed following the injection.
Keratitis due toChaetomiumsp.
Authors: Kaliamurthy Jayaraman , Kalavathy Catti Munuswamy , Nelson Jesudasan Christadoss Arul , Thomas Philip A.
Published: January 2012

Aim. To describe keratitis due toChaetomiumsp. occurring in a 65-year-old woman who presented with a corneal ulcer with hypopyon of the right eye with a history of trauma by vegetable matter.Method. Multiple scrapings were obtained from the ulcer. A lactophenol cotton blue wet mount and a Gram-stained smear of the scrapings were made. Scrapings were also inoculated onto various culture media.Results. Direct microscopy of corneal scrapings revealed moderate numbers of septate fungal hyphae. Greenish-yellow-coloured fungal colonies with aerial mycelium were observed in culture of the corneal scrapes. On the basis of colony characteristics and conidial structure, the fungal isolate was identified asChaetomiumsp. The patient was treated with topical natamycin (5%) hourly and cyclopentolate 1% drops 3 times a day. After 4 weeks of therapy, the hypopyon had disappeared, the epithelial defect had healed, and the stromal infiltration had almost completely resolved; the visual acuity of the eye improved from hand movements to(1/2)/60.Conclusion. Fungi of the genusChaetomium, which are rare causes of human disease (systemic mycosis, endocarditis, subcutaneous lesions), may also cause ocular lesions.