bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of a disintegrin and metalloprotease 10 in
Staphylococcus aureus
α-hemolysin–mediated cellular injury
Authors: Wilke Georgia A. , Wardenburg Juliane Bubeck
Published: July 2010

Staphylococcus aureus
α-hemolysin (Hla), a potent cytotoxin, plays an important role in the pathogenesis of staphylococcal diseases, including those caused by methicillin-resistant epidemic strains. Hla is secreted as a water-soluble monomer that undergoes a series of conformational changes to generate a heptameric, β-barrel structure in host membranes. Structural maturation of Hla depends on its interaction with a previously unknown proteinaceous receptor in the context of the cell membrane. It is reported here that a disintegrin and metalloprotease 10 (ADAM10) interacts with Hla and is required to initiate the sequence of events whereby the toxin is transformed into a cytolytic pore. Hla binding to the eukaryotic cell requires ADAM10 expression. Further, ADAM10 is required for Hla-mediated cytotoxicity, most notably when the toxin is present at low concentrations. These data thus implicate ADAM10 as the probable high-affinity toxin receptor. Upon Hla binding, ADAM10 relocalizes to caveolin 1-enriched lipid rafts that serve as a platform for the clustering of signaling molecules. It is demonstrated that the Hla–ADAM10 complex initiates intracellular signaling events that culminate in the disruption of focal adhesions.
MicroRNA-10a regulation of proinflammatory phenotype in athero-susceptible endothelium in vivo and in vitro
Authors: Fang Yun , Shi Congzhu , Manduchi Elisabetta , Civelek Mete , Davies Peter F.
Published: July 2010

A chronic proinflammatory state precedes pathological change in arterial endothelial cells located within regions of susceptibility to atherosclerosis. The potential contributions of regulatory microRNAs to this disequilibrium were investigated by artery site-specific profiling in normal adult swine. Expression of endothelial microRNA10a (miR-10a) was lower in the athero-susceptible regions of the inner aortic arch and aorto-renal branches than elsewhere. Expression of Homeobox A1 (HOXA1), a known miR-10a target, was up-regulated in the same locations. Endothelial transcriptome microarray analysis of miR-10a knockdown in cultured human aortic endothelial cells (HAEC) identified IκB/NF-κB–mediated inflammation as the top category of up-regulated biological processes. Phosphorylation of IκBα, a prerequisite for IκBα proteolysis and NF-κB activation, was significantly up-regulated in miR-10a knockdown HAEC and was accompanied by increased nuclear expression of NF-κB p65. The inflammatory biomarkers monocyte chemotactic protein 1 (MCP-1), IL-6, IL-8, vascular cell adhesion molecule 1 (VCAM-1), and E-selectin were elevated following miR-10a knockdown. Conversely, knockin of miR-10a (a conservative 25-fold increase) inhibited the basal expression of VCAM-1 and E-selectin in HAEC. Two key regulators of IκBα degradation—mitogen-activated kinase kinase kinase 7 (MAP3K7; TAK1) and β-transducin repeat-containing gene (βTRC)—contain a highly conserved miR-10a binding site in the 3′ UTR. Both molecules were up-regulated by miR-10a knockdown and suppressed by miR-10a knockin, and evidence of direct miR-10a binding to the 3′ UTR was demonstrated by luciferase assay. Comparative expression studies of endothelium located in athero-susceptible aortic arch and athero-protected descending thoracic aorta identified significantly up-regulated MAP3K7, βTRC, phopho-IκBα, and nuclear p65 expression suggesting that the differential expression of miR-10a contributes to the regulation of proinflammatory endothelial phenotypes in athero-susceptible regions in vivo.
Cooperative formation of native-like tertiary contacts in the ensemble of unfolded states of a four-helix protein
Authors: Bruun Susanne W. , Iešmantavičius Vytautas , Danielsson Jens , Poulsen Flemming M.
Published: July 2010

In studies of the ensembles of unfolded structures of a four-helix bundle protein, we have detected the presence of potential precursors of native tertiary structures. These observations were based on the perturbation of NMR chemical shifts of the protein backbone atoms by single site mutations. Some mutations change the chemical shifts of residues remote from the site of mutation indicating the presence of an interaction between the mutated and the remote residues, suggesting that the formation of helix segments and helix-helix interactions is cooperative. We can begin to track down the folding mechanism of this protein using only experimental data by combining the information available for the rate limiting structure formation during the folding process with measurements of the site specific hydrogen bond formation in the burst phase, and with the existence prior to the folding reaction of tertiary structures in the ensemble of otherwise unfolded structures observed in the present study.
Increased activity of
Diaphanous homolog 3
(
DIAPH3
)/
diaphanous
causes hearing defects in humans with auditory neuropathy and in
Drosophila
Authors: Schoen Cynthia J. , Emery Sarah B. , Thorne Marc C. , Ammana Hima R. , Śliwerska Elżbieta , Arnett Jameson , Hortsch Michael , Hannan Frances , Burmeister Margit , Lesperance Marci M.
Published: July 2010

Auditory neuropathy is a rare form of deafness characterized by an absent or abnormal auditory brainstem response with preservation of outer hair cell function. We have identified
Diaphanous homolog 3
(
DIAPH3
) as the gene responsible for autosomal dominant nonsyndromic auditory neuropathy (
AUNA1
), which we previously mapped to chromosome 13q21-q24. Genotyping of additional family members narrowed the interval to an 11-Mb, 3.28-cM gene-poor region containing only four genes, including
DIAPH3
. DNA sequencing of
DIAPH3
revealed a c.-172G > A, g. 48G > A mutation in a highly conserved region of the 5′ UTR. The c.-172G > A mutation occurs within a GC box sequence element and was not found in 379 controls. Using genome-wide expression arrays and quantitative RT-PCR, we demonstrate a 2- to 3-fold overexpression of
DIAPH3
mRNA in lymphoblastoid cell lines from affected individuals. Likewise, a significant increase (≈1.5-fold) in DIAPH3 protein was found by quantitative immunoblotting of lysates from lymphoblastoid cell lines derived from affected individuals in comparison with controls. In addition, the c.-172G > A mutation is sufficient to drive overexpression of a luciferase reporter. Finally, the expression of a constitutively active form of diaphanous protein in the auditory organ of
Drosophila melanogaster
recapitulates the phenotype of impaired response to sound. To date, only two genes, the otoferlin gene
OTOF
and the pejvakin gene
PJVK
, are known to underlie nonsyndromic auditory neuropathy. Genetic testing for
DIAPH3
may be useful for individuals with recessive as well as dominant inheritance of nonsyndromic auditory neuropathy.
3D visualization of HIV transfer at the virological synapse between dendritic cells and T cells
Authors: Felts Richard L. , Narayan Kedar , Estes Jacob D. , Shi Dan , Trubey Charles M. , Fu Jing , Hartnell Lisa M. , Ruthel Gordon T. , Schneider Douglas K. , Nagashima Kunio , Bess Julian W. , Bavari Sina , Lowekamp Bradley C. , Bliss Donald , Lifson Jeffrey D. , Subramaniam Sriram
Published: July 2010

The efficiency of HIV infection is greatly enhanced when the virus is delivered at conjugates between CD4
+
T cells and virus-bearing antigen-presenting cells such as macrophages or dendritic cells via specialized structures known as virological synapses. Using ion abrasion SEM, electron tomography, and superresolution light microscopy, we have analyzed the spatial architecture of cell-cell contacts and distribution of HIV virions at virological synapses formed between mature dendritic cells and T cells. We demonstrate the striking envelopment of T cells by sheet-like membrane extensions derived from mature dendritic cells, resulting in a shielded region for formation of virological synapses. Within the synapse, filopodial extensions emanating from CD4
+
T cells make contact with HIV virions sequestered deep within a 3D network of surface-accessible compartments in the dendritic cell. Viruses are detected at the membrane surfaces of both dendritic cells and T cells, but virions are not released passively at the synapse; instead, virus transfer requires the engagement of T-cell CD4 receptors. The relative seclusion of T cells from the extracellular milieu, the burial of the site of HIV transfer, and the receptor-dependent initiation of virion transfer by T cells highlight unique aspects of cell-cell HIV transmission.
Phosphine-catalyzed asymmetric additions of malonate esters to γ-substituted allenoates and allenamides
Authors: Sinisi Riccardo , Sun Jianwei , Fu Gregory C.
Published: July 2010

Because carbonyl groups are ubiquitous in organic chemistry, the ability to synthesize functionalized carbonyl compounds, particularly enantioselectively, is an important objective. We have developed a straightforward and versatile method for catalytic asymmetric carbon–carbon bond formation at the γ-position of carbonyl compounds, specifically, phosphine-catalyzed additions of malonate esters to γ-substituted allenoates and allenamides. Mechanistic studies have provided insight into the reaction pathway.
Aging and nonergodicity beyond the Khinchin theorem
Authors: Burov S. , Metzler R. , Barkai E.
Published: July 2010

The Khinchin theorem provides the condition that a stationary process is ergodic, in terms of the behavior of the corresponding correlation function. Many physical systems are governed by nonstationary processes in which correlation functions exhibit aging. We classify the ergodic behavior of such systems and suggest a possible generalization of Khinchin’s theorem. Our work also quantifies deviations from ergodicity in terms of aging correlation functions. Using the framework of the fractional Fokker-Planck equation, we obtain a simple analytical expression for the two-time correlation function of the particle displacement in a general binding potential, revealing universality in the sense that the binding potential only enters into the prefactor through the first two moments of the corresponding Boltzmann distribution. We discuss applications to experimental data from systems exhibiting anomalous dynamics.
A
Nitrospira
metagenome illuminates the physiology and evolution of globally important nitrite-oxidizing bacteria
Authors: Lücker Sebastian , Wagner Michael , Maixner Frank , Pelletier Eric , Koch Hanna , Vacherie Benoit , Rattei Thomas , Damsté Jaap S. Sinninghe , Spieck Eva , Le Paslier Denis , Daims Holger
Published: July 2010

Nitrospira
are barely studied and mostly uncultured nitrite-oxidizing bacteria, which are, according to molecular data, among the most diverse and widespread nitrifiers in natural ecosystems and biological wastewater treatment. Here, environmental genomics was used to reconstruct the complete genome of “
Candidatus
Nitrospira defluvii” from an activated sludge enrichment culture. On the basis of this first-deciphered
Nitrospira
genome and of experimental data, we show that
Ca
. N. defluvii differs dramatically from other known nitrite oxidizers in the key enzyme nitrite oxidoreductase (NXR), in the composition of the respiratory chain, and in the pathway used for autotrophic carbon fixation, suggesting multiple independent evolution of chemolithoautotrophic nitrite oxidation. Adaptations of
Ca
. N. defluvii to substrate-limited conditions include an unusual periplasmic NXR, which is constitutively expressed, and pathways for the transport, oxidation, and assimilation of simple organic compounds that allow a mixotrophic lifestyle. The reverse tricarboxylic acid cycle as the pathway for CO
2
fixation and the lack of most classical defense mechanisms against oxidative stress suggest that
Nitrospira
evolved from microaerophilic or even anaerobic ancestors. Unexpectedly, comparative genomic analyses indicate functionally significant lateral gene-transfer events between the genus
Nitrospira
and anaerobic ammonium-oxidizing planctomycetes, which share highly similar forms of NXR and other proteins reflecting that two key processes of the nitrogen cycle are evolutionarily connected.
Neurofibromin regulates corticostriatal inhibitory networks during working memory performance
Authors: Shilyansky Carrie , Karlsgodt Katherine H. , Cummings Damian M. , Sidiropoulou Kyriaki , Hardt Molly , James Alex S. , Ehninger Dan , Bearden Carrie E. , Poirazi Panayiota , Jentsch J. David , Cannon Tyrone D. , Levine Michael S. , Silva Alcino J.
Published: July 2010

Neurofibromatosis type I (NF1) is one of the most common single-gene causes of learning disabilities. Here, we use behavioral working memory probes and electrophysiological studies in a mouse model of NF1 (
Nf1
heterozygous null mutants;

Nf1
+/−

) to demonstrate that (
i
) Neurofibromin regulates prefrontal and striatal inhibitory networks, specifically activity-dependent GABA release and (
ii
) is required for working memory performance, with inhibition-dependent working memory deficits seen in

Nf1
+/−

mice. We find that increased inhibition in medial prefrontal cortex (mPFC) is sufficient to alter persistent activity in a biophysical model of an mPFC microcircuit, suggesting a possible mechanism for

Nf1
+/−

working memory deficits. Accordingly, working memory assays applied during functional MRI (fMRI) studies in human subjects with NF1 reveal hypoactivation of corticostriatal networks, which is associated with impaired working memory performance. Collectively, these integrative mouse and human studies reveal molecular and cellular mechanisms contributing to working memory deficits in NF1.
A non-ring-like form of the Dam1 complex modulates microtubule dynamics in fission yeast
Authors: Gao Qi , Courtheoux Thibault , Gachet Yannick , Tournier Sylvie , He Xiangwei
Published: July 2010

The Dam1 complex is a kinetochore component that couples chromosomes to the dynamic ends of kinetochore microtubules (kMTs). Work in the budding yeast
Saccharomyces cerevisiae
has shown that the Dam1 complex forms a 16-unit ring encircling and tracking the tip of a MT in vitro, consistent with its cellular function as a coupler. Dam1 also forms smaller, nonring patches in vitro that track the dynamic ends of MTs. However, the identity of Dam1’s functional form in vivo remains unknown. Here we report a comprehensive in vivo characterization of Dam1 in the fission yeast
Schizosaccharomyces pombe
. In addition to their dense localizations on kinetochores and spindle MTs during mitosis, we identify that Dam1 is also localized onto cytoplasmic MTs as discrete spots in interphase, providing the unique opportunity to analyze Dam1 oligomers at the single-particle resolution in live cells. Such analysis shows that each oligomer contains one to five copies of Dam1, and is able to “switch-rail” while moving along MTs, precluding the possibility of a 16-unit encircling structure. Dam1 patches track the plus ends of the shortening, but not the elongating, MTs and retard MT depolymerization. Together with Mal3, the EB1-like MT-interacting protein, cytoplasmic Dam1 plays an important role in maintaining proper cell shape. In mitosis, kinetochore-associated Dam1 appears to facilitate kMT depolymerization. Together, our findings suggest that patches, instead of rings, are the physiologically functional forms of Dam1 in pombe. Our findings help establish the benchmark parameters of the Dam1 coupler and elucidate the mechanism of its functions.
Origin of a function by tandem gene duplication limits the evolutionary capability of its sister copy
Authors: Hasselmann Martin , Lechner Sarah , Schulte Christina , Beye Martin
Published: July 2010

The most remarkable outcome of a gene duplication event is the evolution of a novel function. Little information exists on how the rise of a novel function affects the evolution of its paralogous sister gene copy, however. We studied the evolution of the
feminizer
(
fem
) gene from which the gene
complementary sex determiner
(
csd
) recently derived by tandem duplication within the honey bee (
Apis
) lineage. Previous studies showed that
fem
retained its sex determination function, whereas the rise of
csd
established a new primary signal of sex determination. We observed a specific reduction of nonsynonymous to synonymous substitution ratios in
Apis
to non-
Apis fem
. We found a contrasting pattern at two other genetically linked genes, suggesting that hitchhiking effects to
csd
, the locus under balancing selection, is not the cause of this evolutionary pattern. We also excluded higher synonymous substitution rates by relative rate testing. These results imply that stronger purifying selection is operating at the
fem
gene in the presence of
csd
. We propose that
csd's
new function interferes with the function of Fem protein, resulting in molecular constraints and limited evolvability of
fem
in the
Apis
lineage. Elevated silent nucleotide polymorphism in
fem
relative to the genome-wide average suggests that genetic linkage to the
csd
gene maintained more nucleotide variation in today's population. Our findings provide evidence that
csd
functionally and genetically interferes with
fem
, suggesting that a newly evolved gene and its functions can limit the evolutionary capability of other genes in the genome.
ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS
Authors: Ling Shuo-Chien , Albuquerque Claudio P. , Han Joo Seok , Lagier-Tourenne Clotilde , Tokunaga Seiya , Zhou Huilin , Cleveland Don W.
Published: July 2010

Dominant mutations in two functionally related DNA/RNA-binding proteins, trans-activating response region (TAR) DNA-binding protein with a molecular mass of 43 KDa (TDP-43) and fused in sarcoma/translocation in liposarcoma (FUS/TLS), cause an inherited form of ALS that is accompanied by nuclear and cytoplasmic aggregates containing TDP-43 or FUS/TLS. Using isogenic cell lines expressing wild-type or ALS-linked TDP-43 mutants and fibroblasts from a human patient, pulse-chase radiolabeling of newly synthesized proteins is used to determine, surprisingly, that ALS-linked TDP-43 mutant polypeptides are more stable than wild-type TDP-43. Tandem-affinity purification and quantitative mass spectrometry are used to identify TDP-43 complexes not only with heterogeneous nuclear ribonucleoproteins family proteins, as expected, but also with components of Drosha microprocessor complexes, consistent with roles for TDP-43 in both mRNA processing and microRNA biogenesis. A fraction of TDP-43 is shown to be complexed with FUS/TLS, an interaction substantially enhanced by TDP-43 mutants. Taken together, abnormal stability of mutant TDP-43 and its enhanced binding to normal FUS/TLS imply a convergence of pathogenic pathways from mutant TDP-43 and FUS/TLS in ALS.
PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance
Authors: van Oers Johanna M. M. , Roa Sergio , Werling Uwe , Liu Yiyong , Genschel Jochen , Hou Harry , Sellers Rani S. , Modrich Paul , Scharff Matthew D. , Edelmann Winfried
Published: July 2010

The DNA mismatch repair protein PMS2 was recently found to encode a novel endonuclease activity. To determine the biological functions of this activity in mammals, we generated endonuclease-deficient

Pms2
E702K

knock-in mice.

Pms2
EK/EK

mice displayed increased genomic mutation rates and a strong cancer predisposition. In addition, class switch recombination, but not somatic hypermutation, was impaired in

Pms2
EK/EK

B cells, indicating a specific role in Ig diversity. In contrast to
Pms2
−/−
mice,

Pms2
EK/EK

male mice were fertile, indicating that this activity is dispensable in spermatogenesis. Therefore, the PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance and tumor suppression.
The multifunctionality of epistemic parentheticals in discourse
Authors: Dehé Nicole , Wichmann Anne
Published: July 2010

The aim of this study is to identify the relation between the interpretation of epistemic parentheticals in discourse and their prosodic realisation. Data drawn from a corpus of British English speech suggests that epistemic parentheticals (comment clauses such as I think, I believe) convey a spectrum of meaning from propositional to interpersonal. They have long been categorised simply as sentence adverbials with a meaning that relates to the truth value of the proposition. However, a study of their prosodic realisation suggests that they occupy a transitional place in the process of semantic change. They can express a wide range of meanings from propositional (sentential) meaning, through discourse meaning to the status of verbal filler. The analysis draws on theories of discourse, historical change and prosody. It makes an important contribution to the understanding of how prosody conveys apparently subtle shades of meaning that are nonetheless crucial for utterance interpretation, including degrees of speaker certainty, the identification of disfluency and the expression of politeness.
Is machine translation ready yet?
Authors: Garcia Ignacio
Published: July 2010

The default option of the Google Translator Toolkit (GTT), released in June 2009, is to “pre-fill with machine translation” all segments for which a ‘no match’ has been returned by the memories, while the Settings window clearly advises that “[m]ost users should not modify this”. To confirm whether this approach indeed benefits translators and translation quality, we designed and performed tests whereby trainee translators used the GTT to translate passages from English into Chinese either entirely from the source text, or after seeding of empty segments by the Google Translate engine as recommended. The translations were timed, and their quality assessed by independent experienced markers following Australian NAATI test criteria. Our results show that, while time differences were not significant, the machine translation seeded passages were more favourably assessed by the markers in thirty three of fifty six cases. This indicates that, at least for certain tasks and language combinations—and against the received wisdom of translation professionals and translator trainers—translating by proofreading machine translation may be advantageous.
Shifts in repetition vs. shifts in text meaning
Authors: Károly Krisztina
Published: July 2010

This study focuses on the discoursal role of repetition, exploring the way shifts in repetition patterns in text trigger coherence shifts, altering the meaning potential of translations. As repetition in translation has been hypothesized to be affected by certain universals of translation, the paper also offers initial data to support the universals of explicitation and avoiding repetition. Lexical repetitions are investigated using Hoey’s (1991) theory in a corpus of Hungarian—English news texts. Analyses reveal considerable shifts in repetition in translations; however, these differences are not statistically significant. The corpus also provides evidence for repetition shifts affecting the macropropositional structure of target texts, leading to macropropositional shifts, which alter the global meaning of translations compared to sources.
Peroxisome proliferator–activated receptor δ limits the expansion of pathogenic Th cells during central nervous system autoimmunity
Authors: Dunn Shannon E. , Bhat Roopa , Straus Daniel S. , Sobel Raymond A. , Axtell Robert , Johnson Amanda , Nguyen Kim , Mukundan Lata , Moshkova Marina , Dugas Jason C. , Chawla Ajay , Steinman Lawrence
Published: July 2010

Peroxisome proliferator–activated receptors (PPARs; PPAR-α, PPAR-δ, and PPAR-γ) comprise a family of nuclear receptors that sense fatty acid levels and translate this information into altered gene transcription. Previously, it was reported that treatment of mice with a synthetic ligand activator of PPAR-δ, GW0742, ameliorates experimental autoimmune encephalomyelitis (EAE), indicating a possible role for this nuclear receptor in the control of central nervous system (CNS) autoimmune inflammation. We show that mice deficient in PPAR-δ (PPAR-δ−/−) develop a severe inflammatory response during EAE characterized by a striking accumulation of IFN-γ+IL-17A− and IFN-γ+IL-17A+ CD4+ cells in the spinal cord. The preferential expansion of these T helper subsets in the CNS of PPAR-δ−/− mice occurred as a result of a constellation of immune system aberrations that included higher CD4+ cell proliferation, cytokine production, and T-bet expression and enhanced expression of IL-12 family cytokines by myeloid cells. We also show that the effect of PPAR-δ in inhibiting the production of IFN-γ and IL-12 family cytokines is ligand dependent and is observed in both mouse and human immune cells. Collectively, these findings suggest that PPAR-δ serves as an important molecular brake for the control of autoimmune inflammation.
Myeloid cells, BAFF, and IFN-γ establish an inflammatory loop that exacerbates autoimmunity in Lyn-deficient mice
Authors: Scapini Patrizia , Hu Yongmei , Chu Ching-Liang , Migone Thi-Sau , DeFranco Anthony L. , Cassatella Marco A. , Lowell Clifford A.
Published: July 2010

Autoimmunity is traditionally attributed to altered lymphoid cell selection and/or tolerance, whereas the contribution of innate immune cells is less well understood. Autoimmunity is also associated with increased levels of B cell–activating factor of the TNF family (BAFF; also known as B lymphocyte stimulator), a cytokine that promotes survival of self-reactive B cell clones. We describe an important role for myeloid cells in autoimmune disease progression. Using Lyn-deficient mice, we show that overproduction of BAFF by hyperactive myeloid cells contributes to inflammation and autoimmunity in part by acting directly on T cells to induce the release of IFN-γ. Genetic deletion of IFN-γ or reduction of BAFF activity, achieved by either reducing myeloid cell hyperproduction or by treating with an anti-BAFF monoclonal antibody, reduced disease development in lyn−/− mice. The increased production of IFN-γ in lyn−/− mice feeds back on the myeloid cells to further stimulate BAFF release. Expression of BAFF receptor on T cells was required for their full activation and IFN-γ release. Overall, our data suggest that the reciprocal production of BAFF and IFN-γ establishes an inflammatory loop between myeloid cells and T cells that exacerbates autoimmunity in this model. Our findings uncover an important pathological role of BAFF in autoimmune disorders.
MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18
Authors: Salcedo Rosalba , Worschech Andrea , Cardone Marco , Jones Yava , Gyulai Zsofia , Dai Ren-Ming , Wang Ena , Ma Winnie , Haines Diana , O'hUigin Colm , Marincola Francesco M. , Trinchieri Giorgio
Published: July 2010

Signaling through the adaptor protein myeloid differentiation factor 88 (MyD88) promotes carcinogenesis in several cancer models. In contrast, MyD88 signaling has a protective role in the development of azoxymethane (AOM)/dextran sodium sulfate (DSS) colitis-associated cancer (CAC). The inability of Myd88−/− mice to heal ulcers generated upon injury creates an altered inflammatory environment that induces early alterations in expression of genes encoding proinflammatory factors, as well as pathways regulating cell proliferation, apoptosis, and DNA repair, resulting in a dramatic increase in adenoma formation and progression to infiltrating adenocarcinomas with frequent clonal mutations in the β-catenin gene. Others have reported that toll-like receptor (Tlr) 4–deficient mice have a similar susceptibility to colitis to Myd88-deficient mice but, unlike the latter, are resistant to CAC. We have observed that mice deficient for Tlr2 or Il1r do not show a differential susceptibility to colitis or CAC. However, upon AOM/DSS treatment Il18−/− and Il18r1−/− mice were more susceptible to colitis and polyp formation than wild-type mice, suggesting that the phenotype of Myd88−/− mice is, in part, a result of their inability to signal through the IL-18 receptor. This study revealed a previously unknown level of complexity surrounding MyD88 activities downstream of different receptors that impact tissue homeostasis and carcinogenesis.
Pathological role of interleukin 17 in mice subjected to repeated BCG vaccination after infection with Mycobacterium tuberculosis
Authors: Cruz Andrea , Fraga Alexandra G. , Fountain Jeffrey J. , Rangel-Moreno Javier , Torrado Egídio , Saraiva Margarida , Pereira Daniela R. , Randall Troy D. , Pedrosa Jorge , Cooper Andrea M. , Castro António G.
Published: July 2010

Infection usually leads to the development of acquired immune responses associated with clearance or control of the infecting organism. However, if not adequately regulated, immune-mediated pathology can result. Tuberculosis is a worldwide threat, and development of an effective vaccine requires that the protective immune response to Mycobacterium tuberculosis (Mtb) be dissected from the pathological immune response. This distinction is particularly important if new vaccines are to be delivered to Mtb-exposed individuals, as repeated antigenic exposure can lead to pathological complications. Using a model wherein mice are vaccinated with bacille Calmette-Guérin after Mtb infection, we show that repeated vaccination results in increased IL-17, tumor necrosis factor, IL-6, and MIP-2 expression, influx of granulocytes/neutrophils, and lung tissue damage. This pathological response is abrogated in mice deficient in the gene encoding IL-23p19 or in the presence of IL-17–blocking antibody. This finding that repeated exposure to mycobacterial antigen promotes enhanced IL-17–dependent pathological consequences has important implications for the design of effective vaccines against Mtb.
SKY BRIGHTNESS AND TRANSPARENCY IN THE i-BAND AT DOME A, ANTARCTICA
Authors: Zou Hu , Zhou Xu , Jiang Zhaoji , Ashley M. C. B. , Cui Xiangqun , Feng Longlong , Gong Xuefei , Hu Jingyao , Kulesa C. A. , Lawrence J. S. , Liu Genrong , Luong-Van D. M. , Ma Jun , Moore A. M. , Pennypacker C. R. , Qin Weijia , Shang Zhaohui , Storey J. W. V. , Sun Bo , Travouillon T. , Walker C. K. , Wang Jiali , Wang Lifan , Wu Jianghua , Wu Zhenyu , Xia Lirong , Yan Jun , Yang Ji , Yang Huigen , Yao Yongqiang , Yuan Xiangyan , York D. G. , Zhang Zhanhai , Zhu Zhenxi
Published: July 2010

The i-band observing conditions at Dome A on the Antarctic plateau have been investigated using data acquired during 2008 with the Chinese Small Telescope Array. The sky brightness, variations in atmospheric transparency, cloud cover, and the presence of aurorae are obtained from these images. The median sky brightness of moonless clear nights is 20.5 mag arcsec−2 in the SDSS i band at the south celestial pole (which includes a contribution of about 0.06 mag from diffuse Galactic light). The median over all Moon phases in the Antarctic winter is about 19.8 mag arcsec−2. There were no thick clouds in 2008. We model contributions of the Sun and the Moon to the sky background to obtain the relationship between the sky brightness and transparency. Aurorae are identified by comparing the observed sky brightness to the sky brightness expected from this model. About 2% of the images are affected by relatively strong aurorae.
DEPENDENCE OF THE TURBULENT VELOCITY FIELD ON GAS DENSITY IN L1551
Authors: Yoshida Atsushi , Kitamura Yoshimi , Shimajiri Yoshito , Kawabe Ryohei
Published: July 2010

We have carried out mapping observations of the entire L1551 molecular cloud with about 2 pc × 2 pc size in the 12CO(1–0) line with the Nobeyama 45 m radio telescope at the high effective resolution of 22″ (corresponding to 0.017 pc at the distance of 160 pc), and analyzed the 12CO data together with the 13CO(1–0) and C18O(1–0) data from the Nobeyama Radio Observatory database. We derived the new non-thermal line width–size relations, σNT ∝ L
γ, for the three molecular lines, corrected for the effect of optical depth and the line-of-sight integration. To investigate the characteristic of the intrinsic turbulence, the effects of the outflows were removed. The derived relations are (σNT/km s−1) = (0.18 ± 0.010)(L/pc)0.45 ± 0.095, (0.20 ± 0.020)(L/pc)0.48 ± 0.091, and (0.22 ± 0.050) (L/pc)0.54 ± 0.21 for the 12CO, 13CO, and C18O lines, respectively, suggesting that the line width–size relation of the turbulence very weakly depends on our observed molecular lines, i.e., the relation does not change between the density ranges of 102–103 and 103–104 cm−3. In addition, the relations indicate that incompressible turbulence is dominant at the scales smaller than 0.6 pc in L1551. The power spectrum indices converted from the relations, however, seem to be larger than that of the Kolmogorov spectrum for incompressible flow. The disagreement could be explained by the anisotropy in the turbulent velocity field in L1551, as expected in MHD turbulence. Actually, the autocorrelation functions of the centroid velocity fluctuations show larger correlation along the direction of the magnetic field measured for the whole Taurus cloud, which is consistent with the results of numerical simulations for incompressible MHD flow.
Analyzing taxonomic classification using extensible Markov models
Authors: Kotamarti Rao M. , Hahsler Michael , Raiford Douglas , McGee Monnie , Dunham Margaret H.
Published: July 2010

Motivation: As next generation sequencing is rapidly adding new genomes, their correct placement in the taxonomy needs verification. However, the current methods for confirming classification of a taxon or suggesting revision for a potential misplacement relies on computationally intense multi-sequence alignment followed by an iterative adjustment of the distance matrix. Due to intra-heterogeneity issues with the 16S rRNA marker, no classifier is available for sub-genus level, which could readily suggest a classification for a novel 16S rRNA sequence. Metagenomics further complicates the issue by generating fragmented 16S rRNA sequences. This article proposes a novel alignment-free method for representing the microbial profiles using extensible Markov models (EMMs) with an extended Karlin–Altschul statistical framework similar to the classic alignment paradigm. We propose a log odds (LODs) score classifier based on Gumbel difference distribution that confirms correct classifications with statistical significance qualifications and suggests revisions where necessary.

Results: We tested our method by generating a sub-genus level classifier with which we re-evaluated classifications of 676 microbial organisms using the NCBI FTP database for the 16S rRNA. The results confirm current classification for all genera while ascertaining significance at 95%. Furthermore, this novel classifier isolates heterogeneity issues to a mere 12 strains while confirming classifications with significance qualification for the remaining 98%. The models require less memory than that needed by multi-sequence alignments and have better time complexity than the current methods. The classifier operates at sub-genus level, and thus outperforms the naive Bayes classifier of the RNA Database Project where much of the taxonomic analysis is available online. Finally, using information redundancy in model building, we show that the method applies to metagenomic fragment classification of 19 Escherichia coli strains.

Availability and implementation: Source code and binaries freely available for download at http://lyle.smu.edu/IDA/EMMSA/, implemented in JAVA and supported on MS Windows.

Contact:  mallik@kotamarti.com; mhd@lyle.smu.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Dealing with sparse data in predicting outcomes of HIV combination therapies
Authors: Bogojeska Jasmina , Bickel Steffen , Altmann André , Lengauer Thomas
Published: July 2010

Motivation: As there exists no cure or vaccine for the infection with human immunodeficiency virus (HIV), the standard approach to treating HIV patients is to repeatedly administer different combinations of several antiretroviral drugs. Because of the large number of possible drug combinations, manually finding a successful regimen becomes practically impossible. This presents a major challenge for HIV treatment. The application of machine learning methods for predicting virological responses to potential therapies is a possible approach to solving this problem. However, due to evolving trends in treating HIV patients the available clinical datasets have a highly unbalanced representation, which might negatively affect the usefulness of derived statistical models.

Results: This article presents an approach that tackles the problem of predicting virological response to combination therapies by learning a separate logistic regression model for each therapy. The models are fitted by using not only the data from the target therapy but also the information from similar therapies. For this purpose, we introduce and evaluate two different measures of therapy similarity. The models are also able to incorporate phenotypic knowledge on the therapy outcomes through a Gaussian prior. With our approach we balance the uneven therapy representation in the datasets and produce higher quality models for therapies with very few training samples. According to the results from the computational experiments our therapy similarity model performs significantly better than training separate models for each therapy by using solely their examples. Furthermore, the model's performance is as good as an approach that encodes therapy information in the input feature space with the advantage of delivering better results for therapies with very few training samples.

Availability: Code of the efficient logistic regression is available from http://www.mpi-inf.mpg.de/%7Ejasmina/fastLogistic.zip

Contact:  jasmina@mpi-inf.mpg.de

Supplementary information:  Supplementary data are available at Bioinformatics online.
iAlign: a method for the structural comparison of protein–protein interfaces
Authors: Gao Mu , Skolnick Jeffrey
Published: July 2010

Motivation: Protein–protein interactions play an essential role in many cellular processes. The rapid accumulation of protein–protein complex structures provides an unprecedented opportunity for comparative studies of protein–protein interactions. To facilitate such studies, it is necessary to develop an accurate and efficient computational algorithm for the comparison of protein–protein interaction modes. While there are many structural comparison approaches developed for individual proteins, very few methods are available for protein–protein complexes.

Results: We present a novel interface alignment method, iAlign, for the structural alignment of protein–protein interfaces. New scoring schemes for measuring interface similarity are introduced, and an iterative dynamic programming algorithm is implemented. We find that the similarity scores follow extreme value distributions. Using statistical models, we empirically estimate their statistical significance, which is in good agreement with manual classifications by human experts. Large-scale tests of iAlign were conducted on both artificial docking models and experimental structures. In a benchmark test on 1517 dimers, iAlign successfully detects biologically related, structurally similar protein–protein interfaces at a coverage percentage of 90% and an error per query of 0.05. When compared against previously published methods, iAlign is substantially more accurate and efficient.

Availability: The iAlign software package is freely available at http://cssb.biology.gatech.edu/iAlign

Contact:  skolnick@gatech.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
A comparison of several algorithms for the single individual SNP haplotyping reconstruction problem
Authors: Geraci Filippo
Published: July 2010

Motivation: Single nucleotide polymorphisms are the most common form of variation in human DNA, and are involved in many research fields, from molecular biology to medical therapy. The technological opportunity to deal with long DNA sequences using shotgun sequencing has raised the problem of fragment recombination. In this regard, Single Individual Haplotyping (SIH) problem has received considerable attention over the past few years.

Results: In this article, we survey seven recent approaches to the SIH problem and evaluate them extensively using real human haplotype data from the HapMap project. We also implemented a data generator tailored to the current shotgun sequencing technology that uses haplotypes from the HapMap project.

Availability: The data we used to compare the algorithms are available on demand, since we think they represent an important benchmark that can be used to easily compare novel algorithmic ideas with the state of the art. Moreover, we had to re-implement six of the algorithms surveyed because the original code was not available to us. Five of these algorithms and the data generator used in this article endowed with a Web interface are available at http://bioalgo.iit.cnr.it/rehap

Contact:  filippo.geraci@iit.cnr.it
genoPlotR: comparative gene and genome visualization in R
Authors: Guy Lionel , Roat Kultima Jens , Andersson Siv G. E.
Published: July 2010

Summary: The amount of gene and genome data obtained by next-generation sequencing technologies generates a need for comparative visualization tools. Complementing existing software for comparison and exploration of genomics data, genoPlotR automatically creates publication-grade linear maps of gene and genomes, in a highly automatic, flexible and reproducible way.

Availability: genoPlotR is a platform-independent R package, available with full source code under a GPL2 license at R-Forge: http://genoplotr.r-forge.r-project.org/

Contact:  lionel.guy@ebc.uu.se
Interactive and fuzzy search: a dynamic way to explore MEDLINE
Authors: Wang Jiannan , Cetindil Inci , Ji Shengyue , Li Chen , Xie Xiaohui , Li Guoliang , Feng Jianhua
Published: July 2010

Motivation: The MEDLINE database, consisting of over 19 million publication records, is the primary source of information for biomedicine and health questions. Although the database itself has been growing rapidly, the search paradigm of MEDLINE has remained largely unchanged.

Results: Here, we propose a new system for exploring the entire MEDLINE collection, represented by two unique features: (i) interactive: providing instant feedback to users' query letter by letter, and (ii) fuzzy: allowing approximate search. We develop novel index structures and search algorithms to make such a search model possible. We also develop incremental-update techniques to keep the data up to date.

Availability: Interactive and fuzzy searching algorithms for exploring MEDLINE are implemented in a system called iPubMed, freely accessible over the web at http://ipubmed.ics.uci.edu/ and http://tastier.cs.tsinghua.edu.cn/ipubmed/

Contact:  chenli@ics.uci.edu; xhx@ics.uci.edu
The Promise and Pitfalls of Sequence-Based Identification of Plant-Pathogenic Fungi and Oomycetes
Authors: Kang Seogchan , Mansfield Michele A. , Park Bongsoo , Geiser David M. , Ivors Kelly L. , Coffey Michael D. , Grünwald Niklaus J. , Martin Frank N. , Lévesque C. André , Blair Jaime E.
Published: July 2010

Sequences of selected marker loci have been widely used for the identification of specific pathogens and the development of sequence-based diagnostic methods. Although such approaches offer several advantages over traditional culture-based methods for pathogen diagnosis and identification, they have their own pitfalls. These include erroneous and incomplete data in reference databases, poor or oversimplified interpretation of search results, and problems associated with defining species boundaries. In this letter, we outline the potential benefits and drawbacks of using sequence data for identification and taxonomic deductions of plant-pathogenic fungi and oomycetes, using Phytophthora as a primary example. We also discuss potential remedies for these pitfalls and address why coordinated community efforts are essential to make such remedies more efficient and robust.
Determination of Natural Resistance Frequencies in Penicillium digitatum Using a New Air-Sampling Method and Characterization of Fludioxonil- and Pyrimethanil-Resistant Isolates
Authors: Kanetis L. , Förster H. , Adaskaveg J. E.
Published: July 2010

Fungicide resistance was identified in natural populations of Penicillium digitatum, the causal agent of green mold of citrus, to two of three new postharvest fungicides before their commercial use. Using a new air-sampling method where large populations of the pathogen in citrus packinghouses were exposed to agar plates with a continuous, wide-range fungicide concentration gradient, isolates with reduced sensitivity to fludioxonil or pyrimethanil were obtained. Resistance frequencies to fludioxonil and pyrimethanil were calculated as 9.5 × 10–7 to 1.5 × 10–5 and 7.3 × 10–6 to 6.2 × 10–5, respectively. No isolates resistant to azoxystrobin were detected. Isolates with reduced sensitivity to fludioxonil or pyrimethanil were also obtained in laboratory selection studies, where high concentrations of conidial mixtures of isolates sensitive to the three fungicides were plated onto agar amended with each fungicide at 10 μg/ml. Isolates obtained from fludioxonil selection plates in laboratory and packinghouse experiments were placed into two categories based on mycelial growth: moderately resistant isolates had 50% effective concentration (EC50) values of 0.1 to 0.82 μg/ml and highly resistant isolates had EC50 values > 1.5 μg/ml. Isolates resistant to pyrimethanil all had EC50 values >8 μg/ml. Representative isolates of the two categories with reduced sensitivity to fludioxonil varied widely in their virulence and sporulation capacity as measured by the incidence of decay and degree of sporulation on inoculated fruit, respectively, whereas pyrimethanil-resistant isolates were mostly similar to the wild-type isolate. Fungicide sensitivity characteristics for isolates from fludioxonil and pyrimethanil selection plates remained stable after passages on nonamended agar, and disease could not be controlled after treatment with the respective fungicides. Types of fungicide resistance were visualized on thiabendazole- (TBZ) and imazalil-amended selection plates that were exposed in packinghouses where resistance to these fungicides was known to occur. The qualitative, single-site resistance to the benzimidazole TBZ was visualized by two distinct subpopulations in regard to fungicide sensitivity, whereas the quantitative, multi-site resistance to the demethylation inhibitor imazalil was apparent as a continuous density gradient of colonies along the fungicide concentration gradient. Types of resistance could not be assigned to fludioxonil or pyrimethanil because a limited number of resistant colonies was obtained on each plate. Thus, with this new method, we were able to estimate fungicide resistance frequencies as well as characterize and visualize types of resistance within populations of a fungal species. This information will be used to design resistance management strategies for previous and newly registered postharvest fungicides of citrus.